PregnancyMarketResearch PDF

Womens Health Diagnostic Markets
5th
Womens Health Diagnostic Markets

A Market Intelligence Analysis of Manufacturers and Suppliers of Diagnostic
Tests and Systems Used to Diagnose Female Health
A KALORAMA INFORMATION MARKET INTELLIGENCE REPORT
Womens Health Diagnostic Markets: A Market Intelligence Analysis of Manufacturers
and Suppliers of Diagnostic Tests and Systems Used to Diagnose Female Health has been
prepared by Kalorama Information. We serve business and industrial clients in the United States
and abroad with a complete line of information services and research publications.
Kalorama Information Market Intelligence Reports are specifically designed to aid the actionoriented executive by providing a thorough presentation of essential data and concise analysis.
Author: Joseph A. Constance
Publication Date: October 2014

1.0 Executive Summary ................................................................................................................ 1
1.1 Methodology ........................................................................................................................ 5
2.0 Introduction ............................................................................................................................. 6
2.1 Female Health: Room for Improvement ........................................................................... 6
2.2 Perspective on Womens Health ........................................................................................ 7
2.3 The Way Women and Men Develop Disease Is Different................................................ 7
2.3.1 Pain ................................................................................................................................. 8
2.3.2 The Heart ........................................................................................................................ 8
2.3.3 The Brain ........................................................................................................................ 8
2.3.4 Emotions ......................................................................................................................... 9
2.3.5 Bone Structure ................................................................................................................ 9
2.3.6 Alcohol ........................................................................................................................... 9
2.3.7 Drug Side Effects............................................................................................................ 9
2.3.8 Smoking ........................................................................................................................ 10
2.3.9 Fertility ......................................................................................................................... 10
2.3.10 STIs/HIV .................................................................................................................... 10
2.3.11 Autoimmune Disease .................................................................................................. 10
2.3.12 Cancer ......................................................................................................................... 11
2.3.13 Musculoskeletal Health .............................................................................................. 14
2.3.14 Birth Defects ............................................................................................................... 16
2.3.15 Urinary Tract Infections ............................................................................................. 16
2.4 Key Leading Causes of Death in Females ....................................................................... 17
2.5 Demographics .................................................................................................................... 19
2.6 What Claims Womens Lives ........................................................................................... 20
2.7 Key Trends and Issues in Womens Diagnostics ............................................................ 21
2.7.1 OVA1............................................................................................................................ 21
2.7.2 CA-125 ......................................................................................................................... 22
2.7.3 HER2 ............................................................................................................................ 22
TOC
3
2.8 Understanding the Molecular Basis of Disease............................................................... 23
2.8.1 Managing Cancer Disease and Costs through Reimbursement .................................... 24
2.8.2 Ultrasound and Mammography Use Grows ................................................................. 24
3.0 Market Developments in Women's Health Diagnostics .................................................... 26
3.1 Quest and Hologic Team Up ............................................................................................ 26
3.2 Quest Genetic Testing for Breast Cancer Risk............................................................... 27
3.3 Sequenom, Quest Collaborate on Noninvasive Prenatal Testing ................................. 27
3.4 Partnering to Make Personalized Infertility Treatment Possible ................................. 28
3.5 Co-Marketing of Full-Length HLA Gene Sequencing Products .................................. 29
3.6 Acquisition Strengthens Theranostics Development ..................................................... 30
3.7 Trinity Biotech Acquisition .............................................................................................. 31
3.8 Noninvasive Prenatal Test Significantly Reduces False Positive Rate ......................... 32
3.9 Proteome Sciences, Fisher Scientific Sign Agreement on Cancer Tests....................... 33
3.10 Agreement on Fetal and Maternal Monitoring Software ............................................ 33
3.11 Distribution Agreement for OTC Women's Health Diagnostics ................................ 34
3.12 Women's Health Cancer Diagnostics Company Raises $11.3 Million ....................... 35
3.13 Crowd Funding for At-Home Breast Exam Device ..................................................... 35
3.14 $13M Series A Round for Ultrasound Fibroid Device ................................................. 36
3.15 FDA Clears Femur Fracture Test.................................................................................. 36
3.16 FDA 510(k) Clearance for Female Incontinence Device.............................................. 37
3.17 GE PMA for extended labeling for Senographe Mammography ............................... 37
3.18 FDA Clears MicroDose Mammography ....................................................................... 38
3.19 FDA ABUS Approval ...................................................................................................... 39
3.20 FDA Approval for Imaging Software System for Ultrasound .................................... 39
3.21 EU Nod for Breast Tissue Screening System ................................................................ 40
3.22 Cervical Cancer Screening Test Concerns.................................................................... 40
3.23 New Smartphone App Detects Newborn Jaundice in Minutes ................................... 41
4.0 Pregnancy and Ovulation ..................................................................................................... 43
Key Trend ................................................................................................................................ 43
4.1 Perspective on Testing ...................................................................................................... 43
4.1.1 Digital Testing .............................................................................................................. 45
4.1.2 Testing for Placental Growth Factor and Pre-eclampsia .............................................. 45
Copyright 2014 Kalorama Information, LLC.
Reproduction without prior written permission, in any media now in existence or hereafter developed,
in whole or in any part, is strictly prohibited.
TOC
4
4.1.3 Lab Developed Tests .................................................................................................... 46
4.2 OTC Pregnancy Self-Test Market ................................................................................... 47
4.3 Lab-Based Fertility Testing Market ................................................................................ 49
4.4 Lab-Based Torch Testing Market ................................................................................... 51
4.5 Abbott Diagnostics ............................................................................................................ 55
4.6 Alere Inc. ............................................................................................................................ 56
4.7 biomerieux SA ................................................................................................................... 58
4.8 Church & Dwight Co. Inc................................................................................................. 59
4.9 Dialab GMBH .................................................................................................................... 60
4.10 Prestige Diagnostics......................................................................................................... 61
4.11 Roche Diagnostics ............................................................................................................ 62
4.12 Siemens Healthcare Diagnostics .................................................................................... 63
5.0 Bone Density Testing ............................................................................................................ 64
Key Trend ................................................................................................................................ 64
5.1 Alarming Rise of Osteoporosis ......................................................................................... 64
5.2 Propelling the Need for Detection .................................................................................... 65
5.3 DEXA and Competing Technologies ............................................................................... 66
5.4 Bone Densitometer Market .............................................................................................. 67
5.5 GE Healthcare ................................................................................................................... 71
5.6 Hologic ................................................................................................................................ 73
5.7 Osteometer MediTech ....................................................................................................... 74
6.0 Prenatal Screening ................................................................................................................ 75
Key Trend ................................................................................................................................ 75
6.1 Invasive Testing ................................................................................................................. 75
6.2 Noninvasive Testing .......................................................................................................... 76
6.3 The Impact of Prenatal Genetic Testing ......................................................................... 77
6.4 DNA Assay Market ........................................................................................................... 77
6.5 Prenatal Carrier and Fetus Screening Market............................................................... 80
6.6 PerkinElmer ....................................................................................................................... 83
6.7 Quest Diagnostics .............................................................................................................. 85
6.8 ScreenCell .......................................................................................................................... 86

TOC
5
6.9 Sequenom ........................................................................................................................... 87
6.10 Laboratory Corporation of America ............................................................................. 90
7.0 Ultrasound ............................................................................................................................. 91
Key Trend ................................................................................................................................ 91
7.1 History and Perspective .................................................................................................... 91
7.2 Nuchal Translucency......................................................................................................... 92
7.3 Speckle Reduction ............................................................................................................. 93
7.4 Volumetric Imaging .......................................................................................................... 93
7.5 Follicular Tracking ........................................................................................................... 93
7.6 Obstetrics and Gynecology ............................................................................................... 94
7.7 Breast Imaging................................................................................................................... 95
7.8 Ob/Gyn Market ................................................................................................................. 96
7.9 Breast Imaging Market ..................................................................................................... 98
7.10 Analogic .......................................................................................................................... 101
7.11 Philips Healthcare ......................................................................................................... 103
7.12 Siemens Healthcare ....................................................................................................... 105
7.13 GE Healthcare ............................................................................................................... 106
7.14 Hitachi Aloka Medical Ltd. .......................................................................................... 108
7.15 Supersonic Imagine ....................................................................................................... 110
8.0 Mammography .................................................................................................................... 111
Key Trend .............................................................................................................................. 111
8.1 Perspective ....................................................................................................................... 111
8.1.1 Economics of Routine Screening ............................................................................... 112
8.2 Transitioning to Digital................................................................................................... 113
8.3 Computer-Aided Detection............................................................................................. 113
8.3.1 A Second Opinion ...................................................................................................... 114
8.3.2 Analyzing Tumor Characteristics ............................................................................... 114
8.4 Mammography Systems Market.................................................................................... 115
8.5 CAD Market .................................................................................................................... 120
8.6 Carestream Health .......................................................................................................... 123
8.7 FujiFilm Medical Systems USA ..................................................................................... 125
8.8 GE Healthcare ................................................................................................................. 127
TOC
6
8.9 Hologic .............................................................................................................................. 129
8.10 iCAD Inc......................................................................................................................... 131
8.11 Parascript LLC .............................................................................................................. 133
8.12 R2 Technology ............................................................................................................... 134
9.0 Pap Smears .......................................................................................................................... 135
Key Trend .............................................................................................................................. 135
9.1 Testing for Cervical Cancer ........................................................................................... 135
9.1.1 Types of Screening ..................................................................................................... 136
9.2 Cervical Cancer Vaccines ............................................................................................... 137
9.3 A Market Need ................................................................................................................ 137
9.4 IVD Market ...................................................................................................................... 139
9.5 BD ..................................................................................................................................... 143
9.6 BioReference Laboratories ............................................................................................. 145
9.7 BioSciCon ......................................................................................................................... 146
9.8 Hologic .............................................................................................................................. 147
9.9 Innogenetics NV............................................................................................................... 148
10.0 Colposcopy ......................................................................................................................... 149
Key Trend .............................................................................................................................. 149
10.1 Colposcopy Biopsy......................................................................................................... 149
10.2 Abnormal Pap Smear Results ...................................................................................... 150
10.3 Routine Use But Mature Market ................................................................................. 151
10.3.1 Primary and Secondary Screening ............................................................................ 151
10.4 Colposcopy Systems Market ........................................................................................ 152
10.5 CooperSurgical .............................................................................................................. 155
10.6 DySIS Medical ............................................................................................................... 156
10.7 Guided Therapeutics ..................................................................................................... 157
10.8 Leisegang ........................................................................................................................ 158
10.9 NeoDiagnostix ................................................................................................................ 159
11.0 HPV Testing ...................................................................................................................... 160
Key Trend .............................................................................................................................. 160

TOC
7
11.1 HPV Infection ................................................................................................................ 160
11.1.1 Infection in Females ................................................................................................. 161
11.1.2 High Risk Types ....................................................................................................... 161
11.1.3 HPV Major Cause of Cervical Cancer ..................................................................... 162
11.2 HPV Test ........................................................................................................................ 162
11.3 Vaccine Issues ................................................................................................................ 163
11.4 Strong Market Expected............................................................................................... 164
11.4.1 IVD Market............................................................................................................... 165
11.5 Abbott Molecular .......................................................................................................... 168
11.6 Hologic ............................................................................................................................ 170
11.7 Qiagen Benelux BV ....................................................................................................... 172
11.8 Roche Diagnostics .......................................................................................................... 174
12.0 Ovarian Cancer ................................................................................................................. 176
Key Trend .............................................................................................................................. 176
12.1 Types of Ovarian Cancer .............................................................................................. 176
12.2 Pelvic Examinations ...................................................................................................... 177
12.3 Tumor Markers, AFP, HE4 ......................................................................................... 178
12.4 CA-125 Antigen ............................................................................................................. 180
12.5 CA-125 Market .............................................................................................................. 181
12.6 Avant Diagnostics Inc. .................................................................................................. 183
12.7 Biosystems International .............................................................................................. 184
12.8 Fujirebio Diagnostics .................................................................................................... 185
12.9 Myriad Genetics Inc. ..................................................................................................... 187
13.0 Urinary Tract Infections .................................................................................................. 188
Key Trend .............................................................................................................................. 188
13.1 Leading Cause of Morbidity and Death ...................................................................... 188
13.1.1 Impact ....................................................................................................................... 189
13.1.2 Impact on Women .................................................................................................... 190
13.1.3 E. coli the Key Culprit .............................................................................................. 191
13.2 UTI Molecular Testing Market .................................................................................... 192
13.3 i-Health Inc. ................................................................................................................... 195
13.4 Liofilchem ...................................................................................................................... 196
TOC
8
13.5 Rheonix ........................................................................................................................... 197
13.6 Somagen Diagnostics ..................................................................................................... 198
14.0 Neonatal Jaundice ............................................................................................................. 199
Key Trend .............................................................................................................................. 199
14.1 Issues Involving Bilirubin ............................................................................................. 199
14.2 Two Factors in Neonates............................................................................................... 200
14.3 Risk Factors ................................................................................................................... 200
14.4 Smart Phone App .......................................................................................................... 201
14.5 Bilirubin Testing Market .............................................................................................. 202
14.6 Instrumentation Laboratory ........................................................................................ 205
14.7 Nova Biomedical ............................................................................................................ 206
14.8 Siemens Healthcare Diagnostics .................................................................................. 207
14.9 Wako Diagnostics .......................................................................................................... 208
14.10 Roche Diagnostics ........................................................................................................ 209
15.0 Autoimmune Disease ........................................................................................................ 210
Key Trend .............................................................................................................................. 210
15.1 Types of Autoimmune Disease ..................................................................................... 210
15.2 Genetic Factors .............................................................................................................. 211
15.3 Impact on Females ........................................................................................................ 212
15.4 Female Lab-Based Immunoassay Autoimmune Testing Market ............................. 213
15.5 Aesku.Diagnostics .......................................................................................................... 216
15.6 AXA Diagnostics SRL ................................................................................................... 217
15.7 Bio-Rad Laboratories ................................................................................................... 218
15.8 Euroimmun AG ............................................................................................................. 219
15.9 Immco Diagnostics ........................................................................................................ 220
15.10 Kronus .......................................................................................................................... 221
15.11 Phadia ........................................................................................................................... 222
15.12 XDx ............................................................................................................................... 223
16.0 Cystic Fibrosis ................................................................................................................... 224
Key Trend .............................................................................................................................. 224
16.1 Affecting the Entire Body ............................................................................................. 225
TOC
9
16.2 Reduced Life Expectancy ............................................................................................. 225
16.3 Genetics .......................................................................................................................... 226
16.4 Chronic Infections ......................................................................................................... 227
16.5 Females Worse Than Males ......................................................................................... 227
16.6 Genetic Testing Market ................................................................................................ 228
16.7 AutoGenomics................................................................................................................ 232
16.8 GenMark Diagnostics ................................................................................................... 233
16.9 Illumina .......................................................................................................................... 234
16.10 Luminex........................................................................................................................ 235
16.11 ScheBo Biotech AG .................................................................................................. 236
16.12 Sequenom ..................................................................................................................... 237

1.0 Executive Summary ................................................................................................................ 1

Exhibit 1: World Markets for Key Womens Health Diagnostics, 2013-2018 (Pregnancy
and Ovulation Testing, Lab-Based Immunoassay Fertility Testing, Lab-Based
Immunoassay Torch Testing, Bone Densitometers, Prenatal Testing, Prenatal Carrier
and Fetus Screening, Ultrasound OB/GYN, Ultrasound Breast Imaging, Mammography,
Digital Mammography, CAD Systems, Pap Smears, Colposcopy Systems, HPV
Diagnostics, CA-125, Urinary Tract Infection Assays, Neonatal Jaundice Bilirubin,
Autoimmune Diagnostic Assays, Cystic Fibrosis Female Genetic Tests) ............................. 4
2.0 Introduction ............................................................................................................................. 6
Exhibit 2: Leading Causes of Death in Females, US, 2010 .................................................. 19
Exhibit 3: World Life Expectancy at Birth in Selected Countries by Sex, 2013 (France,
Germany, Sweden, United Kingdom, Italy, Spain, Australia, Japan, United States,
South Africa, China, India, Mexico) ...................................................................................... 20
4.0 Pregnancy and Ovulation ..................................................................................................... 43
Exhibit 4: World Market for OTC Pregnancy Self-Tests, 2013-2018 (US/NA, Europe,
China, Brazil, Japan, ROW, Total) ....................................................................................... 48
Exhibit 5: World Market for OTC Pregnancy Self Tests 2014, by Geographic Segment
(US, EU, China, Japan, Brazil, ROW) .................................................................................. 49
Exhibit 6: World Market for Lab-Based Immunoassay Fertility Testing, 2013-2018
(US/NA, Europe, China, Brazil, Japan, ROW, Total) ........................................................ 50
Exhibit 7: World Market for Lab-Based Immunoassay Fertility Testing 2014, by
Geographic Segment (US, EU, China, Japan, Brazil, ROW).............................................. 51
Exhibit 8: World Market for Lab-Based Immunoassay Torch Testing, 2013-2018
(US/NA, Europe, China, Brazil, Japan, ROW, Total) ......................................................... 53
Exhibit 9: World Market for Lab-Based Immunoassay Torch Testing 2014, by
Geographic Segment ............................................................................................................... 54
5.0 Bone Density Testing ............................................................................................................ 64
Exhibit 10: World Market for Bone Densitometers for Female Testing, 2013-2018
(US/NA, Europe, China, Brazil, Japan, ROW, Total) ......................................................... 69
Exhibit 11: World Market for Bone Densitometers for Female Testing 2014, by
List of Exhibits
2
6.0 Prenatal Screening ................................................................................................................ 75
Exhibit 12: World Market for Molecular (DNA) Assays for Prenatal Testing,
2013-2018 (US/NA, Europe, China, Brazil, Japan, ROW, Total) ....................................... 79
Exhibit 13: World Market for Molecular (DNA) Assays for Prenatal Testing 2014, by
Exhibit 14: World Market for Prenatal Carrier and Fetus Screening, 2013-2018 ........... 81
Exhibit 15: World Market for Prenatal Carrier and Fetus Screening 2014, by
7.0 Ultrasound ............................................................................................................................. 91
Exhibit 16: Key Applications for Medical Ultrasound ........................................................ 92
Exhibit 17: World Ultrasound Ob/Gyn Market, 2013-2018 (US/NA, Europe, China,
Brazil, Japan, ROW, Total).................................................................................................... 97
Exhibit 18: World Ultrasound Ob/Gyn Market 2014, by Geographic Segment (US, EU,
China, Japan, Brazil, ROW) .................................................................................................. 98
Exhibit 19: World Ultrasound Breast Imaging Market, 2013-2018 (US/NA, Europe,
China, Brazil, Japan, ROW, Total) ....................................................................................... 99
Exhibit 20: World Ultrasound Breast Imaging Market 2014, by Geographic
Segment (US, EU, China, Japan, Brazil, ROW)................................................................. 100
8.0 Mammography .................................................................................................................... 111
Exhibit 21: World Market for Mammography Equipment, 2013-2018 (US, Europe,
China, Brazil, Japan, ROW, Total) ..................................................................................... 116
Exhibit 22: World Market for Mammography Equipment by Geographic
Segment, 2014 (US, EU, China, Japan, Brazil, ROW)....................................................... 117
Exhibit 23: World Market for Digital Mammography Equipment, 2013-2018
(US, Europe, China, Brazil, Japan, ROW, Total) .............................................................. 118
Exhibit 24: World Market for Digital Mammography Equipment by Geographic
Exhibit 25: World Market for Computer-Aided Detection Systems, 2013-2018
Exhibit 26: World Market for Computer-Aided Detection Systems by Geographic
9.0 Pap Smears .......................................................................................................................... 135
Exhibit 27: World IVD Traditional Pap Test Market, 2013-2018 (US, Europe, China,
Brazil, Japan, ROW, Total).................................................................................................. 141
List of Exhibits
3
Exhibit 28: World IVD Traditional Pap Test Market by Geographic
10.0 Colposcopy ......................................................................................................................... 149
Exhibit 29: World Market for Colposcopy Systems, 2013-2018 (US, Europe, China,
Brazil, Japan, ROW, Total).................................................................................................. 153
Exhibit 30: World Market for Colposcopy Systems by Geographic
11.0 HPV Testing ...................................................................................................................... 160
Exhibit 31: World Market for Female IVD HPV Tests, 2013-2018 (US, Europe,
China, Brazil, Japan, ROW, Total) ..................................................................................... 166
Exhibit 32: World Market for Female IVD HPV Tests by Geographic
12.0 Ovarian Cancer ................................................................................................................. 176
Exhibit 33: World Market for CA-125 Assay, 2013-2018 (US, Europe, China, Brazil,
Japan, ROW, Total) .............................................................................................................. 181
Exhibit 34: World Market for CA-125 Assay by Geographic Segment, 2014 (US, EU,
China, Japan, Brazil, ROW) ................................................................................................ 182
13.0 Urinary Tract Infections .................................................................................................. 188
Exhibit 35: World Market for Molecular Testing for UTIs in Females, 2013-2018
Exhibit 36: World Market for Molecular Testing for UTIs in Females by Geographic
14.0 Neonatal Jaundice ............................................................................................................. 199
Exhibit 37: World Market for POC Bilirubin Testing for Neonatal Jaundice,
2013-2018 (US, Europe, China, Brazil, Japan, ROW, Total) ............................................ 203
Exhibit 38: World Market for POC Bilirubin Testing for Neonatal Jaundice by
Geographic Segment, 2014 (US, EU, China, Japan, Brazil, ROW).................................. 204
15.0 Autoimmune Disease ........................................................................................................ 210
Exhibit 39: World Female Lab-Based Immunoassay Autoimmune Testing Market,
Exhibit 40: World Female Lab-Based Immunoassay Autoimmune Testing Market by
Geographic Segment, 2014 (US, EU, China, Japan, Brazil, ROW).................................. 215
List of Exhibits
4
16.0 Cystic Fibrosis ................................................................................................................... 224
Exhibit 41: World Genetic Testing Market for Cystic Fibrosis in Females,
Exhibit 42: World Genetic Testing Market for Cystic Fibrosis in Females by
Geographic Segment, 2014 (US, EU, BRIC, Japan, ROW) .............................................. 231

1.0 Executive Summary

x
Providing health care to women can be a challenging task requiring the expertise
of many different medical professions. In the US, 13% of women age 18 and over
are only in fair or poor health. Around 12% women of all ages are limited in some
way by a chronic condition.
The women's health arena, both therapeutics and diagnostics, has grown
considerably as a specialty medical field. Once limited to obstetrics and
gynecology, it now includes other fields, such as urology, maternal-fetal
medicine, as well as autoimmune disease and cystic fibrosis. At many clinics and
practices focused on the health of women, a range of specialties are offered,
which often results in a need for specific types of women's health-related testing.
Generally, and from a perspective on women's health, diagnostics are playing an

ever increasing role.
There is a need to improve the understanding of the differences, in terms of

health, between the sexes and to translate that knowledge into improved medical
diagnostics, practice and therapies.
Worldwide, women are living longer than men.
More women die from heart disease each year than from breast, ovarian, and
uterine cancer combined. Heart disease is the number one cause of mortality in
women, killing more women than men each year.

2
x
Colorectal cancer is the third leading cause of cancer deaths in women, killing
almost 30,000 women each year. Autoimmune diseases are collectively the eighth
leading cause of death for women under the age of 65.
Over the next few decades, comprehensive genomics-based health care should be
the norm in the US and much of Europe. In the next decade, genetic tests will
routinely predict individual susceptibility to disease. Diagnoses of many
conditions will be much more thorough and specific than now.
The trend in a mature market for pregnancy testing continues to be the digitization
of testing, especially those tests for use in the home.
Osteoporosis poses a significant health risk, particularly among women, and the
problem is intensifies with age. Osteoporosis is estimated to affect 200 million
women worldwide: about 10% of women aged 60; 20% of women aged 70; 40%
of women aged 80; more than 65% of women aged 90. The disease impacts
approximately 75 million people in Europe, the US and Japan.
New techniques will provide noninvasive alternatives to current invasive prenatal

tests for genetic diseases, such as amniocentesis and chorionic villus sampling
(CVS). Genome-wide sequencing of a fetus might be done simply using a
mother's blood.
Three dimensional (3D) ultrasound is finding more use as it provides greater

detail for diagnosis during pregnancy than the traditional 2D ultrasound.
X-ray mammography, notably digital mammography, continues to dominate

breast screening for the immediate future.
In the US, since the introduction of the Pap Smear 40 years ago, incidence rates of
cervical cancer have dropped by 75%. In low income countries, many women do
not have access to routine screening. It is estimated that in these countries only
5% of women have undergone a Pap smear in the past five years. New HPV
testing has the potential to replace some Pap testing.
There are considerable barriers to setting up cytology-based screening programs,

particularly in developing countries.


3
x
In todays market for HPV testing, only 20% of women over the age of 30 are
screened for HPV using DNA-based tests in conjunction with a standard Pap
smear.
The CA-125 immunoassay is the current gold standard for monitoring patients
diagnosed with ovarian cancer. But the test is not a routine part of a womans
annual checkup.
Urinary tract infections are the leading cause of gram-negative bacteremia. In the
US, these infections account for approximately 8 million office visits and more
than 1 million hospitalizations annually. For women, the lifetime risk of having a
UTI is greater than 50%.
More than 13 million babies experience jaundice annually. More than 9 million of
them are born in developing countries.
Autoimmune disease as a category affects 50 million Americans. It is one of the

top ten causes of death in women under the age of 65. Women are more
susceptible to the diseases, as they are affected 75% more often than men. The
NIH estimates annual direct health care costs for AD to be in the range of $100
billion.
Cystic fibrosis is most common among Caucasians. Worldwide, approximately

70,000 people have cystic fibrosis. Approximately 30,000 Americans have it as
well, making it one of the most common life-shortening inherited diseases. This
disease occurs in one of every 3,200 Caucasian births. Some research shows that
the female hormone estrogen promotes the presence of a particular form of
bacteria which results in more severe symptoms for female cystic fibrosis
patients.


4
Exhibit 1
World Markets for Key Womens Health Diagnostics,
2013-2018
Revenues (in millions)
2013
2015
$689
$721
$773
Lab-Based Immunoassay Fertility Testing $299
$327
$376
Lab-Based Immunoassay Torch Testing
$789
$820
$870
Bone Densitometers
$570
$628
$728
Prenatal Testing
$179
$200
$234
Prenatal Carrier and Fetus Screening
$195
$219
$263
Ultrasound OB/GYN
$788
$880
$1,038
Ultrasound Breast Imaging
$216
$240
$284
Mammography
$713
$754
$818
Digital Mammography
$891
$1,007 $1,208
CAD Systems
$433
$489
$580
Pap Smears
$766
$821
$920
Colposcopy Systems
$138
$147
$163
HPV Diagnostics
$174
$192
$221
CA-125
$ 533
$591
$690
Urinary Tract Infection Assays
$435
$520
$682
Neonatal Jaundice Bilirubin
$17
$18
$21
Autoimmune Diagnostic Assays
$561 $630
$751
Cystic Fibrosis Female Genetic Tests
$57
$73
Pregnancy and Ovulation Testing
$63
2018
Source: Kalorama Information


5
1.1 METHODOLOGY
This report analyzes the current and potential world markets for key diagnostic
tests targeted at womens health. This report generally forecasts future market growth for
these tests to 2018. Market segments covered include the US, Europe, China, Brazil,
Japan and rest of world markets.
This report also reviews the nature and direction of research and trends, and gives
insight into some issues facing the industry. The report profiles several key companies,
including large companies that have made names for themselves in the field, as well as
smaller firms with market niches. These companies are involved in developing and
marketing over the counter (OTC), point of care (POC) in vitro diagnostic (IVD) tests
and screening systems. Some of the companies profiled include: GE Healthcare,
GenMark Diagnostics, Hologic, Immco Diagnostics, Luminex, Nova Biomedical, Philips
Healthcare, Siemens Healthcare, and Somagen Diagnostics, among others.
Market forecasts are based on an examination of current market conditions and on
investigations into the development of new products by key companies. The market data
are generated into multiple year forecasts for different product segments covered in the
report. The information presented in this report is the result of data gathered from
company product literature and other corporate brochures and documents, as well as
information found in the scientific and trade press. In addition, interviews were
conducted with company executives and researchers.

2.0 Introduction
2.1 FEMALE HEALTH: ROOM FOR IMPROVEMENT
Women make more than 75% of the health care decisions in American
households and spend almost two of every three health care dollars. Women also make
more than 65% of physician visits, 62% of prescription drug purchases, and 76% of the
nursing home population. The life expectancy of women is longer than for men and is
climbing steadily due to advancements in medicine. Yet, female health is an area that has
much room for improvement both in the development of products and the treatment of
diseases. There are many disorders that are clearly monopolized by women but research
is lacking in those areas and many of the current product offerings are just mediocre in
terms of diagnosing, treating and curing disease.
Although a woman may know about health screenings she needs, such as a
mammogram, PAP or colorectal screening, she may put herself last, trying to juggle a lot
of responsibilities. Women still shoulder the larger proportion of household and family
maintenance activities, and that means they have less time for focusing on their own
health issues.
Insurance is also a major concern, both for women and for providers. Having
health benefits that cover the cost of prevention and screening, rather than just treatment,
is critical. A lack of insurance sharply compromises the ability to obtain quality health
care.
2.0 Introduction
7
Providing health care to women can be a challenging task requiring the expertise
of many different medical professions. Women also need to be informed decision makers
that help manage their own health including taking steps in preventative care. In the US,
13% of women age 18 and over are only in fair or poor health. Around 12% women of all
ages are limited in some way by a chronic condition.
2.2 PERSPECTIVE ON WOMENS HEALTH

The women's health arena, both therapeutics and diagnostics, has grown
considerably as a specialty medical field. Once limited to obstetrics and gynecology, it
now includes other fields, such as urology, maternal-fetal medicine, as well as
autoimmune disease and cystic fibrosis. At many clinics and practices focused on the
health of women, a range of specialties is offered, which often results in a need for
specific types of women's health-related testing.
Generally, and from a perspective on women's health, diagnostics are playing an
ever increasing role. Many are used to match the right patient with the appropriate
treatment at the right time. Diagnostic testing and screening have an impact on more than
70% of health care treatment decisions. They are the least expensive component of the
health are system, comprising less than 5% of hospital costs and about 1.6% of all
Medicare costs. Some individual tests can cost less than $50 each.
2.3 THE WAY WOMEN AND MEN DEVELOP DISEASE IS DIFFERENT

Gender-specific medical research has demonstrated major differences between the
way male and female physical systems develop and handle disease. Heart disease and
stroke, diabetes and depression are just a few examples of medical conditions that affect
women and men differently. In addition to physical differences, men and women face
different challenges in obtaining and paying for medical services. Economic status, health
insurance coverage, and a woman's role as caregiver equally affect a woman's health. The
interplay between medical, social, and economic issues is critical to understanding the
diverse needs of women.

2.0 Introduction
8
When it involves health, there are many crucial differences between men and
women. Yet many women do not know that they react differently to some medications,
are more vulnerable to some diseases, and may have different symptoms. There is a need
to improve the understanding of the differences, in terms of health, between the sexes and
to translate that knowledge into improved medical diagnostics, practice and therapies.
2.3.1 Pain
Men and women both feel pain differently. When men feel pain their blood
pressure rises. In women, the heart rate rises, and the blood pressure remains stable or
even declines. They also feel different types of pain differently. Women experience
chronic pain longer, more intensely and more often than men. Chronic pain conditions
that are more prevalent in women than in men include fibromyalgia, irritable bowel
syndrome, rheumatoid arthritis and migraines.
2.3.2 The Heart

Women have smaller hearts and arteries than men. The heart also beats faster
while taking longer to relax between beats. Most doctors, however, continue to consider
chest pain as the most important heart attack symptom in both women and men. Women
are also more likely than men to have a second heart attack within a year of the first one.
Heart disease kills 500,000 American women each year over 50,000 more women than
men and strikes women, on average, 10 years later than men. Women are more likely
than men to have a second heart attack within a year of the first one.
2.3.3 The Brain

As men are physically bigger than women, they require a greater number of
neurons for muscle movement. For this reason, men have a bigger brain then women.
This has nothing to do with the intellectual ability. According to an estimate, male brains
have approximately 4% more cells and weigh 100 grams more than female brains.
However, both have a similar brain weight to body weight ratio. Female brains are more

2.0 Introduction
9
compact than male brains in that, although smaller, they are more densely packed with
neurons, particularly in the region responsible for language.
2.3.4 Emotions
Women are more in touch with their feelings and are better able to express them.
The down side to this is that it also opens women up to depression. Women are up to
three times more likely than men to suffer from depression. The lifetime risk of major
depression in women is about 20% to 26%, compared to about 8% to 12% for men.
Women are more prone to depression because of their tendency to dwell on the causes of
negative emotions. Women's emotions are also influenced by hormonal changes,
pregnancy, and menopause, for instance.
2.3.5 Bone Structure

A female's requirement for calcium is greater than her counterparts. Women are
80% more likely to suffer from osteoporosis in old age. Also, as women age, their
estrogen levels decrease and the risk of osteoporosis increases. Women can lose up to
20% of their bone mass in the five to seven years after menopause, making them more
susceptible to osteoporosis. Women comprise nearly 80% of the population suffering
from osteoporosis.
2.3.6 Alcohol
The female body produces less stomach enzyme that breaks down ethanol. After
consuming the same amount of alcohol, women have higher blood alcohol content than
men. According to a study of 43 men and women reported in the New England Journal of
Medicine, women absorb about 30% more alcohol into their bloodstreams than men do.
2.3.7 Drug Side Effects

More evidence is showing that women can suffer greater side effects from drugs
than men. This may be caused by hormone fluctuations, body composition, body weight,
2.0 Introduction
10
and how womens liver and kidneys metabolize drugs. Many drugs achieve different
blood levels and effectiveness depending on when during a menstrual cycle they are
taken. Reproductive hormones also control the time that medicine spends in the gut, and
the metabolic processes that break it down. The difference in woman's muscle-to-fat ratio
is also a factor.
2.3.8 Smoking
Women are at greater risk for certain problems related to smoking than men are.
Women who smoke and use oral contraceptives or other hormonal forms of birth control
have an increased risk of developing blood clots and strokes. Smoking-related diseases
kill more than 140,000 American women annually. Smoking has a more negative effect
on cardiovascular health in women than men.
2.3.9 Fertility
Female fertility decreases after age 35, ending with menopause. But men are
capable of fathering children even into their 60s.
2.3.10 STIs/HIV
Women are two times more likely than men to contract a sexually transmitted
infection (STI). HIV is among the top 10 leading causes of death for all US women aged
25 to 54 and is the leading cause of death for African American women aged 25 to 34.
2.3.11 Autoimmune Disease

Autoimmunity is the failure of an organism to recognize its own constituent parts
as self, which generates an immune response against its own cells and tissues. Any
disease that results from such an aberrant immune response is called an autoimmune
disease. Autoimmunity is often caused by a lack of germ development of a target body,
and as such the immune response acts against its own cells and tissues. Prominent
examples include Celiac disease, diabetes mellitus type 1, systemic lupus erythematosus,
2.0 Introduction
11
Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura and
rheumatoid arthritis.
Three out of four people suffering from autoimmune diseases, such as multiple
sclerosis, rheumatoid arthritis, and lupus, are women. Autoimmune diseases are in the top
10 leading causes of deaths (aged 65 and younger) and are the fourth largest cause of
disability among US women.
Because a persons sex also seems to have some role in the development of
autoimmunity, most autoimmune diseases have been classified as sex-related diseases.
Nearly 75% of those who suffer from autoimmune disease are women, although it is lessfrequently acknowledged that millions of men also suffer from these diseases. According
to the American Autoimmune Related Diseases Association (AARDA), autoimmune
diseases that develop in men tend to be more severe. A few autoimmune diseases that
men are just as or more likely to develop as women, include: ankylosing spondylitis, type
1 diabetes mellitus, Wegener's granulomatosis, Crohn's disease and psoriasis.
The reasons for the sex role in autoimmunity are unclear. Women appear to
generally mount larger inflammatory responses than men when their immune systems are
triggered, increasing the risk of autoimmunity. Involvement of sex steroids is indicated
because many autoimmune diseases tend to fluctuate in accordance with hormonal
changes, such as during pregnancy, in the menstrual cycle, or when using oral
contraception. A history of pregnancy also appears to leave a persistent increased risk for
autoimmune disease. It has been suggested that the slight exchange of cells between
mothers and their children during pregnancy may induce autoimmunity. This would tip
the gender balance in the direction of the female.
2.3.12 Cancer
Cancer is a group of many diseases that can arise in any cell of the body capable
of evading regulatory controls over proliferation and differentiation. Two major
dysfunctions are present in the process of cancer: defective cellular proliferation and
defective cellular differentiation. The rate of normal cellular proliferation differs in each
body tissue. In some tissues, such as bone marrow, hair follicles, and epithelial lining of
the gastrointestinal tract, the rate of cellular proliferation is rapid. In other tissues, such as

2.0 Introduction
12
myocardium, brain, and cartilage, the rate of cellular proliferation is much slower. Cancer
cells usually proliferate in the manner and at the same rate of normal cells of the tissue
from which they arise. However, cancer cells respond differently than normal cells to the
intracellular signals that regulate the state of dynamic equilibrium. Cancer cells divide
indiscriminately and haphazardly. The loss of intracellular control of proliferation may be
a result of a mutation of the stem cells. The stem cells are viewed as the target or the
origin of cancer development.
2.3.12.1LeadingFemaleCancers
The top four cancers affecting women include breast, cervical, endometrial, and
ovarian. In 2012, 1.7 million women were diagnosed with breast cancer worldwide.
Breast cancer is also the most common cause of cancer death among women. There were
522,000 breast cancer deaths in 2012 worldwide. Among women in the US, breast cancer
is the most common cancer, except for skin cancers. The American Cancer Society
estimates that in the US in 2014, there will be approximately 232,670 new cases of
invasive breast cancer diagnosed in women. About 62,570 new cases of carcinoma in situ
(CIS) will be diagnosed, which is non-invasive and is the earliest form of breast cancer.
Approximately 40,000 women will die from breast cancer.
The American Cancer Society estimates that in men in the US in 2014, about
2,360 new cases of invasive breast cancer will be diagnosed, and approximately 430 men
will die from breast cancer. Breast cancer is about 100 times less common among men
than among women.
Incidence rates of invasive female breast cancer for all races combined show five
distinct phases since 1975, when population-based surveillance of cancer began. Between
1975 and 1980, the incidence rate was essentially constant. Between 1980 and 1987,
incidence increased by 4% per year. Between 1987 and 1994, the incidence rate was
essentially constant. Between 1994 and 1999, incidence rates increased by 1.6% annually.
Between 1999 and 2006, incidence rates decreased by 2% annually.
Much of the long-term underlying increase in incidence may be attributed to
changes in reproductive patterns, such as delayed childbearing and having fewer children,
which are recognized risk factors for breast cancer. The rapid increase between 1980 and

2.0 Introduction
13
1987 is due largely to the greater use of mammography screening and increased detection
of breast cancers too small to be felt. During the uptake of mammography, from 1980 to
1987, the incidence rates of smaller tumors, those equal to or less than 2.0 cm, more than
doubled, while rates of larger tumors, 3.0 cm or more, decreased 27%. The slight increase
in overall breast cancer incidence during the later half of the 1990s may reflect increases
in the prevalence of mammography screening, rising rates of obesity, and menopausal
hormone use.
Cervical cancer forms in tissues of the cervix, the organ connecting the uterus and
vagina. It is usually a slow-growing cancer that may not have symptoms but can be found
with regular Pap tests, a procedure in which cells are scraped from the cervix and
examined under a microscope. Cervical cancer is almost always caused by human
papillomavirus (HPV) infection.
For 2014, the American Cancer Society's estimates about 12,360 new cases of
invasive cervical cancer will be diagnosed in the US, and approximately 4,020 women
will die from cervical cancer. Some researchers estimate that non-invasive cervical
cancer (carcinoma in situ) occurs about 4 times more often than invasive cervical cancer.
Cervical cancer was once one of the most common causes of cancer death for
American women. Then, between 1955 and 1992, the cervical cancer death rate declined
by almost 70%. The main reason for this change was the increased use of the Pap test.
This screening procedure can find changes in the cervix before cancer develops. It can
also find cervical cancer early in its most curable stage. The death rate from cervical
cancer has been stable in recent years. The death rate from cervical cancer continues to
decline by about 3% annually.
Uterine cancer and endometrial cancer are terms that are often used
interchangeably. Endometrial cancer is the most common cancer of the female
reproductive organs among American women. It can often be cured, especially when
diagnosed early. The American Cancer Society estimates that about 52,630 new cases of
cancer of the body of the uterus (uterine body or corpus) will be diagnosed in the US in
2014. About 8,590 women will die from cancers of the uterine body. These estimates
include both endometrial cancers and uterine sarcomas. About 2% of uterine body
cancers are sarcomas, so the actual numbers for endometrial cancer cases and deaths are
slightly lower than these estimates.

2.0 Introduction
14
Endometrial cancer is rare in women under the age of 45. Most (about 3 out of 4)
cases are found in women aged 55 and over. The average chance of a woman being
diagnosed with this cancer during her lifetime is about one in 37.
Nearly all endometrial cancers are adenocarcinomas cancers of the glandular
cells. Three less common uterine cancers that do not come from glandular tissue of the
endometrium are classified as uterine sarcomas, but can involve the endometrium. These
are: stromal sarcomas, which develop in the stroma (supporting connective tissue) of the
endometrium; malignant mixed mesodermal tumors that may combine features of
endometrial carcinoma and those of sarcomas; and leiomyosarcomas, which start in the
myometrium the muscular wall of the uterus.
Ovarian cancer is the deadliest of all gynecologic cancers. Ovarian cancer
accounts for approximately 3% of cancers in women. While the ninth most common
cancer among women, ovarian cancer is the fifth leading cause of cancer-related death
among women. The American Cancer Society estimates that in 2014 in the US,
approximately 21,980 women will receive a new diagnosis of ovarian cancer. About
14,270 women will die from ovarian cancer. A woman's risk of getting ovarian cancer
during her lifetime is about 1 in 73. Her lifetime chance of dying from ovarian cancer is
about 1 in 100. These statistics do not include low malignant potential ovarian tumors.
This cancer mainly develops in older women.
2.3.13 Musculoskeletal Health

The changes in a womans body that accompany pregnancy, coupled with the
strain of carrying a growing fetus, place stress on a womans musculoskeletal system.
Back and wrist pain and leg cramps are among the most frequent complaints. More than
two of every three pregnant women complain of back pain at some point. Low back pain
rates increase with advancing maternal age. This type of pain is also greater in women
who have already given birth and in those who have had such back pain during previous
pregnancies. As the uterus enlarges, it moves the bodys center of gravity forward,
causing an increase in the normal curve of the spine. This puts stress on the joints and
ligaments of the lower back. In addition, hormones produced during pregnancy cause the
pelvic ligaments to loosen and the joints to open. This, too, can cause pain. Back pain can

2.0 Introduction
15
be particularly severe if a woman gains more than the recommended amount of weight
during pregnancy.
Wrist pain may occur because of swelling. Another condition that may involve
this area is de Quervains tenosynovitis, an inflammation of the tendons of the back of the
wrist. Leg cramps, particularly at night, are another common symptom during pregnancy.
Such cramps may sometimes signal a calcium deficiency.
On another front, osteoporosis is a disease in which the density and quality of
bone are reduced, leading to weakness of the skeleton and increased risk of fracture.
More than 10 million in the US have osteoporosis. About 18 million others have lost
some bone mass and are likely to develop osteoporosis in the future. More than 80% of
those affected are women. Osteoporosis leads to more than 1.5 million fractures each year
in the US. One out of two women and one out of eight men older than age 50 suffer a
fracture related to osteoporosis at some point during their lives.
Bone loss in women can begin as early as age 25. Worldwide, the lifetime risk for
a woman to have an osteoporotic fracture is 30% to 40%. In men, the risk is about 13%.
Osteoporosis is a widespread public health problem. The costs to national health care
systems from osteoporosis-related hospitalization are staggering. In the US, the cost to
the health care system associated with osteoporotic fractures is approximately $17 billion
annually. This is more than $45 million a day. Each hip fracture represents an estimated
$40,000 in total medical costs.
A womens risk of hip fracture is equal to her combined risk of breast, uterine,
and ovarian cancer. Only half of women who sustain a hip fracture fail to return to their
pre-fracture function level. Independent of bone mineral density (BMD), a previous
fracture is the most important risk factor for future fractures. BMD has both genetic and
environmental components. Because bone density accounts for 70% of bone strength, and
low BMD is the greatest predictor of risk for bone fractures. BMD peaks at 20 to 30 years
of age in both women and men. BMD begins to take a dramatic decline in women at
menopause, but this dramatic decrease does not occur in age-matched men.
In women, the most important determinant of BMD is menopause. In pre- and
peri menopausal women, low BMD can result from an inability to accrue peak bone
mass, loss of bone mass, or both. BMD is an indicator of bone mass, but it does not

2.0 Introduction
16
indicate the quality or strength of bone. BMD is one of many potential risk factors of
osteoporosis. The rate of hip fracture is two to three times higher in women than men.
2.3.14 Birth Defects

Congenital anomalies birth defects impact approximately one in 33 infants
and cause approximately 3.2 million birth defect-related disabilities annually. An
estimated 270,000 newborns die during the first 28 days of life every year from
congenital anomalies. Although congenital anomalies may be genetic, infectious or
environmental in origin, most often it is difficult to identify the exact causes.
Some of the more common birth defects include:
x
Spina bifida, which occurs when the backbone does not fully close;
Heart defects;
Hypospadias, which occurs when the opening for urine in males is abnormally
placed;
Phenylketouria (PKU), which occurs when babies cannot utilize a protein. The
protein builds up in the blood and can cause brain damage.
Fetal alcohol syndrome, in which babies are born with defects caused by the
mothers alcohol use during pregnancy.
2.3.15 Urinary Tract Infections

The urinary tract consists of the bladder, kidneys and two tubes: one that connects
the kidneys to the bladder (the ureter), and one that carries urine out of the body (the
urethra). They filter and remove waste from the bloodstream in the form of urine. Urinary
tract infections (UTIs) are usually caused by E. Coli. UTIs are more common in women
than men. This is partly because the tube that carries urine out of a womans body (the
urethra) is very close to the vagina and rectum. Infections can be passed easily from one
opening to the other. Studies have shown that roughly one in every five women will have
a UTI at some point in her life.

2.0 Introduction
17
Women may have new reason to worry about UTIs. Infection with antibiotic
resistant bacteria is becomingly increasingly common. With the overuse and misuse of
antibiotics, some bacteria have evolved to become resistant to the medication, resulting in
treatment failure and the need for a new approach.
UTIs are the second most common type of infection in the body, accounting for
about 8.1 million visits to health care providers annually. Women are especially prone to
UTIs. A womans urethra is shorter, allowing bacteria quicker access to the bladder.
Also, a womans urethral opening is near sources of bacteria from the anus and vagina.
For women, the lifetime risk of having a UTI is greater than 50%. About 20% of young
women with a first UTI will have a recurrent infection.
There are several types of UTIs, but the most common is uncomplicated acute
cystitis. Women at an increased risk for UTIs include those who engage in frequent
sexual intercourse, have many sexual partners, and frequently use a diaphragm or
spermicide. Other known risk factors include diabetes, recent antibiotic use and estrogen
deficiency, most commonly from drugs or menopause.
But many female patients are unaware of the growing resistance to antibiotics.
Certain types of bacteria have become more resistant than others. Physicians are seeing
increased resistance of E. coli, the most common UTI bacteria, to the commonly used
antibiotics, including trimethoprim/sulfamethoxazole, ampicillin and cephalosporin.
2.4 KEY LEADING CAUSES OF DEATH IN FEMALES

There are several illnesses that are leading causes of death among women. Some
of the key ones include:
x
Sexually Transmitted Infections: Women are two times more likely than men to
contract a sexually transmitted infection. HIV is among the top 10 leading causes of
death for all US women aged 25 to 54 and is the leading cause of death for African
American women aged 25 to 34.
Autoimmune Disease: Three out of four people suffering from autoimmune diseases,
such as multiple sclerosis, rheumatoid arthritis, and lupus, are women. Autoimmune
diseases are in the top 10 leading causes of deaths (age 65 and younger) and are the
fourth largest cause of disability among US women.
2.0 Introduction
18
x
Cancer is the second leading cause of death among women and men. A study of more
than 1 million cancer cases from 45 population-based cancer registries in 17
European countries demonstrated that young women were more likely than young
men to survive cancer, while in older people, men were more likely to survive.
Women with cancer of the head and neck, esophagus, stomach, liver, or pancreas
were less likely to die from cancer than men with the same tumor type, whereas
women with bladder cancer were more likely to die from the disease than
men. Exhibit 2 indicates the leading causes of death in females in the US.

2.0 Introduction
19
Exhibit 2
Leading Causes of Death in Females, US, 2010
All Females, All Ages
Percent*
Heart disease
23.5
Cancer
22.1
Stroke
6.2
Chronic lower respiratory diseases
5.9
Alzheimer's disease
4.7
Unintentional injuries
3.6
Diabetes
2.7
Influenza and pneumonia
2.1
Kidney disease
2.1
Septicemia
1.5
Source: US Centers for Disease Control and Prevention
2.5 DEMOGRAPHICS
Worldwide, women are living longer than men. The largest differences are found
in Eastern Europe, the Baltic States and central Asia. For example, in the Russian
Federation, the difference in favor of women is nearly 11 years. In the developed regions
and central Asia, female life expectancy at birth exceeds that of males by six to eight
years. In developed regions in 1995, the estimated number of women aged 60 and over
made up more than 20% of the total female population. The corresponding proportion of
men was 15%. By the year 2025, the average proportion of elderly women in developed
regions will reach 27% of the female population. Elderly men will account for 22% of all
men. By 2025, the proportion of women aged 60 or older will almost double in eastern
and south-eastern Asia, Latin America and the Caribbean, and northern Africa.
Exhibit 3 indicates life expectancy at birth by sex for certain populations.

2.0 Introduction
20
Exhibit 3
World Life Expectancy at Birth in Selected Countries by Sex, 2013
Country/Region
France
Germany
Sweden
United Kingdom
Italy
Spain
Australia
Japan
United States
South Africa
China
India
Mexico
Expectancy in Years
Male
Female
Developed Countries
79.4
85.2
78.5
83.5
81.4
84.6
79.5
82.5
80.4
85.8
79.5
85.0
80.5
85.5
82.0
87.3
77.4
82.2
Developing Countries
59.0
63.0
74.0
77.0
64.0
67.0
74.2
80.2
Source: World Health Organization.
2.6 WHAT CLAIMS WOMENS LIVES

Women fear breast cancer most. This suggests that even though heart attack,
stroke and other cardiovascular diseases kill women 10 times more every year, certain
diseases, such as breast cancer, HIV and AIDS, receive a large amount of public
attention, which can lead to misperceptions regarding womens health risks.
More women die from heart disease each year than from breast, ovarian, and
uterine cancer combined. Heart disease is the number one cause of mortality in women,
killing more women than men each year. HIV/AIDS is the fifth leading killer of
women aged 35 to 44. Lung cancer is the leading cancer killer of women, taking the lives
of approximately 68,000 women each year. Colorectal cancer is the third leading cause of
cancer deaths in women, killing almost 30,000 women each year. Autoimmune
diseases are collectively the eighth leading cause of death for women under the age of 65,
2.0 Introduction
21
but their impact on mortality is not well captured by traditional reporting of death
statistics.
2.7 KEY TRENDS AND ISSUES IN WOMENS DIAGNOSTICS

Personalized medicine and improved diagnostics hold particular promise for
improving cancer diagnosis and treatment, where small genetic differences can often
impact prognosis and outcomes. The National Cancer Institute (NCI) estimates that more
than 21,000 new cases of ovarian cancer are diagnosed annually and about 15,000 women
die of the disease. Between 1995 and 2005, the Surveillance Epidemiology and End
Results (SEER) program of the National Cancer Institute found the overall five year
survival rate for ovarian cancer patients in 17 geographical areas of the US to be 45.9%.
2.7.1 OVA1
This rate worsens with later diagnosis. For patients with metastasized cancer
(which is 62% of women diagnosed), the five year survival rate drops to 28.2%. It is
thought, therefore, that earlier diagnosis may improve outcomes. Vermillion Inc.,
Fremont, CA, has developed an In Vitro Diagnostic Multivariate Index Assay (IVDMIA),
the OVA1, that uses a blood sample, five well-established biomarkers, and a proprietary
algorithm to produce a numerical score that indicates the likelihood of malignancy of the
womans pelvic mass. The biomarkers include: transthyretin, apolipoprotein A-1, beta 2microglobulin, transferrin, and cancer antigen 125 (CA-125).
The FDA approved the test for use by women 18 years of age or older who have
an ovarian adnexal mass present for which surgery is planned and who have not yet been
referred to an oncologist. The test is not intended as a stand-alone diagnostic nor as a
screening tool. It should be used in conjunction with imaging studies and other clinical
assessments.
OVA1 is intended for use prior to surgery and in many cases before a diagnosis is
confirmed. Vermillion hopes to move up the launch of a second-generation OVA1 test to
the second half of 2015, six months earlier than planned. The company and its
collaborators at Johns Hopkins University have nearly completed development work.

2.0 Introduction
22
Next will be validation. The second-generation OVA1 panel raises the test's specificity.
The Roche Cobas system is the new platform for the test.
2.7.2 CA-125
The current gold standard for monitoring ovarian cancer for treatment success and
disease recurrence, postdiagnosis, is the CA-125 assay. Significantly elevated
concentrations of this marker may indicate the presence of cancer in the ovaries. But
other conditions, such as menstruation and endometriosis, can also elevate CA-125
levels, and the low specificity prevents the tests use as a diagnostic. Research into
human epididymis protein 4 (HE4) has shown the potential to expand the value of CA125.
Combining the CA-125 assay with another test may be an extremely effective
ovarian cancer screening mechanism. Scientists at Fujirebio Diagnostics, Malvern, PA,
have developed a new CA125 + HE4 stratification tool. The CA125 + HE4 test
combination helps connect ovarian cancer patients with the right doctor for the most
optimal outcome. The CA125 + HE4 risk stratification tool is only permitted for use
outside of the US at this time.
2.7.3 HER2
Another evolving trend: Breast cancer patients are also benefiting from
personalized medicine, with tests already existing to help tailor treatment for the more
than almost 200,000 cases diagnosed annually. Physicians routinely run tests to determine
if a patient has human epidermal growth factor receptor-2 (HER2) positive breast cancer,
which is more aggressive but responds better to targeted treatment. HER2-positive
patients must undergo a different treatment regimen than those with HER2-negative
breast cancer.
Clarient, Alisa Viejo, CA, which was purchased by GE Healthcare in 2010, is
marketing its Clarient Insight Dx Mammostrat, a test for estimating the risk for
recurrence in hormone-receptor positive, early stage breast cancer that is independent of
proliferation and grade. Five biomarkers are combined with a defined mathematical

2.0 Introduction
23
algorithm, resulting in a risk index. Mammostrat is clinically validated and has been
studied on more than 4,500 total patients in numerous independent cohorts.
In March 2012, Ventana Medical Systems, Inc., Tucson, AZ, a member of the
Roche Group, received FDA approval for its Inform HER2 Dual ISH DNA Probe
cocktail assay (HER2 Dual ISH) on the Ventana BenchMark Ultra automated slide
staining platform. Originally approved by the FDA in June 2011 for use with the
BenchMark XT instrument, the HER2 Dual ISH assay is now approved for use on both
Ventana BenchMark advanced staining platforms available in the US.
The HER2 Dual ISH assay is intended for use in the determination of HER2 gene
status in breast cancer tissue as an aid in the assessment of patients that may be
considered for treatment with trastuzumab.
2.8 UNDERSTANDING THE MOLECULAR BASIS OF DISEASE

Over the next few decades, comprehensive genomics-based health care should be
the norm in the US and much of Europe. Science will understand the molecular
foundation of diseases, be able to prevent them in many cases, and design accurate,
individualized therapies for illnesses. In the next decade, genetic tests will routinely
predict individual susceptibility to disease. Within two or three decades, novel drugs will
be available that are based on a detailed molecular understanding of common illnesses
like diabetes and high blood pressure. The drugs essentially will be designer therapies
that target molecules logically and are therefore potent without significant side effects.
Through molecular diagnostics, cancer therapies will be matched to a patient's
likely response. Diagnoses of many conditions will be much more thorough and specific
than now. For example, a patient who learns that he has high cholesterol will also know
which genes are responsible, what effect the high cholesterol is likely to have, and what
diet and pharmacologic measures will work best for him.
In the next 50 years, many potential diseases will be cured at the molecular level
before they arise, though large inequities worldwide in access to these advances will
continue to stir tensions. When people become sick, gene therapies and drug therapies
will target individual genes, as they exist in individual people, making for precise,
customized medical treatment. The average life span will reach 90 to 95 years, and a

2.0 Introduction
24
detailed understanding of human aging genes will spur efforts to expand the maximum
span of human life.
2.8.1 Managing Cancer Disease and Costs through Reimbursement

Managing costs and patient outcomes are the largest problems faced by the health
care industry today. One approach that limits spending is the establishment of
reimbursement schedules for all patient services. As cost management pressures continue
to increase, health care systems, worldwide, base their decision whether or not to
reimburse a new product on its impact on patient care.
The reimbursement challenge is felt most acutely by new genome-based cancer
diagnostics because they generally are more expensive than traditional tests. They may
not be successful marketwise unless they can prove to payer groups that they will
improve patient outcome and be cost efficient compared to current therapies. The Centers
for Medicare and Medicaid Services (CMS) decided to increase reimbursement for
BRCA-1 and -2 gene sequencing by 52% to $2,184, effective April 1, 2014, reversing its
November 2013 decision to lower reimbursement for BRCA-1 and -2 gene sequencing to
$1,438. Still, it is low.
2.8.2 Ultrasound and Mammography Use Grows

On another front, ultrasound will continue to be used in a variety of clinical
settings, including obstetrics and gynecology, and breast tumor detection. In addition to
these areas, there is a growing use of ultrasound as a rapid imaging tool for diagnosis in
emergency rooms, and for breast cancer examinations.
And, growth in the mammography systems market place will continue thanks in
part to a growing use of digital mammography systems because of an increased public
awareness of breast cancer, and the high efficiency and low dosage capability of
advanced digital equipment. The use of computer-aided detection (CAD) software aids in
pinpointing tissue densities that might be cancerous. Many digital x-ray product
2.0 Introduction
25
manufacturers have decided to focus their efforts on the mammography market. Some
women who are at high risk for breast cancer benefit more from screening with a
mammogram and a breast ultrasound than from a mammogram alone.

3.0 Market Developments in

Women's Health Diagnostics
3.1 QUEST AND HOLOGIC TEAM UP
In June 2013, Quest Diagnostics and Hologic Inc. entered into a strategic alliance
to more broadly offer testing based n Hologic's Aptima family of products, as well as to
co-develop and promote advanced diagnostic solutions to improve women's health.
Under a non-exclusive agreement with an initial term of five years, the companies
are focusing primarily on clinical areas critical to the health of women. Quest
Diagnostics will transition to a broader offering of services based on Hologic's Aptima
family of products, which includes FDA-approved or cleared assays for HPV, HPV
genotyping, chlamydia, gonorrhea and trichomonas vaginalis. In addition, Quest
Diagnostics will continue to utilize Hologic's ThinPrep liquid-based cytology products.
Quest Diagnostics will also continue to offer Hologic's Aptima HPV mRNAbased assay nationally. The Aptima HPV assay detects messenger RNA over-expressed
from two viral oncogenes that are integral to the development of cervical
cancer. Hologic's Aptima HPV assay detects E6/E7 viral mRNA from 14 high-risk types
of human papillomavirus in cervical specimens.
The companies will also explore opportunities to develop and expand access to
new diagnostics for women's health. In addition, they will implement joint programs to
3.0 Market Developments

27
advance women's health issues with medical associations and patient advocacy groups
and to sponsor research. Financial terms of the collaboration were not disclosed.
3.2 QUEST GENETIC TESTING FOR BREAST CANCER RISK

In October 2013, Quest Diagnostics introduced its BRCAvantage, a suite of four
new lab-developed genetic tests (LDTs) that identify mutations in BRCA1 and BRCA2
genes, which are associated with increased risk of inherited breast and ovarian cancers.
An estimated 5% to 10% of female breast cancers are caused by inherited gene
mutations, with BRCA1 and BRCA2 gene mutations the most commonly identified cause.
BRCA1 and BRCA2 mutations are also associated with increased inherited risk of ovarian,
male breast and other cancers. BRCA testing may be underutilized among appropriate atrisk patients. Quest is addressing this gap, beginning with informed consideration of
BRCA testing in dialogue with a clinician and genetic counselor.
Clinicians can access results of BRCAvantage and Quest's more than 3,000
testing services through the company's secure Care360 connectivity platform, supporting
clinical management of the individual patient across a continuum of care. As part of the
BRCAvantage offering, Quest will provide access to third-party genetic counselors to
clinicians and patients.
3.3 SEQUENOM, QUEST COLLABORATE ON NONINVASIVE PRENATAL

TESTING
In June 2014, Sequenom Inc., San Diego, CA, and Quest Diagnostics, Madison,
NJ, made official an agreement under which Quest is offering national access to
Sequenom Laboratories' MaterniT21 PLUS laboratory-developed test (LDT). Using a
maternal blood sample, the noninvasive prenatal test (NIPT) analyzes chromosomal
material in cell-free fetal DNA of pregnant women at increased risk for fetal
chromosomal abnormalities.
In addition, Quest has a license agreement with Sequenom for certain NIPT
patents and patent applications. The license agreement is the first formed by Sequenom
with a commercial lab in the US. Quest intends to use the intellectual property for the
purposes of developing and validating its own proprietary lab-developed NIPT test. Quest


28
expects to introduce this new offering in 2015. Additional terms of the agreement were
not disclosed.
"Noninvasive prenatal testing is one of the most promising new areas of medicine
because it delivers highly actionable insights for empowering critical health decisions,"
explains Charles Strom, MD, PhD, Senior Medical Director, Genetics, Quest Diagnostics.
"Offering access to this test strongly aligns with our strategy to deliver guideline-backed
testing services based on the most advanced technologies in order to improve healthcare
for patients."
A December 2012 medical opinion from the American Congress of Obstetricians
and Gynecologists and the Society of Maternal Fetal Medicine supports the use of cellfree fetal DNA testing as an option for primary screening for women at increased risk of
aneuploidy (abnormal chromosomal number), including those 35 years of age or older or
who have a history of ultrasound abnormalities in pregnancy.
Physicians will be able to order the test through Quest Diagnostics, which will
forward specimens for testing to Sequenom Laboratories. Estimates suggest about
750,000 pregnancies may be at high risk for fetal chromosomal abnormalities each year
in the US.
3.4 PARTNERING TO MAKE PERSONALIZED INFERTILITY TREATMENT

POSSIBLE
Ferring Pharmaceutical's follicle-stimulating hormone is in development with a
companion diagnostic test from Roche to help improve the clinical management of
infertility treatment. In June 2014, Ferring and Roche announced a collaboration to
combine diagnostic testing technology from Roche with Ferrings human cell line derived
recombinant follicle-stimulating hormone (human rFSH), a gonadotrophin currently in
phase III development.
This combination is intended to make it possible for healthcare professionals to
personalize infertility treatment to a womans specific needs. Under the terms of the
worldwide agreement, Roche will work with Ferring and its global phase III program to
qualify, validate, document and seek regulatory approval for a companion diagnostic test
to be used in combination with Ferrings human rFSH.


29
Currently under development with Ferrings human rFSH, Roche's fullyautomated Elecsys AMH assay aims to assess anti-Mllerian hormone (AMH) levels, a
measure of a womans ovarian reserve and also of her ovarian response to infertility
treatment with gonadotrophin. With this information, doctors will be better able to deliver
a personalized dose of Ferrings human rFSH based on the womans AMH level. Unlike
manual AMH testing that can take up to several hours to produce results, the fully
automated Elecsys AMH test determines hormone levels in 18 minutes, making it
appropriate for routine clinical use.
The ability to tailor a specific dose of gonadotrophin based on a womans
personal AMH level would represent a major step forward in fertility management, says
Pascal Danglas, MD, Executive Vice President, Clinical and Product Development at
Ferring. Personalized dosing according to a womans AMH level, if successful, may
improve the predictability of infertility treatment and, as a result, lower the potential
burden of treatment for women seeking to conceive through assisted reproductive
technology.
A multinational clinical phase III comparative study is attempting to confirm the
efficacy and safety of Ferrings human cell line derived rFSH in a personalized treatment
regimen based on the womans AMH levels. The Esther (Evidence-based Stimulation
Trial with Human rFSH in Europe and Rest of World) program is enrolling 1,150 patients
from 11 countries and from over 30 sites during 2014 and 2015. Additional studies are
planned for US, Japan, China and other parts of Asia.
3.5 CO-MARKETING OF FULL-LENGTH HLA GENE SEQUENCING

PRODUCTS
In June 2014, Pacific Biosciences of California Inc., Menlo Park, CA, which
markets the PacBio RS II DNA Sequencing System, and GenDx, Utrecht, The
Netherlands, involved in sequence-based typing and next-generation sequencing for HLA
typing, announced a co-marketing agreement to offer products for full-length HLA gene
sequencing.
The Human Leukocyte Antigen (HLA) system consists of a large family of highly
variable genes and allelic variants that forms the basis of the human immune system.
There has been an ever growing interest in characterizing the HLA genes in their entirety.

30
High-resolution HLA typing and sequencing of the complete gene enables determination
of even the smallest variations between HLA alleles. HLA allele-specific genotyping is
critical for autoimmune disease-association studies, drug hypersensitivity research and
other applications.
GenDx, which currently offers reagents for the amplification of full-length, Class
I HLA genes, will offer a version of its NGSgo reagent line with barcoded primers
developed with Pacific Biosciences for sequencing on the PacBio RS II DNA sequencing
system. Using the GenDx NGSengine software package to analyze data from the PacBio
system provides customers with an accurate, allele-level HLA typing solution. This new
reagent kit will make it possible to pool full-length, Class I HLA genes from multiple
samples into a single sequencing run.
3.6 ACQUISITION STRENGTHENS THERANOSTICS DEVELOPMENT

In June 2012, Theradiag, the theranostics and in vitro diagnostics company based
in La Vallee, France, and focused on autoimmune disease, acquired Prestizia,
Montpellier,
France,
biotechnology
company
that
is
developing
microRNA technology. MicroRNA are circulating molecules that regulate the expression
of DNA and proteins. Modifying microRNA expression in some diseases, such as AIDS,
cancer, and chronic inflammatory diseases, makes them important diagnostic and
prognostic biomarkers.
The acquisition of Prestizia and its microRNA platform is going to allow
Theradiag to strengthen its development in theranostics with a highly innovative,
patented technology, according to executives. Prestizia acquired an exclusive worldwide
license on a patent for a method of characterizing HIV cell tropism. Prestizias
technology is based on the identification of microRNA signatures. This technology could
pave the way for a large number of clinical applications, including identifying patients
eligible to a treatment for viral diseases including HIV or differentiating types of
cancerous tumors.
The first application of this platform is already being developed, in collaboration
with the Institut de Gntique Molculaire de Montpellier the Molecular Genetics
Institute of Montpellier for finalizing a molecular biology test of HIV tropism to be
marketed in the near future. It is estimated that there are 2 million people with AIDS in

31
the EU and US combined, 10% of whom could benefit from new therapeutic molecules
like Selsentry. Before a prescription for this drug can be written, an HIV tropism test
must be conducted to determine the type of HIV the patient is infected with, and whether
he or she is eligible for treatment. Theradiag is already working with this microRNA
platform to develop new theranostic tests for various pathologies, including cancers and
autoimmune diseases.
3.7 TRINITY BIOTECH ACQUISITION

In July 2013, Trinity Biotech, Bray, Ireland, acquired Immco Diagnostics Inc.,
Buffalo, NY., for more than $32 million. Immco is a diagnostic company specializing in
the development, manufacture and sale of autoimmune test kits on a worldwide basis.
This product line is complemented by specialized reference laboratory services in
diagnostic immunology, pathology and immunogenetics, marketed to US-based reference
laboratories and hospitals.
Currently, more than 50 million Americans are affected by more than 80 different
autoimmune diseases. Autoimmune diseases are now the second leading cause of chronic
illness and the leading cause of death amongst women over 65. The autoimmune market
is divided into two main segments, the first of which is the automated, high volume
segment for standard analytes such as thyroid markers. This segment is dominated by the
large diagnostic players, such as Abbott, Roche and Beckman Coulter, and is growing
slowly. Instead, Immco's position is in the high growth lower throughput, specialty
autoimmune segment, where the competition is limited to a small number of key players,
principally Bio-Rad, Werfen-Inova and Phadia. The principal autoimmune conditions in
this segment are rheumatoid arthritis, vasculitis, lupus, celiac and Crohn's disease,
ulcerative colitis, neuropathy, Hashimoto's and Graves disease.
Meanwhile, the two key technologies employed are immunoflourescence (IFA)
and immunoassay (EIA). Immco offers a range of more than 120 products across all the
main autoimmune segments with its EIA product range running on the DSX/DS2
Instrument platform. The IFA products can be read manually or on Immco's proprietary
IFA reading system, iSight.
Immco sells its products through a network of distributors, mainly outside of the
US. In Europe, Immco's main distribution partner is Menarini, a company with which

32
Trinity already has deep distribution ties. To date, Immco has had very low product sales
in the US due to a lack of FDA product approvals and a sales force. However, Immco has
been successful in harmonizing its complete IFA and EIA product ranges, virtually all of
which have now been FDA 510K cleared.
Immco is further driving expansion with the development of a number of new
diagnostic kits, such as the ImmuLisa Enhanced Cardiolipin Antibody ELISAs, cleared
by the FDA. There is a pipeline of novel assays in development. Meanwhile, the Immco
reference laboratory is in the process of launching exclusive panels of tests for Sjgren's
Syndrome and Chronic Rhinosinusitus, both of which are significantly underdiagnosed
conditions with high incidence rates.
Trinity management believes it can grow Immco's business at a rate in excess of
20% annually.
3.8 NONINVASIVE PRENATAL TEST SIGNIFICANTLY REDUCES FALSE

POSITIVE RATE
In early 2014, Illumina Inc., San Diego, CA, announced that in a direct
comparison of non-invasive prenatal testing (NIPT) using cell free DNA (cfDNA) to
standard prenatal aneuploidy screening in a general obstetrical population, the verifi
prenatal test significantly reduced the rate of false positive results for the detection of
fetal trisomies 21 and 18. In addition, the study demonstrated that the verifi prenatal test
performs consistently well in all pregnant women, regardless of their risk level for fetal
aneuploidy.
Illumina offers the non-invasive verifi prenatal test, formerly offered by Verinata
Health Inc., in its CLIA-certified, CAP-accredited clinical services laboratory, to detect
chromosome abnormalities and aberrations with improved resolution for consistent and
dependable results.
The results of the study, entitled DNA Sequencing versus Standard Prenatal
Aneuploidy Screening, reflect the diverse clinical screening practices and ethnic
variation present throughout the US, and answers questions from the medical and
scientific communities regarding the positive predictive value (PPV) of the verifi prenatal
test in the general obstetric population, says Diana W. Bianchi, M.D., Executive Director
of the Mother Infant Research Institute at Tufts Medical Center, and lead author of the

33
publication. In addition to the significant increase in PPV, the study shows similar fetal
fraction distributions in both high- and low-risk pregnant women. From both a biological
and technical perspective, the verifi prenatal test performs well in pregnant women of all
risk levels.
The results of this study demonstrate that the verifi prenatal test could
significantly improve clinical practice by reducing the number of invasive procedures
needed to clarify false positive results obtained with standard screening, say Illumina
executives.
3.9 PROTEOME SCIENCES, FISHER SCIENTIFIC SIGN AGREEMENT ON

CANCER TESTS
In June 2013, Proteome Sciences, Cobham, UK, announced a technology
agreement with Thermo Fisher Scientific, valued at $2.1 million, to develop advanced
methods to profile changes in key cancer pathways. Proteome Sciences will provide
Thermo Fisher with access to its patents covering a three-stage mass spectrometry (MS3)
fragmentation methodology to deliver significantly improved analysis and accuracy.
Proteome Sciences is receiving cash, and Thermo Fisher is providing a no-cost
lease for mass spectrometry equipment for Proteome Sciences to develop the pathway
assays. In addition Proteome Sciences will continue to develop advanced 20 and 30-plex
Tandem Mass Tags (TMT) for Thermo Fisher for the next additions to the TMT range of
tags.
The MS3 TMT mass spectrometry technique enables mass spectrometers to
determine relative quantitation of proteins in multiple samples simultaneously and with
improved accuracy. The development of personalized medicine requires high-resolution
maps of the protein networks that regulate disease.
3.10 AGREEMENT ON FETAL AND MATERNAL MONITORING SOFTWARE

In November 2012, MindChild Medical Inc., North Andover, MA, and The
University of Oxford signed a sponsored research agreement for the development of
signal processing algorithms for use with the company's Meridian non-invasive fetal


34
heart monitor. MindChild has received Pre-Marketing Notification (510(k)) from the
FDA for the monitor, which can detect minimal fluctuations in the fetal heartbeat.
The Meridian is a fetal monitor that non-invasively measures and displays fetal
heart rate (FHR) in a clinical setting. It acquires and displays the FHR tracing from
abdominal surface electrodes that detect the fetal ECG signal (fECG). The unit may also
be used to measure and display fetal heart rate using direct ECG (DECG) with a fetal
scalp electrode (FSE). The Meridian is designed for women who are at term, in labor,
with singleton pregnancies, using surface electrodes on the maternal abdomen.
More than 85% of the 4 million live births in the US during 2011 required fetal
monitoring during labor and delivery. Current non-invasive Doppler, employing
ultrasound to detect FHR, is subject to loss of fetal heart rate due to maternal/fetal
movement. FSEs that connect directly to the fetus during the later stages of labor and
delivery are associated with increased risk of maternal-fetal infection. There are an
estimated 28,000 fetal monitors spread over 3,400 hospitals in the US, representing an
investment of over $700 million.
3.11 DISTRIBUTION AGREEMENT FOR OTC WOMEN'S HEALTH

DIAGNOSTICS
In August 2011, Paladin Labs Inc., Montreal, Canada, a unit of Endo
Pharmaceuticals, entered into a distribution agreement with Common Sense Ltd., a
privately-owned Israeli company, under which Paladin received the exclusive rights to
market and sell Al-Sense OTC and Vs-Sense OTC in Canada, Latin America and SubSaharan Africa. Al-Sense OTC is a diagnostic product that provides women with a
reliable diagnostic test to detect amniotic fluid leakage during pregnancy from their own
home. If undetected, this condition may cause complications for both the pregnant
woman and her fetus. Vs-Sense OTC is a diagnostic product for the detection of bacterial
vaginosis or trichomonas infection for women of reproductive age.
The products complement Paladin's growing OTC business that consists of nine
consumer brands, including Plan B, Tempra, Anbesol and Zincofax, which generated
over $20 million of revenue in 2010. This transaction expands the company's geographic
footprint in both Sub-Saharan Africa and Latin America, according to executives. AlSense OTC is a non intrusive test with a diagnostic layer incorporated into a panty liner

35
and is targeted at pregnant women sensing unidentified wetness. The test can distinguish
between probable amniotic fluid leakage and urine. Several studies have shown that
preterm premature rupture of the amniotic sac occurs in approximately 10% of
pregnancies. When untreated, this leakage may lead to further complications and may
cause infections to spread from the vagina to the uterus and consequently to the fetus.
Vs-Sense OTC is a self-use swab for women sensing abnormal discharge and
detects bacterial and parasitic infection in vaginal discharge. This self-use swab would
prevent women from unnecessary self-medication, guide and reassure their diagnosis, and
direct them for further medical treatment when the test offers a positive result.
3.12 WOMEN'S HEALTH CANCER DIAGNOSTICS COMPANY RAISES $11.3

MILLION
In April 2013, women's health company DySIS Medical completed an $11.3
million fundraising round in support of its diagnostic devices. DySIS Medical, based near
Edinburgh, Scotland develops and markets the DySIS colposcope, which has been shown
to substantially improve the accuracy of detecting early stages of cervical cancer. The
system was recommended for procurement by the UK National Institute for Health and
Clinical Excellence in August 2012.
Research has shown that DySIS detected 97% of all cases of cervical cancer
caused by the most prevalent form of the HPV. According to the same clinical trial,
traditional methods detect only 55% of early stage cancer.
3.13 CROWD FUNDING FOR AT-HOME BREAST EXAM DEVICE

In August 2013, California medtech startup Eclipse Breast Health Technologies
launched a $650,000 crowd-funding campaign to kick-start its hand-held palm-sized
scanning device that creates a digital map of a womans breast. It essentially a home
breast health exam device. As of August 2014, a little more than $10,000 has been raised.
The Eclipse device uses a 100% safe cross physics combination of sensors and
low level photons (LED lights) to gather images and acquire data. One moves the Eclipse
device over the entire area of each breast, and the images will automatically connect to
make one large image of the entire breast that can be saved for reference. The only


36
energy used in gathering these images is a harmless low-power LED light that measures
micro-pressure points onto a soft sensor pad.
The funds raised through Indiegogo will help Eclipse move their working
prototypes into beta pilot production.
3.14 $13M SERIES A ROUND FOR ULTRASOUND FIBROID DEVICE

In June 2013, Mirabilis Medica raised up to $13 million in a Series A1 round and
tapped a new CEO to lead the clinical development of its ultrasound treatment for uterine
fibroids. The Bothell, WA-based medical device company said it closed on an initial $7
million round led by GSR Ventures, including $4 million in cash and a $3 million
conversion of debt to equity. Charter Life Sciences also participated in the round.
Mirabilis plans to use the funds to back the development of its high-intensity
focused ultrasound technology for fibroids, which are benign tumors fed by blood vessels
in the uterus. The Mirabilis trans-abdominal system heats up part of the fibroid so that
cells die and the fibroids shrink. The company has treated more than 50 patients in
clinical studies outside the US.
3.15 FDA CLEARS FEMUR FRACTURE TEST

In August 2013, Hologic Inc., Bedford, MA, received FDA clearance for the
company's Single Energy (SE) Femur Exam on a dual energy x-ray absorptiometry
(DXA) platform for the assessment of features associated with atypical femur fractures
(AFFs). This capability assists clinicians in their assessment of potential AFF in patients
who have been on anti-resorptive treatments, such as bisphosphonates.
The new assessment option is offered exclusively on Hologic's Horizon DXA
platform, a soon to be commercialized product line of bone densitometers. This 15second SE Femur Exam is designed to produce a high resolution image of the entire
femur with a very low effective radiation dose. An AFF assessment can be performed at
the time of a hip bone density scan with little or no patient repositioning and a minimal
increase in exam time.
The company developed its Single Energy Femur Exam to provide clinicians with
the critical information needed to effectively manage patient care and improve fractureCopyright 2014 Kalorama Information, LLC.

37
related outcomes. An atypical femur fracture is an extremely debilitating fracture, in
many instances much worse than a normal osteoporosis-related hip fracture. While these
fractures are uncommon, the morbidity associated with them is significant. Recently
published studies indicate that patients who suffer an AFF face extensive in-patient
hospitalization, are at high risk for complications, and often report poorer health and
function after the fracture.
3.16 FDA 510(K) CLEARANCE FOR FEMALE INCONTINENCE DEVICE

In August 2012, Zynex Inc., Lone Tree, CO, a provider and developer of noninvasive medical devices for electrotherapy, stroke rehabilitation, neurological diagnosis
and cardiac monitoring, received FDA 510(k) clearance on its InWave medical device.
The InWave device is manufactured, marketed and sold through the company's
Zynex Medical subsidiary. This device is used primarily for treating female urinary
incontinence the involuntary loss of bladder or bowel control. According to the
National Association for Continence, urinary incontinence affects 200 million people
worldwide, and it is believed that 80% of those sufferers are women.
Zynex, founded in 1996, operates under three primary business segments: Zynex
Medical, Zynex NeuroDiagnostics and Zynex Monitoring Solutions. Zynex Medical
engineers, manufactures, markets and sells its own design of electrotherapy medical
devices for electrotherapy, used for pain management and rehabilitation. Zynex Medical's
product lines are fully developed, FDA-cleared and commercially sold world-wide.
Zynex NeuroDiagnostics, sells the company's proprietary NeuroMove device
designed to help stroke and spinal cord injury patients and is expanding into markets for
EMG, EEG, sleep pattern, auditory and nerve conductivity neurological diagnosis devices
through product development and acquisitions. Zynex Monitoring Solutions has been
established to develop and market medical devices for non-invasive cardiac monitoring.
3.17 GE PMA FOR EXTENDED LABELING FOR SENOGRAPHE

MAMMOGRAPHY
In July 2013, GE Healthcare submitted a premarket approval application that adds
a breast tomosynthesis option to its Senographe Essential mammography system. The


38
company wants to extend FDA premarket approval for its Senographe Essential system
by incorporating 3D breast imaging to the modality's approved clinical applications.
The company is basing its hopes on results of a study showing that Senographe
digital breast tomosynthesis is equal with full-field digital imaging in detecting breast
cancer.
GE Healthcares flagship digital mammography system is an upgradeable
platform that enables a variety of breast procedures from in-office or mobile screening to
advanced diagnostic procedures. GE considers Senographe Essential its flagship digital
mammography system, and the company designed the tomosynthesis option as an add-on
for the approximately 1,700 systems in use in the US.
3.18 FDA CLEARS MICRODOSE MAMMOGRAPHY

In February 2013, Royal Philips Electronics received 510(k) clearance from the
FDA for its MicroDose SI system, the first full-field digital mammography (FFDM)
system on the market with the capability to enable future Single-Shot Spectral Imaging
applications. Philips is working on future software applications like Spectral Breast
Density Measurement, which will build upon the MicroDose SI technology.
High breast density is a known risk factor for breast cancer. Women with high
breast density,as seen on a mammogram, are four to five times more likely to get breast
cancer than women with low breast density . Additionally, high breast density features a
high proportion of connective tissue, which blocks x-rays, making it difficult for
clinicians to interpret breast images.
As a result, categorization of breast density has become mandatory in many
countries and several states in the US. But there is not yet a standardized method for
assessing breast density, which has limited making use of the density categorization for
clinical decisions. The most frequently used method of breast density assessment is
subjective manual and visual inspection of the image. But different radiologists may give
different scoring of breast density for the same image.
Philips believes that spectral imaging technology will be important in helping
clinicians to assess breast density and provide personalized care to women. MicroDose SI
uses digital photon-counting technology, which enables clinicians to conduct exams using
a low radiation dose without compromising image quality.


39
Philips has further advanced this technology with Single-Shot Spectral Imaging,
which is built upon the fact that breast density is subject to different tissue types and
materials that absorb x-rays at various energies. The technology powering the MicroDose
SI uses this fundamental behavior of x-rays, allowing clinicians to see more than just a
shadow in mammogram images by separating high and low energy x-ray within one
single exposure.
3.19 FDA ABUS APPROVAL

In June 2014, GE Healthcare announced FDA approval and the US launch of its
new breast imaging technology, the Invenia ABUS, proven to help clinicians find 35.7%
more cancers in women with dense breasts than mammograms alone. The Invenia ABUS
uses 3D ultrasound technology to image women with dense breast tissue in
approximately 15 minutes, offering features that conform to a woman's body and provide
more enhanced images.
This launch comes at a time when there is growing awareness of the increased
risk of cancer for women with high breast density. The more dense breast tissue a woman
has, the higher her risk of developing breast cancer often up to four to six times greater
risk than women who do not have dense breast tissue.
GE Healthcare designed the Invenia ABUS with the patented Reverse Curve
transducer to conform to a woman's anatomy, for better comfort and image performance.
Further, the system uses Compression Assist, a feature which applies light levels of
compression automatically to the breast for increased ease and image reproducibility. GE
is rolling out the Invenia ABUS nationwide in 2014.
3.20 FDA APPROVAL FOR IMAGING SOFTWARE SYSTEM FOR ULTRASOUND

In May 2014, Clearview Diagnostics Inc. Piscataway, NJ, received FDA
approval to market its imaging software, ClearView HD. The ClearView Image
Enhancement System uses proprietary patent-pending technology to significantly
enhance the ultrasound images used for breast cancer diagnosis.
Ultrasound imaging is especially useful in women with dense breast tissue,
found in up to 50% of the female population and especially prevalent in younger

40
women, where traditional mammogram screening can fail to find the cancer. Clearview
Diagnostics is a Rutgers University technology start-up.
3.21 EU NOD FOR BREAST TISSUE SCREENING SYSTEM

Dune Medical Devices Inc.'s intra-operative tissue assessment tool for early-stage
breast cancer surgery, the MarginProbe System, received Premarket Approval (PMA) by
the FDA in January 2013. The technology significantly improves surgeons ability to
intra-operatively identify "cancer on the margin and significantly reduce pathologically
positive margins following a patients initial lumpectomy surgery.
In February 2013, Dune Medical Devices received CE approval for compliance
with the European Union's medical directive for its next generation MarginProbe System
console. The MarginProbe System Type 1.2 is a more compact and portable version of
the MarginProbe System console, which will allow users greater flexibility while locating
the hardware component of the MarginProbe System in their operating theaters.
It is estimated that 60 up three-quarters of breast cancer cases will undergo a
lumpectomy procedure as their initial treatment versus mastectomy, which involves the
removal of the whole breast. Lumpectomy in combination with radiation therapy is as
effective in combating breast cancer as mastectomy, if cancer cells are not present on the
rim or edge of the removed tissue, also known as "clean margins." Research shows there
is no significant difference in overall survival between the two procedures. But if there is
cancer at the edge, or a "positive margin," the risk of recurrence increases significantly.
3.22 CERVICAL CANCER SCREENING TEST CONCERNS

With cervical cancer screening, women visit a gynecologist every year for a
Pap smear to be taken. But now women have a newer option that combines the Pap with
DNA testing plus the first approved alternative to the Pap smear.
The National Institutes of Health indicates that the Pap reduced US cervical
cancer incidence and deaths by more than 60% since the 1950s. In 2012, with the advent
of molecular testing, screening guidelines were updated to include testing for HPV,
which is responsible for almost all cervical cancers.


41
The new guidelines recommend women either have only a Pap every three years
or a Pap-HPV combination every five years if the most recent results are normal.
But in May 2014, the FDA approved Roche's cobas HPV test as a first-line test,
rather than Pap cytology, as part of a cervical cancer screening strategy. The test was
initially approved by the FDA in April 2011 to screen patients age 21 and older with
abnormal Pap test results as well as to co-test with Pap in women ages 30 to 65 to assess
the presence or absence of high-risk human papillomavirus genotypes. The test is
performed on Roche's cobas 4800 system, an automated molecular diagnostic instrument
platform.
Yet, there are concerns. A drawback to HPV testing is that almost everyone who
has sexual relations has been exposed to HPV. Most people's immune systems will
eliminate the virus within a few months or up to several years. So, one positive HPV test
is typically not a concern to physicians. Some experts believe that the Roche test could be
an alternative, but the HPV-Pap combination may be the optimum and most accurate
option for patients for the immediate future.
3.23 NEW SMARTPHONE APP DETECTS NEWBORN JAUNDICE IN MINUTES

Scientists at the University of Washington have developed a smartphone
application that checks for jaundice in newborns. It can deliver results within minutes. It
could serve as a screening tool to determine whether a baby needs a blood test the gold
standard for detecting high levels of bilirubin.
The app, called BiliCam, uses a smartphones camera and flash and a color
calibration card the size of a business card. A parent or health care professional would
download the app, place the card on her babys belly, then take a picture with the card in
view. The card calibrates and accounts for different lighting conditions and skin tones.
Data from the photo are sent to the cloud and are analyzed by machine-learning
algorithms, and a report on the newborns bilirubin levels is sent almost instantly to the
parents phone.
For the most part, both doctors and parents assess jaundice by looking for the
yellow color in a newborns skin, but this visual assessment is only moderately accurate.
The university team developed BiliCam to be easy to use and affordable for both


42
clinicians and parents, especially during the first several days after birth when it is
crucial to check for jaundice.
Researchers ran a clinical study with 100 newborns and their families at the
university Medical Center. They used a blood test, the current screening tool used in
hospitals, and BiliCam to test the babies when they were between two and five days old.
They found that BiliCam performed as well as or better than the current screening tool.
Although it wouldnt replace a blood test, BiliCam could let parents know if they should
take that next step.
The researchers plan to test BiliCam on up to 1,000 additional newborns,
especially those with darker skin pigments. The algorithms will then be robust enough to
account for all ethnicities and skin colors. The scientists have filed patents on the
technology, and within a couple of years hope to have Federal Drug Administration
approval for the BiliCam app that parents can use at home on their smartphones.

4.0 Pregnancy and Ovulation

KEY TREND
The trend in a mature market for pregnancy testing continues to be the digitization
of testing, especially those tests for use in the home. Digital tests are extremely accurate.
They not only indicate whether a woman is pregnant, but also how far along the
pregnancy is. These tests will continue to be optimized in the future.
4.1 PERSPECTIVE ON TESTING

Many home pregnancy tests typically maintain a 99% accuracy rate or greater.
Modern pregnancy tests seek out chemical markers associated with pregnancy. These
markers are found in urine and blood, and pregnancy tests require sampling one of these
substances.
The
first
of
these
markers
to
be
discovered, human
chorionic
gonadotropin (hCG), is produced by the trophoblast cells of the fertilized ovum

(blastocyst).
Most chemical tests for pregnancy look for the presence of hCG in the blood or
urine. hCG can be detected in urine or blood after six to twelve days after fertilization.
Quantitative blood (serum beta) tests can detect hCG levels as low as 1 mIU/mL, while
urine tests have published detection thresholds of 20 mIU/mL to 100 mIU/mL, depending
on the assay. Qualitative blood tests generally have a threshold of 25 mIU/mL, and so are
less sensitive than some available home pregnancy tests. Most home pregnancy tests are
based on lateral-flow technology. Accuracy claims can be somewhat misleading.

44
The problem lies in how these tests also imply that this accuracy could be
expected if the test is administered as early as the day of a missed period. A 2004 study
published in The American Journal of Obstetrics and Gynecology by Dr. Laurence Cole
and researchers at the University of New Mexico explained that claims of some
pregnancy tests may be misleading due to the high degree of variation in the amount of
hCG occurring in the urine on any given day after implantation occurs. Researchers
found that for early detection of pregnancy, most tests were not sensitive enough to detect
hCG on the first or second day after a womens missed period. The OTC sector for
pregnancy and ovulation includes tests available in pharmacies and other retail
establishments. This POC test segment is mature and competitive.
One issue of concern: Many women are not screened for chlamydia and
gonorrhea infection during their pregnancy, and follow-up testing is not always
performed as medically recommended for those who test positive for chlamydia,
according to a study published online in the American Journal of Obstetrics and
Gynecology (AJOG) in May 2012. The findings, based on an analysis of laboratory tests
of 1.3 million pregnant women, highlight gaps between medical guidelines and clinical
practice in screening for two sexually transmitted infections that pose health risks for
pregnant women and their newborn babies.
Conducted by scientists at Quest Diagnostics and Rutgers University, the study
examined de-identified results of 1,293,423 pregnant women between 16 to 40 years of
age in the US who were tested by the company between 2005 and 2008.
Chlamydia and gonorrhea are the two most commonly reported sexually
transmitted infections in the US and infect up to 100,000 and 13,200 pregnant women,
respectively, annually. Left untreated, the infections can raise health risks for pregnant
women, such as early onset of labor, and for newborns, such as potentially serious eye
infections and pneumonia. Once identified, the infections are easily treated with
antibiotics.
Despite national recommendations, the study found that only 59% and 57% of
pregnant women were tested at least once for chlamydia and gonorrhea, respectively.
Among women in the high-risk 16 to 24 year age group, only 69% were tested for
gonorrhea.


45
4.1.1 Digital Testing
Digital tests represent key innovation in this market. Inverness Medical
Innovations, now Alere, introduced the worlds first Unipath Clearblue brand digital
pregnancy test in 2003, followed in 2004 with a Clearblue digital ovulation predictor. In
2006, the company introduced a digital pregnancy test in the UK.
In May 2003,
Inverness received FDA clearance to market its Clearblue Easy Digital pregnancy test,
the first test to display pregnancy test results in words. The digital display spells out
pregnant or not pregnant, negating any guesswork. Even if there are low levels of hCG
present, the test clearly displays the result in words so that there is no need to interpret
lines. The digital testers can also prevent false results caused by user error. If there is not
enough urine on the stick, the test will give an error message.
Then more innovation came onto the market scene. Inverness Clearblue digital
pregnancy test with Conception Indicator rapid pregnancy test also indicates an
approximate date of conception. If the test is positive, pregnant will be indicated in
words on the display along with the Conception Indicator result. This is displayed as an
estimate of how many weeks have occurred since conception. Digital tests retail for
approximately $1 above other brand name pregnancy tests.
4.1.2 Testing for Placental Growth Factor and Pre-eclampsia

Placental Growth Factor (PlGF), produced by the placenta, is a homodimeric
disulfide linked protein. Mammalian cells produce the N-glycosylated form. PlGF
belongs to the vascular endothelial growth factor (VEGF) family and binds primarily to
vascular endothelial growth factor receptor 1 (VEGFR-1) also known as Fms-like
tyrosine kinase-1 (Flt-1). The soluble form of VEGFR-1 (sVEGFR-1, sFlt-1) also binds
PlGF and when present in circulation, binding to the receptor reduces the free fraction of
PlGF capable of stimulating the membrane bound receptors.
PlGF is an angiogenic factor, which is a vasodilator that increases the diameter of
existing arteries. Very low levels of circulating free angiogenic factors may contribute to
vascular endothelial dysfunction, which is one of the symptoms of pre-eclampsia, a
hypertension disorder affecting 5% to 8% of pregnancies.


46
The concentration in maternal serum of PlGF is reduced in a high proportion of
pregnancies destined to develop pre-eclampsia. The reduction is significant in the first
trimester, making PlGF an ideal marker for early screening for the elevated risk of preeclampsia.
Outside the US, PerkinElmer is marketing the Delfia Xpress PlGF kit for the
quantitative determination of PlGF in maternal serum. In normal uncomplicated
pregnancy free, unbound PlGF levels increase during the first and second trimester and
then decline. The level of PlGF is typically decreased in maternal serum during both the
first and the second trimesters of pregnancy in women who later develop pre-eclampsia.
This solid-phase, two-site fluoroimmunometric assay is based on the direct
sandwich technique in which monoclonal antibodies and polyclonal antibodies are
directed against the PlGF molecule.
PerkinElmer also is marketing the PreeclampsiaScreen | T1 serum screening test
to more precisely detect asymptomatic patients in the first trimester of pregnancy who are
at high risk, allowing for earlier identification, management and intervention.
Alere is also marketing a test for Plgf, the Alere Triage PLGF test, which is a
fluorescence immunoassay used along with the Alere Triage Meter for the quantitative
determination of PLGF in ethylenediaminetetraacetic acid-anticoagulated plasma
samples. Together with other diagnostic and clinical information, the test aids in the
diagnosis of pre-eclampsia.
4.1.3 Lab Developed Tests

In July 2014, the FDA announced that it would start regulating medical laboratory
developed tests (LDTs), including pregnancy tests, indicating that these tests must be
validated before they are used clinically. These are tests developed and performed by a
single laboratory, with all samples being sent to that laboratory.
The decision has been fiercely opposed by those who believe that FDA regulation
is not needed and would significantly increase the cost and time needed to develop tests.
There are concerns that regulating LDTs may force some laboratories to opt out of
providing the tests, given the added required paperwork for approval. These tests include
biochemical tests used to determine pregnancy. Some LDTs yield better results than FDA

47
approved tests. But companies that have done the clinical studies to gain FDA approval
are competing against very similar tests that get to market without such testing and
oversight.
While the uses of LDTs are often the same as the uses of FDA-cleared or
approved in vitro-diagnostic tests, some labs may choose to offer their own test. For
example, a hospital lab may run its own vitamin D assay, even though there is an FDAcleared test for vitamin D currently on the market. The FDA does not consider diagnostic
devices to be LDTs if they are designed or manufactured completely, or partly, outside of
the laboratory that offers and uses them.
The FDA plans to phase in the requirements over time and would focus oversight
on the tests with the highest level of risk to patients from a wrong result. Tests for rare
diseases, which might be uneconomical to develop if they need FDA approval, would be
exempted.
4.2 OTC PREGNANCY SELF-TEST MARKET

The market for over the counter (OTC) self-pregnancy tests continues to grow,
although slightly, at an estimated 2% to 3% annual rate, as seen in Exhibits 4 and 5. The
market is expected to remain mature, although there may be more of a slight uptick in
business if world economics grow, and employment pictures brighten.
Test
manufacturers were negatively impacted by poor economic conditions, which led to a

high number of couples postponing having children as a result of unemployment and
financial insecurity issues.
The OTC sector for pregnancy and ovulation includes tests available in
pharmacies and other retail establishments. The major pharmacy chains also sell their
own home brand test kits manufactured by companies in the market and other OEM
companies. Home kits have experienced some growth as more women enjoy using these
tests in the privacy of their own homes. The pharmacy house brands have been selling for
about half the price of brand name kits, generally $5 to $10 compared with $10 to $15.


48
Exhibit 4
World Market for OTC Pregnancy Self-Tests
2013-2018 (US/NA, Europe, China, Brazil, Japan, ROW, Total)
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$284.0
156.2
46.9
17.5
106.5
78.1
689.2
2014
289.7
159.3
48.3
18.0
108.6
81.2
705.1
2015
295.5
162.5
49.7
18.6
110.8
84.4
721.5
2016
301.4
165.8
51.2
19.2
113.0
87.8
738.4

2017
307.4
169.1
52.7
19.8
115.3
91.3
755.6
2018
314.0
172.5
54.3
20.4
117.6
95.0
773.8

49
Exhibit 5
World Market for OTC Pregnancy Self Tests
2014,
by Geographic Segment (US, EU, China, Japan, Brazil, ROW)
3%
11%
41%
15%
23%
7%
US
European Union
China
Japan
ROW
Brazil
4.3 LAB-BASED FERTILITY TESTING MARKET

Infertility is a serious worry for many couples because the issue can significantly
alter the life of the couple. But the outlook for infertility is not overly bleak. A study from
the National Institute of Environmental Health Sciences found that the majority of
women up to age 39 who did not become pregnant in their first year did become pregnant
in their second year without medical assistance. For women between ages 27 and 34, only
6% were unable to conceive in their second year. And for 35- to 39-year-old women, only

50
9% were unable to conceive in their second year, given their partner was younger than 40
years of age.
Immunoassays are gaining importance in post genomic medicine. They are used
to measure the physiological elements expressed by genes, including proteins, hormones,
and enzymes. The immunoassay business of the next five to 10 years will see continuing
automation of routine immunoassays, such as tests for the thyroid, anemia, proteins,
fertility, and the like. In addition, there will be the migration of more and more
immunoassays onto core lab workstations; the design of more sensitive, automated,
homogeneous techniques; and the search for an ideal point-of-care platform.
More than 7 million Americans, or approximately 12% of the population in their
reproductive years, are infertile, according to the Centers for Disease Control and
Prevention (CDC). As more couples address fertility issues and are presented with
different treatment options, the market for fertility testing, namely lab-based
immunoassays, should be strong, with growth in the 4% to 5% range annually worldwide,
as seen in Exhibits 6 and 7.
Exhibit 6
World Market for Lab-Based Immunoassay Fertility Testing,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$121.0
84.0
23.6
8.6
37.0
25.0
299.2
2014
126.0
88.2
24.5
8.9
38.9
26.0
312.5
2015
132.3
92.6
25.5
9.3
40.8
27.0
327.5
2016
138.9
97.2
26.5
9.7
42.8
28.1
343.2

2017
145.8
102.1
27.6
10.1
44.9
29.2
359.7
2018
153.1
107.2
28.7
10.5
46.7
30.4
376.6

51
Exhibit 7
World Market for Lab-Based Immunoassay Fertility Testing
2014,
by Geographic Segment (US, EU, China, Japan, Brazil, ROW)
3%
12%
8%
41%
8%
28%
US
European Union
China
Japan
ROW
Brazil
4.4 LAB-BASED TORCH TESTING MARKET

Torch testing or screening encompasses tests for a group of infectious diseases
that can infect pregnant women and cause birth defects in their infants or their death. The
diseases include:
x
Toxoplasma gondii (toxoplasmosis): A parasite that can be acquired from

ingesting cysts from the feces of infected cats, drinking unpasteurized milk, or
eating undercooked contaminated meat. Infection early in pregnancy can cause


52
miscarriage. Later in pregnancy it can cause eye infections, and mental
retardation.
x
Other: Infections that may be screened for at the same time include Parvovirus
B19, chicken pox, and syphilis.
Rubella: Infection early in pregnancy can cause birth defects, such as heart
disease, growth retardation, and eye defects. It can also cause problems later in
childhood such as hearing loss.
Cytomegalovirus (CMV): This virus is transmitted through body secretions,

including breast milk, as well as sexual contact. Infection can cause death, hearing
loss and mental retardation.
Herpes simplex virus (HSV): A common infection that is spread by oral and
genital contact. Most infections are spread to infants during the birth process.
Infected infants may have localized infections of the mouth, eyes or skin, and
some may have disseminated infection. Infant mortality from neonatal infection
can be very high.
In practice, testing often is targeted toward high-risk groups, or women from areas
where the prevalence of the diseases is high. In these situations, the screening serves to
identify women with active infection as well as those who lack immunity to the diseases.
Using Torch testing to diagnose infections is becoming less common since more
specific and sensitive tests, which do not rely on the detection of antibodies, are available.
However, the need for Torch testing will continue. The tests are undergoing some
changes, namely a change in recommendations to use screening tests that detect specific
antibodies to syphilis (which are new) rather than using non-syphilis specific screening
tests (which is the traditional method).
The market for Torch testing is therefore mature and can expect minimal growth
in the 2% annual range, as seen in Exhibits 8 and 9.


53
Exhibit 8
World Market for Lab-Based Immunoassay Torch Testing,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$311.6
246.0
67.7
24.6
82.0
57.4
789.3
2014
317.8
250.1
69.0
25.1
83.6
58.5
804.1
2015
324.2
255.1
70.4
25.6
85.3
59.7
820.3
2016
330.7
260.2
71.8
26.1
87.0
60.9
836.7

2017
337.3
265.4
73.2
26.6
88.7
62.1
853.3
2018
344.0
270.7
74.7
27.1
90.5
63.3
870.3

54
Exhibit 9
World Market for Lab-Based Immunoassay Torch Testing 2014, by
Geographic Segment
10%
7%
3%
39%
9%
31%
US
European Union
China
Japan
ROW
Brazil


55
4.5 ABBOTT DIAGNOSTICS

Abbott Park, IL
http://international.abbottdiagnostics.com/home.cfm
Abbott Diagnostic Division markets a broad range of diagnostic systems
analyzers and reagents worldwide to hospitals, blood banks, commercial clinical
laboratories, physicians office laboratories, and other diagnostic locations. For
centralized laboratories, Abbott markets chemistry and immunoassay systems and
reagents, hematology products, molecular diagnostic assays, histology, blood banking
assays, pharmacogenetics assays, and many others.
Abbott is a leader in automated immunoassay analyzers, and immunoassaychemistry analyzers, for centralized laboratories, such as reference labs and hospital labs.
The Architect family of instruments is a portfolio of fully automated, integrated
immunoassay and chemistry instruments, as well as separate immunoassay and chemistry
modules.
Among its many products, Abbott offers immunoassay-chemistry assays targeted
at cancer, cardiac, drugs of abuse-toxicology, fertility and pregnancy, general chemistry,
infectious disease (congentitals, hepatitis, retrovirus), metabolic, proteins, renal, sepsis,
therapeutic drug monitoring, and the thyroid.


56
4.6 ALERE INC.

Waltham, MA
http://www.alere.com
Alere, formerly Inverness Medical Innovations, Inc., has three reportable
operating segments: professional diagnostics, health information systems (formerly health
management), and consumer diagnostics. Net sales for 2013 totaled $3 billion. Alere has
a direct presence in 36 countries. Its products are available in more than 100 countries.
North America accounts for about 63% of the companys product sales; Europe, 17%;
Asia Pacific, 11%; and 9%, Latin America and Africa.
The company is a manufacturer of home pregnancy test kits and fertility monitors.
Since 2007, Clearblue has been produced and distributed by SPD Swiss Precision
Diagnostics GmbH, a 50/50 joint venture between Procter & Gamble and Alere. Major
brands include the ClearBlue home pregnancy test and the ClearPlan Easy fertility
monitor. Inverness Clearblue digital pregnancy test, launched in 2008, with Conception
Indicator rapid pregnancy test also indicates an approximate date of conception. If the test
is positive, pregnant will be indicated in words on the display along with the
Conception Indicator result. This is displayed as an estimate of how many weeks have
occurred since conception. The companys professional pregnancy tests are generally
urine-based, CLIA-waived rapid tests in dipstick or cassette format.
The company also markets other products relating to women's health, such as
prenatal vitamins. Alere sells an array of other medical diagnostic products, such as tools
to detect osteoporosis, mononucleosis, and sexually transmitted diseases. In addition,
Alere sells the Smartcare brand of dietary supplements. The company's focus on women's
health issues comes following the sale of its business in home blood glucose monitoring
test kits to Johnson & Johnson in 2001.
Alere brings together 18 diagnostic and health management companies with
expertise in over 100 disease categories. The companys brands range from over-thecounter tests to lab-based diagnostics to integrated home monitoring solutions. The
companys goal has been to get more tests out of centralized labs and into doctors offices


57
and the home. The plan relies on buying IVD companies, distributors, and managed care
groups that can help Inverness achieve the goal.
Inverness has been a leader in rapid point-of-care diagnostics that focus on
infectious disease, cardiology, oncology, drugs of abuse and womens health. Inverness
also markets the Clearview line of immunochemical fecal occult blood tests.


58
4.7 BIOMERIEUX SA
Marcy l'Etoile, France
www.biomerieux-diagnostics.com
bioMrieux is involved in in clinical diagnostics. The company also markets
industrial products for microbiological control and for food and water applications.
Within the clinical diagnostics segment, bioMrieux markets to lab professionals, blood
bank professionals, and health care professionals.
For the lab professionals, bioMrieux offers microbiology, immunodiagnostics,
and molecular diagnostics products. For blood bank professionals, the company offers
products for microbial detection and sterility testing, and also for serological screening
for transfusion transmitted diseases.
bioMrieux markets the Vidas immunoassay analyzers for small to medium-sized
laboratories. These automated immunoassay analyzers are being marketed to both clinical
laboratories and satellite laboratories. These analyzers have a reagent menu offering over
85 different immunoassays, covering HIV, Hepatitis, Torch testing, D-dimer, Emergency,
tumor markers, among others.


59
4.8 CHURCH & DWIGHT CO. INC.

Princeton, NJ 08543
www.churchdwight.com
Church & Dwight, founded in 1846, develops, manufactures and markets a broad
range of household, personal care and specialty products. The company focuses its
marketing efforts principally on its eight power brands. These brands include Arm &
Hammer, (used in multiple product categories such as baking soda, carpet deodorization
and laundry detergent), Trojan Condoms, XTRA laundry detergent, OxiClean pre-wash
laundry additive, Nair depilatories, First Response home pregnancy and ovulation test
kits, Orajel oral analgesics and Spinbrush battery-operated toothbrushes.
The companys consumer products business is organized into two segments:
Consumer Domestic, which encompasses both household and personal care products, and
Consumer International, which primarily consists of personal care products. The
company has eight key brands representing approximately 80% of its consumer sales.
These power brands include Arm & Hammer, Trojan, Oxiclean, among others. About
45% of the companys domestic consumer products are sold under the Arm& Hammer
brand name and derivative trademarks.
First Response continues to be the number one brand in the home pregnancy and
ovulation test kit business category. The company also markets First Response Rapid
Result test kit, designed to tell a woman if she is pregnant within one minute after taking
the test and Answer, which competes in the value segment of the home pregnancy and
ovulation test kit market. In 2009, the company launched an at-home female fertility test
under the First Response brand name.


60
4.9 DIALAB GMBH

Wiener Neudorf, Austria
www.dialab.at
Dialab GmbH was founded in 1972. The company manufactures and markets a
wide range of diagnostic tests and equipment for areas such as clinical chemistry,
immunoturbidimetric
tests
(protein
immunoassays),
serology,
blood
grouping,
coagulation reagents, ELISA tests, drugs of abuse liquid immune assays, therapeutic drug
monitoring, and different types of point of care assays.
For POC testing, the company markets urine strips, blood glucose monitoring
devices and test strips, and DiaQuick rapid tests. Dialab offers immunoassays for:
autoimmune diseases; infectious diseases (HIV, hepatitis B, hepatitis C, Torch testing);
fertility testing; steroids; thyroid testing; and tumor markers.
The DiaQuick rapid tests are immunochromatographic tests, and include tests for
pregnancy and fertility testing, and for pregnancy and fertility testing in the home.


61
4.10 PRESTIGE DIAGNOSTICS

Antrim, United Kingdom
www.prestigediagnostics.co.uk
Prestige Diagnostics develops, manufactures, and distributes clinical diagnostics
and POC products for the global market. The company markets a range of clinical
diagnostic products including blood grouping products, clinical chemistry tests, ELISA
kits (for infectious diseases, thyroid function, tumor markers, and Torch testing), febrile
antigens, hemostasis (blood clotting) tests, latex serology products, syphilis tests, and
rapid tests.
Prestige Diagnostics markets a range of ELISA tests that include tests for
infectious diseases, thyroid function, tumor markers, and Torch. In the rapid test market,
the company markets cassettes and strips for fertility, sexually transmitted diseases,
cardiac markers, tumor markers, infectious diseases, and other tests.


62
4.11 ROCHE DIAGNOSTICS

Indianapolis, IN
https://www.poc.roche.com/poc/rewrite/home/en_US
Roche is the world's largest supplier of clinical diagnostics products. Roche has
led the IVD market since its merger with Boehringer Mannheim. Business areas in
Roches Diagnostics Division are: Professional Diagnostics; Diabetes Care; Molecular
Diagnostics; Applied Science; and Tissue Diagnostics.
Immunoassays for laboratories and professional point-of-care applications are
included in the Professional Diagnostics business. For the central laboratory, Roche
offers automated analyzers under the cobas name. These automated systems have both
clinical chemistry and immunoassay modules.
The immunoassay menu for the cobas analyzer series includes assays for
fertility/hormones, among many other areas.


63
4.12 SIEMENS HEALTHCARE DIAGNOSTICS

Tarrytown, NY
www.siemens.com/diagnostics
Siemens Health care Diagnostics offers a portfolio of diagnostic products that
provide more effective ways to assist in the diagnosis, monitoring and management of
disease.
For laboratories, Siemens offers its Clinitest hCG pregnancy test for rapid
instrument-read-and-reported test results. Laboratories can apply the patients sample to
the Clinitek Status+ Analyzer. The analyzer automatically checks each test strip for
humidity exposure and identifies Siemens test strips. The unit offers a point-of-care
urinalysis menu for routine testing, detection of early kidney disease and hCG pregnancy
testing. It is CLIA-waived. The analyzer can be upgraded to support connectivity to the
patients electronic medical record or other data management options and offers a
comprehensive urine test menu.
Siemens Healthcare Diagnostics offers fully automated immunoassay platforms
that include: AdviaCentaur XP Immunoassay System; Advia Centaur CP Immunoassay
System; Immulite 2000 XPi Immunoassay System; and Immulite 1000 Immunoassay
System. The Advia Centaur XP Immunoassay System test menu includes assays for
allergy, anemia-iron metabolism, autoimmune, bone metabolism, cardiac, diabetes,
growth, hepatitis, inflammation, metabolic, oncology, reproductive/endocrinology,
infectious disease, therapeutic drug monitoring, thyroid, Torch testing, veterinary, and
other tests.

5.0 Bone Density Testing

KEY TREND
Within the next 25 years, more than 20% of the U.S. population, more than 70
million people, will be 65 years old. Osteoporosis poses a significant health risk,
particularly among women, and the problem is intensifies with age. Osteoporosis is
estimated to affect 200 million women worldwide: about 10% of women aged 60; 20% of
women aged 70; 40% of women aged 80; more than 65% of women aged 90. The disease
impacts approximately 75 million people in Europe, the US and Japan.
Each year, 1.5 million adults suffer an osteoporotic fracture. A woman's risk of
hip fracture is equal to her risk of breast, uterine, and ovarian cancer combined. Nearly
three times as many women have an osteoporotic fracture as have a heart attack. A
variety of technologies have been used to assess skeletal health, the most common of
these is dual-emission x-ray absorptiometry (DEXA), which measures the spine, hip, or
total body. Recent advances in this imaging technology have made the assessment of
skeletal health faster and more accurate.
5.1 ALARMING RISE OF OSTEOPOROSIS

Osteoporosis is caused by a reduction of the mineralized material in the bone, and
causes an overall weakening of the affected bones and increases the risk of fracture.
Osteoporosis occurs when bone is not being replaced at the same rate as it is lost.
Usually, bone is continually formed and removed in equal amounts. It occurs sooner if

65
the amount of bone established when young is less than average. Osteoporosis is
characterized by bones that are less dense than, and thus not as strong as, normal bone.
Osteoporosis increases the risk of fracture with even minor trauma, such as a fall
from standing height, or even from a cough or sneeze. After each osteoporotic fracture,
there is a greater chance of a future fracture. After one vertebral fracture, the risk grows
for a subsequent, nonvertebral fracture by up to threefold. Future fractures often occur in
a year, contributing to an avalanche of events that might cause an eventual disability or
even death. It has been reported that 15% of patients who sustain a hip fracture are able to
return to unassisted ambulation after a half-year. But nearly one-quarter of patients who
have had hip fractures die within a year.
There are many who have a lower than normal bone mass and are at a high risk of
developing osteoporosis. Women are four times more likely to develop osteoporosis than
men. Other risk factors include older age, a family history of osteoporosis, a small and
thin stature, an inactive lifestyle, smoking, alcohol, and the use of certain medications
including steroids. As people are living longer and leading more sedentary lives, the
incidence of osteoporosis is expected to continue rising.
5.2 PROPELLING THE NEED FOR DETECTION

The alarming rise of osteoporosis has propelled the need for early detection of the
disease, and has pushed demand for bone densitometers. A bone densitometer is
characterized by the technology used in the system. The world market for these
densitometers is dominated by DEXA systems, which measure bone mineral density
(BMD).
The absolute amount of bone as measured by BMD testing generally correlates
with bone strength and its ability to bear weight. The BMD generally is measured using a
DEXA scan. By measuring BMD, it is possible to predict fracture risk in the same
manner that measuring blood pressure can help predict the risk of stroke.
It is important to remember that BMD cannot predict the certainty of developing a
fracture. It can only predict risk.
The purpose of BMD testing is to help predict the risk of future fracture. The
information from a BMD test is used to aid a decision as to whether prescription


66
medicine therapy is needed to help reduce the risk of fracture. Additionally, if a patient
has a fracture or is planning orthopedic surgery, a diagnosis of osteoporosis might affect
the surgical plan.
5.3 DEXA AND COMPETING TECHNOLOGIES

A DEXA scanner produces two x-ray beams, and often focuses on two main
areas, the hip and spine. Although osteoporosis involves the whole body, measurements
of BMD at one site can be predictive of fractures at other sites. There are small DEXA
scanners called peripheral DEXA machines, which often measure BMD at the heel
(calcaneus), shin bone (distal tibia), or kneecap (patella). Quantitative computed
tomography (QCT) also can be used to assess BMD. However, the amount of radiation
exposure using CT is higher than with DEXA and the cost is greater. For these reasons,
QCT is not in general clinical use. Ultrasound is a relatively new diagnostic tool for
measuring BMD.
An early diagnosis of osteoporosis is needed to prevent complications and
unnecessary suffering. Imaging technology is used to identify the presence of
osteoporosis and to calculate bone mass using semiquantitative or quantitative methods.
Conventional radiography is typically used for the former, and densitometric techniques
for the latter.
DEXA, the most widely used method of diagnosing osteoporosis in clinical
practice, can be applied to all skeletal sites where osteoporotic fractures occur. These
include the lumbar spine and proximal femur (total hip, femoral neck, trochanter, and
Ward's area) in the central skeleton. DEXA can also be applied to peripheral skeletal
sites, such as the forearm and calcaneus, using either full-sized or dedicated peripheral
DEXA scanners.
DEXA provides the mass of bone mineral content in grams and the projected area
of the measured site in square centimeters. BMD is taken as the bone mineral content
divided by the area and is given in units of g/cm2. Densitometric findings are expressed
as a planar density.
QCT differs from DEXA in that it provides separate estimates of the bone mineral
density for trabecular and cortical bone. This is provided as a true volumetric mineral
density in mg/cm3. The technique can be performed at axial sites and peripheral sites.

67
QCT techniques have seen their use limited because they give off a high radiation
dose. They are not precise, which limits the techniques applicability to longitudinal
assessments. They require a high degree of operator dependence, and need a large
operating area.
Ultrasound may also be used to measure parameters relevant to bone mineral
density and to assess tissue properties. Ultrasound devices are small, measurements can
be made quickly and easily, no ionizing radiation is involved, and the cost of the device is
low compared with DEXA and CT modalities. Most quantitative ultrasound devices are
used to predict the risk of osteoporotic fracture. Ultrasound waves are affected by the
elasticity and structure of the material they are passing through and can potentially yield
information on bone fragility.
Ultrasound can be applied to children, newborns, and preterm infants as well as to
the adult population to assess bone status. Microimaging tools are being developed to
examine specific aspects of bone quality. Once these new technologies are available in
clinical practice, the efficacy of ultrasound in managing osteoporosis should improve.
5.4 BONE DENSITOMETER MARKET

The market for bone densitometry is significant, especially among women.
Osteoporosis more commonly occurs in females. Women are four times more likely to be
diagnosed with the disease than men. Nearly 90% of hospitalizations noting an
osteoporosis diagnosis and an injury occur among female patients. Overall, the rate of
hospitalization for injurious osteoporosis by gender is about 150 stays per 100,000
population for females and 20 stays per 100,000 population for males, which is more than
seven times greater for women than for men.
Osteoporosis is primarily a disease of the elderly, so the aging market will
continue to push demand for detection systems. Nearly 90% of hospital stays citing
injurious osteoporosis occur among patients aged 65 years and over. The average age of
patients with injurious osteoporosis is 79.5 years, more than 21 years older than the
average hospitalization patient, 58.1 years. The rate of hospitalization for injurious
osteoporosis usually increases with age for both males and females. For males, patients
under the age of 45 years have a rate of 1 stay per 100,000 population. This increases to
nearly 500 stays per 100,000 population for males aged 85 and older. For females under

68
the age of 45 years, the rate of hospitalizations involving an injury likely due to
osteoporosis is about 2 stays per 100,000 population. This increases to almost 2,400 stays
per 100,000 for females over the age of 85. Female hospitalization rates for injurious
osteoporosis are five times greater than rates for males among patients 65 years and older.
The direct care expenditures for osteoporotic fractures is in the range of $20
billion annually and growing. Osteoporosis-related fractures are a main cause of
disability and mortality. What is spurring the market for osteoporosis testing and for bone
densitometers is the emphasis on early detection of the disease, as well as increased
patient awareness of the condition. Moreover, drug companies continue to introduce new
therapeutics targeted at osteoporosis, which encourages screening for the disease.
There is room for growth in testing worldwide. According to the International
Osteoporosis Foundation, Nyon, Switzerland, BMD measurement is not well utilized in
many European countries. There is a limited availability of densitometers, restrictions in
personnel permitted to perform scans, a low awareness of usefulness of BMD testing, and
limited or nonexistent reimbursement for the procedure. From 1990 to projections in
2050 the number of hip fractures for women and men aged 50 to 64 in Latin America will
increase by 400%. For age groups older than 65 the increase will reach 700%. Latin
Americans will suffer an estimated 655,648 hip fractures in 2050, at an estimated direct
cost of $13 billion. There are extremely limited numbers of DXA machines available in
Africa and the Middle East.
Osteoporosis is greatly underdiagnosed and undertreated in Asia, even in the most
high risk patients who have already fractured. The problem is particularly acute in rural
areas. In the most populous countries like China and India, the majority of the population
lives in rural areas, where hip fractures are often treated conservatively at home instead of
by surgical treatment in hospitals. DXA technology is considered expensive and is not
widely available in most developing Asian countries, especially in rural areas. But
perceptions are gradually changing, with a growing awareness of osteoporotic disease
and concerns for the growing elderly population.
Given a growing awareness for osteoporosis testing, including the potential for
growth in underutilized areas, the market for bone densitometers used for testing women
is expected to grow at an annual rate of approximately 5%, as can be seen in Exhibits 10
and 11.


69
Most of the major manufacturers of bone densitometry equipment are making
their systems more efficient while adhering to new safety guidelines designed to make
these machines safer. However, patient advocacy groups are still not satisfied with the
amount of radiation exposure many patients require.
Exhibit 10
World Market for Bone Densitometers for Female Testing,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$222.3
140.4
32.2
11.7
117.0
46.8
570.4
2014
233.4
147.4
33.8
12.3
122.7
49.1
598.7
2015
245.1
154.8
35.5
12.9
129.0
51.6
628.9
2016
257.4
162.6
37.3
13.5
135.5
54.2
660.5

2017
270.3
170.7
39.2
14.2
142.2
56.9
693.5
2018
283.8
179.2
41.2
14.9
149.4
59.7
728.2

70
Exhibit 11
World Market for Bone Densitometers for Female Testing
2014,
by Geographic Segment
2%
8%
20%
39%
25%
6%
US
European Union
China
Japan
ROW
Brazil


71
5.5 GE HEALTHCARE
Waukesha, WI
www.gehealthcare.com
GE is a diversified technology, media and financial services company. GE
Healthcare offers expertise in medical imaging and information technologies, medical
diagnostics, patient monitoring systems, drug discovery and biopharmaceutical
manufacturing technologies. GE Healthcare is an $18 billion unit of General Electric.
Worldwide, the health care unit employs about 46,000 people in more than 100 countries.
The unit manufacturers, sells and services a wide range of medical equipment
including equipment for magnetic resonance (MR), computed tomography (CT), positron
emission tomography (PET) imaging, x-ray, patient monitoring, diagnostic cardiology,
nuclear imaging, ultrasound, bone densitometry, anesthesiology and oxygen therapy,
neonatal and critical care, and therapy.
GE Healthcare markets a number of bone densitometry systems. These include
the Prodigy for Bone Health with low dose radiation, the lightweight Lunar Achilles, the
small footprint Lunar DPX NT, a full-size, pencil-beam, bone densitometry system, and
the compact DPX Bravo.
The demand for the companys premium system, the Lunar iDXA, has remained
strong globally in both the osteoporosis and body composition for athletic performance
markets. Lunar iDXA offers research-grade image resolution and exacting precision,
designed to provide a high degree of clinical confidence across different body types.
The company also markets portable quantitative ultrasound systems that measure
bone properties at the heel without the use of ionizing radiation.
GE Healthcares enCORE software is designed to enhance clinical assessment.
enCORE v16, recently approved by FDA, offers two software applications, Complete
Pediatrics and Ortho Knee. Complete Pediatrics gives physicians, concerned with the
bone and developmental health of pediatric patients, a low dose method of monitoring
total body BMD over the entire pediatric age range from birth to 20 years of age.
Orthopedic surgeons have for many years used DXA to test for and monitor the
osteoporotic status of their patients. enCORE v16 and the Ortho Knee application give

72
orthopedic surgeons, concerned with bone health around an artificial knee, a low dose
method of measuring periprosthetic BMD.


73
5.6 HOLOGIC
Bedford, MA
www.hologic.com
Hologic is a developer, manufacturer and supplier of diagnostic and medical
imaging systems. Its core business units are focused on osteoporosis assessment,
mammography and breast biopsy, direct-to-digital x-ray for general radiography
applications and mini C-arm imaging for orthopedic applications.
For the 12 months ended Sept. 28, 2013, company revenues totaled approximately
$2.5 billion, compared to revenues of about $2 billion in the previous fiscal year. Hologic
addresses the issue of bone health with its DXA systems that feature innovations in bone
densitometry technology. Hologic DXA systems are powered by the companys OnePass
technology whose single-sweep scanning technology. The systems utilize a multi-element
digital detector array paired with true fan-beam acquisition geometry, enabling rapid,
dual-energy bone density measurements. OnePass scanning is designed to eliminate beam
overlap errors and image distortion.
Patients suffering from osteoporosis are often treated with bisphosphonates to
prevent or slow the loss of bone mass. Recent studies have linked bisphosphonate therapy
with the potential for increased risk of atypical femur fractures. Atypical Femur Fracture
assessment is offered on the companys Horizon family of DXA systems. Hologic also
offers vertebral fracture assessment technology, High Definition Instant Vertebral
Assessment (IVA-HD) improves the detection of vertebral fractures.
Hologic also is marketing the Sahara bone sonometer, which is an ultrasound
modality for bone assessment for the office-based physician. Ultrasound bone sonometry
provides precise quantitative assessment of skeletal status. It is useful in identifying
patients at risk of developing osteoporosis and for assessing their risk of future fracture.


74
5.7 OSTEOMETER MEDITECH

Signal Hill, CA
www.osteometer.com
Osteometer MediTech's focus is on offering office based scanners and
densitometers for the diagnosis of osteoporosis. For the past few years, Osteometer
MediTechs main product has been the DTX-200 DexaCare, a forearm scanner based on
dual energy x ray absorptiometry technology (DEXA). Several thousand systems have
been sold in more than 50 countries.
Osteometer A/S was founded in 1989. The first densitometer developed by
Osteometer was an isotope based system, the DT-100. This was followed by the
introduction of the DTX-100, which used a single energy X-ray source. In 1992,
Osteometer A/S expanded its activities by introducing biochemical kits for the
determination of bone turnover. This feature is incorporated in the software for the DTX200 DexaCare and DexaCare G4 bone densitometers, providing assessment of the annual
bone loss and future risk prediction for developing osteoporosis. But it is a software
feature not available in the US.
In the early 1990s, Osteometer separated into two companies, Osteometer
MediTech A/S, specializing in office based scanners and densitometers for the diagnosis
of osteoporosis, and Osteometer BioTech A/S, specializing in biochemical markers of
bone and cartilage metabolism. In 1998, Osteometer MediTech A/S was acquired by US
based OSI Systems Inc., and the company relocated to California.

6.0 Prenatal Screening

KEY TREND
New techniques will provide noninvasive alternatives to current invasive prenatal
tests for genetic diseases, such as amniocentesis and chorionic villus sampling (CVS). For
instance, using a blood sample from a mother-to-be, researchers at the Chinese University
of Hong Kong have mapped the entire genome of her fetus, potentially opening the door
for widespread noninvasive prenatal screening for genetic problems.
Genome-wide sequencing of a fetus might be done simply using a mother's blood.
Noninvasive prenatal diagnosis would allow couples at risk of passing on an inherited
condition to their child to avoid a 1% risk of miscarriage associated with invasive
diagnostic tests, such as amniocentesis.
6.1 INVASIVE TESTING

Prenatal diagnosis, also known as prenatal screening, involves testing for diseases
or conditions in a fetus before it is born. The basis of prenatal screening is the analysis of
the 23 pairs of chromosomes that every human being has. Using a variety of techniques a
cytogeneticist examines the number, shape and staining pattern of these chromosomes to
detect extra chromosomes, missing chromosomes, or rearranged chromosomes. The more
common disorders include Down syndrome (chromosome 21 trisomy), Turners
syndrome, Fragile X syndrome for mental retardation, neural tube defects, spina bifida,

76
inherited diseases (cystic fibrosis, Thalassemia, Canavan disease, Tay-Sachs, sickle cell
disease), chronic myelogenous leukemia (CML), and Burkitts lymphoma.
Common prenatal testing procedures include amniocentesis, ultrasonography
serum marker testing and genetic screening. Physicians and patients find it useful to
diagnose high-risk pregnancies early so that delivery can be scheduled in a tertiary care
hospital where the baby can receive appropriate care.
Diagnostic prenatal testing can be performed invasively or non-invasively. One
invasive method involves probes or needles inserted into the uterus, e.g. amniocentesis,
which can be done from about 14 weeks of gestation, and usually up to about 20 weeks.
CVS, which determines chromosomal or genetic disorders in the fetus, can be done
earlier, between 9.5 and 12.5 weeks of gestation. But this procedure may be slightly more
risky to the fetus.
6.2 NONINVASIVE TESTING

The future for prenatal noninvasive testing lies in an alternative to invasive
amniocentesis and CVS. Some fetal cells circulate in the maternal blood during
pregnancy, so research has focused on trying to develop a blood-based prenatal test. The
area is moving forward significantly, thanks to tests from Illumina and others that harness
cell-free DNA and circulating fetal cells. LabCorp has introduced a new test that screens
for a variety of fetal chromosomal abnormalities with a single non-invasive blood draw
from the mother. The informaSeq Prenatal Test is available through LabCorps Integrated
Genetics specialized testing group.
CombiMatrix, Irvine, CA, has a marketing and distribution agreement with
Sequenom, a manufacturer of an NIPT test, by which Sequenom is marketing
Combimatrix CMA prenatal testing services. Sequenom's MaterniT21 PLUS is one of the
largest selling NIPT tests available.
Research is ongoing. For example, Canadian scientists at the University of British
Columbia are leading a Canadian study that could overhaul prenatal care for Canadian
women. The study aims to prove the effectiveness of non-invasive prenatal tests (NIPTs)
and determine if they should be publicly funded. NIPTs require only a blood draw from
the mother as early as 10 weeks gestation to determine with 99% accuracy whether her
fetus has chromosomal abnormalities associated with Down syndrome, Triploidy 13 or

77
18 and Monosomy X. NIPTs work by analyzing cell-free fetal DNA in the mothers
blood. These tests provide information earlier, and pose significantly less risk.
Clinical use of NIPTs is growing because of the advantages it offers over the
conventional prenatal screening and diagnostic methods, such as maternal serum
screening, nuchal translucency scan, amniocentesis and CVS. These advantages include
safety, accuracy, and no risk of miscarriage.
6.3 THE IMPACT OF PRENATAL GENETIC TESTING

New genetic knowledge is making it possible to test prenatally for a wide range of
fetal genetic characteristics. One consequence will be an expansion of reasons for
selective abortion following prenatal testing. It will likely become possible for patients to
request prenatal testing and abortion not only for serious diseases but also relatively mild
diseases, late-onset diseases, treatable diseases, elevated risks for common diseases, and
eventually nondisease characteristics, such as height and body build.
Two main ethical views concerning prenatal testing have evolved. Prenatal testing
should be restricted to the most severe disorders, involving profound retardation, severe
physical handicaps, or prolonged physical suffering. Patients' requests for prenatal tests
should be honored except for diseases considered to be too minor. Other views have also
appeared. Physicians should honor requests for prenatal testing for diseases, including
relatively minor ones, but not requests pertaining to nondisease characteristics, and all
requests for prenatal tests should be honored.
A growing number of gene defects that cause diseases have been identified.
6.4 DNA ASSAY MARKET

The number of pregnant women receiving prenatal tests has been increasing over
the past decade, not without controversy as many pro-life groups fear that testing leads to
the termination of many pregnancies. Significant advances in prenatal genetic testing will
soon force society to confront a host of difficult ethical, practical and legal questions. I
think within the next five, and almost certainly 10 years, we will see an enormous
expansion of prenatal fetal genetic testing in this country, says Stanford University law
professor Hank Greely. New technology will make it possible to easily and cheaply check

78
millions of fetuses for genetic disorders ranging from Down syndrome to cystic fibrosis,
and will likely lead to a significant increase in terminated pregnancies.
As the cost of genetic sequencing declines, doctors will be able to cheaply and
easily identify fetal DNA within the mothers bloodstream and test it for genetic
disorders.
About 5,500 children are born each year with Down syndrome, and about 1,500
children born with similar, but more serious, chromosomal genetic disorders. Cell-free
fetal DNA tests screen for Trisomy 13, 18, and 21. Also known as Down syndrome,
Trisomy 21 affects one in every 691 babies in the US, according to the National Down
Syndrome Society. Some tests also screen for more obscure conditions like Turner and
Triploid syndromes, and can even determine the babys sex. The cost of the test runs
anywhere from $800 to $2,000, and more insurance companies are covering the test. The
availability of each test varies from state to state in the US.
Many prenatal tests are lab developed tests. The prenatal test industry is highly
fragmented and served by many labs, primarily in western Europe, Japan and North
America. In the US, large reference labs including Orchid Biosciences, LabCorp, and
Quest Diagnostics undertake prenatal testing.
The increase in prenatal testing should continue with about 10 million annual
pregnancies occurring in the US, EU, Canada, Australia and Japan. For example,
amniocentesis is recommended for all pregnancies when the mother is 35 years or
older. This represents a steadily growing market. It encompasses 14% of all pregnancies
in the US alone. Given the continued interest in and growth of prenatal testing, the market
for DNA-based assays for prenatal testing should experience about a 4% to 6% annual
growth rate in the near term, as seen in Exhibits 12 and 13.


79
Exhibit 12
World Market for Molecular (DNA) Assays for Prenatal Testing,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$75.9
38.9
12.2
4.4
29.6
18.5
179.5
2014
80.5
41.2
12.7
4.6
31.4
19.1
189.5
2015
85.3
43.7
13.2
4.8
33.3
19.7
200.0
2016
90.4
46.3
13.7
5.0
35.3
20.3
211.0

2017
95.8
49.1
14.2
5.2
37.4
20.9
222.6
2018
101.5
52.0
14.8
5.4
39.6
21.5
234.8

80
Exhibit 13
World Market for Molecular (DNA) Assays for Prenatal Testing
2014,
2%
10%
16%
42%
23%
7%
US
European Union
China
Japan
ROW
Brazil
6.5 PRENATAL CARRIER AND FETUS SCREENING MARKET

In addition to DNA-based assays, another prenatal testing market involves
prenatal chromosome analysis. Testing of genetic material carrier screening can be
performed as a prenatal screening tool to assess whether would be parents have an
autosomal or X-linked recessive gene that, when combined in a child, will produce a
serious disorder in that child. The basis of prenatal screening is an analysis of the 23 pairs
of chromosomes that every human being has. Using a variety of techniques, a

81
cytogeneticist examines the number, shape and staining pattern of these chromosomes to
detect extra chromosomes, missing chromosomes, or rearranged chromosomes.
The more common disorders include Down syndrome (chromosome 21 trisomy),
Turners syndrome, Fragile X syndrome for mental retardation, neural tube defects, spina
bifida, such inherited diseases as cystic fibrosis, Thalassemia, Canavan disease, TaySachs, and sickle cell disease, chronic myelogenous leukemia, and Burkitts lymphoma.
Fragile X syndrome is the most common inherited cause of intellectual disability.
It is caused by a growing repetition of the cytosineguanineguanine trinucleotide
segment of the fragile X mental retardation 1 (FMR-1) gene, which leads to altered
transcription and loss of function of the FMR-1 gene. Fragile X syndrome occurs when
expansion of the FMR-1 triplet repeat occurs. Men and women can be affected.
Prevalence of the syndrome is 1 in 3,600 males and 1 in 4,000 to 6,000 females.
The world market for prenatal carrier and fetus screening will see strong growth
up to 7% annually, as seen in Exhibits 14 and 15.
Exhibit 14
World Market for Prenatal Carrier and Fetus Screening,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$90
52.0
11.0
4.0
28.0
10.0
195.0
2014
95.4
55.6
11.6
4.2
30.0
10.3
207.1
2015
101.1
59.5
12.2
4.4
32.1
10.6
219.9
2016
107.2
63.7
12.8
4.6
34.3
10.9
233.5

2017
113.6
68.2
13.4
4.8
36.7
11.2
247.9
2018
121.0
73.0
14.1
5.0
39.3
11.5
263.9

82
Exhibit 15
World Market for Prenatal Carrier and Fetus Screening
2014,
5%
2%
14%
46%
6%
27%
US
European Union
China
Japan
ROW
Brazil


83
6.6 PERKINELMER
Waltham, MA
www.perkinelmer.com
PerkinElmer is involved in health sciences and photonics markets. The company
is a provider of scientific instruments, consumables and services to the pharmaceutical,
biomedical, environmental testing and general industrial markets. PerkinElmer is a leader
in two fast growing segments: genetic screening, which includes both neonatal and
prenatal/maternal health screening; and digital x-ray imaging.
The companys Human Health segment revenue reached more than $1.2 billion in
2013, up from approximately $1.17 billion in 2012. The increase in the companys
Human Health segment revenue during 2013 was due to growth in its diagnostics
business from continued expansion of its prenatal, newborn and infectious disease
screening products, as well as increased demand for the companys informatics offerings
and in-vivo imaging systems in the research market.
Among its prenatal testing products, PerkinElmer offers three alternative
platforms for maternal and fetal health monitoring: random access, batch processing or
semi-automatic platforms. Delfia Xpress (not available in the US) is a random access,
compact bench-top instrument. It is targeted to both antenatal clinics and hospital
laboratories, providing serum biochemistry results. Delfia Xpress features complete
barcoding of reagents and supports sample barcoding to assure positive identification.
Wallac AutoDelfia is a cost-effective batch analyzer for a high throughput environment.
It will perform all operations automatically and give final results either by analyte or
patient. Wallac Victor2 D is a manual reader, which is supported by a complete set of
optimized sample handling instruments. It is an alternative for labs requiring a less
automated option for Delfia assays. PerkinElmer, through its subsidiary NTD
Laboratories Inc., is a provider of prenatal screening for Down syndrome, trisomy 18/13
and open neural tube defects in the US. Outside the US, PerkinElmer works directly with
health care providers, supplying screening platforms, assay kits and computer software to
support the strategies of individual screening programs.
The company also provides newborn screening systems, offering a tandem mass
spectrometry (MS/MS) kit as an aid to screening for inborn errors of metabolism.

84
PerkinElmer also offers Ultra-Screen, a first-trimester prenatal screening protocol
designed to provide patient-specific risk assessment for certain chromosomal
abnormalities, through its clinical test subsidiary, NTD Laboratories. The company also
holds a global licensing agreement to develop assay kits for the Adam12 biochemical
marker, which has broad potential in maternal health screening for fetal chromosomal
abnormalities. The company has secured global rights for Placental Protein 13 (PP13), a
new maternal serum marker under investigation that has shown potential for early
detection of pre-eclampsia in low-risk groups.
Also available is the companys prenatal BACs-on-Beads (BoBs) in vitro
diagnostic assay for rapid prenatal testing of multiple genetic diseases, for use in the
European Union. The companys Signature Genomics Laboratories has launched its new
Signature Precision Panel| Prenatal diagnostic test for the rapid testing of 15 common and
severe chromosomal disorders.
PerkinElmer also markets its GSP Genetic Screening Processor, a high throughput
batch analyzer, which is used by public health laboratories worldwide as part of newborn
screening programs. The GSP is an automated multiplex platform able to quantitatively
and qualitatively analyze blood spot samples for irregularities.
In 2009, the company acquired Sym-Bio LifeScience Co., a major supplier of
diagnostics instruments and related reagents, particularly in the area of infectious
diseases, to hospitals in China. PerkinElmer has used this acquisition to expand its access
to the hospital market segment in China, offering a larger base from which to expand its
prenatal and newborn screening business in the country.


85
6.7 QUEST DIAGNOSTICS

Madison, NJ
www.questdiagnostics.com
Quest Diagnostics is the top reference lab in the US. The company offers a broad
access to diagnostic testing services through its national network of laboratories and
patient service centers. Quest Diagnostics is a pioneer in developing innovative new
diagnostic tests. The company generated 2013 revenues of approximately $7.1 billion.
Today, the core of Quest Diagnostics business is rooted in routine and pathology
tests. Along with its main competitor, Laboratory Corp. of America (LabCorp), Quest is a
major supplier of cancer histology and pharmacodiagnostic tests to physicians and
hospital labs. Quest Diagnostics impacts the lives about one-third of American adults
each year. The company serves about half of the physicians and hospitals in the US, has a
workforce of about 41,000 employees and operates more than 2,200 patient service
centers.
Quest Diagnostics offers the XSense test, a Fragile X Syndrome test for autism
and mental retardation using molecular technology. The test is highly accurate, and may
be suitable for high-volume population screening and diagnostic testing on a range of
patients, including women and newborns. Approximately one in 1,500 males and one in
4,000 to 6,000 females worldwide are born with FXS.
Quest Diagnostics is offering physicians access to Panorama, a non-invasive
prenatal test developed by Natera. Panorama uses cell-free fetal DNA in circulating
maternal blood to screen for chromosomal abnormalities associated with trisomy 21
(Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome) and
monosomy X (Turner syndrome). Panorama can be used as early as the ninth week of
pregnancy. Physician clients of Quest Diagnostics can forward specimens for testing to
Natera's CLIA-certified laboratory in San Carlos, CA, which developed and validated the
Panorama test.


86
6.8 SCREENCELL
Sarcelles, France
www.screencell.com
ScreenCell was founded to design and produce a simple technique allowing for
the filtering of rare circulating cells to yield a circulating tumor cell (CTC) population
amenable to cellular and molecular characterization.
ScreenCell designed a full range of point of care devices compatible with existing
IVD assays and platforms. ScreenCell is creating technologies allowing CTCs to become
potential end points in future oncology therapeutic arsenals, by filtering out healthy live
tumor cells, thus enabling: molecular biology, cell culture, and enumeration and
cytomorphology evaluation.
The technology has also demonstrated its advantages for the isolation of
circulating fetal cells (CFCs) drawn from peripheral blood of pregnant women,
potentially leading to a significantly facilitated and cost-effective process for prenatal
diagnosis of genetic diseases. The technology may be gaining traction via a number of
collaborations.


87
6.9 SEQUENOM
San Diego, CA
www.sequenom.com
Sequenom is a molecular diagnostic testing and genetics analysis company
targeting products for biomedical research, translational research, molecular medicine
applications, and agricultural, livestock, and other areas of research. The companys
development and commercialization efforts in various diagnostic areas include
noninvasive womens health related and prenatal diagnostics, age-related macular
degeneration diagnostics, oncology, infectious diseases, and other disorders and diseases.
The company is primarily focused on developing and commercializing prenatal
screening and diagnostic tests using its foundational, patent protected, noninvasive,
circulating cellfree fetal (ccff) nucleic acid based assay technology. This technology
uses a simple maternal blood draw for a prenatal diagnosis or risk assessment in order to
provide reliable information about the status of the fetus early in pregnancy.
The companys prenatal revenue reached approximately $120 million in 2013,
while its genetic analysis revenue reached about $42 million.
In 2010, the company launched noninvasive Rhesus D (RhD) genotyping and
Fetalxy sex determination laboratory developed tests (LDTs) using the ccff technology,
which was licensed from Isis Innovation Ltd., the technology transfer company of
the University of Oxford. Sequenom also launched, in September 2009, a noninvasive
molecular based cystic fibrosis carrier screening LDT.
In the US, there are approximately 528,000 pregnancies in RhD negative women
every year, and almost all of these women could benefit from an assessment of the RhD
type of the fetus. RhD type can be determined by an invasive procedure, such as
amniocentesis or CVS, but both procedures involve risk to the fetus. Currently in the US,
most RhD negative women are managed without knowing the fetal RHD status. The
benefits of the new noninvasive genotyping test include: its use as an aid to physicians in
creating a more informed strategy to manage the care of pregnant RhD negative women;
a reduction in the need for invasive procedures, such as amniocentesis or CVS; first
trimester detection; and its use as a control to confirm the presence of fetal DNA,


88
ensuring that a RHD negative result for a female fetus is due to the measurement of fetal
rather than maternal nucleic acid in the sample.
In 2010, the company launched the SensiGene Fetal RHD Genotyping test, which
is powered by its SEQureDx technology. With SEQureDx technology, rather than
harvesting placental tissue cells (as is required for CVS), or entering the uterus to sample
the amniotic fluid surrounding the baby (as is done with genetic amniocentesis), this
technology extracts and analyzes DNA material directly from a maternal blood sample.
SEQureDx technology utilizes circulating cell-free fetal nucleic acids in maternal plasma
to examine variances in the genetic material of the fetus, such as aneuploidies.
In July 2014, Sequenom launched the VisibiliT laboratory-developed test in
international markets. The VisibiliT test utilizes maternal age, fetal fraction and the
relative amount of chromosomal material for chromosomes 21 and 18 to generate a
highly accurate, personalized risk score. The VisibiliT test is for pregnant women who
want information about common fetal trisomies (Down syndrome and Edwards
syndrome), have a single gestation pregnancy, and whose pregnancies are considered to
be at average risk. The test can also report fetal gender. With the VisibiliT test,
Sequenom Laboratories fulfills its goal to expand its noninvasive prenatal testing menu
with the development of a low-cost test by year-end that facilitates international access.
In June 2014, Sequenom and Quest Diagnostics made official an agreement under
which Quest will offer national access to Sequenom Laboratories' MaterniT21 PLUS
laboratory-developed test. Using a maternal blood sample, the noninvasive prenatal test
(NIPT) analyzes chromosomal material in cell-free fetal DNA of pregnant women at
increased risk for fetal chromosomal abnormalities. Sequenom's MaterniT21 PLUS is one
of the largest selling NIPT tests available. In the first half of 2014, Sequenom
accessioned more than 80,000 MaterniT21 PLUS tests, and more than 100,000 total test
samples for all its LDTs, compared to 73,000 MaterniT21 PLUS tests and 91,200 tests in
total for the first half of 2013.
CombiMatrix, Irvine, CA, has a marketing and distribution agreement with
Sequenom, by which Sequenom is marketing Combimatrix CMA prenatal testing
services.
In October 2014, Sequenom and Isis Innovation announced that Sequenom has
purchased noninvasive prenatal testing intellectual property from Isis for $14.55 million,

89
which includes $3.2 million as the final royalty payment due to Isis under a prior
agreement and the waiver of $2.1 million in paid legal fees that Isis owed to Sequenom,
with additional downstream payments contingent on revenues exceeding certain
thresholds.
Under the terms of the agreement, Sequenom is the owner of global intellectual
property for noninvasive prenatal genetic diagnostic testing on paternally inherited fetal
nucleic acids derived from maternal plasma or serum. Sequenom previously had
exclusive rights to this intellectual property under a licensing agreement with Isis
Innovation established in 2005. As part of the purchase agreement, Isis has rights in
certain fields of use.
The patents purchased from Isis Innovation will enable Sequenom to strengthen
its intellectual property position worldwide.


90
6.10 LABORATORY CORPORATION OF AMERICA

Burlington, NC
www.labcorp.com
Laboratory Corporation of America Holdings commercializes new diagnostic
technologies and embraces genomic testing. With annual revenues of $5.8 billion in
2013, over 34,000 employees worldwide, and more than 220,000 clients, LabCorp offers
more than 4,000 tests ranging from routine blood analyses to reproductive genetics to
companion diagnostics. LabCorp clients include physicians, government agencies,
managed care organizations, hospitals, clinical labs, and pharmaceutical companies.
In August 2014, the company made available the informaSeq Prenatal Test, which
is an advanced, non-invasive, next-generation prenatal screening assay that can assess
risk for multiple fetal chromosomal aneuploidies, or abnormalities in the number of
chromosomes, from a single maternal blood draw. There are testing options for several
additional common sex-related aneuploidies. The test is offered through Integrated
Genetics, part of the LabCorp Specialty Testing Group of laboratories that offer advanced
esoteric and genomic testing.
The informaSeq Prenatal test is performed using Illumina sequencing technology
to generate test data, offering high detection rates (sensitivity) and low false positive rates
(specificity), even in samples with a lower fraction of fetal DNA fragments.

7.0 Ultrasound
KEY TREND
Knowledge of the harmful effects of radiation exposure continues to promote the
use of ultrasound in clinical markets. Hand-carried ultrasound units have are changing
and expanding the diagnostic ultrasound market by serving existing clinical markets more
efficiently. They also are creating new point-of-care applications for which ultrasound
had been either too cumbersome or too expensive to be used before. Three dimensional
(3D) ultrasound is finding more use as it provides greater detail for diagnosis during
pregnancy than the traditional 2D ultrasound. For example, clinicians are using 3D to
accurately measure the fetal skull to estimate gestational age. Multi-dimensional
ultrasound is also being used to help parents see if any aspect of the fetus is malformed.
7.1 HISTORY AND PERSPECTIVE

Ultrasound continues to be a low-cost and effective imaging technology that can
help radiologists and others gather significant clinical data about patients without the use
of radiation. Ultrasound is well suited to many patients. No other imaging option gives
patients a real-time look at their anatomy or openly encourages discussions with
physicians about their symptoms and the evidence of disease on the monitor.
Ultrasound imaging systems have become commonplace in many offices of
cardiologists, obstetricians, surgeons, and urologists, among other specialists. New
applications, such as the use of ultrasound in administering emergency medicine, along
7.0 Ultrasound
92
with new hand-held portable systems are helping to further fuel the medical marketplace
for the technology. In addition, ultrasound systems attract users simply because of their
emphasis on user-friendliness, compactness and mobility.
Key medical uses for ultrasound can be seen in Exhibit 16.
Exhibit 16
Key Applications for Medical Ultrasound
Obstetrics and Gynecology
x Measuring the size of the fetus to determine the due date.
x Determining the position of the fetus to learn if it is breech.
x Checking the position of the placenta to see if it is improperly developing over the
opening to the uterus (cervix).
x Determining the number of fetuses in the uterus.
x Checking the sex of the baby, if the genital area can be clearly seen.
x Checking the fetus growth rate by making many measurements over time.
x Detecting ectopic pregnancy, the life-threatening situation in which the baby is implanted
in the mother's Fallopian tubes instead of in the uterus.
x Determining whether there is appropriate amniotic fluid cushioning the baby.
x Monitoring the baby during specialized procedures, such as amniocentesis.
Cancer
x Imaging tumors of the ovary and breast.
7.2 NUCHAL TRANSLUCENCY

The use of nuchal translucency (NT) to assess whether the baby has an increased
risk for Downs syndrome or other chromosomal disorders, as well as major heart
congenital heart problems, is increasing. NT uses ultrasound to measure the translucent
area in the tissue at the back of a developing baby's neck.

7.0 Ultrasound
93
7.3 SPECKLE REDUCTION

Other new techniques have been optimizing ultrasound. Speckle reduction,
volumetric imaging, and elastography make it possible to reduce artifacts, improve the
contrast of an image, reduce image noise, and better gauge tissue stiffness to detect subtle
hard-to-spot abnormalities. These technologies offer ultrasound the potential to increase
its accuracy, repeatability, and efficiency and help keep the modality competitive with
other cross-sectional imaging modalities.
The dots speckle that occur in ultrasound imaging are caused by the
interference of energy from randomly distributed scatters that are too small to be resolved
by the imaging system. Essentially, speckle is generated when acoustic waves scatter off
small particles in the target being scanned. Speckle degrades both the spatial and contrast
resolution of ultrasound images and reduces the diagnostic value of the images. Reducing
speckle has several advantages. These include higher perceived tissue contrast, which
facilitates the identification of points of increased or decreased echogenicity. Reductions
also decrease image noise, which can make the image more pleasing to the eye.
Disadvantages include a reduction in frame rate caused by the need to send and receive
beams from different directions; a possible loss in spatial resolution; and loss of acoustic
enhancement and shadowing, which is often important in diagnosis.
7.4 VOLUMETRIC IMAGING

On another front, the acquisition of image data from a volume of tissue
volumetric imaging can be achieved by moving an ultrasound transducer through an
area or organ perpendicular to the plane of the transducer, rather than simply sampling
the volume with a small series of images. The result is a series of parallel slices that
represent the volume of tissue that has been scanned.
7.5 FOLLICULAR TRACKING

Follicular tracks a womans menstrual cycle. It can lead to a greater understanding
of a womans ovulation pattern. One of the biggest challenges in fertility as women age
involves the suitability of your eggs. The quality and number of eggs produced can be

7.0 Ultrasound
94
greatly affected by a womans age. The poor quality of eggs is related to a general decline
of pregnancy rates as women get older.
When determining whether to conceive, women should have follicular tracking
performed. This will help to identify whether a woman is ovulating and, if she is, the scan
will additionally pinpoint the exact time when the follicle ruptures and releases the egg.
This information enables a couple to plan intercourse to optimize their chances of
conception.
Follicle tracking involves a series of vaginal ultrasound scans, starting from day 9
to day 20 of a womens menstrual cycle. These scans make it possible to observe the
follicles developing in an ovary. This technique is replacing the counting of a womans
follicles after she had been given stimulants.
7.6 OBSTETRICS AND GYNECOLOGY

The main uses of ultrasonography include the diagnosis and assessment of early
pregnancy. The gestational sac can be visualized as early as four-and-a-half weeks of
gestation and the yolk sac at about five weeks. The viability of the fetus can be
documented in the presence of vaginal bleeding in early pregnancy. Fetal heart motion is
usually detectable by seven weeks. If this is observed, the probability of a continued
pregnancy is greater than 97%. Missed abortion and blighted ovum will usually give the
picture of a deformed gestational sac and the absences of any fetal poles or heart beat.
Ultrasound is indispensable in the early diagnosis of ectopic pregnancies. An
ectopic pregnancy is one in which the fertilized ovum is implanted in any tissue other
than the uterine wall. Most ectopic pregnancies occur in the Fallopian tube tubal
pregnancies. Only 2% of ectopic pregnancies occur outside of the fallopian tubes. But
implantation can also occur in the cervix, ovaries, and abdomen. Ectopic pregnancy
occurs at a rate of 19.7 cases for every 1,000 pregnancies in North America and is a
leading cause of maternal mortality in the first trimester. Greater awareness of risk factors
and improved technologybiomarkers and ultrasonographymake it possible to
identify ectopic pregnancy before the development of life-threatening events.
Ultrasound-based fetal body measurements reflect the gestational age of the fetus.
This is particularly true in early gestation. Ultrasonography also is valuable in
determining the number of fetuses and their presentations. Hydramnios and
7.0 Ultrasound
95
oligohydramnios, excessive or decreased amount of amniotic fluid, can be detected by
ultrasound. Some structural abnormalities in the fetus can be detected by an ultrasound
scan.
Ultrasound is a relatively non-invasive way to view the reproductive organs in the
pelvis to determine the nature and extent of structural abnormalities present. Many
gynecologic disorders do not show early symptoms, and ultrasound can often diagnose
problems well before a patient may know a problem exists. Uterine size and shape can be
determined. Common problems such as uterine fibroid tumors, which can cause pain and
bleeding and interfere with fertility, can be localized, measured, and followed over time
to help determine their significance. The thickness of the endometrial lining can be
measured in patients who experience abnormal uterine bleeding to help rule out cancer as
a cause of their bleeding.
Ultrasound also makes it possible to determine the size of the ovaries. Cysts
inside and outside of the ovary can be measured and their characteristics determined.
Ovulatory function of the ovaries can also be assessed by serial ultrasound exams.
7.7 BREAST IMAGING

Breast ultrasound, also known as sonography or ultrasonography, is frequently
used to evaluate breast abnormalities that are found with diagnostic mammography or
during a clinical breast exam performed by a doctor. Ultrasound is able to obtain images
of the breast from almost any angle and is excellent at imaging cysts. Additionally,
ultrasound can often quickly determine if a suspicious area is in fact a cyst or an
increased density of solid tissue, which may require a biopsy to determine if it is
malignant.
Although breast ultrasound has excellent contrast resolution, it has lacked the
detailthe spatial resolutionof conventional mammography. Physicians use ultrasound
to evaluate breast abnormalities that have been found with screening or diagnostic
mammography or during a clinical breast exam. Ultrasound may help detect some breast
masses and is the best way to determine whether a cyst is present without placing a
needle into the area of concern to aspirate fluid. Ultrasound is also useful in helping
physicians guide a biopsy to determine whether a breast abnormality is cancerous.

7.0 Ultrasound
96
Screening ultrasound combined with mammography improves breast cancer
detection in high-risk women, but the combination also can cause a spike in the number
of false positives, according to the American College of Radiology Imaging Network
6666 trial. These results may render ultrasound less attractive than MRI in this patient
population. "Supplemental screening ultrasound has the potential of depicting small,
node-negative breast cancers not seen on mammography," wrote Dr. Wendie Berg, Ph.D.,
et al in the Journal of the American Medical Association (2008;299[18]:2151-2163).
One recent advancement involves automated breast ultrasound (ABUS), which
provides 3D renderings of transverse, sagittal and coronal views of the breast. The
coronal view is unique because such an angle is not possible with 2D ultrasound. Some
believe that ABUS should not replace handheld ultrasound in a diagnostic breast center
but rather should be used in conjunction with it or play a role in screening breast
ultrasound. Others believe that women with abnormally dense breasts should always be
referred for ultrasound as a secondary check.
7.8 OB/GYN MARKET

Ultrasound has had a foothold in obstetrics for many years, monitoring the fetus
during pregnancy. The market for this segment will continue to increase as simple
ultrasound systems are replaced by 3D and 4D units, which will vastly increase scan
clarity and optimize diagnosis, and still be a less expensive modality.
By using volumetric images 3D and 4D ultrasound as an adjunct to 2D
ultrasound, physicians are expanding their diagnostic capabilities, boosting diagnostic
confidence levels, and consulting better with patients. With 4D in particular, physicians
are using the element of time to further assess and diagnose obstetrical and gynecological
conditions. An increasing number of womens health centers are using 3D and 4D tools
on their premium ultrasound systems as a complement to their 2D imaging capabilities.
Birth defects occur in one in 33 births about 3%. Approximately 270,000
newborns die during the first 28 days of life each year from congenital anomalies. The
most common severe congenital anomalies are heart defects, neural tube defects and
Down syndrome. Volume ultrasound is used for assessing and diagnosing certain
congenital fetal abnormalities such as malformations of the face, limbs, skeletal
structures, and organs. And, 3D and 4D ultrasound are being used in gynecology to detect
7.0 Ultrasound
97
structural problems of the uterus and diagnose ovarian tumors, endometrial polyps, and
fibroids. Both 3D and 4D ultrasound imaging enhance diagnosis because they improve
the ability to see certain types of things, such as skeletal abnormalities, more clearly.
Physicians may use the technologies to examine spina bifidia. They may use it to look at
the heart. Doctors can look at the facial bones for cleft palate. They can examine the
suture lines of the skull. They can apply color Doppler with the 3D or 4D to look at the
surface anatomy of the placenta and where the blood vessels are going. 3D and 4D
ultrasound will eventually find a market in the early diagnosis of congenital heart defects,
which are present in about 1% of live births, according to the American Heart
Association.
With this positive market environment for ultrasound, the modalitys use in
clinical Ob/Gyn applications should grow at a 4% to 6% annual rate, as seen in Exhibits
17 and 18. It is estimated that the use of ultrasound for breast imaging represents about
15% of the overall ultrasound market.
Exhibit 17
World Ultrasound Ob/Gyn Market,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$288.8
206.3
81.7
29.7
107.3
74.3
788.1
2014
306.1
218.7
85.7
31.2
113.7
77.3
832.7
2015
324.5
231.8
90.0
32.8
120.5
80.4
880.0
2016
343.9
245.7
94.5
34.4
127.7
83.6
929.8

2017
364.5
260.4
99.2
36.1
135.4
86.9
982.5
2018
386.4
276.1
104.2
37.9
143.5
90.4
1,038.5
7.0 Ultrasound
98
Exhibit 18
World Ultrasound Ob/Gyn Market
2014,
4%
9%
14%
10%
US
37%
26%
European Union
China
Japan
ROW
Brazil
7.9 BREAST IMAGING MARKET

Also driving the ultrasound market will be its use in imaging the breast.
Ultrasound is becoming an important adjunct to mammography because it can eliminate
the need for biopsy in up to about 30% of positive mammographies. The market for
breast imaging using ultrasound is minimal currently. It represents less than 5% of the
overall medical ultrasound market. Undergoing breast ultrasound in addition to standard
mammography can find more cancers in high-risk women, particularly those with dense
breast tissue. With mammography, a woman has about a one in 40 chance that a biopsy
will turn out not to be cancer. With the addition of ultrasound, that chance is one in 10.

7.0 Ultrasound
99
What is holding back growth in this market segment is that there are not enough
physicians or ultrasound technicians trained for ultrasound for the modality to be a viable,
widely used screening tool right now, even just for high-risk women. On average,
physicians can only perform three to five ultrasounds per hour, compared to as many as
50 mammograms in an hour. Still this segment is expected to experience growth in about
the 4% to 6% range annually, as seen in Exhibits 19 and 20.
Exhibit 19
World Ultrasound Breast Imaging Market,
2013-2018
REGION
US/NA
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$88
72.6
8.5
3.1
30.8
13.2
216.2
2014
93.3
77.0
8.8
3.2
32.3
13.6
228.2
2015
98.9
81.6
9.2
3.3
33.9
14.0
240.9
2016
104.8
86.5
9.6
3.4
35.6
14.8
254.7

2017
111.1
91.7
10.0
3.5
37.4
15.2
268.9
2018
117.8
97.2
10.4
3.6
39.3
15.7
284.0
7.0 Ultrasound
100
Exhibit 20
World Ultrasound Breast Imaging Market
2014,
1%
6%
14%
4%
41%
34%
US
European Union
China
Japan
ROW
Brazil

7.0 Ultrasound
101
7.10 ANALOGIC
Peabody, MA
www.analogic.com
Analogic is a designer and manufacturer of health and security systems and
subsystems sold primarily to original equipment manufacturers (OEMs). The company is
involved in CT, digital radiography, ultrasound, MRI, patient monitoring and advanced
signal processing technology.
The companys highlights for fiscal year 2014, ended July 31, 2014, included:
revenue of $518 million, down 6% from fiscal 2013. Ultrasound segment revenue was
$40.4 million for the fourth quarter of fiscal 2014, down 8% from revenue of $43.7
million in the same period of fiscal 2013, due to fulfillment delays related to timing of
orders received during the quarter. In the fiscal year, ultrasound revenue was $152.5
million, up 2% from the prior year.
The companys custom ultrasound subsystems include spectral Doppler, color
flow mapping, and proprietary front-end electronics. The Flex Focus (B-K Medical A/S)
is the newest member of Analogic's family of ultrasound systems. It is a small, mobile
system. With Quantum Technology, image quality is greatly improved. Image quality
advancements include improved contrast resolution as well as new grayscale maps and
new image pre-sets, making it easier and quicker to obtain the highest quality images.
Founded in 2000, Ultrasonix Medical Corp. was acquired by Analogic In March
2013. Ultrasonix-branded diagnostic ultrasound systems are ideal for point-of-care
markets and procedure-driven applications. B-K Medical A/S, Analogics subsidiary in
Herlev, Denmark, develops and markets ultrasound systems for such applications as
surgery, urology, breast scanning, and obstetrics/gynecology, as well as transducers. B-K
has enhanced Analogics capabilities as an OEM supplier of ultrasound systems and
subsystems. An extensive network of distributors connects B-K Medical with Eastern
Europe, the Middle East, Asia, and the rest of the world.
Sound Technology Inc., a wholly owned subsidiary, develops and manufactures
ultrasound transducers and probes for a broad range of clinical applications. These
products are supplied to a global customer base of ultrasound system OEMs, including B-

7.0 Ultrasound
102
K Medical. Recent additions to the company's ultrasound product platforms include: 3-D
and 4-D endocavity probes for real-time volumetric imaging; biplane endocavity probes;
probes for minimally invasive surgery; and high-frequency phased arrays for pediatric
and neonatal applications.

7.0 Ultrasound
103
7.11 PHILIPS HEALTHCARE

Andover, MA
www.healthcare.philips.com
Philips posted 2013 sales of more than $30 billion, and employs approximately
115,000 employees with sales and services in more than 100 countries. The Philips
Healthcare business accounted for approximately 40% of the parent Philips overall sales,
and is the companys largest contributor to sales. The unit offers more than 450 products
and services in more than 100 countries.
Philips has ultrasound offerings for general imaging, critical care, cardiology,
emergency medicine, regional anesthesia, intervention, regional anesthesia, vascular and
womens health care.
In December 2013 at the 99th Annual Meeting of the Radiological Society of
North America, Philips showcased its Epiq premium ultrasound system. The system
features the Philips proprietary nSight Imaging architecture that creates images with
optimal resolution down to the pixel level. The Epiq has a number of applications,
including cardiology, general imaging and women's health.
Combining 2D and 3D image quality in the same transducer and a host of
quantification, clinical performance, and information management tools, the new iE33
xMatrix echo system facilitates the management of patients with cardiac disease,
including heart failure, valvular disease, and congenital heart disease.
In the area of ultrasound cardiology, the company offers the iE33 xMatrix, which
combines 2D and 3D image quality in the same transducer and a host of easy-to-use
quantification, clinical performance, and information management tools. Also on the
market is the HD11 XE, which can perform 3D/4D imaging, including 3D Fetal Echo
STIC for evaluating fetal hearts during routine obstetrical exams, as well as specialized
requirements for breast, transesophageal, pediatric, vascular, and musculoskeletal
ultrasound. It is a complete, digital imaging system. Also on the market are the Philips
Sonos 7500 system featuring Live 3D Echo for cardiology; and the Philips EnVisor C
system.

7.0 Ultrasound
104
In the area of general imaging, the iU22 system combines advanced technologies
and imaging on a user-centric ergonomically-designed cart. The company also offers its
SonoCT real-time compound imaging. By scanning up to nine lines of sight and
combining them in real time, SonoCT provides advanced spatial and contrast resolution
with improved artifact suppression. SonoCT-based products include the iE33
echocardiography system, the iU22, the high definition HD11 XE, as well as the En Visor
and HDI 5000 systems.
Philips Healthcare also is marketing the HD9, targeted at women's health
applications. HD9 includes 3D and 4D capabilities and is suitable for obstetrics,
gynecology, and breast imaging. It can also handle general imaging, adult and pediatric
cardiology, general pediatric imaging, and urology.
Philips also offers tissue aberration correction technology and algorithms, devised
initially to look at obese patients. The technology compensates for speed of sound
variations of dense tissue, improving detail resolution and conspicuity of lesion details.

7.0 Ultrasound
105
7.12 SIEMENS HEALTHCARE

Deerfield, IL
www.siemens.com
The Siemens Healthcare Sector offers its customers products and solutions for the
entire range of patient care from a single source from prevention and early detection to
diagnosis, and on to treatment and aftercare. Siemens Healthcare employs about 51,000
employees worldwide. In fiscal year 2012, ended Sept. 30, the Sector posted revenue of
about $18.7 billion and a profit of around $2.5 billion.
Siemens offers ultrasound products for cardiovascular, OB/GYN, radiology and
point-of-care applications. Among the company's products is the Acuson SC2000
ultrasound system, a cardiac ultrasound platform that combines ultra-high data rate echo
engine with a suite of advanced applications. The system can quantify ventricular
function, optimize reproducibility using automated measurement tools, and use integrated
workflow protocols and measurements. For OB/GYN and radiology applications, there is
the Acuson S3000 system, which offers high density transducers, including the 8C3 HD
transducer with an expanded field-of-view and excellent resolution at depth even on third
trimester patients. A multi-modality review makes it possible to view previous exams
alongside real-time ultrasound for more accurate follow up examinations.
The Acuson Freestyle ultrasound system is designed to meet the needs of pointof-care clinicians during ultrasound-guided procedures or for quick look assessments.
The system offers wireless, cable free transducers, and can be used for a variety of
applications in the hospital or clinical setting.
In the past, the company has marketed the Cypress echocardiography system, an
all-digital, phased array system. It provides 2D in fundamental and harmonic modes, MMode, color flow, spectral Doppler, as well as digital image storage, direct DICOM
networking, stress echo, and contrast agent imaging. The all-digital Sonoline G60 S
ultrasound system is a portable, multi-specialty ultrasound system providing
comprehensive solutions in flexibility, workflow, and performance in all applications.
Siemens also offers a number of ultrasound transducers.

7.0 Ultrasound
106
7.13 GE HEALTHCARE
Waukesha, WI
URL: www.gehealthcare.com
GE Healthcare is an $18 billion unit of General Electric. Worldwide, the health
care unit employs about 46,000 people in more than 100 countries. In November 2012,
GE Healthcare acquired U-Systems, Inc., a Sunnyvale, CA, manufacturer of ultrasound
products specifically designed for breast applications.
GE is marketing the somov
Automated Breast Ultrasound, the first ultrasound system on the market approved in the
US for breast cancer screening as an adjunct to mammography for asymptomatic women
with greater than 50% dense breast tissue and no prior breast interventions. The somov
ABUS received approval by the FDA for breast cancer screening in the US, and has also
been indicated for screening in Canada and the European Union. The specially shaped
transducer of the somo-v Automated Breast Ultrasound System (ABUS) can
automatically scan the entire breast in about one minute to produce several images for
review.
Among its other ultrasound products, GE is promoting point-of-care ultrasound
systems. Products include pocket-sized ultrasound; portable, touch-screen systems; and
compact console systems. Generally, the systems cover a range of clinical specialties,
including musculoskeletal, rheumatology, anesthesia, pain management, surgery,
interventional, and emergency and critical care applications. The company's Vscan is a
handheld, pocket-sized ultrasound technology that provides real-time black and white
anatomic and color-coded blood flow images. The Logiq P5 is a portable ultrasound
system that features enhanced 4D capabilities and a portfolio of transducers.
The Logiq E9 with XDclear makes it possible to visualize blood flow without the
limitations of Doppler; integrate real-time ultrasound with previously acquired CT, MR,
PET, or ultrasound images; and visually track positioning during a scan. The Logiq S8 is
targeted at vascular, breast, abdomen, cardiology, and musculoskeletal imaging.
GEs Logiq E9 has the ability to simultaneously display side-by-side-or even one
laid over the other in a 3D model-gray-scale or color ultrasound data and CT, MR, or
PET data. GE has designed new editions of its Logiq e compact and a new edition of the
Logiq Book XP Enhanced compact. CrossXBeam software enhances image clarity by
7.0 Ultrasound
107
defining continuous boundaries of anatomy and improving overall image resolution. GE
Healthcare also offers the Voluson 730 Expert for womens healthcare. The Expert is the
system of choice for sites with a large percentage of high-risk obstetrics and gynecology,
such as perinatology and maternal fetal medicine labs. With Voluson 730, it is possible to
acquire and construct volumetric images in real timeup to 40 volumes per second. GE
Healthcare also offers ultrasound transducers for a broad variety of applications.

7.0 Ultrasound
108
7.14 HITACHI ALOKA MEDICAL LTD.

Tokyo 181-8622 Japan
www.hitachi-aloka.co.jp
As a full-line supplier of medical imaging equipment in Japan, Hitachi Medical
founded Hitachi Medical Systems America to give itself a direct link to the US medical
market. The companies market diagnostic imaging products. Hitachi Medical's success is
built on the foundation of a $80.9 billion, global electronics company with more than
356,000 employees worldwide. Hitachi Medical Systems America is responsible for the
marketing and support of all Hitachi diagnostic imaging products in the US. For fiscal
year 2013, Hitachi Medical had approximately $160 billion in sales. In November 2013,
the parent Hitachi announced plans to make Hitachi Medical a wholly owned subsidiary,
in an effort to bolster the group's medical equipment business against competitors.
Hitachi currently owns 61.7% of the subsidiary.
In December 2010, Hitachi Medical acquired the majority of the shares of Aloka,
a manufacturer of diagnostic ultrasound and bone densitometry systems. Aloka became a
wholly-owned subsidiary of Hitachi Medical in March 2011, and its name was changed
to Hitachi Aloka Medical Ltd. The company employs more than 1,300. Hitachi Aloka
Medical encompasses the ultrasound division of both Hitachi Medical and Aloka. As a
result of the acquisition of Aloka, Hitachi Medical has taken its position as one of the
world's largest ultrasound companies.
Hitachi Aloka Medical America has responsibility for all sales, service, marketing
and clinical application support of Aloka America ultrasound equipment and Hitachi
ultrasound systems of Hitachi Medical Systems America. On the market are ultrasound
systems for surgery, general imaging, radiology, wound care, cardiology and women's
health applications.
Alokas ultrasound systems have been sold in the US through distributors since
the early 1970s. In January 1991, Aloka America began direct sales of ultrasound units.
Alokas diagnostic ultrasound systems can be used in virtually any clinical environment
in surgery, womens health care, emergency medicine, musculoskeletal, peripheral
vascular, urology, and general imaging applications. Aloka provides customized systems
and transducers.
7.0 Ultrasound
109
The company has manufactured more than 100 different specialty transducers,
including its next-generation Hemispheric Sound Technology (HST) probes.
The HST transducer incorporates an array of transducer elements that create
sound sources close to an ideal hemispherical shape. Transducers are available for
abdominal, breast, endovaginal, endorectal, and pediatric applications, among other uses.
Among its ultrasound products, Hitachi Aloka has small compact, portable
systems as well as powerful consoles designed for the medical center environment,
including the compact ultrasound system, the ProSound a6, and a February 2012 released
digital diagnostic ultrasound system, the F37.

7.0 Ultrasound
110
7.15 SUPERSONIC IMAGINE

Aix-en-Provence, France
http://www.supersonicimagine.com
SuperSonic Imagine specializes in ultrasound medical imaging. The company
designs, develops, and markets an ultrasound system, Aixplorer, with a unique ultrasound
imaging technology, called MultiWave Technology.
This technology enables Aixplorer to image two types of waves to better
characterize tissue: an ultrasound wave to ensure impeccable image quality and a shear
wave, ShearWave Elastography, to compute and display true tissue stiffness in real time
by acquiring images nearly 200 times faster than conventional systems. Aixplorers
UltraFast Doppler combines color and pulsed wave Doppler into one.
In 2009, SuperSonic Imagine was granted 510(k) clearance by the FDA and CE
mark in Europe for the marketing of Aixplorer. Distribution agreements have been signed
with companies, such as Hologic for the breast market in the US and Canon for the
market in Japan. SuperSonic Imagines distribution network has more than 35 partners
worldwide. In October 2013, the FDA cleared SuperSonic Imagine to market its
Aixplorer MultiWave ultrasound device for the ShearWave elastography system's
quantification capabilities.
Aixplorer's UltraFast imaging platform images up to 200 times faster than
conventional ultrasound, simultaneously imaging and computing the velocity of the
generated waves. Its electronic palpation displays real-time quantitative (kPa) tissue
elasticity on a color-coded map.
ShearWave elastography also provides evaluation of multifocal stiff tissue,
dynamic analysis of elasticity changes, and longitudinal follow-up of tissue abnormalities
and treatment.

8.0 Mammography
KEY TREND
X-ray mammography, notably digital mammography, continues to dominate
breast screening for the immediate future. Some have estimated that in the US market,
digital has captured more than three-quarters of the share of the mammography market
away from analog. Worldwide the estimate for digitals share is somewhat less at about
60%. These percentages will grow because of digitals improved diagnostic accuracy. In
2013, approximately 232,340 new cases of invasive breast cancer were diagnosed among
US women, as well as an estimated 64,640 additional cases of in situ breast cancer.
Approximately 39,620 US women were expected to die from breast cancer. Only lung
cancer accounts for more cancer deaths in women.
8.1 PERSPECTIVE
A mammogram, an x-ray-based image of the breast, is used to locate tumors and
cysts. This widely publicized diagnostic tool helps determine the difference between
noncancerous and cancerous disease. The breast is difficult to image, so high resolution
mammography is required to detect potential tumors, but the extent of exposure to x-rays
must be kept as low as possible to prevent possible side effects through regular screening.
Approximately 600,000 cases of breast cancer are diagnosed annually in the developed
world. Most have a mammography that confirms the diagnosis. There are two types of
mammograms that are available. The first is the screen-film (or analog) mammography,
8.0 Mammography
112
and the second is full field digital mammography (FFDM). In screen-film mammography,
x-ray beams are captured on a film cassette. In FFDM, x-ray beams are captured on
digital detectors. The detector converts the x-ray beams into electronic signals, which are
then electronically imaged. A great number of hospitals and imaging centers have made
the transition to digital mammography as part of a transition to PACS or simply to
improve efficiencies.
Digital images are insensitive to exposure variations, so retakes are minimized.
Digital technology reduces exam times. Image processing provides improved visibility
from the chest wall to the skin line. The technique reduces storage space requirements
and transfers information more easily. An important issue and concern, as with any
modality, is compatibility among the systems of different vendors.
8.1.1 Economics of Routine Screening

Mammographies do well to save lives by detecting most breast cancer at an early
stage through screening. There also are economics involved. It is estimated that the cost
of treating early-stage breast cancer is approximately $12,000 per patient, while a latestage treatment costs nearly $150,000. Moreover, digital mammography devices are able
to use much lower doses of x-ray, which gives them an advantage over traditional filmbased modalities. In addition, the use of computer-aided detection (CAD) software aids in
pinpointing tissue densities that might be cancerous. Many digital x-ray product
manufacturers are focusing their efforts on the mammography market.
In 2014, a Norwegian Research Council study found that routine mammography
screening can reduce breast cancer mortality rates by almost 30%. The researchers
estimated that approximately one breast cancer death could be prevented for every 368
women screened with mammography. A British review in 2012 concluded that for every
life mammograms save, about three other women are unnecessarily treated for a cancer
that would never have threatened their lives. But other research has indicated that
mammograms do not lessen the risk of dying from breast cancer.
The US Preventive Services Task Force recommends women begin biannual
mammograms at 50, while the American Cancer Society recommends yearly

8.0 Mammography
113
mammograms from age 40. In many Western European countries, women are offered
mammograms every other year from age 50 to 70.
8.2 TRANSITIONING TO DIGITAL

Digital imaging has led to an improvement and renaissance in the traditional x ray
modality. Digital x ray images are sharper and cleaner than film-based x-rays images are.
Many fluoroscopic x ray procedures have benefited greatly from the use of digital
technology. But start-up costs are expensive. A digital medical x-ray system can cost
from $180,000 to $500,000 while an analog film system can cost from $20,000 to
$80,000. Computed radiography (CR) systems, in which an imaging plate made of
photostimulable phosphor, and not film, is used, can range in price from $130,000 to
$200,000. But digital imaging is more productive and time efficient.
An increasing number of hospitals are networking to share patient data, and are
budgeting increasing amounts of money for IT technology. Digital technology is
contributing to growth in radiology centers by letting radiologists read diagnostic images
from a large network of imaging centers.
Significant advances in mammography have occurred in the past decade. The use
of FFDM has increased for both screening mammography and confirmation of disease.
These high-quality digital images have demonstrated to have the same diagnostic
accuracy of film-screen mammography in a general screening population. Digital
mammography has been shown to be superior over screen-film mammography in
younger women with dense breasts. For women with a genetic predisposition for breast
cancer, such as the BRCA mutations, FFDM has been instrumental for more intensified
early detection programs, especially for younger women, such as from 25 to 30 years of
age.
8.3 COMPUTER-AIDED DETECTION

Commercially available for film-based and digital mammography systems, and to
improve sensitivity and reduce variability among readers of mammography screenings,
computer-aided detection (CAD) systems use algorithms to identify suspicious regions of
interest in the breast. CAD aids the radiologist in detecting potential abnormalities for the

8.0 Mammography
114
radiologist to re-review. The radiologist, not CAD, makes the diagnosis if a clinically
significant abnormality exists and whether further diagnostic evaluation is warranted.
CAD is an adjunct to mammography to decrease errors in perception a failure to
see an abnormality. CAD systems are intended to be used only after the radiologist has
completed an evaluation of the images without CAD, and has made an initial decision
whether any abnormal areas require recall of the patient for further work-up.
8.3.1 A Second Opinion

Currently, CAD provides a second opinion to a radiologist in locating suspicious
regions within mammograms. Next, radiologists will ultimately be able to use computerextracted lesion characteristics when performing a diagnosis to assess whether the tumor
is cancerous. The market for this type of quantitative image analysis is expanding beyond
screening and toward application of risk assessment, diagnosis, prognosis, and response
to therapy, and in using data to identify how tumor characteristics apply to disease states.
This could lead to the comparison of a tumor's characteristics with thousands of
similar cases, enabling the exploration of complex relationships among tumor
characteristics across large populations, which may ultimately contribute to the design of
patient-specific treatments.
It could also be used to study the association between a tumor's observable
characteristics and cell-level data for the emerging field of imaging and genomics, which
aims to identify genes that influence the risk for disease. While results are promising for
digital mammograms, researchers are extending their analysis to breast ultrasounds and
MRIs due to the need for clinical validation within a larger screening population.
8.3.2 Analyzing Tumor Characteristics

Additional market potential for CAD: Through studies between image-based
characteristics and genomics, investigators will potentially be able to determine which
tumor characteristics are related to and which complement genetic findings, with the
ultimate goal of merging them to include both genetic and environmental contributions in

8.0 Mammography
115
clinical decisions. Researchers are now using data-mining methods to identify those
potential relationships.
The FDA approved CAD for breast imaging in 1998. Spurring its use has been
Medicares coverage, which began in 2001. In the US, the technique is used on a large
majority of screening mammograms, with annual direct Medicare costs exceeding $30
million, according to a 2010 study in the Journal of the American College of Radiology.
However, there are some issues that could dampen market growth a little. In an
analysis of mammograms from more than 160,000 elderly women, use of CAD was
associated with a slightly higher rate of breast cancer diagnosis. The increase was mainly
because of more diagnoses of ductal carcinoma in situ (DCIS), Joshua J. Fenton, MD,
from the Center for Healthcare Policy and Research and Comprehensive Cancer Center,
University of California, Davis, and colleagues reported in the April 16, 2013 issue of
the Annals of Internal Medicine. However, in the study the rate of invasive breast cancer
overall was similar with and without CAD.
8.4 MAMMOGRAPHY SYSTEMS MARKET

With an emphasis being placed on breast cancer screening in developed and
underdeveloped countries, the market for traditional mammography systems should grow
annually by about 3%, while the market for digital systems will experience approximately
5% to 6% annual growth during the forecast period. Digital growth will be spurred by the
replacement of older analog equipment.
Digital mammography has surpassed the market for film-based systems in size
both in the US and worldwide. While the US and European markets for traditional
mammography systems are somewhat mature and offering little growth, digital growth in
these geographic areas will be stronger. On the other hand, the BRIC and other
developing countries offer greater traditional film mammography system growth. The
markets for mammography and digital mammography systems, as separate markets, can
be seen in Exhibits 21, 22, 23 and 24.

8.0 Mammography
116
Exhibit 21
World Market for Mammography Equipment,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$180.0
181.1
82.5
30.0
97.5
142.5
713.6
2014
183.6
184.0
85.0
30.9
99.5
149.6
732.6
2015
187.3
189.0
87.6
31.8
101.5
157.1
754.3
2016
191.0
192.0
90.2
32.8
103.5
165.0
774.5

2017
194.8
196.0
92.9
33.8
105.6
173.3
796.4
2018
198.7
200.0
95.7
34.8
107.7
182.0
818.9
8.0 Mammography
117
Exhibit 22
World Market for Mammography Equipment
by Geographic Segment,
2014
4%
25%
20%
14%
US
25%
12%
European Union
China
Japan
ROW
Brazil

8.0 Mammography
118
Exhibit 23
World Market for Digital Mammography Equipment,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$550.0
206.0
19.8
7.6
90.0
18.0
891.4
2014
588.5
217.4
20.8
8.0
94.5
18.9
948.1
2015
629.7
228.3
21.8
8.4
99.2
19.8
1,007.2
2016
673.8
239.7
22.9
8.8
104.2
20.8
1,070.2

2017
721.0
251.7
24.0
9.2
109.4
21.8
1,137.1
2018
771.5
264.3
25.2
9.7
114.9
22.9
1,208.5
8.0 Mammography
119
Exhibit 24
World Market for Digital Mammography Equipment
2014
1%
2%
2%
10%
23%
US
62%
European Union
China
Japan
ROW
Brazil

8.0 Mammography
120
8.5 CAD MARKET

Medicare and most private insurance companies in the US consider CAD
reimbursable. Annual screening mammograms and CAD are a covered benefit.
Mammograms for the routine screening of asymptomatic women, whether or not family
members have had breast cancer, or whether or not physician recommended, are
considered screening. Payment is generally made for one routine screening mammogram
and CAD procedure per calendar year for asymptomatic women 40 years of age or older.
Additionally, physician recommended mammograms are covered for women under age
40, regardless of the reason performed.
CAD has matured quickly since the late 1990s, when R2 Technology, now part of
Hologic, received the first CAD license from the FDA for its ImageChecker system.
Moreover, CAD is being used to detect other types of cancer beyond breast cancer,
including cancers of the lung, pancreas and colon. Growing consumer awareness about
detecting cancer in its early stages is helping to spur the use of CAD in breast
applications.
The world market for CAD should grow annually in the 6% range in the near
term, especially if manufacturers are able to further optimize CAD software. This rate of
growth will occur mostly in developed countries, while growth elsewhere will be in the
3% range. Data are seen in Exhibits 25 and 26. In the US, the majority of mammography
systems, nearly 95%, are bundled with CAD. In Europe, and elsewhere, where CAD is
used less extensively, it is on approximately 25% or less of systems.

8.0 Mammography
121
Exhibit 25
World Market for Computer-Aided Detection Systems,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$220.0
120.0
13.8
5.0
60.0
15.0
433.8
2014
233.2
127.2
14.4
5.2
64.0
15.6
459.6
2015
250.0
134.8
15.0
5.4
67.8
16.2
489.2
2016
265.0
142.9
15.6
5.6
71.9
16.8
517.8

2017
280.9
151.5
16.2
5.8
76.2
17.5
548.1
2018
297.8
160.6
16.8
6.0
80.8
18.2
580.2
8.0 Mammography
122
Exhibit 26
World Market for Computer-Aided Detection Systems
2014
3% 1%
3%
14%
51%
28%
US
European Union
China
Japan
ROW
Brazil

8.0 Mammography
123
8.6 CARESTREAM HEALTH

Rochester, NY
www.carestreamhealth.com
Carestream Health is a leading health imaging and IT solutions company, offering
a suite of traditional and digital solutions to dental, medical, molecular imaging systems
and non-destructive testing customers. The company originated as a business unit within
Eastman Kodak Co. and brings more than 110 years of experience in health imaging, and
more than 1,000 patents in digital and film imaging and IT. The companys 2013 revenue
was approximately $2.4 billion. It employs 7,000 worldwide and is present in 170
countries.
Among its mammography products, Carestream Health markets mammography
PACS, mammography CR systems, mammography printing systems, and mammography
film systems, as well as film products for mammography. Carestream Health and its
subsidiaries continue to use the Kodak brand with its products. The companys
mammography CR Systems include the Kodak DirectView CR 850, CR 950 and CR 975
Systems. These systems deliver CR images with mammography quality when coupled
with Kodak DirectView CR Mammography Cassettes and EHR-M screens. Kodak also
markets a Mammography CAD System that scans, digitizes and analyzes conventional
analog films. The companys DryView 5850 Laser Imager makes it possible to print
high-resolution mammography and general radiography images.
In November 2010, Carestream Health received final approval from the FDA for
its computed radiography system for mammography. The company has begun
commercial distribution of this mammography CR system in the US. The DirectView CR
Mammography Feature captures mammography images digitally and can be used in the
same clinical applications as traditional screen-film mammography systems. The
company has been selling its CR mammography system in Europe, Greater Asia, Japan,
Latin America and Canada for several years, and has installed thousands of systems in
clinics, breast imaging centers and hospitals of all sizes. The CR mammography system
received PreMarket Approval under the FDAs Class III standards. These are the FDA's
most stringent requirements and require extensive scientific and regulatory evidence that
the device is safe and effective before it can be placed on the market.

8.0 Mammography
124
The FDA has reclassified new FFDM systems under Class II controls, which
require only that the product be substantially equivalent to a currently marketed device.
This reclassification will allow Carestream Health to more rapidly bring new
enhancements to the radiology market. Carestream Healths mammography option is
available when purchasing a new Carestream CR system, or as an upgrade to installed
models, and can be used for both general radiography and mammography exams.
The company offers a digital portfolio of womens health care solutions that includes:
digitizing systems for converting film images for softcopy comparison; mammography
modules for its RIS/PACS platform; a multi-modality breast imaging workstation that
allows reading of all breast imaging modalities as well as general radiology exams; CAD
solutions; and high-resolution output to DryView Laser Imaging Systems.

8.0 Mammography
125
8.7 FUJIFILM MEDICAL SYSTEMS USA

Stamford, CT
www.fujifilmusa.com
Fuji has been a provider of medical image and information products and
technologies for acquiring, processing, presenting, managing and storing diagnostic
images. As the diagnostic imaging market continues its transformation from film-based to
digitally-driven products, Fuji's suite of products, including conventional film, imagers,
Fuji Computed Radiography (FCR) and Synapse Picture Archiving and Communication
Systems (PACS), target the needs of radiology departments.
In July 2010, FujiFilm passed a significant milestone, selling more than 1000
Aspire ClearView digital mammography systems. The systems flexibility and
exceptional image quality provided by the CR-based FFDM system have made it a
popular choice among breast imaging facilities of all sizes.
Now in its second generation, the Aspire ClearView was the first FDA approved
CR-based FFDM solution available in the US. The system provides Fujifilms 50 micron
resolution and dual-side reading technology. Its high throughput and small footprint make
it ideal for in-room or centralized placement. It is offered in a single slot and four-slot
design, and can also perform general x-ray imaging.
Aspire Cristalle, Fujifilms newest digital mammography system, combines
Hexagonal Close Pattern image capture technology and intelligent image processing,
optimizing contrast and dose based on breast density. With this technology, hexagonal
pixels distribute the electrical field more efficiently than traditional square pixels,
capturing stronger signals with less noise and interference. The system also has the ability
to do breast tomosynthesis studies.
In June 2013, the FDA approved iCAD's SecondLook mammography CAD on the
next generation PowerLook Advanced Mammography Platform (AMP), for FujiFilms
Aspire HD Full-Field Digital Mammography System. The Aspire HD is a digital
mammography system equipped with Fujifilm's next generation direct to digital detector
technology. The detector has a proprietary panel structure with a double layer of
amorphous selenium that was developed by combining Fujifilm's Device Development
Technology and Vacuum Deposition Technology. The first layer efficiently converts xCopyright 2014 Kalorama Information, LLC.
8.0 Mammography
126
rays into electrical signals, while the second layer employs Direct Optical Switching
Technology that captures high resolution and low noise image electrical signals rather
than using electrical switches, such as conventional TFTs. The system delivers 50m fine
pixel size (higher resolution) and low noise.
In November 2006, FujiFilm signed a US distribution agreement with Siemens for
Fuji's Computed Radiography for Mammography (FCRm). In addition to FCRm being
sold by Fuji's direct sales force, Siemens added Fuji's FCRm Full Field Digital
Mammography system to its product portfolio for both new and existing Siemens'
customers, complementing Siemens own Mammomat NovationDR FFDM system. And
the Fujis FCRm can be used in mobile mammography environments. In April 2008, the
FDA gave its nod to sales of FCRm combined with CAD technology, iCADs
SecondLook. SecondLook identifies potential cancers with patented artificial
intelligence, image processing, and pattern recognition technology. Also, the companys
DryPix 7000 printer has clearance from the FDA for use with FFDM devices.

8.0 Mammography
127
8.8 GE HEALTHCARE
Waukesha, WI
www.gehealthcare.com
GE Healthcare is an $18 billion unit of General Electric. Worldwide, the health
care unit employs about 46,000 people in more than 100 countries.
The Healthcare unit manufacturers, sells and services a wide range of medical
equipment including equipment for magnetic resonance (MR), computed tomography
(CT), positron emission tomography (PET) imaging, x-ray, patient monitoring, diagnostic
cardiology, nuclear imaging, ultrasound, bone densitometry, anesthesiology and oxygen
therapy, neonatal and critical care, and therapy.
For mammography, GE Healthcare sells both analog (the Performa) and digital
products (the Senographe). At the heart of GE Healthcares digital x-ray products is the
Revolution ASi detector a single-piece ASi flat panel with a cesium iodide scintillator.
It is used in the Revolution XQ/i digital chest X-ray system, the Revolution XR/d general
purpose digital x-ray system and the Senographe 2000D FFDM system. In August 2007,
GE Healthcare received FDA approval for its mobile Senographe Essential full-field
digital mammography system, one of its Senographe family of FFDM products. The
Senographe Essential features a large digital detector, advanced ergonomic design,
optimized patient comfort, and enhanced workflow. Essential is a leading mobile
mammography product on the market, featuring all the advantages of the company's
Senographe platform.
Also on the market is GE Healthcares SenoBright contrast-enhanced spectral
mammography (CESM), which is designed to provide doctors with the information
needed to give a diagnosis within a day, immediately or soon after an initial screening. It
is intended as an adjunct to mammography or ultrasound. CESM generates images of the
breast using two different x-ray energy levels, and digitally combines the images. The
resulting image hides dense breast tissue from view, and highlights any areas with
increased blood supply.
In September 2013, the FDA granted premarket approval for Parascripts
AccuDetect, a computer-aided detection (CAD) system for digital mammography. The

8.0 Mammography
128
software is approved for digital mammography systems manufactured by GE Healthcare
and Philips Healthcare.
In September 2014, the FDA announced approval of GE Healthcares SenoClaire,
GEs new breast tomosynthesis solution designed with a 3D imaging technology.
Tomosynthesis allows a radiologist to take multiple pictures of each breast from various
angles, which differentiates it from a traditional mammogram, which takes a single image
in two directions. In collaboration with Massachusetts General Hospital, GE developed
SenoClaire technology that uses a low-dose short x-ray sweep around the positioned
breast with nine exposures acquired with a step-and-shoot method, removing the potential
motion from the tube helping to reduce blur and increase image sharpness.

8.0 Mammography
129
8.9 HOLOGIC
Bedford, MA
www.hologic.com
applications and mini C-arm imaging for orthopedic applications.
One area that received a great deal of attention is the companys work on breast
tomosynthesis, which makes it possible to obtain 3D images of the breast and to view one
slice at a time by removing the images of the overlying and underlying tissue that
complicate an ordinary breast x-ray. The greater clarity of the resulting image leads to
important clinical benefits, such as increasing the breast cancer detection rate and
decreasing the number of false readings. The FDA has approved a device for 3D
mammography breast tomosynthesis. Hologics Selenia Dimensions 3D system was
approved in February 2011. In May 2013, the FDA approved the Selenia Dimensions
System with C-View Software that provides digital 2D and 3D images for the screening
and diagnosis of breast cancer.
Hologic had received a CE mark for the Selenia Dimensions 2D/3D system in
September 2008. Hologic 2D/3D Selenia Dimensions systems are already in operation
throughout Europe, the Middle East, South Africa, Brazil, Thailand, Canada, and Mexico.
The companys Selenia full field digital mammography system is based on the
proprietary, amorphous selenium DirectRay digital detector, which directly converts xrays to electronic signals.
Hologic also markets screen-film mammography systems, the M-IV Series.
In terms of marketing and sales, in the US, Hologic sells and services its products
through a direct sales and service force and a network of independent distributors.
Hologic sells its systems in international markets through a network of independent
distributors, as well as a direct sales and service force in Belgium. The company offers its
products in Latin America, including Argentina, Brazil and Chile, and in Pacific Rim
countries, including Japan, Australia, The Peoples Republic of China, South Korea,

8.0 Mammography
130
Thailand and Taiwan, by working with local sales representatives and distributors or by
entering into strategic marketing alliances in those countries.
For Hologics fiscal year ended Sept. 28, 2013, the company had revenues of
about $2.5 billion. The company developed CAD software tools for its mammography
products and visualization tools for MRI. Mammography CAD is used by radiologists as
a second pair of eyes when reading a womans mammogram. Use of this technology
provides reviewers with the potential to detect findings that might otherwise be
overlooked during the review process, thus potentially increasing cancer detection.

8.0 Mammography
131
8.10 ICAD INC.

Nashua, NH
www.icadmed.com
iCAD develops, engineers, manufactures and markets computer aided detection
(CAD) products for the early detection of breast cancer and other health related
conditions. The companys PowerLook Advanced Mammography Platform (AMP) is the
next generation digital mammography CAD platform that provides radiologists with the
ability to customize their CAD solution to meet the needs of their individual work
environment. PowerLook AMP is an extendable platform upon which all future
mammography CAD offerings from iCAD will be built. The platform's modular design
provides the option to choose the products and functionality needed, such as the
company's SecondLook Digital v7.2 CAD, SecondLook Premier CAD and the Volpara
Automated BreastDensity Assessment software.
SecondLook CAD systems, which feature algorithms that incorporate information
from thousands of mammography images, can detect up to 72% of actionable missed
breast cancers an average of 15 months earlier than screening mammography alone.
Second Look Digital CAD system has been available with digital mammography systems
from GE, Hologic and Siemens. iCAD believes that it has gained share in the digital
mammography segment of the CAD market through OEM sales relationships with
General Electric, Hologic and Siemens. Siemens is offering iCADs TotalLook system as
an option for use with its Mammomat Novation full-field digital mammography system,
through Siemens global sales and distribution channels. TotalLook, introduced by iCAD
at the end of 2005, provides customers with a comprehensive film-to-digital product,
making it easier for womens health centers to transition from film to digital
mammography. This technology assists radiologists in comparing breast images year-toyear to detect subtle changes that may be indicative of breast cancer.
And in April 2008, the FDA approved sales of Fujifilms CR mammography
product, FCRm, combined with Second Look. Meanwhile, iCADs Howtek Fulcrum
digitizer converts x-ray film and radiographs into digital images. The images can be used
for fast clinical determinations and precise diagnostic evaluations in PACS, teleradiology,
centralized reading and other applications.

8.0 Mammography
132
In June 2013, the FDA approved iCAD's use of its SecondLook mammography
CAD on the next generation PowerLook Advanced Mammography Platform (AMP), for
FujiFilms Aspire HD Full-Field Digital Mammography System. In January 2013, iCAD
received FDA approval for use of the companys next generation mammography CAD
platform, PowerLook Advanced Mammography Platform with Digital CAD for Philips
MicroDose Full-Field Digital Mammography System.
In September 2014, iCAD announced that, in addition to Volpara Density
volumetric breast density assessment software, Volpara Analytics and Volpara Dose
solutions are available as part of iCADs PowerLook Advanced Mammography Platform.
With the addition of these quantitative breast imaging tools, radiologists will be able to
evaluate the performance of all major digital mammography and tomosynthesis units and
obtain patient-specific dose information to make treatment decisions in real time.

8.0 Mammography
133
8.11 PARASCRIPT LLC

Longmont, CO
www.parascript.com
Parascript is a developer of intelligent document recognition (IDR) solutions.
Drawing from a long history of cursive and handprint recognition, Parascripts solutions
are powered by software that is always learning. Parascript products have applications in
forms processing, postal and financial automation, fraud prevention, and cancer
screening.
In September 2013, Parascript announced FDA premarket approval of its
AccuDetect 6.1 Computer-Aided Detection (CAD) system for digital mammography.
AccuDetect is indicated for use in screening mammography to identify areas suspicious
for breast cancer, for radiologist review, after completing an initial read.
AccuDetect is approved for digital mammography systems manufactured by GE
Healthcare and Philips Healthcare. The software works by using complimentary
algorithms and patented voting methods to help radiologists more accurately detect
cancers while lowering the incidence of patients sent for unnecessary diagnostic workups.
AccuDetect focuses on dense and extremely dense breasts, in which cancer can be
more difficult to detect. In one study, the system provided: 85% sensitivity, 43%
specificity and 1.5 false positives per four-view study on dense breasts.

8.0 Mammography
134
8.12 R2 TECHNOLOGY
Santa Clara, CA
http://www.hologic.com/en/breast-screening/imagechecker/digital-cad-systems
R2 Technology has long been involved in the development and commercialization
of computer aided detection (CAD). The R2 ImageChecker system was the first CAD
system approved by the FDA for use with film-based mammography in 1998 and for
digital mammography in 2001. ImageChecker CT can be used to improve the detection of
actionable lung nodules during review of multi-slice CT chest exams.
In July 2006 Hologic purchased R2 Technology, adding it to its portfolio of
womens health products. Hologic now offers a broad range of options for digital
mammography CAD. The company's Cenova system is designed to provide quality
detection algorithms on flexible server technologies. The Cenova server accommodates
popular direct capture full-field digital mammography (FFDM) detectors and a broad
range of display environments.
The clinical value of R2 ImageChecker CAD is realized when CAD marks are
displayed to the radiologist. The display of digital CAD marks depends on the viewing
solution chosen. Whatever display is selected, basic RightOn CAD marks appear the
same on all displays. To get the most from the company's ImageChecker CAD system,
the company suggests selecting the display with the most advanced CAD capabilities.
The company's SecurView DX is a fully-featured diagnostic mammography
workstation with optional multimodality capabilities for breast MRI and breast
ultrasound.
Meanwhile, MeVis Medical Solutions AG, Bremen, Germany, has acquired the
CT business of R2 Technology. The acquisition includes R2 products, technology and
intellectual property for CAD, advanced visualization and analysis of multi-slice CT
exams. MeVis provides a wide variety of disease-oriented software solutions for imagebased medicine and the addition of the R2 CT CAD provides the foundation for
expanding the company's portfolio of workflow-optimized solutions for pulmonary
imaging and oncology.

9.0 Pap Smears

KEY TREND
cervical cancer have dropped by 75%. In low income countries, many women do not
have access to routine screening. It is estimated that in these countries only 5% of women
have undergone a Pap smear in the past five years. New HPV testing has the potential to
replace some Pap testing.
Approximately 130 million pap smears are performed every year worldwide.
Cervical cancer has become the easiest gynecological cancer to prevent. Still, the
American Cancer Society estimates that in the US in 2014, about 12,360 new cases of
invasive cervical cancer will be diagnosed, and approximately 4,020 women will die
from cervical cancer. It was surprising to some that new guidelines issued in 2012 eased
pap smear testing recommendations from each year to every three years. In 2010,
according to the CDC, 73.7% of women had a Pap smear within the previous three years.
9.1 TESTING FOR CERVICAL CANCER

The Papanicolaou test, also termed the Pap smear, Pap test, cervical smear, or
smear test, is a screening test used in gynecology to detect premalignant and malignant
processes in the ectocervix, the portion of the cervix projecting into the vagina, detecting
potentially pre-cancerous changes, called cervical intraepithelial neoplasia (CIN) or
cervical dysplasia, which are usually caused by sexually transmitted HPV.
9.0 Pap Smears

136
Prior to the introduction of the Pap test, carcinoma of the cervix was a leading
cause of cancer death in women. Since the introduction of the Pap test, a regular program
of pap smear screening, with appropriate follow-up, can reduce cervical cancer incidence
by up to 80%. Failure to prevent cancer by the Pap test can occur for many reasons,
including not having regular screening, lack of appropriate follow up of abnormal results,
and sampling and interpretation errors.
In the US, more than half of all invasive cancers occur in women that have never
had a Pap smear; an additional 10% to 20% of cancers occur in women that have not had
a Pap smear in the preceding five years. About 25% of US cervical cancers were in
women that had an abnormal Pap smear, but who did not have appropriate follow-up. The
woman did not return for care, or the clinician did not perform recommended tests or
treatment. Adenocarcinoma of the cervix has not been shown to be prevented by Pap
tests. In the UK, which has a Pap smear screening program, adenocarcinoma account for
about 15% of all cervical cancers.
9.1.1 Types of Screening

In the conventional Pap smear, the physician collecting the cells smears them on a
microscope slide and applies a fixative. In general, the slide is sent to a laboratory for
evaluation. Studies of the accuracy of conventional cytology generally indicate a
sensitivity of 72% and specificity of 94%. Since the mid-1990s, techniques based on
placing the sample into a vial containing a liquid medium that preserves the cells have
been increasingly used. The media are primarily ethanol-based for Sure-Path (TriPath
Imaging) and methanol for ThinPrep (Cytyc Corp.)
In areas where Pap smear screening is not available or affordable, other methods
of testing have been evaluated. Visually inspecting the cervix, using acetic acid (VIA) or
Lugols iodine (VILI) to highlight precancerous lesions so they can be viewed with the
naked eye, shifts the identification of precancers from the laboratory to the clinic. Such
procedures eliminate the need for laboratories and the transport of specimens, require
very little equipment and provide women with immediate test results. Medical
professionals can perform the procedure, provided they receive adequate training and
supervision. As a screening test, VIA may perform as well as or better than cervical
cytology in accurately identifying pre-cancerous lesions.
9.0 Pap Smears

137
But cytology provides higher specificity (fewer false positives) than VIA. Like
cytology, one of the limitations of VIA is that results are highly dependent on the
accuracy of an individual's interpretation. Increased false positives are particularly
important in a screen-and-treat setting, since over-treatment and resulting impairment of
fertility is more likely.
Still, VIA can offer significant advantages over Pap in low-resource settings,
particularly in terms of increased screening coverage, improved follow-up care and
overall program quality. Due to the need for fewer specialized personnel and less
infrastructure, training, and equipment with VIA, public health systems can offer cervical
cancer screening in more remote, and less equipped, health care settings and can achieve
higher coverage.
9.2 CERVICAL CANCER VACCINES

Worldwide, there are two HPV vaccines on the market Gardasil from Merck
and Cervarix from GlaxoSmithKline. Both are highly effective in preventing infection
with virus types 16 and 18, which are together responsible for approximately 70% of
cervical cancer cases globally. They are also highly efficacious in preventing
precancerous cervical lesions caused by these types. One vaccine is also highly
efficacious in preventing anogenital warts, a common genital disease which is virtually
always caused by infection with HPV types 6 and 11.
The primary target group in most of the countries recommending HPV
vaccination is young adolescent girls. Data from clinical trials and initial post-marketing
surveillance conducted in several continents show both vaccines to be safe.
9.3 A MARKET NEED

The mainstay of the histology lab is the Pap smear to screen for cervical cancer
along with traditional stains used for all types of biopsied tissue. Approximately 130
million Pap tests are performed annually worldwide, approximately 55 million to 60
million of which are in performed in the U.S., 45 million in the EU, 10 million in Japan
and 20 million in the rest of the world.

9.0 Pap Smears

138
There has been a recent decrease in the number of Pap tests performed in the US,
partially due to a decline in doctor visits, which can be attributed to the continued
economic downturn and also to recent changes in cervical cancer screening guidelines.
Further, laboratory consolidation leads to price erosion due to volume purchase discounts.
In the US, cervical cancer screening guidelines were changed in November 2009.
Women now are being told that they should get their first screening for cervical cancer
including a Pap test at age 21. The previous recommendation was to start Pap tests three
years after becoming sexually active or at age 21, whichever came first. And, rather than
have an annual Pap test, most women need to be screened every other year or less,
depending on their age, according to the new guidelines. Similar guidelines have been
initiated in Canada and Europe. Nevertheless, Pap testing is a large market that
contributes at least $2 billion to lab revenues. Pap tests cost about $5 to perform and the
average price charged by laboratories is $15 to $20.
There are also a number of cervical cancer screening programs in operation,
worldwide. In 2008, European Union guidelines for cervical screening introduced the
alternative to use HPV testing as the primary diagnostic test, provided that
implementation was piloted in an organized fashion with stringent evaluation. The
Swedish and UK programs are among the first to follow these guidelines. Japan,
Australia, Singapore, Hong Kong, Taiwan and Korea have national screening programs.
In Korea, the national screening program has coverage of about 55%, and so the country
still has a high cervical cancer rate.
There are two markets to consider regarding Pap testing. The US market is mature
and is well known. Approximately 100 million American women are at risk.
Approximately 55 million to 60 million Pap tests are administered annually in the US.
About 20 million American women do not undergo testing. But 3.5 million women test
positive and are subject to further diagnostic procedures. Approximately 2.5 million are
found to have benign conditions. About 600,000 are found with severe dysplasia and are
subject to diagnostic therapy procedures that remove the lesions. About 40,000
intraepithelial cancers are removed. In the US in 2014, about 12,360 new cases of
invasive cervical cancer will be diagnosed, and approximately 4,020 women will die
from cervical cancer.

9.0 Pap Smears

139
The Pap test reduced the mortality of cervical cancer for 85% of women between
1955 and 2005. Recently, this test has been combined with HPV testing. New guidelines
have included HPV infection in categorization of the degree of the disease. Additional
technologies have been added in order to improve the original Pap test.
But with all these improvements, the Pap test has become expensive and not
affordable in lesser developed areas of the worldthe second market. At of the end of
2013, there were 7.125 billion people worldwide, and about half of them were women.
Worldwide, at least 1.7 billion women are at risk for cervical cancer.
Approximately 2,800 women in the UK are diagnosed with cervical cancer each
year. As many as 1,100 UK women die from the disease, which is the twelfth most
common cancer for UK women.
WHO reports that about 500,000 women worldwide develop cervical cancer
annually, and half of them die. Three out of four come from the developing countries.
Developed countries protect their women with the Pap test. Developing countries cannot
afford the cost of Pap test that could cost up to $100. By some estimates, developing
countries cannot afford more than a $5 test, which is a low price that cannot be offered by
the current technologies on this market.
9.4 IVD MARKET

Continuous improvements have perfected the Pap test in the last decade.
Monolayer preparation has become an important development in cytology sample
preparation. It is a key element in the automated reading of cytological samples, such as
the Pap smear, urine cytology, bone marrow, cerebral, and spinal fluid. Hologics
ThinPrep is the major product in this area. Automated pap smear systems are available
from Hologic/Cytyc, BD/Tripath, Roche/Ventana, Molecular Diagnostics, AccuMed
International and Neuromedical Systems.
Liquid-based Pap tests using liquid transport media, such as ThinPrep, currently
account for approximately 75% of the Pap tests performed in the US, Europe and Japan.
The most successful liquid and automated Pap smear analysis systems are
available from Hologic/Cytyc, Roche/Ventana Medical and BD/Tripath. These
companies claim that their products are used in approximately 90% of the Pap tests

9.0 Pap Smears

140
performed in the US. After almost 20 years on the market, Hologics ThinPrep system
has become the state-of-the-art in cervical cell preparation for Pap and other cytology
tests.
In traditional Pap testing, cervical scrapings are placed on a slide by the physician
and sent to a laboratory for Pap smear analysis. Then in the 1990s, a new trend
developed. Pap smear cervical scrapings were transported in liquid media instead of
being deposited on a microscope slide. This approach has been commercialized by
Hologic (ThinPrep) and Becton Dickinson. This technique facilitated automation of the
Pap smear procedure.
cervical cancer have dropped by 75%. Pre-cancerous cells can take 10 to 15 years to
develop into cancer so early detection is very important in treating cervical cancer.
Fortunately, more than 90% of this type of cancer is curable if the disease is detected and
treated early enough. Routine exams such as Pap smears can greatly reduce ones risks of
contracting and dying from cervical cancer. Although the Pap smear test has greatly
reduced the number of cervical cancer-related deaths, its market will see some
competition from new HPV tests. As the role of HPV in contributing to cancer has
emerged in recent years, screening for HPV has started to rival the Pap. Still, for women
aged 30 and older, Pap and HPV co-testing is suggested and is less likely to miss an
abnormality, such as a lower false-negative rate, than Pap testing alone.
For these reasons, the IVD market for the Pap test is expected to remain constant
and see growth at approximately 3% to 4% annually, as indicated in Exhibits 27 and 28.

9.0 Pap Smears

141
Exhibit 27
World IVD Traditional Pap Test Market,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$316
197.5
52.3
19.0
118.5
63.0
766.3
2014
325.5
205.4
54.4
19.8
123.2
65.1
793.4
2015
335.3
213.6
56.6
20.6
128.1
67.1
821.3
2016
345.4
230.7
58.9
21.4
133.2
69.1
858.7

2017
355.8
240.0
61.3
22.3
138.5
71.2
889.1
2018
366.5
249.6
63.8
23.2
144.0
73.5
920.6
9.0 Pap Smears

142
Exhibit 28
World IVD Traditional Pap Test Market
2014
2%
15%
8%
41%
26%
8%
US
European Union
China
Japan
ROW
Brazil

9.0 Pap Smears

143
9.5 BD
Franklin Lakes, NJ
www.bd.com
BD (Becton Dickinson, and company) is a leading medical technology company
that partners with customers and stakeholders to address many of the worlds most
pressing and evolving health needs. Its innovative solutions are focused on improving
drug delivery, enhancing the diagnosis of infectious diseases and cancers, supporting the
management of diabetes and advancing cellular research. BD has nearly 30,000
associates in 50 countries. The companys 2013 fiscal year revenues totaled about $8
billion, compared to $7.7 billion in 2012.
BD Diagnostics is a leading provider of products for the safe collection and
transport of diagnostics specimens, as well as instruments and reagent systems to
accurately detect a broad range of infectious diseases, healthcare-associated infections
(HAIs) and cancers. The BD Diagnostics segment focuses on improving health
outcomes for patients by providing laboratories with solutions that improve quality,
enhance laboratory system productivity and inform medical decisions. BD Diagnostics
offers integrated systems for specimen collection, automated blood culturing systems,
molecular testing systems for infectious diseases and womens health, microorganism
identification and drug susceptibility systems, liquid-based cytology systems for cervical
cancer screening (BD SurePath Pap Test), rapid diagnostic assays, plated media, and
microbiology laboratory automation.
On the instrument side, it manufactures the BD Phoenix Automated Microbiology
System for identification and susceptibility testing, the BD Viper XTR and ProbeTec ET
Systems for chlamydia and gonorrhea testing, and the Viper LT real-time PCR platform
used for chlamydia, gonorrhea and high-risk HPV testing. BD Biosciences focuses on
continually advancing the science and applications associated with cellular analysis. BD
Biosciences offers innovative cell sorters and analyzers that support all aspects of
research and clinical flow cytometry.
In 2006, BD acquired TriPath Imaging Inc. for approximately $350 million.
TriPath Imaging developed a complete line of cytology preparation and analysis products
including the SurePath Liquid Based Pap Test and the FocalPoint GS Imaging System.
9.0 Pap Smears

144
The BD SurePath liquid-based Pap test is a cell preparation process intended for use in
the screening and detection of cervical cancer and its precursor conditions. The BD
FocalPoint GS Imaging System uses advanced software algorithms to analyze cell based
slides and assist in the diagnosis of cervical disease.
BD has enhanced the SurePath and FocalPoint products through further
development of the BD Totalys MultiProcessor and SlidePrep instruments. The BD
Totalys MultiProcessor automates the BD SurePath cell enrichment process which helps
to visualize the diagnostically relevant cells from a cell based sample and integrates a
sample aliquot option for downstream molecular testing. The BD Totalys SlidePrep
creates individual cell based slides including discrete slide staining.
In February 2014, BD achieved the CE/IVD marking for the BD Onclarity HPV
Assay on the new BD Viper LT System. The BD Onclarity HPV Assay targets E6/E7
DNA oncogenes and is designed to provide physicians access to broader High Risk
HPV genotype information beyond types 16 and 18 to guide informed treatment
decisions for their patients. The BD Onclarity HPV Assay reports results on six discrete
HR HPV genotypes (16, 18, 31, 45, 51 and 52) with the remaining eight high-risk
genotypes reported in three small groups: (33, 58), (35, 39, 68) and (56, 59, 66).
Individual and grouped HR HPV genotype results are obtained from the same sample
with no additional processing steps required.
The BD Viper LT System is a bench-top molecular platform that automates
sample processing, nucleic acid extraction, Real-Time Polymerase Chain Reaction (RTPCR) amplification and detection and result reporting with minimal user intervention.
BD is developing a highly competitive Women's Health portfolio, and these new
devices used to enhance cancer screening are all linked though a DataLink interface that
provides full chain of custody from sample collection to diagnostic reporting while
improving efficiency in the lab.

9.0 Pap Smears

145
9.6 BIOREFERENCE LABORATORIES

Elmwood Park, NJ
www.bioreference.com
BioReference Laboratories is a national clinical diagnostic laboratory that
provides testing, information and related services to physician offices, clinics, hospitals,
employers and governmental units. The companys menu is routine, gene-based and
esoteric laboratory testing services with a focus on esoteric testing, molecular diagnostics,
anatomical pathology, genetics, women's health (Pap and cervical cancer), which
includes blood-based cancer pathology and associated diagnostics, women's health and
genetic sequencing.
Bioreference Laboratories is one of the top full service laboratories in the US. It
is a clinical testing lab servicing physician offices with a focus on esoteric testing,
molecular diagnostic, anatomical pathology and correctional health care. GenPath is its
national oncology laboratory and GeneDx, which specializes in rare genetic diseases and
is BioReference Labs' genetics lab.

9.0 Pap Smears

146
9.7 BIOSCICON
Rockville, MD
www.bioscicon.com
Biomedical Science Consulting Company is a woman-owned, small business
start-up biotechnology company focused on development of its proprietary MarkPap
technology.
The MarkPap System is an assembly of in vitro diagnostic devices and procedures
that may have practical application in cervical cancer screening for the improvement of
Pap test. It is also a research tool used to study cervical acid phosphatase in relation to the
development of cervical pre-cancerous lesions and their transformation into cancer.
In addition, the MarkPap test could be used for determination of acid phosphatase
in other epithelial tumors (oral, breast, lung, laryngeal, thyroid, colon, prostate) where
this enzyme has been related to the tumor biology and has been considered as a target for
new chemotherapies.
The proprietary MarkPap products and laboratory services available for
commercialization include: the MarkPap Test (method, assay, procedure); the MarkPap
Research Kit; and MarkPap Accessories. In the US, all MarkPap products are for research
only, not for diagnostic use. In other countries, selected products will be available
according to the local governmental regulations. Selected products from the MarkPap
pipeline are available for licensing in the US and abroad.

9.0 Pap Smears

147
9.8 HOLOGIC
Bedford, MA
www.hologic.com
applications and mini C-arm imaging for orthopedic applications. For the 12 months
ended Sept. 28, 2013, revenues totaled about $2.5 billion, compared to revenues of about
$2 billion in the previous fiscal year.
Among its various products, the company markets its ThinPrep Pap test, with
annual sales of more than $500 million, which is a modified Pap test technique designed
to reduce some of the technical problems inherent in the traditional type of Pap smear. In
the traditional Pap test, cell samples are obtained from the vagina, cervix, and cervical
canal and spread on a glass slide. In the ThinPrep Pap test, cell samples are collected
using a special brush that is immediately washed in a special fluid. The ThinPrep system
filters out the cells from the solution and deposits them in a thin uniform monolayer on a
glass slide. The ThinPrep Pap method has some significant advantages. It removes
contaminants, such as blood and mucus, which frequently obscure cells in the traditional
Pap smear. The monolayer of cells is easier to examine under the microscope. This
results in an increased rate of detection of abnormal cells.

9.0 Pap Smears

148
9.9 INNOGENETICS NV
Gent, Belgium
www.innogenetics.com
Innogenetics develops and markets a wide range of diagnostic assays with a focus
on molecular diagnostics and multiparameter testing. The companys products are sold in
more than 90 countries through its six subsidiaries and a large number of distributors. In
December 2008, Solvay Pharmaceuticals acquired Innogenetics. In February 2010,
Abbott Laboratories completed the acquisition of Solvay Pharmaceuticals. To alleviate
competition concerns raised by the European Commission, Abbott sold Innogenetics to
Fujirebio in September 2010. The company changed its name to Fujirebio Europe In
October 2013.
In June 2008, Innogenetics received the CE Mark for its new and expanded HPV
genotyping test, the INNO-LiPA HPV Genotyping Extra. The kit makes possible the
genotyping of 28 different HPV genotypes, of which 18 are high-risk types for the
possible development of cervical cancer. The test is based on Innogenetics patented
SPF10 primers. The information provided by the INNO-LiPA HPV Genotyping Extra
can serve as an important complement to Pap smear testing, and current DNA-based HPV
screening tests.

10.0 Colposcopy
KEY TREND
In the US alone, more than $6 billion is spent annually on the screening, diagnosis
and treatment of women with cervical cancer. Diagnosing cervical cancer is a long and
uncertain process, requiring repeat visits by anxious patients. There are considerable
barriers to setting up cytology-based screening programs, particularly in developing
countries. The trend is for alternative approaches to cytology for cervical cancer
prevention.
10.1 COLPOSCOPY BIOPSY

A colposcopy is a diagnostic procedure in which a doctor removes tissue samples
from the cervix in order to examine them. During this process, the doctor uses a
colposcope, a magnifying tool. Colposcopes are large electric gynecological microscopes
with a light source that can yield levels of detail about a womans cervix, vagina and
vulva, looking for signs of disease.
When abnormalities are found with a Pap smear, colposcopy is performed to more
accurately detect premalignant and malignant lesions. The results of this procedure may
show evidence of dysplasia, cancer, HPV or atypical squamous cells of undetermined
significance (ASCUS).
A colposcopy biopsy is an important tool in the detection and prevention of
cervical cancer. With the colposcope, gynecologists and other physicians are able to
10.0 Colposcopy
150
carefully inspect cervical and vaginal tissue. The colposcope itself is comprised of a
single or double eyepiece through which a physician can look to view the cervix. A light
dial and a magnifying dial make it possible to adjust the intensity of illumination,
magnification and focus. The lens that is placed in front of the vagina emits a beam of
light that can be aimed at different areas along the cervical wall.
A woman may need to undergo a colposcopy if her doctor believes that she may
have cervical or vaginal cancer, dysplasia, severe inflammation, or another medical
condition that cannot be diagnosed with other medical tests. A colposcopy is performed
when a woman reports pain or discomfort in her cervix, or when her Pap smear results
reveal abnormalities. A gynecologist can carefully inspect cervical surface tissue with a
colposcope in order to make a proper diagnosis of HPV, dysplasia, cancer, or another
condition. The procedure is usually painless and is performed on an outpatient basis.
Skilled doctors typically perform colposcopies in less than 20 minutes. When an
abnormality is discovered with a colposcope, the doctor will carefully scrape a sample of
tissue from the surface of the cervix for further analysis. A biopsy can confirm a
diagnosis.
10.2 ABNORMAL PAP SMEAR RESULTS

A gynecologist might suggest a colposcopy biopsy if a woman has abnormal Pap
test results. An abnormal Pap test might be the result of an infection, which can lead to
cervical cancer, or it might be caused by natural changes in the cervical cells. During
a colposcopy, the doctor can determine if the cell changes are minor or if the tissues are
abnormal enough to require a biopsy. A colposcopy might also be used to examine sores
or warts on the vagina or cervix.
Colposcopies can also be used to identify infections, physical abnormalities, and
some other conditions. Sometimes, a doctor will recommend a colposcopy just to be sure
that there are no emergent conditions of concern in women who are at risk, like women
with repeat abnormal pap smears or HPV.

10.0 Colposcopy
151
10.3 ROUTINE USE BUT MATURE MARKET

Colposcopy is now routinely used for diagnosing cervical cancer and other tissue
abnormalities in female organs, after an abnormal Pap smear. In most countries,
colposcopy is used to evaluate women who have abnormal cytology. In some countries,
namely countries in Central and Eastern Europe and parts of Latin America, colposcopy
is incorporated into the routine gynecological examination of women. There are no data
to support the use of colposcopy as a primary screening test, and this is not generally
recommended. Colposcopy should be used to triage abnormal smears and not used as a
diagnostic tool on its own.
The market is quite mature and its growth, for the most part, is fueled by
replacement sales. Still, some growth can be attributed to the expansion or creation of
new health care facilities.
10.3.1 Primary and Secondary Screening

The markets for colposcopy systems include primary cervical cancer screening.
Despite its success as a public health measure, many consider a Pap test as relatively
insensitive and poorly reproducible. Inadequate sampling, the scarcity of aberrant cells in
some samples and the subjectivity of morphologic interpretation are recognized
limitations of cytology. In addition, equivocal and mild cytological abnormalities are
extremely common in young women, but most of these lesions regress spontaneously.
These difficulties cause physicians to struggle with a range of patient management and
care decisions. Pap tests are repeated frequently in order to overcome the test's high rate
of false negative results, caused by low sensitivity. A colposcopy may be required to
determine if cancer exists.
Another market for colposcopy systems is secondary cervical cancer testing:
When abnormal or aberrant results are returned from diagnostic tests, the patients'
samples are reflexively tested by other methods to confirm the results and provide more
detailed medical information. Approximately 7% of Pap tests are diagnosed with
abnormal cells atypical squamous cells of undetermined significance (ASCUS) and
require secondary, or reflex, testing. The diagnosis of ASCUS is poorly reproducible. In
addition, about 10% of patients diagnosed with ASCUS have undetected cancer.
10.0 Colposcopy
152
The reflex test determines whether the sample has been infected with specific
strains of HPV that have been linked to the development of cancer. Epidemiological
studies have implicated the infection of cervical cells by specific strains of HPV to be
necessary for the development of cervical cancer. However, research has also
demonstrated that an HPV infection is not sufficient to develop cancer. This lack of
sufficiency means that other factors or changes in cervical cells must occur for cancer to
develop.
This provides physicians with a difficult scenario. Patients who have abnormal
Pap tests and are negative by HPV testing will likely not develop cervical cancer, but are
still monitored more closely. Patients who have abnormal Pap tests and are positive by
HPV testing could develop cervical cancer, but many do not. These patients are referred
for colposcopy.
10.4 COLPOSCOPY SYSTEMS MARKET

About 3.5 million women have abnormal or aberrant Pap test results each year. Of
these 3.5 million women, 60% are tested for HPV infection. Because HPV infects about
90% of the population, the vast majority of these tests return positive results. This leads
to very high, greater then 55%, referral rates to colposcopy. However, only about 20% of
referred patients have cervical lesions identified by colposcopy. Of the approximately 1.5
million women referred for colposcopy, about 300,000 of them have identifiable cervical
lesions and require further treatment.
The market for colposcopy systems will continue to grow modestly in about a
range of 4% annually as long as cervical cancer and the traditional Pap test remain
areas of concern. Replacement sales will help with the growth, as will new health care
facilities. The market can be seen in Exhibits 29 and 30.
Advances in technology will help drive future market growth, such as the
development of a mobile colposcope. At its heart it is a simple mobile phone that is
enhanced by a mobile phone camera and a set of algorithms that enable advanced
screening for cancer. As of May 2014, Mobile OCT, Tel Aviv, Israel, had partnered with
Partners in Health, Massachusetts General Hospitals Global Health group, and the
Scripps Medical Center, to pilot its advanced prototype in Kenya, Haiti, Mexico, and the
10.0 Colposcopy
153
US. The $400 device comprises a case, colposcope, handle and adjustable lighting.
Traditional colposcopes can be in the $10,000 or higher price range.
Exhibit 29
World Market for Colposcopy Systems,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$57.0
37.8
6.2
2.2
21.0
14.0
138.2
2014
58.7
38.9
6.5
2.3
21.8
14.6
142.8
2015
60.5
40.1
6.8
2.4
22.7
15.2
147.7
2016
62.3
41.3
7.1
2.5
23.6
15.8
154.5

2017
64.2
42.5
7.5
2.6
24.5
16.4
157.7
2018
66.1
43.8
7.9
2.8
25.5
17.1
163.2
10.0 Colposcopy
154
Exhibit 30
World Market for Colposcopy Systems
2014
2%
10%
41%
15%
28%
4%
US
European Union
China
Japan
ROW

Brazil
10.0 Colposcopy
155
10.5 COOPERSURGICAL
Trumbull, CT
www.coopersurgical.com
CooperSurgicals products fall into three main segments based on the point of
health care delivery: hospital, office and clinic. Since its inception in 1990,
CooperSurgical has steadily grown its market presence and distribution system by
developing and purchasing products, and acquiring companies that complement its
business focus. The companys focus is on womens health. It has an established
customer base serving well over 65% of women's health care providers with sales
approaching $200 million.
The companys products include digital colposcopy systems, the Leisegang line of
colposcopes, and Leep electrosurgery equipment, as well as instruments and treatment
disposables. The Leisegang OptiK LED colposcopes utilize light emitting diodes for
improved lighting. All Leisegang colposcopes possess a convergent observation path of
ray, which is similar to the eye without optics. Accurate fine focusing is achieved by
ergonomically positioned adjustment drives for height control and focus. A working
distance of 300 mm makes it possible to employ instruments for treatments under
colposcopical view without any problems.
Leep of the cervix is the removal of the outside portion of the cervix which
contains the abnormal cells. CooperSurgical markets a comprehensive LEEP system,
including fully mobile electrosurgical workstations, LEEP-coated instruments, and
disposable accessories.

10.0 Colposcopy
156
10.6 DYSIS MEDICAL

Livingston, UK
www.dysismedical.com
DySIS Medical designs, develops, manufactures, and markets imaging systems
focusing on the non-invasive, in-vivo detection of cancerous and pre-cancerous lesions.
The first product on the market is the DySIS colposcope, which is used for the noninvasive, in vivo detection and diagnosis of cancerous and pre-cancerous lesions of the
cervix. The DySIS colposcope is CE-marked in Europe.
In July 2014, DySIS Medical announced that it has been approved by an
independent Institutional Review Board (Ethical and Independent Review Services, Corte
Madera, CA) to begin enrollment in a major clinical trial in colposcopy, with potentially
50 clinical sites and 9,000 subjects.
The main objective of the "Improved Practice Outcomes and Value Excellence in
Colposcopy" study is to quantify shifts in colposcopy practice and outcome
improvements in US community-based cervical screening colposcopy examinations after
the introduction of the DySIS Colposcope with Advanced Cervical Scan. Data and
findings will be used for presentations, articles, health economics assessments and for
educating payers.

10.0 Colposcopy
157
10.7 GUIDED THERAPEUTICS

Norcross, GA
www.guidedinc.com
Guided Therapeutics has developed a platform technology for the early detection
of disease that leads to cancer. Based on its patented biophotonic technology, the
products use light to detect disease at the cellular level and provide painless and
immediate results at the time of the examination.
The companys first non-invasive cancer detection product is the LuViva
Advanced Cervical Scan. LuViva is in use in Canada, Latin America, Europe, Asia and
Africa and is under premarket application (PMA) review by the FDA. LuViva is designed
to determine the true likelihood of treatable cervical disease that may lead to cancer in
women aged 16 years and over who have been screened for cervical cancer and have an
abnormal result.
About 80% or more women with an abnormal result at this point in the testing
process will eventually be diagnosed as having a false positive result, but after having an
unnecessary colposcopy and biopsy. A one-minute scan with LuViva can rule out about
40% of the false-positive cases immediately without the need for colposcopy and biopsy.
LuViva has also been shown in clinical trials to identify disease up to two years earlier
than colposcopy and biopsy.
LuViva has also shown promise as a potential screening tool in the developing
world to be used where the Pap test or HPV test are not widely available. In August 2014,
Guided Therapeutics announced that it would begin enrollment in a multi-center clinical
trial to expand claims for the LuViva Advanced Cervical Scan to include front-line
screening for cervical cancer.

10.0 Colposcopy
158
10.8 LEISEGANG
Berlin, Germany
www.leisegang.de
Since 1948, Leisegang has specialized in the manufacture of colposcopes. The
company offers a range of colposcopes, ranging from a simple standard colposcope with
different levels of magnification to advanced photo-video colposcopes with integrated or
external camera.
All Leisegang colposcopes are available worldwide. In the US, they are available
from CooperSurgical. In 2010, CooperSurgical's LEEP and cryosurgery products and
gynecology instruments were bundled into Leisegangs new ColpoSuite, which enables
Leisegang to provide a comprehensive solution for dysplasia consultations.
Leisegang is a unit of Galileo Corp., Sturbridge, MA. Galileo develops,
manufactures and markets a variety of fiber optic and electro-optic products that transmit,
sense or intensify light or images. The company's core competency in glass sciences is
fundamental to developing and manufacturing its products, which include medical,
scientific, optical components and systems and office product applications.

10.0 Colposcopy
159
10.9 NEODIAGNOSTIX
Gaithersburg, MD
www.neodiagnostix.com
Identifying the genetic abnormalities of cancer using molecular diagnostic testing
is the premise on which NeoDiagnostix was founded. NeoDiagnostix is merging
molecular DNA technologies with a portfolio of proprietary biomarkers that have been
closely linked to oncologic disease. The company wants to provide clinicians with a
patient specific molecular profile that will provide insights into cancer, leading to
improved or individualized patient care.
The companys flagship product, the Cervical DNA Dtex test was launched in
2007 for the early detection of chromosomal changes that signal the development of
cervical cancer.
DNA damage to chromosomal biomarkers 3q26 and 5p15 in HPV-infected
cervical and dysplastic cells may be more predictive of the progression to disease. The
Cervical DNA Dtex test uses florescent in-situ hybridization (FISH) technology to
identify the irreversible DNA damage to cervical cells as defined by multiple copies of
3q26 and 5p15. Used in conjunction with Pap and HPV testing, the Cervical DNA Dtex
test can assist physicians in identifying which LSIL and ASCUS HPV+ patients may be
at risk of progressing to severe dysplasia.
NeoDiagnostix is also developing molecular diagnostic tests for cervical, breast,
pancreatic, and colorectal cancer, and for melanoma.

11.0 HPV Testing

KEY TREND
In the US, there occur more instances of genital HPV infection than any other
sexually transmitted disease. About 5.5 million new cases of sexually transmitted HPV
infections are reported every year, although 6.2 million new infections are estimated to
occur, according to the American Social Health Association. Approximately 20 million
Americans are infected with HPV. At least half of sexually active men and women
acquire a genital HPV infection at some point in their lives. HPV is so common that at
least 70% of people who are sexually active will get a genital HPV infection at some
point in their lives.
screened for HPV using DNA-based tests in conjunction with a standard Pap smear.
HPV DNA-based testing is now a primary screening tool for cervical cancer for women
ages 25 and older. Look for more similar tests to reach the market. This leaves room for
market growth.
11.1 HPV INFECTION

The human papillomavirus (HPV) is a member of the papillomavirus family of
viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish
productive infections only in the stratified epithelium of the skin or mucous membranes.
While the majority of the nearly 200 known types of HPV cause no symptoms in most
11.0 HPV Testing

161
people, some types can cause warts. Others can, in a minority of cases, lead to cancers of
the cervix, vulva, vagina and anus in women, or cancers of the anus and penis in men.
More than 30 to 40 types of HPV are typically transmitted through sexual contact
and infect the anogenital region. Some sexually transmitted HPV types may cause genital
warts. Persistent infection with high-risk HPV types, which are different from the ones
that cause skin warts, may progress to precancerous lesions and invasive cancer. HPV
infection is a cause of nearly all cases of cervical cancer. But, most infections with these
types do not cause disease.
11.1.1 Infection in Females

Most HPV infections in young females are temporary and have little long-term
significance. About 70% of infections disappear within one year, and 90% in two
years. However, when the infection persists, in 5% to 10% of infected women, there is a
high risk of developing precancerous lesions of the cervix, which can progress to invasive
cervical cancer. This process can take up to 20 years, providing many opportunities for
detection and treatment of the pre-cancerous lesion. Progression to invasive cancer can be
almost always prevented when standard prevention strategies are applied. Still, the
lesions cause considerable burden necessitating preventive surgeries which do in many
cases involve loss of fertility.
11.1.2 High Risk Types

About a dozen HPV types, including types 16, 18, 31 and 45, are high-risk types
because they can lead to cervical cancer, as well as anal cancer, vulvar cancer, vaginal
cancer and penile cancer. The most common of the high-risk strains of HPV are types 16
and 18, which cause about 70% of all cervical cancers. Several types of HPV, particularly
type 16, have been found to be associated with oropharyngeal squamous cell carcinomas
(OSCC), a form of head and neck cancer. HPV-induced cancers often have viral
sequences integrated into the cellular DNA. Some of the HPV early genes, such as E6
and E7, are known to act as oncogenes that promote tumor growth and malignant
transformation. Oral infection with HPV increased the risk of oropharyngeal cancer
independent of tobacco and alcohol use.
11.0 HPV Testing

162
Most HPV infections are cleared rapidly by the immune system and do not
progress to cervical cancer. Because the process of transforming normal cervical cells
into cancerous ones is slow, cancer occurs in people who have been infected with HPV
for a long time, usually over a decade or more (persistent infection).
Sexually-transmitted HPVs also cause a major portion of anal cancers and
approximately 25% of cancers of the mouth and upper throat. The latter commonly are
found in the tonsil area, and HPV is linked to the increase in oral cancers in non-smokers.
Studies show a link between HPV infection and penile and anal cancer.
11.1.3 HPV Major Cause of Cervical Cancer

Persistent HPV infections are recognized as the major cause of cervical cancer.
The American Cancer Society estimates that in 2014 there will have been diagnosed
approximately 12,360 new cases of invasive cervical cancer. About 4,020 women will
have died from the disease. Some researchers estimate that non-invasive cervical cancer
(carcinoma in situ) occurs about 4 times more often than invasive cervical cancer.
Studies have also found that oral HPV infection is a strong risk factor for
oropharyngeal cancer cancer that forms in tissues of the oropharynx, which is the
middle part of the throat and includes the soft palate, the base of the tongue and
the tonsils. Researchers found that an oral HPV infection and past HPV exposure increase
the risk of oropharyngeal squamous cell cancer, regardless of tobacco and alcohol use,
two other important risk factors for this disease.
Certain types of HPV are high risk because they lead to abnormal cell changes
and can cause genital cancers, cervical cancer as well as cancer of the vulva, anus, and
penis. Virtually all cervical cancers more than 99% are caused by these high-risk
HPV viruses. The most common of the high-risk strains of HPV are types 16 and 18,
which cause about 70% of all cervical cancers.
11.2 HPV TEST

When infection with high-risk HPV types occurs, there usually are no symptoms.
Often, the first clue is a Pap test result that is abnormal, which has been the gold standard
for many decades. But as the role of HPV in contributing to cancer has emerged in recent
11.0 HPV Testing

163
years, screening for HPV has started to rival the Pap. One study of more than one million
women found that the HPV test was more successful in assessing cervical cancer risk
than the Pap smear.
In the July 2014 study, women with a negative HPV test had half the risk of
developing cancer over three years as women who had a negative Pap test, and similar
rates to women who were negative on both tests (known as a co-test). Because most cases
of cervical cancer are caused by an infection with HPV, women who do not show signs of
the virus are at a very low risk of developing the cancer, which is even than women who
have a negative Pap test. The National Cancer Institute indicates that HPV primary
screening might be a viable alternative to Pap screening.
In April 2014, the FDA approved Roches cobas HPV DNA-based test as a
primary screening tool for cervical cancer for women ages 25 and older. The test screens
for the strains most commonly linked to the cancer, HPV 16 and HPV 18, and for other
strains. The FDA offered some guidance, advising that women who test positive for HPV
16 or HPV 18 to undergo a colposcopy, so that doctors could better examine any
abnormal cells.
A number of tests are approved by the FDA for detecting clinically significant
levels of any of 13 to 14 high-risk HPV types, including: the Digene HC2 High-Risk
HPV DNA test (Qiagen, Gaithersburg, MD); the Cervista HPV HR test (Hologic,
Bedford, MA); and the cobas 4800 HPV test (Roche Molecular Systems, Pleasanton,
CA). Cervista High-Risk and HC2 High-Risk tests indicate the presence of one or more
of the high risk types but does not indicate a specific type. The cobas test also provides
individual detection of HPV 16 and 18, as does the Cervista. None of the HPV tests are
approved for use in men, adolescents, or detection of infection in partners.
11.3 VACCINE ISSUES

Gardasil became the first HPV vaccine to be approved by the FDA in 2006. Two
vaccines are currently available to prevent infection by HPV, Gardasil, marketed by
Merck and Cervarix, marketed by GlaxoSmithKline. Both protect against initial infection
with HPV types 16 and 18, which cause most of the HPV associated cancer cases.
Gardasil also protects against HPV types 6 and 11, which cause 90% of genital warts.

11.0 HPV Testing

164
Several countries have included the HPV vaccine into their national vaccination
programs. Several states in the US have or are considering making HPV vaccinations
mandatory for teenagers and even preteens before theyre allowed to attend school.
But the vaccines provide little benefit to women who have already been infected
with HPV types 16 and 18, which include most sexually active females. For this reason
the vaccine is recommended primarily for those women who have not yet been exposed
to HPV during sex.
Gardasil is licensed for females age 9 through 26 and Cervarix is licensed for
females age 10 through 25. The Centers for Disease Control and Prevention recommends
that all girls who are 11 or 12 years old have the three shots of either brand of HPV
vaccine to protect against cervical cancer and precancer. Girls and young women age 13
through 26 should receive all three doses of an HPV vaccine if they have not received all
doses yet.
11.4 STRONG MARKET EXPECTED

screened for HPV using DNA-based tests in conjunction with a standard Pap smear.
Thus, there is a growth opportunity in this market. Roche offers its cobas HPV test while
other IVD companies are developing positive-negative detection tests that indicate
whether a woman is infected with HPV, and follow-up genotyping tests.
The CDC has reported that the prevalence of HPV-16 may be at least two-fold
higher in women compared to men. Women of all races had an HPV-16 prevalence of
17.9%, compared to 8% for men. As expected, prevalence of HPV-16 among study
participants increased with the number of lifetime sex partners. Only 7% of people with
one lifetime sex partner had the infection compared to 20.1% of people with 50 or more
lifetime sex partners.
HPV is likely the most common sexually transmitted disease (STD) among
young, sexually active people. Type 16 is the cause of approximately half of cervical
cancers worldwide. Types 16 and 18 together account for about 70% of cervical cancers.

11.0 HPV Testing

165
11.4.1 IVD Market
The market for HPV testing should experience steady growth in the 4% to 5%
range annually in the near term, as seen in Exhibits 31 and 32. It is estimated that the US
market for HPV testing is only about one-third penetrated. The potential worldwide
market at saturation is $1 billion annually. Approximately 65% of HPV infections appear
in women and 35% in men.
But strong future growth may be in jeopardy. In October 2011, the US Preventive
Services Task Force, announced that it would not endorse HPV screening for cervical
cancer and favors, giving Pap tests only every three years in women between ages 21 and
65. The Task Force said there was insufficient evidence to justify it for women over age
30. In expressing skepticism of the tests, it said the current evidence is insufficient to
assess the balance of benefits and harms of HPV testing, alone or in combination with
Pap tests. Nevertheless, the womens lobby is quite strong and growth in this market is
derived from the increased availability of HPV testing and consumer demand. But
physicians are still reticent, and test reimbursement is not a given. The HPV-Pap atypical
squamous cells of undetermined significance (ASCUS) reflex combination has been well
reimbursed.
It took Digene, now part of Qiagen, more than a decade to convince the medical
community that infection with certain strains of HPV is a precursor for cervical cancer.
Since then, HPV testing has progressed from an esoteric test on Pap smears of cervical
fluid, to a reflex test for abnormal ASCUS Pap results to confirm an HPV infection to a
market cleared first line test independent of the Pap test.
This last development opens a huge market for HPV testing where organized Pap
test programs do not exist. It also has had huge impact for womens health. Research has
shown that HPV on self-collected cervical fluid samples was comparable to those
collected via a physician or healthcare professional.
Such companies as Qiagen, Becton Dickinson and Roche Diagnostics have
developed systems that automate the processing of ThinPrep and SurePath vials, allowing
these samples to join the core lab for HPV, Chlamydia, gonorrhea and other analyte
analysis on molecular analyzers. Qiagen markets the QIAensemble Decapper for liquid
cytology vials and Becton Dickinson offers the automated Totalys MultiProcessor.

11.0 HPV Testing

166
The market opened up and numerous companies began offering market cleared
HPV tests from cervical fluid samples on molecular analyzers including Qiagen, Abbott
Diagnostics, Becton Dickinson, Cepheid, Hologic and Roche Diagnostics. Then Roche
Diagnostics pushed the envelope with FDA clearance for its cobas HPV Test screen
without a previous Pap test.
It is estimated some that in the US, approximately 45% of Pap tests are also
accompanied by an HPV test even when the HPV with Pap. This low acceptance level
indicates that physicians are not following evidence-based guidelines that support HPV
plus Pap testing for women over age 30 as a cost effective and sensitive screen for
cervical abnormalities. This illustrates the power of the traditional Pap smear. Further,
HPV DNA tests are expensive. In fact in some countries, women co-pay to have their
cervical scrapings transported in a liquid sample vial instead of being smeared onto a
glass slide.
Exhibit 31
World Market for Female IVD HPV Tests,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$75.6
46.8
11.9
4.3
25.2
10.8
174.6
2014
79.4
49.1
12.4
4.5
26.5
11.2
183.1
2015
83.4
51.6
12.9
4.7
27.9
11.6
192.1
2016
87.6
54.2
13.4
4.9
29.3
12.1
201.5

2017
92.0
57.0
13.9
5.1
30.8
12.6
211.4
2018
96.6
60.0
14.5
5.4
32.3
13.1
221.9
11.0 HPV Testing

167
Exhibit 32
World Market for Female IVD HPV Tests
2014
3%
14%
6%
43%
7%
27%
US
European Union
China
Japan
ROW
Brazil

11.0 HPV Testing

168
11.5 ABBOTT MOLECULAR

Abbott Park, IL
www.abbottmolecular.com
Abbotts 2013 sales totaled $21.8 billion. The companys Molecular units sales
totaled $473 million. Abbott markets a broad range of diagnostic systems analyzers
and reagents worldwide to hospitals, blood banks, commercial clinical laboratories,
physiciansoffice laboratories, and other diagnostic locations. For centralized
laboratories, Abbott markets chemistry and immunoassay systems and reagents,
hematology products, molecular diagnostic assays, histology, blood banking assays,
pharmacogenetics assays, and many others.
Abbott is a leader in automated immunoassay analyzers, and immunoassaychemistry analyzers, for centralized laboratories, such as reference labs and hospital labs.
The Architect family of instruments is a portfolio of fully automated, integrated
immunoassay and chemistry instruments, as well as separate immunoassay and chemistry
modules.
As of September 2014, Abbott's RealTime High Risk HPV Test became available
in Europe as a tool for first-line screening. The test is able to identify women at increased
risk for development of cervical cancer or the presence of high-grade disease. The Abbott
test has been clinically validated in many significant studies conducted in European
countries in recent years and the intended use has been expanded to include first-line
primary screening.
Based on research, HPV primary screening has several benefits compared to the
current method of examining cervical samples using Pap smears or cervical cytology.
Most importantly, it allows physicians to identify more women with abnormal cervical
cells and if HPV isn't present, rule out the possibility of a patient developing cervical
cancer in the next few years. Unresolved HPV infections may cause genital warts and
cervical cancer. Women showing precancerous cervical cell changes caused by HPV can
be treated to remove the abnormal cells.
Abbott's RealTime High Risk HPV assay has been available in Europe since 2008
on the companys automated m2000 RealTime System. The Abbott RealTime HIV-1

11.0 HPV Testing

169
assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for
the quantitation of HIV-1 on the automated m2000 System, or with m24sp extraction in
human plasma from HIV-1 infected individuals over the range of 40 to 10,000,000
copies/mL.
Abbotts assay is intended for use in conjunction with clinical presentation and
other laboratory markers for disease prognosis and for use as an aid in assessing viral
response to antiretroviral treatment, as measured by changes in plasma HIV-1 RNA
levels. This assay is not intended to be used as a donor screening test for HIV-1 or as a
diagnostic test to confirm the presence of HIV-1 infection. The assay is intended to detect
14 high risk HPV genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and to
partially genotype 16 and 18 from other high risk genotypes.

11.0 HPV Testing

170
11.6 HOLOGIC
Bedford, MA
www.hologic.com
applications and mini C-arm imaging for orthopedic applications. For the 12 months
ended Sept. 28, 2013, company revenues totaled approximately $2.5 billion, compared to
revenues of about $2 billion in the previous fiscal year.
In June 2008, Third Wave Technologies Inc. became a subsidiary of Hologic. The
merger provided Hologic with a platform for opportunities in molecular diagnostics.
Third Waves HPV tests were a natural adjunct to Hologics (Cytyc) ThinPrep Pap test.
Third Waves Cervista HPV HR (high risk) screening test is designed to detect the
14 high-risk types of HPV known to cause cervical cancer. In addition, the Cervista HPV
16/18 test is the first HPV test approved for genotyping for HPV high risk types 16 and
18. These two HPV molecular diagnostic tests offer a competitive challenge to Qiagen's
HPV molecular diagnostic assay, which had been the only such product in the US
approved by the FDA.
The Cervista HPV HR test was Hologics first entry to the HPV test market. It
was the first HPV DNA test approved by the FDA in more than 10 years since the launch
of Qiagens test. The test is slowly losing market share to Gen-Probes HPV products.
In July 2012, Hologic announced the Netherlands Society for Pathology has
approved the use of the Hologic Cervista HPV HR test in the Dutch national cervical
screening program. The National Institute for Public Health and the Environment in the
Netherlands suggests routine pap testing and HPV HR triage for the ASCUS/LSIL (or
atypical squamous cells of undetermined significance / low-grade squamous
intraepithelial lesion) testing for women over the age of 30 in order to identify those most
likely to develop cervical cancer.
Additional Aptima women's health assays, such as Aptima Trichomonas vaginalis
and Aptima HPV are expected to be added to the PANTHER menu as they progress

11.0 HPV Testing

171
through the regulatory process, and several other qualitative and quantitative assays are
currently in development. The Panther can also be used to test urine and genital samples
for chlamydia and gonorrhea.
In November 2013, Hologic received FDA clearance to market its Aptima HPV
16 18/45 genotype assay on the Panther system. The Aptima HPV 16 18/45 genotype
assay was CE marked in December 2011 and received FDA approval on the Hologic
high-throughput Tigris system in October 2012. The assay is the first (according to
Hologic) FDA-approved test for genotyping human papillomavirus (HPV) types 16, 18
and/or 45. The test is performed from a sample drawn from Hologics ThinPrep liquid
cytology specimen. The addition of HPV genotype 45 is designed to help identify more
women at risk for adenocarcinoma, with minimal impact to colposcopy rates.
The Aptima HPV 16 18/45 genotype assay is intended to test specimens from
women with Aptima HPV assay positive results. The FDA has approved the test for two
uses: In patients 21 years and older with atypical squamous cells of undetermined
significance (ASC-US) cervical cytology results; In patients 30 years and older, the
Aptima HPV 16 18/45 genotype assay can be used to test samples from women with
Aptima HPV assay positive results.
In July 2013, Hologic received FDA clearance to market the companys Aptima
HPV assay for use on the fully-automated Panther system. The Aptima HPV test is
performed with Hologic's ThinPrep liquid cytology specimen and can be tested before
and after it has been processed for cytology testing on the ThinPrep 2000 system. The
Aptima HPV assay detects messenger RNA overexpressed from the E6 and E7 viral
oncogenes in 14 high-risk HPV types associated with cervical cancer and precancerous
lesions. The Aptima HPV assay was CE-marked in 2008 and received FDA approval on
the Hologic high- throughput Tigris system in 2011.

11.0 HPV Testing

172
11.7 QIAGEN BENELUX BV

Venlo, The Netherlands
www.qiagen.com
Qiagen, a Netherlands holding company, is a leading global provider of sample
and assay technologies. The company has developed and markets more than 500 sample
and assay products as well as automated solutions for such consumables. The company
provides its products to molecular diagnostics laboratories, academic researchers,
pharmaceutical and biotechnology companies, and applied testing customers for
forensics, animal or food testing and pharmaceutical process control.
Qiagens assay technologies include one of the broadest panels of molecular
diagnostic tests available worldwide. This panel includes the Digene HPV hc2 test, which
is regarded as a "gold standard" in testing for high-risk types of HPV, the primary cause
of cervical cancer, as well as a broad suite of solutions for infectious disease testing and
companion diagnostics.
It is estimated that the companys HPV product sales totaled about $210 million
in 2013. Qiagens clinical business is focusing on market and product expansion and is
moving from a base in infectious diseases to cancer testing and personalized medicine.
Qiagens portfolio includes FDA approved assays for HPV (Digene HPV) and chlamydia
as well as CE-labeled tests for the detection of HIV, HCV, hepatitis B virus (HBV),
cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes-simplex virus (HSV),
influenza, multiple bacteria and respiratory viruses, personalized healthcare assays such
as KRAS, EGFR, as well as many other target diseases.
Qiagen offers several products for screening and genotyping of HPV viruses. The
companys Digene HC2 HPV Test, the most validated and sensitive diagnostic for
detection of high-risk HPV, has long been recognized as the "gold standard" and is
widely used in developed countries and large cities in emerging markets. The test is
indicated both for co-testing with cytology to screen women age 30 and older as well as
to determine the need for colposcopy or biopsy referral for women with borderline
abnormal cytology results.
Qiagen developed the careHPV Test in collaboration with PATH, Seattle, WA, an
international nonprofit organization, to expand access to HPV screening in low-resource
settings. The careHPV Test was the first molecular diagnostic to screen for high risk

11.0 HPV Testing

173
HPV, and is designed for low-resource clinical settings, such as areas lacking electricity,
water or modern laboratory infrastructure. The careHPV test targets areas in Asia, Latin
America, Eastern Europe and Africa. Clinical studies with the careHPV Test have been
conducted in China, Nigeria, Rwanda and Thailand in parallel with PATH demonstration
trials in China, India, Uganda and Nicaragua.
The careHPV Test is manufactured by the company in Shenzhen, China, making
the "country of origin" approval a critical milestone. Many countries are able to use this
approval by the China Food and Drug Administration for their own regulatory approval,
instead of conducting lengthy and costly local regulatory submissions.
The careHPV Test plays a central role in QiagenCares, the company's
collaboration with non-governmental organizations and governments to expand access to
cervical cancer screening in resource-poor regions. Qiagen intends to donate 1.5 million
HPV tests to improve life in the world's poorest nations. It has partnered with HPV
vaccine manufacturer Merck & Co. to implement public programs to fight cervical cancer
in developing countries, starting in Rwanda.
QiagenCares has also helped clinicians in Brazil install the careHPV device on
mobile units to conduct cervical cancer screening in remote areas. El Salvador's
government, working with the nonprofit group Basic Health International, is evaluating
the integration of careHPV into a national screening program. Projects in South Africa
and Burkina Faso have also used careHPV.
In May 2013, Qiagen signed an agreement with Calmette Hospital (Phnom Penh,
Cambodia) for a pilot project aiming to implement the optimal HPV screening for
Cambodian women.
For urban areas in the developing world, and for industrialized countries with
established laboratories and a robust healthcare infrastructure, Qiagen is developing the
QIAensemble system, a next-generation HPV DNA testing platform with enhanced
instrumentation and automation to increase the speed, volume and testing menu of the
companys Hybrid Capture 2 system.
With the careHPV Test, the Digene HPV Test and the new QIAensemble
platform, Qiagen offers HPV DNA testing solutions customized for settings ranging from
rural health clinics with no electricity to sophisticated, high-throughput labs running
thousands of HPV tests per day.
11.0 HPV Testing

174

Indianapolis, IN
http://www.roche-diagnostics.us/Pages/default.aspx
Roche is a global healthcare company that markets both pharmaceutical and
diagnostic Products. Sales for the whole company total about $49 billion. In 2013, the
Roche Group employed over 85,000 people worldwide, invested about $9 billion in
research and development. Genentech is a wholly owned member of the Roche Group.
Roche is the majority shareholder in Chugai Pharmaceutical of Japan.
The major news for Roche in 2014 was the FDAs approval of the cobas HPV
Test for use as a first-line primary screening test for cervical cancer in women 25 and
older. The approval followed the 2014 unanimous recommendation from the
Microbiology Devices Panel of the FDAs Medical Devices Advisory Committee,
making the cobas HPV Test the first and only HPV test in the US that is approved for
first-line primary screening.
Prior to the approval of this additional claim, HPV tests had been used as a
follow-up for Pap results and as an adjunct to Pap in women 30 years and older. The
cobas HPV Test provides both pooled high-risk HPV DNA results and individual
detection of HPV 16 and HPV 18, the two types responsible for about 70% of cervical
cancer. The FDAs decision to approve the expanded use for the cobas HPV Test was
based on results from the landmark Athena trial, which enrolled more than 47,000
women. The study demonstrated that one in four women who are HPV 16 positive will
have cervical disease within three years and that nearly one in seven women with normal
Pap cytology who were HPV 16 positive actually had high-grade cervical disease that
was missed by cytology.
The cobas HPV Test received FDA approval in April 2011 for screening patients
age 21 and older with abnormal cervical cytology results and for use adjunctively with
normal cervical cytology in women ages 30 and over to assess the presence or absence of
high-risk HPV genotypes. Roche submitted its Premarket Approval (PMA) supplement
for the cervical cancer primary screening indication with the FDA in June 2013.
The test is performed on the cobas 4800 System, which offers automation of
nucleic acid purification, PCR set-up and real-time PCR amplification and detection to
11.0 HPV Testing

175
help laboratories achieve maximum efficiency. The system also runs the cobas CT/NG
Test (chlamydia/gonorrhea), the cobas BRAF V600 Mutation Test, and the cobas
epidermal growth factor receptor (EGFR) Mutation Test.

12.0 Ovarian Cancer

KEY TREND
The CA-125 immunoassay and a vaginal ultrasound are the most reliable methods
for diagnosing ovarian cancer. CA-125 is the current gold standard for monitoring
patients diagnosed with ovarian cancer. The CA-125 test is not a routine part of a
womans annual checkup. Screening, although not for women with an average risk of
ovarian cancer, could be done using the CA-125 test. Ultrasound is another option. A
CA-125 test costs about $80, while an ultrasound runs at $600. A key trend is to improve
the limitations of current ovarian cancer by using panels of blood-based protein tests.
12.1 TYPES OF OVARIAN CANCER

Ovarian cancer is cancer of the ovaries, the egg-releasing and hormone-producing
organs of the female reproductive tract. Cancerous cells divide and multiply in an
abnormal fashion. Ninety percent of all ovarian cancers develop in the cells lining the
surface, or epithelium, of the ovaries and are called epithelial cell tumors. About 15% of
epithelial cancers are considered low malignant potential (LMP) tumors. These tumors
occur more often in younger women, and are more likely to be caught early, so prognosis
is good. Ovarian LMP tumors have abnormal cells that may become cancer, but usually
do not. This disease usually remains in the ovary. When disease is found in one ovary, the
other ovary should also be checked carefully for signs of disease. Germ cell
tumors develop in the egg-producing cells of the ovary, and comprise about 5% of
12.0 Ovarian Cancer

177
ovarian tumors. These tumors are usually found in teenage girls or young women. The
prognosis is good if found early, but as with other ovarian cancers, early detection is
difficult.
Ovarian cancer can develop at any age, but is most likely to occur in women who
are 50 years or older. More than half of the cases are among women who are aged 65
years and older. Industrialized countries have the highest incidence of ovarian cancer.
Caucasian women, especially of Ashkenazi Jewish descent, are at somewhat higher risk.
African-American and Asian women are at a slightly lower risk. The risk of developing
the disease increases with age. Ovarian cancer is the fourth most common cancer among
women in the US, and the second most common gynecologic cancer. The American
Cancer Society estimates that for 2014 in the US, about 21,980 women will receive a new
diagnosis of ovarian cancer. About 14,270 women will die from the disease.
Ovarian cancer accounts for 5% of all cancers among women and causes more
deaths than any other female genital tract cancer;
Approx. 12 in 1,000 women in the US over 40 years of age will develop ovarian
cancer, but only two or three of these will be cured;
Occurs at all ages, including infancy and childhood;
A minority of cases will be familial.
12.2 PELVIC EXAMINATIONS

Routine pelvic exams do not benefit women who have no symptoms of
disease and who are not pregnant. They may cause harm. In June 2014, the American
College of Physicians recommended that doctors quit performing the exams as a
screening tool. Pelvic exams are appropriate for women with symptoms, such as
vaginal discharge, abnormal bleeding, pain, urinary problems, or sexual dysfunction.

12.0 Ovarian Cancer

178
12.3 TUMOR MARKERS, AFP, HE4

Scientists at Georgia Institute of Technology, Atlanta, GA, are using patterns
of metabolites found in blood as biomarkers to detect ovarian cancer. Using mass
spectrometry, the researchers have been able to differentiate between serum samples
taken from patients with ovarian cancer and those from unaffected individuals.
Ovarian cancer is a relatively rare cancer, so a functionally useful
diagnostic test has to be 99% accurate or you are going to get too many false
positives, says John McDonald, chief scientist of the Ovarian Cancer Institute and
associate dean for biology development in the School of Biology.
McDonald teamed with colleagues to sort molecules in the serum based on
their weight and electrical charge. They focused on metabolites as opposed to
proteins or peptides because they would obtain better quantification and higher
resolution for the smaller molecules that comprise the human metabolome.
The research team was able to detect patterns of key metabolites in the blood.
Using an artificial intelligence computer program, they were able to train the
computer to distinguish patterns of small metabolites found in the blood of cancer
patients from those of control subjects. The scientists first used serum samples from
known cancer patients and unaffected individuals to establish metabolomic patterns
that were present at different levels in the two groups. The machine learning program
identified a pattern consisting of only a few dozen metabolites, among thousands of
candidates, which could be used to distinguish between women with ovarian cancer
and women with non-cancerous conditions.
Once these patterns were identified, the researchers tested the patterns of the same
metabolites in a different set of serum samples from other patients with and without
cancer. The researchers identified the samples with 99% accuracy. The identity of the key
metabolites and the role they may play in ovarian cancer is still under investigation, but
the development of an accurate and reliable diagnostic test will save lives when combined
with existing therapies.
Another Georgia Tech biomarker study indicated that the stiffness of an ovarian
cancer cell could be measured to predict its metastatic potential. Metastatic cells usually
are soft. The softness enables the cells to more easily invade blood vessels or lymph

12.0 Ovarian Cancer

179
systems. Scientists used atomic force microscopy to measure the stiffness of healthy and
metastatic ovarian cancer cells. The investigators found that the degree of stiffness
seemed to be correlated to the cells metastatic potential. These parameters could be
another useful biomarker in evaluating metastatic cells in ovarian and other forms of
cancer. Additional research is needed before this biomarker approach can be used
clinically.
Another tumor marker is alpha-fetoprotein (AFP). AFP is used to help detect and
diagnose cancers of the liver, testes, and ovaries. It is often ordered to monitor people
with chronic liver diseases such as cirrhosis or chronic hepatitis, because they have an
increased lifetime risk of developing liver cancer. A doctor may order an AFP test, along
with imaging studies, to try to detect liver cancer when it is in its earliest, and most
treatable, stages.
A relatively new test, called AFP-L3%, is sometimes also ordered to compare the
amount of total AFP to the amount of one of the AFP variants called AFP-L3. The AFPL3% test is not yet widely used in the US but has gained wider acceptance in other
countries such as Japan. The test is used to help evaluate the risk of developing
hepatocellular carcinoma, especially in those with chronic liver disease. An increase in
the percentage of L3 to total AFP indicates an increased risk of rapidly developing this
disease and also of having less chance of survival.
Human epididymis protein 4 (HE4), a relatively new marker for ovarian
carcinoma, is the product of the WFDC2 (HE4) gene that is overexpressed in patients
with ovarian carcinoma. HE4 is among the most frequently upregulated genes in
epithelial ovarian carcinomas based on gene expression profiles. HE4 has shown promise
as a complement to CA-125.
Fujirebio Diagnostics has made available an HE4 marker. HE4 has emerged as
one of the most promising markers for early disease diagnosis. It is frequently overexpressed in ovarian cancer, whereas its expression in normal tissues, including the
ovary, is low. Moreover, HE4 circulates in the bloodstream of patients with serous and
endometrioid ovarian cancer.
HE4 was first associated with the human epididymis. HE4 belongs to the family
of whey acidic four-disulfide core proteins. Fujirebio Diagnostics has developed an
ELISA kit for the quantitative measurement of HE4 in patient blood. The HE4 test has
12.0 Ovarian Cancer

180
been cleared by the FDA for use as an aid in monitoring recurrence or progressive disease
in patients with epithelial ovarian cancer. The test can currently be ordered through Quest
Diagnostics and LabCorp in the US.
The HE4 assay is to be used as an aid in monitoring the recurrence or progressive
disease in patients with epithelial ovarian cancer. Testing should be used in conjunction
with other clinical methods used for monitoring ovarian cancer.
Fujirebio Diagnostics also is offering the CA125 + HE4 stratification tool. The
CA125 and HE4 test combination helps connect ovarian cancer patients with the right
doctor for the most optimal outcome.
12.4 CA-125 ANTIGEN

CA-125 is an antigen present on 80% of nonmucinous ovarian carcinomas. It is
defined by a monoclonal antibody (OC-125) that was generated by immunizing
laboratory mice with a cell line established from human ovarian carcinoma. It circulates
in the serum of patients with ovarian carcinoma and was therefore investigated for
possible use as a marker. CA-125 is often elevated in patients with ovarian cancer. Its
level follows the patient's clinical course. With surgical resection or chemotherapy, the
level correlates with patient response. Thus, it is superior to other markers. The CA-125
is elevated in other cancers including endometrial, pancreatic, lung, breast, and colon
cancer, and in menstruation, pregnancy, endometriosis, and other gynecologic and nongynecologic conditions.
The CA-125 assay is a blood test to determine the level of CA-125. A series of
CA-125 tests may be performed to see if the amount of the marker in the blood is
remaining stable, increasing or decreasing. A rising CA-125 level usually indicates
cancer, while a stable or declining value is more characteristic of a cyst. The CA-125
level should never be used alone to diagnose ovarian cancer. It is elevated in about 80%
of women with ovarian cancer, but in 20% of the cases it is not. In addition, it could be
elevated because of a non-ovarian cancer, or it can be elevated with non-malignant
gynecologic conditions, such as endometriosis or ectopic pregnancy. During menstruation
the CA-125 level may be elevated, so the test is best done when the woman is not having
her menstrual period. Abbott, Roche and Fujirebio Diagnostics, Tokyo, Japan, are among
those companies that market CA-125 assays.
12.0 Ovarian Cancer

181
12.5 CA-125 MARKET

The CA-125 protein was identified as a tumor marker in the 1980s and has been
used by doctors to watch for relapse in patients who have been treated for ovarian cancer.
Understanding how changing CA125 levels reflect risk of cancer is an important
breakthrough that could shift the diagnosis of ovarian cancer much earlier, to a stage
when interventions with surgery, radiation, chemotherapy, or medications are more
effective. Ovarian cancer remains a formidable challenge. Ovarian cancer is the fifth
leading cause of cancer death among women in the US and has the highest mortality rate
of all gynecologic cancers. Given this environment and an emphasis on testing, the
market for the CA-125 assay for monitoring, and potentially screening for, the cancer is
expected to grow at a 5% to 6% annual rate, as seen in Exhibits 33 and 34.
Exhibit 33
World Market for CA-125 Assay,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$236.5
137.5
36.3
13.2
71.5
38.5
533.5
2014
250.7
144.4
37.7
13.7
75.1
40.0
561.6
2015
265.7
151.6
39.2
14.2
78.9
41.6
591.2
2016
281.6
159.2
40.8
14.8
82.8
43.3
622.5

2017
298.5
167.2
42.4
15.4
86.9
45.0
655.4
2018
316.4
175.6
44.1
16.0
91.2
46.8
690.1
12.0 Ovarian Cancer

182
Exhibit 34
World Market for CA-125 Assay
2014
3%
13%
7%
44%
7%
26%
US
European Union
China
Japan
ROW
Brazil

12.0 Ovarian Cancer

183
12.6 AVANT DIAGNOSTICS INC.

Scottsdale, AZ
www.avantdiagnostics.wordpress.com
Avant Diagnostics, formerly Arrayit Diagnostics Inc., is a 47% owned subsidiary
of Arrayit Corp., a life sciences company. Avant Diagnostics is developing OvaDx, a
microarray-based test that measures the activation of the immune system in blood
samples in response to early stage ovarian tumor cell development. This new test detects
approximately 100 proteomics biomarkers. This test is being developed for presymptomatic testing for ovarian cancer, to identify early stage development of ovarian
tumor cells.
A May 2013 Arrayit Corp. newsletter reports that over 200 patients were analyzed
in blind-format, retrospective studies with effectively 100% accuracy in identifying
patients with ovarian cancer at varying stages. This newsletter also reports that Arrayit is
aiming to raise funds to conduct a two-phase clinical trial that will include a 50 patient
retrospective followed by a 2,000 patient prospective study.
In September 2014, American Liberty Petroleum Corp. announced plans to
acquire Avant Diagnostics. American Liberty Petroleum Corp. intends to accelerate
development of OvaDx, as well as to initiate the development of new tests.

12.0 Ovarian Cancer

184
12.7 BIOSYSTEMS INTERNATIONAL

Evry, France
www.biosys-intl.com
BioSystems International was founded in 2004 by Laszlo Takacs, Barry Karger,
William Hancock, and Andras Guttman and a core group of former Pfizer scientists. The
company has a proprietary monoclonal antibody based proteomics technology (mAb
proteomics) which it is using for development of blood-based diagnostics for cancer and
chronic diseases, and for development of a line of innovative antibody arrays.
The company and the Laboratory Medicine of University of Debrecen, Hungary,
have developed a monoclonal antibody-based diagnostic tool that is being tested in
plasma samples from patients with lung, breast, colon, prostate, and ovarian, and in the
appropriate control plasma samples. This project is funded by the Hungarian
governments National Office for Research and Technology.

12.0 Ovarian Cancer

185
12.8 FUJIREBIO DIAGNOSTICS

Malvern, PA
www.fdi.com
Fujirebio Diagnostics is involved in the production of in vitro diagnostics, and
biomarkers. The parent company, Fujirebio Inc., a leading health care company in Japan
with a focus on diagnostics, acquired Fujirebio Diagnostics in 1998. In June 2006, CanAg
Diagnostics of Sweden, now called Fujirebio Diagnostics AB, joined Fujirebio
Diagnostics to strengthen the company's product offerings, distribution network, and
research and development capabilities.
Fujirebio Diagnostics specializes in the manufacturing of manual assay products,
reagents and controls distributed worldwide, as well as custom-developed products for
use through its worldwide network of distribution partners.
Fujirebio Diagnostics is marketing its CA-125II biomarker for ovarian cancer.
CA 125II is an antigen (tumor marker) frequently elevated in the serum of women with
primary epithelial invasive ovarian cancer. However, not all women with ovarian cancer
will have elevated CA 125II levels. CA 125II can also be elevated in patients with
nonmalignant conditions, such as pericarditis, cirrhosis, severe hepatic necrosis,
endometriosis (Stages II-IV), first trimester pregnancy, and ovarian cysts or in patients
with non-ovarian malignancies, such as uterine carcinoma, hepatoma, pancreatic
adenocarcinoma, and lung cancer.
The CA 125II test is performed periodically to aid in the detection of residual
ovarian carcinoma in patients who have undergone first-line therapy and would be
considered for diagnostic second-look procedures.
Fujirebio Diagnostics also is marketing HE4 marker. HE4 has emerged as one of
the most promising markers for early disease diagnosis. HE4 was first associated with
the human epididymis. HE4 belongs to the family of whey acidic four-disulfide core
proteins.
Fujirebio Diagnostics has developed an ELISA kit for the quantitative
measurement of HE4 in patient blood. The HE4 test has been cleared by the FDA for use
as an aid in monitoring recurrence or progressive disease in patients with epithelial

12.0 Ovarian Cancer

186
ovarian cancer. The test can currently be ordered through Quest Diagnostics and LabCorp
in the US.
The HE4 assay is to be used as an aid in monitoring the recurrence or progressive
disease in patients with epithelial ovarian cancer. Testing should be used in conjunction
with other clinical methods used for monitoring ovarian cancer.
Fujirebio Diagnostics also is offering the CA125 + HE4 stratification tool. The
CA125 and HE4 test combination helps connect ovarian cancer patients with the right
doctor for the most optimal outcome.

12.0 Ovarian Cancer

187
12.9 MYRIAD GENETICS INC.

Salt Lake City, UT
www.myriad.com/about-myriad
Myriad Genetics is a molecular diagnostic company dedicated to the discovery
and commercialization of tests to assess a person's risk of developing disease, guide
treatment decisions and assess risk of disease progression and recurrence. Myriad's
molecular diagnostic tests are based on an understanding of the role genes play in human
disease and were developed with a commitment to improving an individual's decisionmaking process for monitoring and treating disease. Myriad is focused on strategic
directives to introduce new products, including companion diagnostics, as well as
expanding internationally.
Approximately 11% to 15% percent of ovarian cancer cases are caused by
mutations in the BRCA1 or BRCA2 genes. People who carry a mutation in either of
these genes have a condition called Hereditary Breast and Ovarian Cancer (HBOC)
syndrome.1-3 They have an up to 44 percent risk of developing ovarian cancer by age 70.
In addition, mutation carriers who have already been diagnosed with cancer have a
significantly increased risk of developing a second cancer in the future. Patients with
Lynch syndrome are also at higher risk of developing ovarian, colon and uterine cancers.
Myriad offers genetic testing that can be used to identify people who carry a
BRCA1 or BRCA2 gene mutation or have Lynch syndrome. The Myriad myRisk test
evaluates evaluating multiple clinically-significant genes and detecting more people who
may be at risk for hereditary ovarian cancer. Studies have shown that testing with Myriad
myRisk increases mutation detection between 40% and 50%.

13.0 Urinary Tract Infections

KEY TREND
Urinary tract infections (UTIs) will continue to be a leading health care
expenditure for a range of patients. Sexually active young women are disproportionately
affected, but several other populations, including elderly persons and those undergoing
genitourinary instrumentation or catheterization, are also at risk. UTIs are the leading
cause of gram-negative bacteremia. In the US, these infections account for approximately
8 million office visits and more than 1 million hospitalizations annually. For women, the
lifetime risk of having a UTI is greater than 50%. UTIs in men are not as common as in
women but can be serious when they occur.
Molecular testing for UTI will continue to evolve as part of routine test menus.
13.1 LEADING CAUSE OF MORBIDITY AND DEATH

It has been estimated that more than 11 million women in the US had a presumed
UTI for which they took a prescription medication. UTIs cost an estimated $140 per case
to treat, and account for $1.6 billion spent annually for outpatient treatment. A healthy
female with a UTI will, on average, have six days of symptoms and more than two days
of restricted activities.
Unresolved nosocomial UTIs may account for as many as 56,000 deaths per year.
Most UTIs are caused by a variety of bacteria, including Escherichia coli (E. coli), found
in feces. Because the openings of the bowel, vagina and urethra are very close together, it

189
is easy for the bacteria to spread to the urethra and travel up the urinary tract into the
bladder and sometimes up to the kidneys.
Infection occurs when the bacteria cling to the opening of the urethra and
multiply, producing an infection of the urethra, called urethritis. Some women are more
prone to UTIs than others because the cells in their vaginal areas and in their urethras are
more easily invaded by bacteria. Women with mothers or sisters who have recurring
UTIs also tend to be more susceptible. The risk of a UTI also is greater if a woman is past
menopause.
Any abnormality of the urinary tract that blocks the flow of urine, such as a
kidney stone or significant prolapse of the uterus or vagina, also can lead to an infection
or recurrent infections. Illnesses that affect the immune system, such as diabetes, AIDS
and chronic kidney diseases, increase the risk of UTIs. A weak bladder can also make it
difficult to empty completely, allowing bacteria to grow.
When women develop UTIs during pregnancy, the bacteria are more likely to
affect the kidneys. Hormonal changes and repositioning of the urinary tract during
pregnancy may make it easier for bacteria to invade the kidneys. Such infections in
pregnant women can lead to urosepsis, kidney damage, high blood pressure and
premature delivery of the baby.
13.1.1 Impact
UTIs are the fourth most common type of hospital acquired infection (HAI) in the
US. They comprise 13% of HAIs reported, totaling about 93,000 infections annually.
Approximately two-thirds of UTIs in acute care hospital settings are believed to be
catheter-associated. According to the 2012 CDC National and State HAI Progress Report,
in 2012, an estimated 54,500 catheter-associated UTIs (CAUTIs) occurred in hospital
critical care units and inpatient wards. An estimated 13,000 deaths, a mortality rate of
2.3%, are attributed to UTIs annually in the US.
CAUTIs lead to longer length of hospital stay and are the leading cause of
secondary bloodstream infections. Up to 25% of hospitalized patients will have a urinary
catheter at some time during their hospital stay. Studies have found a strong correlation
between catheter use greater than six days and the development of a CAUTI. The

190
mortality rate increases to approximately 10% when the patient also has a secondary
bacteremia bloodstream infection as a result of the UTI. The estimated treatment cost
per infection ranges from $750 to $1,000. Estimated total treatment cost in the US ranges
from $340 million to $450 million annually.
Limited data are available from low- and middle-income countries. However,
recent analysis by WHO found that health care-associated infections are more frequent in
resource-limited settings than in developed countries. At any given time, the prevalence
of health care-associated infection varies between 5.7% and 19.1% in low- and middleincome countries. The average prevalence is significantly higher in high- than in lowquality studies (15.5% vs 8.5%, respectively). The proportion of patients with ICUacquired infection ranged from 4.4% to 88.9%, with a frequency of overall infections as
high as 42.7 episodes per 1,000 patient days. This is almost three times higher than in
high-income countries. Furthermore, in some developing countries, the frequency of
infections associated with the use of central lines and ventilators and other invasive
devices can be up to 19 times higher than those reported from Germany and the US.
Projects across the US had shown remarkable success in reducing infection rates
by adhering to basic standards for hand hygiene, disinfection of patients, sterile handling
of equipment and proper use of antibiotics. But at many hospitals those successes have
yet to overcome an entrenched medical culture. Despite promising improvements in a few
areas of health care, the hospital community is not achieving the more substantial strides
that are needed to address persistent gaps in quality and access.
13.1.2 Impact on Women

Women are more prone to UTIs than men because, in females, the urethra is much
closer to the anus than in males, and women lack the bacteriostatic properties of prostatic
secretions. UTIs also more commonly progress to bladder infections in females due to the
much shorter length of the female urethra. Among the elderly, UTI frequency is roughly
equal proportions in women and men. This is due, in part, to an enlarged prostate in older
men. As the gland grows, it obstructs the urethra, leading to increased difficulty in
urination. Because there is less urine flushing the urethra, there is a higher incidence of
colonization.


191
The prevalence for UTIs increases greatly in young sexually active women, up to
20% of whom have acute cystitis each year. This prevalence is increased by a previous
UTI, and in some populations, nearly 50% half of women with cystitis had one or more
recurrences within one year of follow-up. Up to 60% of women have had a UTI at some
point during their lifetime.
Nearly 20% of women who have had a UTI will have another, and 30% of those
who have had two will have a third. About 80% of those who have had three will have a
fourth. Some women are more prone to UTIs than others because the cells in their vaginal
areas and in their urethras are more easily invaded by bacteria. In young sexually active
women, sex is the cause of up to 90% of bladder infections, with the risk of infection
related to the frequency of sex.
13.1.3 E. coli the Key Culprit

Approximately 85% of UTIs are caused by Escherichia coli, which is the most
common hospital-acquired infection. According to several studies, women who use a
diaphragm are more likely to develop a UTI than women who use other forms of birth
control. Researchers also have found that women whose partners use a condom with
spermicidal foam also tend to have growth of Escherichia coli bacteria in the vagina.
To some extent, the symptoms of UTI are proportionate to the rate of bacterial
growth. Unlike other common uropathogens, such as chlamydia and mycoplasma, E. coli
grows quickly. Patients with E. coli infections typically describe abrupt onset and a rapid
increase in symptom severity. UTIs which seem to develop over a few weeks, which first
present with penile or urethral discharge, or which present without frequency and urgency
are more likely to be related to other organisms.
Bacteria frequently exhibit a preference for specific types of tissue. For example,
chlamydia and mycoplasma are typically confined to the urethra and reproductive tract.
E. coli, by contrast, is not discriminating; it can infect the urethra, bladder, kidneys, and
bloodstream.


192
13.2 UTI MOLECULAR TESTING MARKET

There will continue to be a steady market for tests that can diagnose UTIs. UTIs
are the fourth most common type of hospital acquired infection (HAI) in the US. They
comprise 13% of HAIs reported, totaling about 93,000 infections annually.
Approximately two-thirds of UTIs in acute care hospital settings are believed to be
catheter-associated. According to the 2012 CDC National and State HAI Progress Report,
in 2012, an estimated 54,500 catheter-associated UTIs (CAUTIs) occurred in hospital
critical care units and inpatient wards. An estimated 13,000 deaths, a mortality rate of
2.3%, are attributed to UTIs annually in the US.
There is significant interest in developing newer rapid diagnostics for detecting
UTIs. The ability to obtain rapid, definitive point of care diagnosis of UTIs will have a
favorable impact on its management. A new generation of biosensors based on microand nanotechnologies offer the potential for highly sensitive molecular diagnosis. With
continuing technology advancements and clinical acceptance, they could lead to a
significant shift in diagnosis and treatment.
The market for molecular testing for UTIs in women can be seen in Exhibits 35
and 36. The use of molecular platforms for this type of testing is expected to see
significant growth due to technological advancements. Many labs are transferring tests
for hospital acquired infections and UTIs from culture to molecular platforms. Some
biochip and array-based tests allow laboratories to screen for hospital acquired infections
in a single test.


193
Exhibit 35
World Market for Molecular Testing for UTIs in Females,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$180.0
103.5
32.2
11.7
67.5
40.5
435.4
2014
198.0
113.9
34.8
12.6
73.6
43.3
476.2
2015
217.8
125.3
37.6
13.6
80.2
46.3
520.8
2016
239.6
137.8
40.6
14.7
87.4
49.5
569.6

2017
263.6
151.9
43.8
15.9
95.3
53.0
623.5
2018
290.0
167.1
47.3
17.2
103.9
56.7
682.2

194
Exhibit 36
World Market for Molecular Testing for UTIs in Females
2014
3%
9%
41%
16%
24%
7%
US
European Union
China
Japan
ROW

Brazil

195
13.3 I-HEALTH INC.

Cromwell, CT
www.i-healthinc.com
i-Health Inc., formerly Amerifit, a wholly owned subsidiary of DSM Nutritional

Products, is a consumer health and wellness company that develops, markets and
distributes branded products that support natural wellness. i-Health Inc. holds the top
brand position in all of its key product categories and can be found in most major mass,
club, drug, grocery and specialty stores.
i-Health Inc.s AZO brands are intended to relieve UTI symptoms and to maintain
a healthy urinary tract. The AZO brand of products aid in the prevention and treatment of
urinary tract pain and discomfort, the prevention and treatment of yeast infections, and
relief from feminine itch.
AZO Test Strips are available for home use and test for both white blood cells and
nitrites. It is possible for a patient to test for UTIs in the home and call a doctor with
results.


196
13.4 LIOFILCHEM
Roseto degli Abruzzi, Italy
www.liofilchem.net
Since 1983, Liofilchem has been involved in the production of bacteriology
products. Its catalogue contains approximately 2,000 items classified into two main
categories: clinical and industrial microbiology. Liofilchem produces dehydrated culture
media, selective supplements, ready to use culture media in plates, tubes, bottles and slide
systems, microbial identification and susceptibility testing systems, antibiotic discs in
cartridges, systems for the chemical and microbial screening of food, and sterilization
process control systems. The company is present in over 60 countries with agents and
distributors. In addition, Liofilchem performs OEM and private label production in
several countries.
Liofilchem is marketing dip slides for the screening of urinary infections. The
company also sells chromogenic culture media under the Chromatic brand in powder
form or ready to use in petri dish or bottle formats. The chromogenic culture media are:
Chromatic Candida, Chromatic Coli/Coliform, Chromatic Salmonella and Chromatic
Detection for UTIs.


197
13.5 RHEONIX
Ithaca, NY
www.rheonix.com
Rheonix,
developer
of
molecular
diagnostics,
has
developed
the
EncompassMDx platform, a highly customizable technology that performs fully

automated, complex molecular assays in an easy-to-use and economical format on the
Rheonix Card cartridge. With both the Rheonix Card and EncompassMDx products,
Rheonix is well-positioned to penetrate key molecular diagnostic market sectors, from
reference labs through point-of-care.
The EncompassMDx is a fully automated, fully integrated device that combines
molecular and immunoassay testing. The UTI Card is able to diagnose UTIs with strain
specificity directly from urine in a three-hour period on an easy-to-use instrument.


198
13.6 SOMAGEN DIAGNOSTICS

Edmonton, Alberta, Canada
www.somagen.com
Somagen Diagnostics is a leading provider of clinical diagnostics solutions. The
company continues to build on a 25 year history. Somagen specializes in a wide range of
in-vitro diagnostic products to include cellular pathology, assisted reproductive
technology, microbiology, chemistry, industrial microbiology, hematology, and
immunology.
Somagen Diagnostics Alfred 60 and HB&L automated systems are designed for
urine culture and offer high sensitivity and specificity. Using patented light scattering
technology the Alfred 60 and HB&L are able to monitor bacteria replication activity from
the inoculum into specific culture broths and provide real time growth curves.
Quantitative bacterial count results are reported in CFU/ml.
A specific eugonic broth has been developed to guarantee optimized aerobic
pathogen bacteria growth. Broths are contained in sterile vials with pierceable hermetic
seals, reducing contaminations. Samples are incubated at 37C and constantly mixed
avoiding sedimentation, flotation and growth anomalies typical of several microorganisms. Only live bacteria are detected while interference from non-replicating
substances such as erythrocytes, leukocytes, dead cells and salts present in the sample are
eliminated during the initial zero reading.

14.0 Neonatal Jaundice

KEY TREND
More than 13 million babies experience jaundice annually. More than 9 million of
them are born in developing countries.
A large majority of cases of neonatal hyperbilirubinemia, neonatal jaundice, are
mild and correct themselves over the first few weeks of life. However, persistently high
concentrations
of
bilirubin
interfere
with
cellular
processes,
and
may
be
neurotoxic. Kernicterus is a form of neonatal jaundice that causes brain damage. Maternal
factors for jaundice: Infants of mothers with diabetes have higher incidence. Use of some
drugs may increase the incidence. There will continue to be a need for testing for this
condition.
14.1 ISSUES INVOLVING BILIRUBIN

Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is
found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted
in bile and urine, and elevated levels may indicate certain diseases. It is responsible for
the yellow color of bruises, urine, and the yellow discoloration in jaundice.
About 60% to 70% of healthy newborns develop hyperbilirubinemia, an elevated
serum bilirubin concentration, in the first week of life in the US. Severe
hyperbilirubinemia, in where there is a total serum bilirubin of more than 95%, occurs in
8% to 9% of neonates during their first week of life. The risk for neonatal

200
hyperbilirubinemia is higher in male neonates and increases progressively with
decreasing gestational age.
Bilirubin is created by the activity of biliverdin reductase on biliverdin, a green
tetrapyrrolic bile pigment which is also a product of heme catabolism. Bilirubin, when
oxidized, reverts to become biliverdin once again. This cycle, in addition to the
demonstration of the potent antioxidant activity of bilirubin, has led to the belief that
bilirubin's main physiologic role is as a cellular antioxidant.
Neonatal jaundice, a yellowing of the skin and other tissues of a newborn infant,
can be caused by a bilirubin level of more than 85 umol per liter in neonates. This
condition is common in upwards of 70% of newborns. In neonates the dermal icterus is
first noted in the face, and as the bilirubin level rises, it proceeds caudal to the trunk and
then to the extremities.
14.2 TWO FACTORS IN NEONATES

In neonates, jaundice tends to develop because of two factors: the breakdown
of fetal hemoglobin as it is replaced with adult hemoglobin, and the relatively immature
hepatic metabolic pathways which are unable to conjugate and so excrete bilirubin as
quickly as an adult. This causes an accumulation of bilirubin in the blood
hyperbilirubinemia leading to the symptoms of jaundice. If the neonatal jaundice does
not clear up with simple phototherapy, there may be other causes such as biliary atresia,
bile duct paucity, Alagille's syndrome, alpha 1 and other pediatric liver diseases. The
evaluation for these will include blood work and a variety of diagnostic tests.
Prolonged neonatal jaundice is serious. Severe neonatal jaundice may indicate the
presence of other conditions contributing to the elevated bilirubin levels, of which there
are a large variety of possibilities. These should be detected or excluded as part of the
differential diagnosis to prevent the development of complications.
14.3 RISK FACTORS

Risk factors for neonatal jaundice include:


201
x
Maternal factors: Infants of mothers with diabetes have higher incidence. Use of
some drugs may increase the incidence.
Genetics and familial risk: Incidence is higher in infants with siblings who had
significant neonatal jaundice and particularly in infants whose older siblings were
treated for neonatal jaundice. Incidence is also higher in infants with
mutations/polymorphisms in the genes that code for enzymes and proteins
involved in bilirubin metabolism, and in infants with homozygous or
heterozygous glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency and
other hereditary hemolytic anemias. Combinations of such genetic variants appear
to exacerbate neonatal jaundice.
Nutrition: Incidence is higher in infants who are breastfed or who receive

inadequate nutrition. When inadequate feeding volume is involved, increased
enterohepatic circulation of bilirubin probably contributes to prolonged jaundice.
Birth weight and gestational age: Incidence is higher in premature infants and in
infants with low birth weight.
Congenital infection.
Race: Incidence is higher in East Asians and American Indians and is lower in
African Americans.
Geography: Incidence is higher in populations living at high altitudes.
Among other causes, a family history can lead to neonatal jaundice, if there has
been anemia, splenectomy, or bile stones in family members or a known heredity for
hemolytic disorders; if there has occurred liver disease; or if there has been maternal
illness suggestive of a viral or other infection, maternal drug intake, delayed cord
clamping, or birth trauma with bruising.
14.4 SMART PHONE APP

In August 2014, University of Washington engineers and physicians developed a
smartphone application that checks for jaundice in newborns and can deliver results to

202
parents and pediatricians within minutes. It could serve as a screening tool to determine
whether a baby needs a blood test the gold standard for detecting high levels of
bilirubin.
The app, called BiliCam, uses a smartphones camera and flash and a color
calibration card the size of a business card. A parent or health care professional would
download the app, place the card on her babys belly, then take a picture with the card in
view. The card calibrates and accounts for different lighting conditions and skin tones.
Data from the photo are sent to the cloud and are analyzed by machine-learning
algorithms, and a report on the newborns bilirubin levels is sent almost instantly to the
parents phone.
A noninvasive jaundice screening tool is available in some hospitals and clinics,
but the instrument costs several thousand dollars and is not feasible for home use.
Currently, both doctors and parents assess jaundice by looking for the yellow color in a
newborns skin, but this visual assessment is only moderately accurate. The university
researchers developed BiliCam to be easy to use and affordable for both clinicians and
parents, especially during the first several days after birth when its crucial to check for
jaundice.
The scientists ran a clinical study with 100 newborns and their families at UW
Medical Center. They used a blood test, the current screening tool used in hospitals, and
BiliCam to test the babies when they were between two and five days old. They found
that BiliCam performed as well as or better than the current screening tool. Though it
wouldnt replace a blood test, BiliCam could let parents know if they should take that
next step.
The researchers plan to test BiliCam on up to 1,000 additional newborns,
especially those with darker skin pigments. The algorithms will then be robust enough to
account for all ethnicities and skin colors. This could make BiliCam a useful tool for
parents and health care workers in developing countries where jaundice accounts for
many newborn deaths.
14.5 BILIRUBIN TESTING MARKET

Neonatal hyperbilirubinemia is extremely common because almost every newborn
develops an unconjugated serum bilirubin level of more than 30 mol/L during the first

203
week of life. Abnormally high concentrations of bilirubin occur in 70% of newborns and
present as jaundice the number one condition requiring medical attention in this age
group. Given this, the market for bilirubin testing for neonatal jaundice should continue
to show respectable growth, in the 4% range annually, as can be seen in Exhibits 37 and
38. Kalorama estimates that the neonatal jaundice segment represents about half of the
POC market for bilirubin testing.
Exhibit 37
World Market for POC Bilirubin Testing for Neonatal Jaundice,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$7.3
5.4
1.0
0.36
2.1
1.4
17.56
2014
7.5
5.6
1.04
0.37
2.2
1.5
18.21
2015
7.8
5.8
1.09
0.38
2.3
1.6
18.97
2016
8.1
6.0
1.13
0.40
2.4
1.7
19.73

2017
8.4
6.3
1.17
0.42
2.5
1.8
20.59
2018
8.8
6.6
1.22
0.44
2.6
1.9
21.56

204
Exhibit 38
World Market for POC Bilirubin Testing for Neonatal Jaundice
2014
2%
12%
8%
42%
6%
30%
US
European Union
China
Japan
ROW

Brazil

205
14.6 INSTRUMENTATION LABORATORY

Bedford, MA
www.ilww.com
Founded in 1959, Instrumentation Laboratory has operations worldwide. It is part
of the Werfen Group, a global health care corporation marketing in vitro diagnostic
products, medical devices and scientific instruments. The companys product lines
include critical care systems, hemostasis systems and information management systems.
Instrumentation Laboratorys strength is in coagulation and critical care testing in
hospitals.
In 2009, Instrumentation Laboratory released the GEM Premier 4000 critical care
analyzer, (BG/Lytes/Glu/Lac/Hct) with integrated CO-Oximetry. The company also
launched a Total Bilirubin assay on the GEM Premier 4000 in Europe. In July 2010, the
FDA granted 510(k) clearance for the assay. The total bilirubin assay provides results in
90 seconds, avoiding the hour-long wait for results from a laboratory using traditional
chemistry methods.


206
14.7 NOVA BIOMEDICAL

Waltham, MA
www.novabiomedical.com
Nova Biomedical develops fast whole blood analyzers to support the care of
critically ill patients. In addition, Nova provides point of care, hand held meter and strip
based systems for glucose, ketone, lactate and creatinine testing. Nova employs more
than 800 people worldwide. The company has sales and service subsidiaries in six
countries and distributors in more than 80 other countries.
Nova has incorporated total bilirubin (tBil) to the test menu on its Stat Profile
Critical Care Xpress 13 analyzer. Stat Profile Critical Care Xpress is a consolidated stat
analyzer with up to 20 measured whole blood tests, and 29 calculated tests on. Thirteen
standard menus provide a choice of popular critical care assays. Critical Care Xpress can
be configured with any custom test menu that is created from the Critical Care Xpress
menu choices.
Nova also manufactures a series of BioProfile automated chemistry and cell
analysis analyzers for the rapid testing of key nutrients, metabolites, gases and cell status
in cell culture and fermentation media. Nova develops and manufactures blood glucose
test strips and monitors for self-testing by diabetics. The company also operates a
contract development and manufacturing division that develops and manufactures various
diagnostics.


207
14.8 SIEMENS HEALTHCARE DIAGNOSTICS

Tarrytown, NY
www.siemens.com/diagnostics
Siemens Health Care Diagnostics offers a portfolio of diagnostic products that
provide more effective ways to assist in the diagnosis, monitoring and management of
disease. The unit offers a broad portfolio of diagnostic solutions that include a variety of
diagnostic systemsintegrated chemistry, immunoassay, routine chemistry, automation,
hematology, hemostasis, microbiology, diabetes, urinalysis, blood gas monitoring and
molecular testing.
In 2006, Siemens made its move into in vitro diagnostics. The company acquired
Diagnostics Products Corp., the Bayer Diagnostics Division (without Bayer Diabetes
Care) and Dade Behring.
Siemens is offering an FDA cleared and CE Marked neonatal total bilirubin
application on its RapidLab 1245 and 1265 blood gas analyzers. Test results are available
in 60 seconds.


208
14.9 WAKO DIAGNOSTICS

Richmond, VA
www.wakodiagnostics.com
Wako Diagnostics is a division of Wako Chemicals USA Inc. Since 1978, Wako
Diagnostics has been promoting diagnostic reagents in the US market. The company
offers test kits for unique analytes, as well as routine testing. Wako Chemicals USA Inc.
is a wholly owned subsidiary of Wako Pure Chemical Industries Ltd. of Japan.
Wako is a manufacturer of clinical diagnostic reagents, including its Direct
Bilirubin V and Total Bilirubin V for in vitro diagnostic use.
Both products are based on a chemical oxidation method, utilizing vanadate as an
oxidizing agent. They show good correlation with conventional methods, practically no
interference by coexisting substances, and are ready-to-use liquid type reagents.


209

Indianapolis, IN
http://www.roche-diagnostics.us/Pages/default.aspx
Roche is a global healthcare company that markets both pharmaceutical and
diagnostic Products. Sales for the whole company total about $49 billion. In 2013, the
Roche Group employed over 85,000 people worldwide, invested about $9 billion in
research and development. Genentech is a wholly owned member of the Roche Group.
Roche is the majority shareholder in Chugai Pharmaceutical of Japan.
Roche is marketing the cobas b 123 POC blood gas analyzer designed for health
professionals at the point of care (POC). The cobas b 123 POC system has many
infection control and safety features that mark the analyzer for parameter testing
throughout the hospital setting.
The analyzer measures 17 parameters including blood gases (pH; pCO2; pO2),
electrolytes (Na+; K+; Ca2+; Cl-; Hct), metabolites (Lactate; Glucose) and Co-oximetry
(tHb, SO2; O2Hb; COHb; MetHb; HHb and total bilirubin), with a throughput of 30
samples per hour. An extended panel of test parameters gives an overall perspective of a
patients condition.

15.0 Autoimmune Disease

KEY TREND
Autoimmune disease as a category affects 50 million Americans. It is one of the
top ten causes of death in women under the age of 65. Women are more susceptible to the
diseases, as they are affected 75% more often than men. The NIH estimates annual direct
health care costs for AD to be in the range of $100 billion. Scientists have found
autoimmune characteristics in many of the more common diseases, such as arthritis, liver
disease, atherosclerosis, celiac disease, and diabetes antiphospholipid syndrome, among
other illnesses. In the future, automation will be important for autoimmune testing.
Autoimmune test kits will be developed for mainstream immunoanalyzers so that they
could be run alongside routine chemistry/immunoassay tests. Tests will be developed that
can test for several diseases simultaneously.
15.1 TYPES OF AUTOIMMUNE DISEASE

The diseases that fall into the autoimmune category include:
x
Alopecia areata;
Autoimmune hemolytic anemia;
Autoimmune hepatitis;
Dermatomyositis;

211
x
Type 1 diabetes;
Graves disease;
Guillain-Barr syndrome;
Some myocarditis;
Multiple sclerosis;
Pernicious anemia;
Psoriasis;
Rheumatoid arthritis;
Systemic sclerosis;
Systemic lupus erythematosus
Thyroiditis.
15.2 GENETIC FACTORS

Autoimmunity is the failure of an organism to recognize its own constituent parts
as self, which allows an immune response to occur against its own cells and tissues. Any
disease that results from such an aberrant immune response is called an autoimmune
disease. Autoimmunity is often caused by a lack of germ development of a target body
and as such the immune response acts against its own cells and tissues. Essentially,
autoimmune diseases occur when the immune system mistakenly recognizes the body's
own proteins as foreign invaders and begins producing antibodies that attack healthy cells
and tissues.
Most autoimmune disorders are thought to be multifactorial many factors are
involved in causing a health problem. The factors are usually both genetic and
environmental. A combination of genes from both parents, in addition to unknown
environmental factors, produces the trait or condition. Multifactorial traits do recur in
families because they are partly caused by genes. The environmental factors are generally
thought to trigger an immune response to certain environmental influences, such as viral


212
infections or sunlight. Once an autoimmune disease is present in a family, other relatives
may be at risk to develop the same autoimmune disease, or a different autoimmune
disease. A positive family history of autoimmune disorders means that there is a genetic
predisposition that may increase a mothers risk or a childs risk to develop an
autoimmune disease.
Certain individuals are genetically susceptible to developing autoimmune
diseases. This susceptibility is associated with multiple genes plus other risk factors.
Three main sets of genes are suspected in many autoimmune diseases. These
genes are related to: immunoglobulins; T-cell receptors; and the major histocompatibility
complexes (MHC). The first two, which are involved in the recognition of antigens, are
inherently variable and susceptible to recombination. These variations enable the immune
system to respond to a very wide variety of invaders, but may also give rise
to lymphocytes capable of self-reactivity.
15.3 IMPACT ON FEMALES

A person's sex also seems to have some role in the development of autoimmunity,
classifying most autoimmune diseases as sex-related diseases. Nearly 75% of those who
suffer from autoimmune disease are women, although it is less-frequently acknowledged
that millions of men also suffer from these diseases. According to the American
Autoimmune Related Diseases Association (AARDA), autoimmune diseases that develop
in men tend to be more severe. A few autoimmune diseases that men are just as or more
likely to develop as women include: ankylosing spondylitis, type 1 diabetes mellitus,
Wegener's granulomatosis, Crohn's disease and psoriasis.
The reasons for the sex role in autoimmunity are unclear. Women appear to
generally mount larger inflammatory responses than men when their immune systems are
triggered, increasing the risk of autoimmunity. Involvement of sex steroids is indicated
by how many autoimmune diseases tend to fluctuate in accordance with hormonal
changes, for example, during pregnancy, in the menstrual cycle, or when using oral
contraception. A history of pregnancy also appears to leave a persistent increased risk for
autoimmune disease.
The fact that women have enhanced immune systems compared to men increases
women's resistance to many types of infection, but also makes them more susceptible to

213
autoimmune diseases. Autoimmune diseases have been cited in the top 10 leading causes
of all deaths among US women age 65 and younger. Moreover, these diseases represent
the fourth largest cause of disability among women in the US. Different ethnic groups are
more susceptible to certain autoimmune diseases. In lupus, for example, African
American, Hispanic, Asian and Native American women are two to three times more
likely to develop the disease than Caucasian women. And 9 of 10 people who have lupus
are women.
15.4 FEMALE LAB-BASED IMMUNOASSAY AUTOIMMUNE TESTING

MARKET
Despite the advances achieved in detecting autoimmune disease, the overall lack
of awareness among the public with regard to autoimmune disease and its complications
has challenged market growth for diagnostics. On the horizon, companies are developing
tests that harness groups of biomarkers The ability to screen a patient with several
biomarkers associated with several autoimmune diseases will improve diagnostic
accuracy and will positively impact the autoimmune disease diagnostics market.
Such novel biomarker panels will offer advantages to health care givers who
diagnose such complications. While using single biomarkers may offer some help to
laboratory personnel, the development of complex biomarker panels could help
characterize the type of disease, its status, progression and response to therapy of many
autoimmune complications. Given new advances in science finding their way to the
market place, the market for autoimmune disease diagnostics should see modest growth
at about 6% annually. Testing for these diseases in women comprise 75% of this
segment, as seen in Exhibits 39 and 40.


214
Exhibit 39
World Female Lab-Based Immunoassay Autoimmune Testing
Market,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$232.0
162.4
41.5
15.1
63.8
46.4
561.2
2014
246.0
172.1
44.0
16.0
67.6
49.2
594.9
2015
260.8
182.4
46.6
17.0
71.7
52.2
630.7
2016
276.4
193.3
49.4
18.0
76.0
55.3
668.4

2017
293.0
204.9
52.4
19.1
80.6
58.6
708.6
2018
310.6
217.2
55.5
20.2
85.4
62.1
751.0

215
Exhibit 40
World Female Lab-Based Immunoassay Autoimmune Testing
Market
by Geographic Segment, 2014
4%
8%
11%
41%
7%
29%
US
European Union
China
Japan
ROW
Brazil


216
15.5 AESKU.DIAGNOSTICS
Wendelsheim, Germany
www.aesku.com
Aesku.Diagnostics is a research-based provider of IVD kits and instruments for

the diagnosis and prognosis of autoimmune diseases. The company incorporates a group
of companies that include Aesku.Diagnostics (autoimmunity in-vitro diagnostics),
Aesku.Therapy (autoimmune therapies), and Aesku.Systems (lab automation).
The company has also established and supports Aesku.Kipp Institute, a non-profit
institute that conducts basic research and technology transfer in autoimmunity.
Aesku.Diagnostics offers the Aeskulisa ELISA test kits, as well as IFA reagents
and blot reagents. The companys ELISA reagents include a wide range of autoimmune
ELISA tests. These are microtiter-based tests for 42 different parameters. This includes
both routine and research based kits for autoimmune diseases in areas, such as
rheumatology, thrombosis, vasculitis, thyroid, gastroenterology, diabetes, hepatology,
and hemostasis, among other areas.


217
15.6 AXA DIAGNOSTICS SRL

Rome, Italy
www.axadiagnostics.com
AXA Diagnostics became an operating company in 2009, offering a range of
ELISA and IFA tests for the diagnosis of autoimmune diseases. The company now offers
ELISA autoimmune products that detect a wide range of markers characteristic of various
autoimmune diseases.
AXA Diagnostics also offers autoimmune tests based on IFA, immunoblotting,
immunodot, and Immunoquick technologies. The Immunoquick products are
immunochromatographic tests.
In addition, AXA Diagnostics offers other products, including bacteriology
products for sexually transmitted disease diagnostics, virology products for HSV
diagnostics, and obstetrics products. In instrumentation, AXA offers the SkyLAB 752
Analyzer, an immunoassay system that automates the processing of diagnostic tests that
utilize ELISA and IFA technologies.


218
15.7 BIO-RAD LABORATORIES

Clinical Diagnostics Group
Hercules, CA
www.bio-rad.com
Bio-Rad Laboratories has been involved in the in vitro diagnostics business for
more than four decades. Company sales totaled more than $2.1 billion in 2013. The
companys Clinical Diagnostics Group manufactures a variety of diagnostic test kits used
for HIV-1 and HIV-2, Hepatitis A, B, C, Syphilis, Aspergillus, and autoimmune diseases,
and tests used for the detection of genetic disorders and food-borne pathogens.
Bio-Rads growth comes from its strength in multi-niche markets including
infectious
disease
immunoassays,
diabetes
hemoglobin
A1c,
autoimmnune
immunoassays, neonatal screening, blood typing, microbiology media, and quality

control products. The company offers diagnostic kits, controls, instrumentation, and
supplies for autoimmune testing by IFA and EIA.
In the area of autoimmune diseases, Bio-Rad offers products for non-organ
specific systemic autoimmune testing; vasculitis testing; anti-phospholipid testing; and
gastrointestinal testing, among other products.


219
15.8 EUROIMMUN AG
Lbeck, Germany
www.euroimmun.com
Euroimmun was founded in 1987. The company produces reagents for medical
laboratory diagnostics with a focus on test systems for the diagnosis of autoimmune
diseases, infectious diseases and allergies. The test methods employed are predominantly
indirect immunofluorescence, microplate ELISA, various blot techniques (Western blot,
Euroassay, Euroline, Euroline-WB) and all molecular biology techniques.
Euroimmun offers a large menu of ELISA tests and enzyme immunoassays for
the diagnosis of autoimmune and infectious diseases.


220
15.9 IMMCO DIAGNOSTICS

Buffalo, New York
www.immco.com
Immco Diagnostics focuses on autoimmune disease diagnostics. In September
2013, the company was acquired by Trinity Biotech for $32.75 million.
Immco markets autoimmune disease diagnostic tests under the ImmuGlo
(immunofluoresence assay), ImmuLisa (ELISA), ImmuBlot (Western blot assay), and
ImmuStripe (line immunoassay) brands. In addition, the company offers several
instruments for use with its autoimmune disease tests. These instruments include: the
Immco i-Sight IFA system for image acquisition and interpretation of cell and tissue
based indirect immunofluorescence (IIF) diagnostics; the Zenit UP all in one Automated
ELISA Microplate and IFA slide Processor; the ThunderBolt EIA Platform with total
automation in an open, compact system; the DSXTM, a fully automated four plate
ELISA processing system, capable of performing multiple assays per plate; and the DS2,
a complete ELISA processing system for laboratories with lower volume requirements.


221
15.10 KRONUS
Star, ID
www.kronus.com
Kronus is a provider of immunodiagnostic reagents and test kits to the research

and clinical laboratory marketplace. The company offers more than a dozen
immunoassay test kits and related laboratory reagents useful in the assessment of various
autoimmune and endocrine and metabolic disorders.
The company offers autoimmune diagnostics for pancreas, neuromuscular,
neuroimmunologic, adrenal and thyroid-related disease.


222
15.11 PHADIA
Uppsala, Sweden
www.phadia.com
Phadia, purchased by Thermo Fisher Scientific in 2011, develops, manufactures
and markets complete blood test systems to support the clinical diagnosis and monitoring
of allergy, asthma and autoimmune diseases. The company was previously a division of
the Pharmacia and Pfizer groups. The acquisition of Phadia was a major step forward in
Thermo Fishers strategy to enhance its global presence in specialty diagnostics, a key
growth platform.
Phadia has supplied more than seven out of 10 allergy laboratory tests worldwide
and four out of 10 autoimmunity tests to laboratories throughout Europe.
Phadia had been transitioning from its focus on allergy testing to autoimmune
immunoassays on its ImmunoCap analyzers. The ImmunoCAP symptom profiles provide
quantitative measurements of specific IgE levels, supporting the prognosis, diagnosis and
follow-up of allergic patients.
Tests are available for the following autoimmune diseases: rheumatoid arthritis,
vasculitis/Goodpasture syndrome, connective tissue diseases, antiphospholipid syndrome,
autoimmune thyroiditis, celiac and inflammatory diseases.


223
15.12 XDX
Brisbane, CA
www.xdx.com
In March 2014, XDx changed its name to CareDx. The company applies
genomics technologies to the development of molecular diagnostic assays that translate a
patient's immune status into clinically actionable information. The company has one
product on the market, the AlloMap Molecular Expression Testing system.
The proprietary molecular expression technology used by the company to develop
AlloMap testing for heart transplant patient management may be applicable to the posttransplant management of recipients of other organs. The application of gene expression
testing to other diseases that involve the activity of the immune system, such as
autoimmune and chronic inflammatory diseases, is also being explored.
AlloMap Molecular Expression Testing is a noninvasive gene expression test used
to help identify heart transplant recipients with stable allograft function who have a low
probability of moderate/severe acute cellular rejection at the time of testing in
conjunction with a standard clinical assessment. AlloMap testing measures the expression
levels of 20 genes from a blood sample. The combined expression of these genes is
represented as an AlloMap test score.
The company is also pursuing other areas of transplant surveillance, such as the
use of cell-free DNA (cfDNA) as a biomarker for rejection.

16.0 Cystic Fibrosis

KEY TREND
Cystic fibrosis is most common among Caucasians. Worldwide, approximately
70,000 people have cystic fibrosis. Approximately 30,000 Americans have it as well,
making it one of the most common life-shortening inherited diseases. This disease occurs
in one of every 3,200 Caucasian births. Some research shows that the female hormone
estrogen promotes the presence of a particular form of bacteria which results in more
severe symptoms for female cystic fibrosis patients. With genetically predisposed cystic
fibrosis, the rise and spread of the disease is more common in certain ethnic groups, such
as in people with northern European lineage. For this reason, the US has the largest
population of cystic fibrosis patients, while smaller countries in the northern hemisphere,
like Ireland, have a high proportion of the disease within their general population.
However, increasing globalization is contributing to a spread of genetic diseases like
cystic fibrosis, leading public health organizations in parts of the world previously
unaffected by the disease to begin addressing best practices for researching, diagnosing,
and treating the disease.
Cystic fibrosis is diagnosed in males and females equally. Individuals with cystic
fibrosis can be diagnosed before birth by genetic testing or by a sweat test in early
childhood. Ultimately, lung transplantation is often necessary as the illness worsens. New
testing techniques are evolving to improve diagnosis of the disease.

225
16.1 AFFECTING THE ENTIRE BODY

Cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation
within the pancreas. Difficulty with breathing is the most serious symptom. This results
from frequent lung infections that are treated with, though not cured by, antibiotics and
other medications. A multitude of other symptoms, including sinus infections, poor
growth, diarrhea, and infertility result from the effects of the disease on other parts of the
body.
The hallmark symptoms of cystic fibrosis are salty tasting skin, poor growth and
poor weight gain despite a normal food intake, the accumulation of thick, sticky mucus,
frequent chest infections and coughing or shortness of breath. Males can be infertile due
to congenital absence of the vas deferens. Symptoms often appear in infancy and
childhood, such as bowel obstruction due to meconium ileus in newborn babies. As the
child grows, he or she will need to exercise to release mucus in the lung alveoli. Ciliated
epithelial cells in the patient have a mutated protein that leads to abnormally viscous
mucus production.
16.2 REDUCED LIFE EXPECTANCY

Cystic fibrosis brings with it reduced life expectancy. The average life expectancy
of a person with cystic fibrosis is 32 years. The life expectancy of cystic fibrosis patients
has been increasing over the past 40 years. In the 1980s, the life expectancy of people
with the disease was 14 years. A decade ago, the life expectancy was around 18 years. It
has been estimated that there has been more than 10 year increase in the average life
expectancy of affected people in North America.
Mortality in cystic fibrosis is associated with chronic obstructive pulmonary
disease. Respiratory failure is the primary cause of death among more than 90% of
persons with cystic fibrosis. Until the 1980s, deaths typically occurred during childhood
or adolescence, but the majority of persons now survive into adulthood. From 1974 to
1994, the international median age of death from cystic fibrosis increased from 8 years to
age 21 years. In the US, the median age of death from cystic fibrosis in 2000 was 24
years, with 5% of deaths occurring before 10 years of age, 25% before age 17 years, and
75% before 35 years of age. Because of an increasing life expectancy, the median age of


226
death understates survival. From 1969 to 2001, the median predicted age of survival
increased from age 14 years of age to 33 years.
More than 90% of affected infants survive beyond one year. Studies show that the
life expectancy of children eventually will exceed 40 years. Life expectancy of
individuals with adequate pancreatic function can be more than 50 years. Around 1,000
new cases of cystic fibrosis are diagnosed each year.
About 1 in 2,500 babies in the UK are born with cystic fibrosis. More than 9,000
people currently have cystic fibrosis in the UK. Approximately 80% of patients are
diagnosed by the age of three. About 10% of patients are diagnosed at the age of 18, and
3% patients are diagnosed in adulthood.
16.3 GENETICS
Cystic fibrosis is caused by a mutation in the gene for the protein cystic fibrosis
transmembrane conductance regulator (CFTR). This gene is required to regulate the
components of sweat, digestive juices, and mucus. Although most people without cystic
fibrosis have two working copies of the CFTR gene, only one is needed to prevent cystic
fibrosis. Cystic fibrosis develops when neither gene works normally. Therefore, cystic
fibrosis is considered an autosomal recessive disease. Two copies of the gene must be
mutated for a person to be affected by an autosomal recessive disorder. The disease is
most common among Caucasians.
The most common CFTR mutation, F508, is a deletion () of three nucleotides
that results in a loss of the amino acid phenylalanine (F) at the 508th position on the
protein. This mutation accounts for approximately two-thirds of cases worldwide and
90% of cases in the US. However, there are more than 1,400 other mutations that can
produce the disease. Lung disease occurs, resulting from clogging of the airways due to
mucus build-up, decreased mucociliary clearance and inflammation. Inflammation and
infection will cause injury and structural changes to the lungs, leading to a variety of
symptoms.


227
16.4 CHRONIC INFECTIONS

The lungs of individuals with cystic fibrosis are colonized and infected by
bacteria from an early age. These bacteria, which often spread among individuals with
cystic fibrosis, thrive in the altered mucus, which collects in the small airways of the
lungs. This mucus leads to the formation of bacterial microenvironments known as
biofilms, which are difficult for immune cells and antibiotics to penetrate. Viscous
secretions and persistent respiratory infections repeatedly damage the lung by gradually
remodeling the airways which makes infection even more difficult to eradicate.
In the initial stage of cystic fibrosis, common bacteria such as Staphylococcus
aureus and Hemophilus influenza colonize and infect the lungs. Eventually,
Pseudomonas aeruginosa, and sometimes Burkholderia cepacia, dominate. By 18 years
of age, 80% of patients with classic cystic fibrosis harbor P. aeruginosa, and 3.5% harbor
B. cepacia. Once within the lungs, these bacteria adapt to the environment and develop
resistance to commonly used antibiotics. Pseudomonas can develop special
characteristics that allow the formation of large colonies, known as mucoid
Pseudomonas, which are rarely seen in people that do not have cystic fibrosis.
16.5 FEMALES WORSE THAN MALES

In May 2012, scientists with the Respiratory Research Division of the Department
of Medicine, Royal College of Surgeons in Ireland (RCSI) published a study which
represents a major breakthrough in understanding why females with cystic fibrosis do
worse than males. The study is the first to show that the female hormone estrogen
promotes the presence of a particular form of bacteria which results in more severe
symptoms for female cystic fibrosis patients. In addition, females who were taking the
oral contraceptive pill, which decreases the amount of naturally occurring estrogen in
their bodies, were found to have lower levels of the problematic bacteria.
The research found that estrogen promoted the presence of a mucoid form of the
bacterium Pseudomonas aeruginosa in the lungs of women with cystic fibrosis. These
mucoid type of Pseudomonas aeruginosa are coated in a slimy layer which makes them
more difficult to treat with antibiotics. They also are more difficult to clear with the

228
body's own natural defenses which leads to significant lung inflammation, explaining, at
least in part, why females with cystic fibrosis often have a worse outcome.
Meanwhile, in February 2014, Stanford University researchers developed a test
for people with cystic fibrosis, who suffer chronic lung infections. The test, taken by
sampling sweat, shows that smaller amounts of CFTR are necessary to stop cystic fibrosis
symptoms than previously thought, according to Jeffrey Wine, a professor of psychology
and biology who is the director of Stanford's Cystic Fibrosis Research Laboratory. The
new test determines the ratio between two types of sweat in each individual by using dyes
to form bubbles on the skin. That ratio accounts for differences in sweat volume
between a conditioned athlete and a sedentary person, for example and reveals an
individuals CFTR levels.
16.6 GENETIC TESTING MARKET

Cystic fibrosis is the most common autosomal recessive disorder in the Caucasian
population, and the need for testing will continue to be an issue and a market
opportunity. Highly accurate and affordable cystic fibrosis genetic tests are needed to
address the market for carrier screening and as a tool for diagnosing the disease in
newborns. Moreover, the trend will be for some companies to offer panels of singlenucleotide polymorphism (SNP)-based tests for many genetic diseases, including cystic
fibrosis, Tay-Sachs, spinal muscular atrophy, and others. What will be key for these tests
will be their ease-of-use and consumer friendliness qualities that will make such tests
appealing, although there are ethical and societal implications of such screening tests as
their availability and scope grow.
There are concerns for market growth in this segment. The patent process does
not work well when licenses are unavailable, or when they are granted at very high
royalty rates. In some instances, exclusive licenses to gene patents, most of which are
held by academic institutions or based on taxpayer-funded research, are blocking
competition in the testing market and are not so much spurring the development of new
technologies for gauging disease risk, according to researchers at the Duke University
Institute for Genome Sciences and Policy (IGSP), Durham, NC.


229
As single-gene tests give way to multi-gene or even whole-genome scans,
exclusive patent rights could slow promising new technologies and business models for
genetic testing even further. These findings emerge from a series of case studies that
examined genetic risk testing for 10 clinical conditions, including breast and colon
cancer, cystic fibrosis, and hearing loss. In seven of the conditions, exclusive licenses
have been a source of controversy, but in no case was the holder of exclusive patent
rights the first to market with a test.
That finding suggests that while exclusive licenses have proven valuable for
developing drugs and biologics that might not otherwise be developed, in the world of
gene testing they are mainly a tool for clearing the field of competition, and that is a surefire way to irritate your customers, both doctors and patients, says Robert Cook-Deegan,
director of the IGSP Center for Genome Ethics, Law and Policy. Its notable that a gene
linked to cystic fibrosis is not subject to an exclusive license, yet there is now a vibrant
market for tests to identify carriers of the cystic fibrosis gene. This suggests the problem
is not patents, per se, but how they are being licensed, particularly by universities.
The case studies, originally undertaken at the request of the US Secretary of
Health and Human Services Advisory Committee on Genetics, Health and Society
(SACGHS), show that gene patenting itself is not necessarily the main problem. Rather,
the concern is a troublesome combination of overly broad patents that are exclusively
licensed to single companies.
More than two-thirds of the patents examined in the case studies are held by
universities or other nonprofit institutions that depend on government or nonprofits for
much of their biomedical research funding, often including the research leading to gene
patents. Yet university licensing practices can end up harming genetic testing laboratories
at other universities, or preventing development of alternative tests that might offer
improved accuracy, lower cost or the ability to test for multiple gene mutations
simultaneously.
Despite the issues involving genetic and molecular testing patents, the market for
genetic testing for cystic fibrosis will grow at about a 4% to 5% annual rate in the near
term, as seen in Exhibits 41 and 42. Female patients constitute about half of this market.
The mutations screened by genetic testing vary, based on an individuals race or
ethnicity, or if a family member has the disease. More than 10 million Americans are

230
carriers of one mutation of the cystic fibrosis gene. Among Caucasian Americans, about
one in 29 people carry one mutation of the gene. In other races or ethnicities, one in 46
Hispanic Americans, one in 65 African Americans and one in 90 Asian Americans carry
a mutation of the gene.
Exhibit 41
World Genetic Testing Market for Cystic Fibrosis in Females,
2013-2018
REGION
US
EUROPE
CHINA
BRAZIL
JAPAN
ROW
TOTAL
2013
$25.2
16.8
4.6
1.7
4.2
5.4
57.9
2014
26.5
17.6
4.8
1.8
4.4
5.6
60.7
2015
27.8
18.5
5.0
1.9
4.6
5.8
63.6
2016
29.2
19.4
5.2
2.0
4.8
6.0
66.6

2017
30.7
20.4
5.4
2.1
5.0
6.2
69.8
2018
32.2
21.4
5.6
2.2
5.2
6.5
73.1

231
Exhibit 42
World Genetic Testing Market for Cystic Fibrosis in Females

2014
9%
7%
42%
14%
28%
US
European Union
BRIC
Japan
ROW


232
16.7 AUTOGENOMICS
Vista, CA
www.autogenomics.com
Founded in 1999, AutoGenomics is privately held and designs, develops,
manufactures and markets an automated, microarray-based multiplexing diagnostic
platform that can be used to assess disease signatures with novel genomic and proteomic
markers in the areas of personalized medicine, womens health, oncology, genetic
disorders and infectious disease.
With the discovery of genes and their link to various disease states, the
AutoGenomics platform facilitates the way patients are diagnosed, monitored and
managed, facilitating personalized medicine and advances in drug selection and dosing.
The companys Infiniti System is a multiplexing, continuous flow, random access
microarray platform that offers genetic marker detection with varying options in
automation and throughput.
AutoGenomics Infiniti CFTR-31Analyzer, which is CE-Marked, makes possible
the genetic testing of 25 known markers for CFTR. Testing for these markers in adults of
reproductive age can serve as an aid in newborn screening for cystic fibrosis and also as a
diagnostic test to confirm cystic fibrosis in newborns and children.


233
16.8 GENMARK DIAGNOSTICS

Carlsbad, CA
www.genmarkdx.com
GenMark Diagnostics is a provider of automated, multiplex molecular diagnostic
testing systems that detect and measure DNA and RNA targets to diagnose disease and
optimize patient treatment. Revenue for the year ended Dec. 31, 2013 was $27.4 million,
compared to $20.5 million for the prior year, an increase of 34%.
Utilizing GenMark's proprietary eSensor detection technology, GenMark's
eSensor XT-8 system, a multiplexed molecular diagnostics system, supports a broad
range of molecular diagnostic tests with a compact workstation and self-contained,
disposable test cartridges.
GenMark currently markets four tests that are FDA cleared for IVD use: the
Cystic Fibrosis Genotyping Test, Respiratory Viral Panel, Thrombophilia Risk Test, and
Warfarin Sensitivity Test. A number of other tests, including HCV Genotyping, 2C19
Genotyping, and 3A4/3A5 Genotyping are available for research use only.
With the XT-8, the target DNA is mixed with the signal probe solution. If the
applicable target DNA is present, hybridization to the signal probes occurs immediately.
The solution is pumped through a cartridges microfluidic chamber and the target
DNA/signal probe complex completes the reaction with the pre-assembled capture probe.
Voltage is swept across each electrode and target DNA is analyzed by electrochemical
detection.


234
16.9 ILLUMINA
San Diego, CA
www.illumina.com
Illumina is a developer, manufacturer, and marketer of life science tools and
integrated systems for the analysis of genetic variation and function. The company
markets sequencing- and array-based solutions for genotyping, copy number variation
analysis, methylation studies, and gene expression profiling of DNA and RNA. It is
dominant in the sequencing market. Revenue for 2013 totaled more than $1.4 billion, up
from more than $1.1 billion in 2012.
In the area of cystic fibrosis, the company offers the MiSeqDx Cystic Fibrosis
System, the first FDA-cleared in vitro diagnostic (IVD) next generation sequencing
platform offering a complete solution for accurate, comprehensive cystic fibrosis testing.
One platform, the MiSeqDx instrument, runs both the MiSeqDx Cystic Fibrosis 139Variant Assay and the MiSeqDx Cystic Fibrosis Clinical Sequencing Assay, optimizing
the laboratory workflow.
The 139-variant assay detects 139 CFTR variants, providing the largest panel of
clinically relevant and functionally verified variants as defined in the CFTR2 database.
The clinical sequencing assay sequences all protein coding regions and intron/exon
boundaries of the CFTR gene, two large deletions (exon 2,3 and exon 22,23), two deep
intronic mutations (1811+1.6Kb A>G and 3849+10Kb C>T), and indels in
homopolymeric regions such as the 2184delA deletion.


235
16.10 LUMINEX
Austin, TX
www.luminexcorp.com
Luminex develops, manufactures and markets proprietary biological testing
technologies with applications throughout the diagnostic and life sciences industries.
Revenues for 2013 totaled more than $213 million, up from more than $202 million in
2012.
In 2009, Luminex received FDA clearance to market the xTAG Cystic Fibrosis 39
Kit v2. The xTAG Cystic Fibrosis Kit is a device used to simultaneously detect and
identify a panel of mutations and variants in the CFTR gene in human blood specimens.
xTAG technology utilizes a universal tag system that allows easy optimization
and expansion of molecular diagnostic assays. The xTAG test is used to screen potential
parents to determine if they are carriers of cystic fibrosis-causing gene mutations, and as
an aid in newborn screening and in confirmatory diagnostic testing in newborns and
children. It is the next generation of Luminexs first xTAG Cystic Fibrosis Kit that was
first cleared by the FDA in May 2005.
The test screens for the 23 CFTR gene mutations and for variants recommended
by the American College of Medical Genetics and American College of Obstetricians and
Gynecologists, as well as for 16 additional CFTR gene mutations in blood.


236
16.11 SCHEBO BIOTECH AG

Giessen, Germany
www.schebo.com
ScheBo-Biotech AG is a private company founded in 1989 by the biochemists
and molecular biologists Ursula Scheefers-Borchel, Ph.D., and Hans Scheefers, Ph.D.
The company is active in the areas of gastroenterology, oncology, food analysis, and
veterinary diagnostics.
In 1993, ScheBo-Biotech launched ScheBo Pancreatic Elastase 1 ELISA. Two
test kits are available for determination of pancreatic elastase 1. A stool test quantifies
pancreatic elastase 1 in stool, and can be used to diagnose or exclude pancreatic exocrine
insufficiency, which can be caused by conditions such as chronic pancreatitis, cystic
fibrosis, pancreatic tumor, cholelithiasis or diabetes mellitus.
ScheBo-Biotech also offers a serum test to quantify pancreatic elastase 1 in
serum. This test can be used to diagnose or exclude acute pancreatitis.


237
16.12 SEQUENOM
San Diego, CA
www.sequenom.com
Sequenom is a molecular diagnostic testing and genetics analysis company
targeting products for biomedical research, translational research, molecular medicine
applications, and agricultural, livestock, and other areas of research. The companys
development and commercialization efforts in various diagnostic areas include
noninvasive womens health related and prenatal diagnostics, age-related macular
degeneration diagnostics, oncology, infectious diseases, and other disorders and diseases.
Total company revenue reached more than $162 million in 2013, up from more than $89
million in 2012.
Sequenom Laboratories provides molecular based, laboratory developed tests,
with a focus principally on prenatal diseases and conditions and ophthalmological
diseases and conditions. Sequenom Bioscience provides technology and research use only
tools (the MassArray System platform, chip and reagent consumables, software and
biomarker assay panels) for genetic analysis and applications in translational research,
clinical research, pharmacogenomics, oncology, and agricultural genomics.
Through Sequenom Laboratories, the company markets its HerediT CF LDT, a
carrier screen test to help identify individuals who may have an increased risk of having
certain cystic fibrosis genetic mutations. This test has been expanded to include screening
for a broad set of phenotypically relevant genetic mutations selected from the leading
Johns Hopkins CFTR2 database.


PregnancyMarketResearch PDF

Încărcat de

Informații document

Descriere originală:

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

PregnancyMarketResearch PDF

Încărcat de

Drepturi de autor:

Formate disponibile

Womens Health Diagnostic Markets

Womens Health Diagnostic Markets

Copyright 2014 Kalorama Information, LLC.

Copyright 2014 Kalorama Information, LLC.

Copyright 2014 Kalorama Information, LLC.

1.0 Executive Summary ................................................................................................................ 1

Copyright 2014 Kalorama Information, LLC.

1.0 Executive Summary

Generally, and from a perspective on women's health, diagnostics are playing an

There is a need to improve the understanding of the differences, in terms of

Worldwide, women are living longer than men.

1.0 Executive Summary

New techniques will provide noninvasive alternatives to current invasive prenatal

Three dimensional (3D) ultrasound is finding more use as it provides greater

X-ray mammography, notably digital mammography, continues to dominate

There are considerable barriers to setting up cytology-based screening programs,

Copyright 2014 Kalorama Information, LLC.

1.0 Executive Summary

Autoimmune disease as a category affects 50 million Americans. It is one of the

Cystic fibrosis is most common among Caucasians. Worldwide, approximately

Copyright 2014 Kalorama Information, LLC.

1.0 Executive Summary

Lab-Based Immunoassay Fertility Testing $299

Lab-Based Immunoassay Torch Testing

Prenatal Carrier and Fetus Screening

Ultrasound Breast Imaging

Urinary Tract Infection Assays

Neonatal Jaundice Bilirubin

Autoimmune Diagnostic Assays

Cystic Fibrosis Female Genetic Tests

Pregnancy and Ovulation Testing

Source: Kalorama Information

Copyright 2014 Kalorama Information, LLC.

1.0 Executive Summary

Copyright 2014 Kalorama Information, LLC.

2.2 PERSPECTIVE ON WOMENS HEALTH

2.3 THE WAY WOMEN AND MEN DEVELOP DISEASE IS DIFFERENT

Copyright 2014 Kalorama Information, LLC.

2.3.2 The Heart

2.3.3 The Brain

Copyright 2014 Kalorama Information, LLC.

2.3.5 Bone Structure

2.3.7 Drug Side Effects

2.3.11 Autoimmune Disease

Copyright 2014 Kalorama Information, LLC.

Copyright 2014 Kalorama Information, LLC.

Copyright 2014 Kalorama Information, LLC.

2.3.13 Musculoskeletal Health

Copyright 2014 Kalorama Information, LLC.

Copyright 2014 Kalorama Information, LLC.

2.3.14 Birth Defects

2.3.15 Urinary Tract Infections

Copyright 2014 Kalorama Information, LLC.

2.4 KEY LEADING CAUSES OF DEATH IN FEMALES

Copyright 2014 Kalorama Information, LLC.

Chronic lower respiratory diseases

Influenza and pneumonia

Source: US Centers for Disease Control and Prevention

Copyright 2014 Kalorama Information, LLC.

Source: World Health Organization.

2.6 WHAT CLAIMS WOMENS LIVES

2.7 KEY TRENDS AND ISSUES IN WOMENS DIAGNOSTICS