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General Epidemiology

and Demography

Epidemiological Studies

István Kiss, MD., PhD


istvan.kiss@aok.pte.hu

Department of Preventive Medicine


Possible Categorization of
Epidemiological Studies

• Descriptive – analytical

• Retrospective – concurrent – prospective

• Observational – experimental
Descriptive Studies
Descriptive studies

• No hypothesis is formulated

• No analysis is performed

(in clean form)


• Gottlieb M.S., Schroff R., Schanker H.M., et al. (1981) 'Pneumocystis carinii
pneumonia and mucosal candidiasis in previously healthy homosexual men:
evidence of a new acquired cellular immunodeficiency', The New England
Journal of Medicine 305:1425-31.

• Hymes, K.B., Greene, J. B., Marcus, A., et al. (1981) 'Kaposi's sarcoma in
homosexual men: A report of eight cases', Lancet 2:598-600

• Siegal FP, Lopez C, Hammer GS, Brown AE, Kornfeld SJ, Gold J, Hassett J,
Hirschman SZ, Cunningham-Rundles C, Adelsberg BR, et al.: Severe
acquired immunodeficiency in male homosexuals, manifested by chronic
perianal ulcerative herpes simplex lesions. N Engl J Med. 1981 Dec
10;305(24):1439-44.

• Lerner CW, Tapper ML.: Opportunistic infection complicating acquired


immune deficiency syndrome. Clinical features of 25 cases. Medicine
(Baltimore). 1984 May;63(3):155-64.
Case Report
(not a true epidemiological study)

 Description of a case (patient, someone with a health


related condition), in a manner that information is
provided for certain disease-associated conditions as
well

 Pure disease or syndrome descriptions are less useful


for epidemiologists

 Aggregating case reports might describe new


syndromes or generate hypotheses (AIDS)
Case-series

• Set of case descriptions (clinical)

• Common characteristics can be identified

• A complete set of case-series (population based case-series) for a well-


defined area is called registry or register (in contrast to the clinical case
series, rates can be calculated)

• Registries provide information on disease burden in a country, help in


resource allocation

• Data can be linked to ecological information units


Cross Sectional Studies
(prevalence studies, surveys)

 It can be a descriptive or an analytical study

 They measure exposure and disease at the same time

 Gives information on disease and risk factor prevalence


(prevalence ratio can be calculated for diseases)

 Lack of temporality (in relation to order of risk factors and diseases)

 Since prevalence is used (and not incidence), survival factors also affect
the results
The Epidemiology of Major Depressive Disorder. Results From
the National Comorbidity Survey Replication (Kessler et al, JAMA)
The Epidemiology of Major Depressive Disorder. Results From
the National Comorbidity Survey Replication (Kessler et al, JAMA)

• The prevalence of Major Depressive


Disorder for lifetime was 16.2% (95%
confidence interval [CI], 15.1-17.3) (32.6-35.1
million US adults)

• The 12-month prevalence was 6.6% (95%


CI, 5.9-7.3) (13.1-14.2 million US adults).
Plaque measurements among 12-year-old volunteers by
Strategic Health Authority. England, 2008/09.

(NHS Dental Epidemiology Programme Survey)


Epidemiology of erectile dysfunction: results of the
'Cologne Male Survey‚ (Braun et al, Int J Impot Res)
• A newly developed and validated questionnaire on male
erectile dysfunction was mailed to a representative population
sample of 8000 men, 30-80 y of age in the Cologne urban
district. The response included 4489 evaluable replies (56.1%).
The response rates in different age groups ranged from 49.2%
to 68.4%. Regular sexual activity was reported by 96.0%
(youngest age group) to 71.3% (oldest group). There were
31.5%-44% of responders who were dissatisfied with their
current sex life. The prevalence of ED was 19.2%, with a
steep age-related increase (2.3-53.4%) and a high co-morbidity
of ED with hypertension, diabetes, pelvic surgery and 'lower
urinary tract symptoms'.
Analytical Studies
Analytical Studies
 A hypothesis is formulated and tested

As precisely as possible!!!

“Babies who are breast-fed have less illness than babies who are
bottle-fed.”

“Babies who are exclusively breast-fed for three months or


more will have a reduction in the incidence of hospital
admissions for gastroenteritis of at least 30% over the first
year of life.”

 Cause-effect relationship can be revealed


Ecological Studies vs.
Ecological Assignment (analysis)

• Ecological study – data collected on group level


(called also as correlational study)

• Ecological analysis – data analysed at group level


(from existing individual information)

• Boundaries are not sharp

• One variable may be an ecological, the other may be an


individual variable
Breast Cancer Mortality and Dietary Fat Intake

Carroll, K.K, Cancer Res, 1975.


Ecological study
(Correlational study)

• Generates hypotheses
• Fast, cheap, easy to perform
• Can focus attention to special problems (region,
disease, population)

• No control for confounding


• Data represent average exposures
Association between the rate of suicide and proportion of Protestant
religion in four Prussian provinces (Durkheim, 1951.)

Suicide Rate
per 100,000
30

20

10

0
0 0.2 0.4 0.6 0.8 1
As non-Protestants in a province became more in the minority, these individuals,
Proportion
rather than Protestants, may have been more likely to commit suicide. Protestant
The ecological fallacy

• Statistical meaning:
The tendency of correlation coefficients to be larger
when an association is assessed at the group level
than when it is assessed at the individual level.

• Common usage in the epidemiology:


The tendency seen in ecological studies does not
necessarily reflect reality (as described in individual
studies).
Ecological fallacy: Example

Salt intake – hypertension

• Good between-country correlation

• Correlation on individual level is difficult to demonstrate

• A possible cause: different proportion of individuals


below/above threshold
25

20

15

10

0
0 5 10 15 20 25 30
Atomistic fallacy

• Individual level observations are not necessarily true on


population level.

Examples:

• Infant mortality – birthweight

• CHD mortality – income

• Suicide – income
Case-Control Studies
Case-control studies

Most frequently performed epidemiological studies

Exposed
Cases
Not Exposed

Exposed
Controls
Not Exposed
Case-control Studies
• Directionality is the key determinant of whether a study
is cohort or case-control (Kramer-Boivin model).

• A cohort study is one in which subjects are investigated


forward from exposure to outcome.

• A case-control study is one in which subjects are


investigated backwards from outcome to exposure.
Case-control studies
History

• The (possibly) first case-control study:


Broad Street pump episode investigation (1854,
Whitehead).

• First modern case-control study:


Janet Lane-Claypon’s study on breast cancer and
reproductive history (1926).

• Four case-control studies on smoking and lung cancer


(1950) established the method.
Case-control studies

Selection of cases:

• Incident cases

• Prevalent cases

Incident cases are preferable in order to reduce recall bias


and overrepresentation of cases with long duration.
Case-control studies

 Selection of controls

› The same source as cases


› Comparability is important (controls must mirror potential biases
in the case group)
› They must be at risk of disease
› Controls should come from the same „study base” than cases
› Matching
 individual
 frequency-based

› Avoid overmatching (only for known risk factors)


Case-control studies

• Multiple controls can be used for one case


• (not more than 4, there is no more gain in power)

• Note: The case group does not necessarily represents


all the cases (ideally they should)
Case-control studies

• Analysis:

• Unmatched (OR)
a
c a*d
_____ _____
OR= =
b b*c
d
Case-control studies:
Paired analysis (for one control)

Cases
Exposed Unexposed
Controls

Exposed --- R
Unexposed S ---

McNemar chi2 = (R - S)2/(R + S)

(|R - S| - 1)2)/(R + S) (corrected)


Case-control studies

 Strength
› Fast, relatively cheap (study population is not big)
› Can be used to study rare diseases
› Can study the effects of multiple exposures
› Helps to understand new diseases

 Limitations
› No incidence rates
› No direct risk estimation is provided (no RR)
› Rare exposures can not be investigated
› Possibility of bias (recall, selection)
› Only one single disease can be studied
› Effect of matching variables covered
Case-control studies

• Famous case-control studies:

• On the association between smoking and lung cancer by


Doll.

• Maternal DES use and vaginal adenocarcinoma in girls


and young women (Herbst)

Carcinoma No
DES 7 1
No 0 32
Case-control studies
Sample size considerations

Sample Size

Parameter
n=20 n=50 n=500
Computed

OR 2.0 2.0 2.0

p-value 0.500 0.200 0.001

95% CIs 0.5, 7.7 0.9, 4.7 1.5, 2.6


Cohort Studies
Cohort Studies

• Also called follow-up studies, incidence studies,


panel studies, longitudinal studies, or prospective
studies

• Needs an initially disease-free population


(screening)
Cohort Studies
Cohort studies

• Prospective

• Retrospective

• (Historical prospective)
(past and present exposure assessment)
Cohort studies

 Selection of the exposed population


(by exposure / not by exposure)
› Common exposures – general population
› Rare exposures – special exposure groups
› If non-exposed participants are matched to the exposed participants:
exposure-control design

 Comparison group
› Must be similar to the exposed cohort (confounding)
› Internal (one cohort – participants divided into exposed and non
exposed categories)
› General population rates as comparison
› Sometimes multiple cohorts needed
Cohort studies

Further considerations for cohort selection

• Special resource groups (e.g., alumni, physicians, nurses)

• Geographically or facility-defined groups (e.g., Three


Mile Island, hospitals with specialized maternity care)
Cohort studies
 Exposure assessment
› Existing data (unbiased, simple, cheap, but quality may be
inadequate, necessary information – e.g. on confounders – may be
missing)

› Questionnaires (cheap, all the necessary factors can be surveyed,


but may be biased, participants may not have the necessary
information)

› Measurement (most accurate, but most expensive)


 Can be used as validation tool on a small subgroup
 Sometimes must be repeated
 Exposure changes over the time
 Newly identified exposures
Cohort studies
• Gives incidence data on the covered time
period

• Analysis: Disease
+ -
Exposure
+ a b
- c d

Relative risk Rate ratio


a/(a+b) ratio of the two
RR =
c/(c+d) incidence densities
Cohort studies

Strengths:
• Can elucidate temporal relationship between exposure and disease
(hence, “strongest” observational design for establishing cause and effect
relationship).

• Minimizes bias in the ascertainment of exposure (e.g. recall bias).


• Particularly efficient for study of rare exposures.
• Can examine multiple effects of single exposure.
• Can yield information on multiple exposures (limited).
• Allows direct measurement of incidence of disease in exposed and
non-exposed groups (calculation of relative risk).
Cohort studies

Limitations:

 Not efficient for the study of rare diseases.


 Can be very costly and time consuming.
 Often requires a large sample size.
 Losses to follow-up can affect validity of results (may be
related to exposure/disease!).
 Nonparticipation can lead to selection bias.
 Changes over time in diagnostic methods may lead to biased
results.
Cohort studies

• Famous cohort studies

• Framingham Heart Study


• The Offspring Study

• British Doctors Study

• Nurses’ Health Study


The Framingham Study

• 5,127 men and women between ages 30


and 62 years and were at the time of entry
free of cardiovascular disease (1948-1952).

• Cohort was examined every 2 years and by


daily surveillance of hospitalizations at
Framingham Hospital.
William B. Kannel, MD,
Director of the Framingham Heart Study,
Pioneer in Cardiovascular Epidemiology,
1923–2011
British Doctors Cohort
•Exposure: Smoking information from subjects based on a short postal questionnaire

•Current smokers
•Age started smoking
•Amount consumed currently
•Method of smoking

•Past smokers
•Same as above
•Date stopped smoking

•Never smoked regularly (≤1 cigarette/year for one year)


British Doctors Cohort

•Outcome:
•Mortality ascertained by looking-up death certificates
•Cause of death is filled in by a physician or the coroner

•Analysis:
•Compare rates of death according to level of self-reported
smoking
Typical Questions about Smoking

Type of smoking (cigarettes, cigars, pipes)


Have you ever smoked regularly?
How old were you when you started to smoke?
How many cigarettes per day do you smoke now?
If you stopped completely, how long ago was this?
Metrics of Exposure to Tobbacco Smoke

• The following indices can be estimated:


• Type of smoking (cigarettes, cigars, pipes)
• Duration (time since starting)
• Time since quitting
• Average intensity (e.g. No. of cigarettes/day)
• Frequency (e.g. percent time smoked in a week)
• Current smoking status
Metrics of Exposure

• Cumulative exposure:
frequency of smoking x intensity x duration

• E.g., 1 pack per day x 20 cigarettes/pack x 365 days/years =


219,000 cigarette-days = 30 pack-years

• Lagged cumulative exposure


(e.g., excluding last 10 years of smoking)
British Doctors

• Amount smoked at time of administration of first


questionnaire:
Non-smokers:
Current: 1-14 cigs/day
15-24
≥ 25

• These groups represent sub-cohorts defined by exposure at


time of entry into study

• However, information obtained during follow-up can


change exposure status, so these sub-cohorts would not be
fixed
British Doctors Cohort: Men
Survey period 1st Quest 2nd Quest 3rd Quest 4th Quest

Known to have N/A 3122 7301 10634


died
Presumably alive N/A 31318 27139 23806

Replied 40,637 (69%) 30,810 (98.4%) 26,163 (96.4%) 23,299 (97.9%)

Did not reply 18,963 508 1156 507

Reasons for
nonresponse
Too ill NA 31 65 21
Refused NA 36 63 102
Not found NA 72 403 22
Other NA 369 445 362
British Doctors Study: Lung Cancer in men among
current smokers from data obtained at last questionnaire

Age-standardized Mortality Rate


death rate (10-5) Ratio

Non smokers 10 1
Cigarettes only 140 14 (=140/10)
Pipe and/or cigars 58 5,8 (=58/10)
Mixed 82 8.2
Cigarettes only (No. per day)
1-14 78 7.8
15-24 127 12.7
≥25 251 25.1
Nested case-control study

Population

Develop Do Not
Disease Develop
Disease

Subgroup
”Cases” Selected as
“Controls”
Migrant Studies
Migrant studies
„vary environment, keep genetics constant”

• Migrant studies compare incidences:

• among ethnically similar individuals living in native


environment

With
• incidences in a group of ethnically similar individuals who have
moved to a new environment

And with
• incidences in the original population of this new environment
Cancer incidence in Japan and Hawaii

Hawaii, 1968-72
Tumor Gender Japan Japanese Caucasian

Esophageal Male 150 46 75


Stopmach Male 1,331 397 217
Colon Male 78 371 368
Rectum Male 95 297 204
Lung Male 237 379 962
Prostate Male 14 154 343
Breast Female 335 1,221 1,869
Cervix Female 329 149 243
Uterus Female 32 407 714
Ovary Female 51 160 274
Migrant studies

• Cancer rates among Japanese immigrants in the US


approached the US rates after 2 generations

• European immigrants migrated to Israel experience a


low incidence of multiple sclerosis, if they migrated
when they were younger than 14 year old. In older
immigrants these effect was not present.
Experimental
(Interventional) Studies
Experimental (Interventional) Studies

• Therapeutical
• Almost always on individual level
• Clinical trial

• Preventive
• On individual level
• Field trial
• Involving entire populations
• Community level
Study design for clinical and field trials

(Bhopal)
Factors affecting
clinical and/or field trials
• Placebo effect (tendency to report an improvement)

• Compliance – non compliance (measurement is important)

• Hawthorne effect (changes in behavior because of being observed)

• Blinding (simple – double – triple)

• Randomization („randomized controlled trial”)

• Intention to treat analysis (once randomized always analyzed)


Crossover Trial

Randomized

Treatment A Treatment B

Group 2
Group 1

Group 2
Group 1

Group 2 Group 1
Crossover trial

• Permits within-patient comparisons


• Patients serves also as self-controls

• Analysis is more complex than in simple clinical trial


• Interactions between treatments
• „Carry over” effect
Importance of field trials

• CARET

• ATBC

On beta-carotene supplementation
Retrospective studies: Dietary carotenoids and lung cancer risk

Ziegler et al 1984, 1986 Carotenoids Decreased (significant)

Samet et al, 1985 Carotenoids Decreased (significant)

Byers et al, 1987 Carotenoids Decreased (significant)

Pastorino et al, 1987 Carotenoids Decreased (significant)

Marchand et al, 1989 β-carotin Decreased (significant)

Prospective studies: Serum or plasma carotenoids and lung cancer risk

Stahelin et al, 1984, 1990 β-carotene Lower (significant)

Nomura et al, 1985 β-carotene Lower (significant)

Menkes et al, 1986 β-carotene Lower (significant)

Wald et al, 1988 β-carotene Lower (significant)

Connett et al, 1989 β-carotene Lower (significant)


Effect of -carotene supplementation on the
risk of lung cancer

• ATBC (Finnland, >29.000 smokers)


β-carotene (20 mg/day/5-8 years)
Lung cancer (18%);

• CARET (USA, 18 000 participants)


30 mg ß-carotene and 25,000 IU retinil-
palmitate
Lung cancer 28%
-carotene intake in Hungary

Men Women Recommendation

-carotene 2,2 mg 2,3 mg DACH 2000:


2-4 mg
(Zajkás et al)
Regular intake and supplementation
levels of -carotene

mg/day
35
30
25
20
15
10
5
0
Men Women Supplement
Factors affecting the antioxidant/prooxidant
properties of -carotene

• Concentration
• Presence of certain prooxidant compounds
• Oxigene-concentration
• pO2 below 50 Hgmm (peak at 15 Hgmm) - antioxidant
• Between 50-100 Hgmm looses its antioxidant activity
• Above 100 Hgmm prooxidant
• Presence of other antioxidants (e. g. Vitamin E)
Evidence Based Medicine:
Evidence-pyramide

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