"THE THREE MAIN TASKS OF THE CLINICIAN ARE DIAGNOSIS, PROGNOSIS, AND TREATMENT.

OF THESE DIAGNOSIS IS BY FAR THE MOST IMPORTANT, FOR UPON IT THE SUCCESS OF THE OTHER TWO DEPENDS." The natural history of disease 2nd ed. Oxford University Press, 1948

RYLE J.A.

What I will be sharing with you Today?

1.What is evidence based laboratory medicine?

2.What are the components of EBLM? 3. How to ask a question? 4. How to acquire information? 5.How to analyze the information?

6.How to apply the information?

7.Critics view of EBLM.

What is Evidence based Medicine ?

EBLM Conscientious explicit and judicious use of current best evidence in Laboratory medicine for making well informed decision

COMPONENTS OF EBLM

Individual expertise

Best external evidence

EBLM

Patients values & expectation

Why evidence based Medicine?

Increased innovation Greater knowledge Increased workload More spending Patient expectation

New technologies New treatments & Diagnostics More patient visits Salary and other costs More knowledge from internet

Legal aspects

What are the justification for an evidence based medicine?

Constant requirement for information Constant addition of new information

Limited time availability

The poor quality of access to good information

What is particular to laboratory medicine? Limited number and poor quality of studies linking test Results to patients benefits. The poor perception of the value of diagnostic tests. The ever increasing demand for tests. The disconnected approach to resource allocation.

Silo budgeting

How to practice ?
1. Identification of question
2. Track down the best evidence

ASK Acquire

3. Critical assessment of the best evidence. Appraise

4. Implementation of best practice.

ACT

5. Evaluate

AUDIT

Elements of EBLM

Convert a clinical situation into a searchable, (and hopefully answerable) question using

PICO
PATIENT INTERVENTION COMPARISON OUTCOME

Patient refers to atient or Problem the person presenting with the ntervention problem, or more simply, to the omparison problem itself. Both concepts are utcome important in searching.

atient or Problem
ntervention omparison utcome

Intervention refers to the action taken in response to the problem. This is often a drug or surgical procedure, but it can take many forms

atient or Problem ntervention

omparison utcome

Comparison refers to the benchmark against which the intervention is measured. Often it refers to another treatment, no treatment, or a placebo.

atient or Problem
ntervention omparison utcome

Outcome refers to the anticipated result of the intervention.

How to apply this for EBLM?

QUESTIONS TO BE ASKED
CARO C: Case A: Assay R: Reference O: Outcome QUESTIONS
What are the patient characteristics, conditions, symptoms, demographics ? Which procedure or strategy is considered ? What is the standard procedure, the comparator ?

What is the interest, the diagnostic validity ? Sensitivity, specificity, predictive values, prognosis ?

Types of question

Type I : Regarding diagnostic accuracy of the test

1.Patients presenting to the emergency department With shortness of breath. 2.How well does N terminal pro B type natriuretic peptide 4. Predict heart failure as assessed by 3. The cardiac ejection fraction measured by Echocardiography

Type II : Related to the value of test in improving Patients outcomes.

1. Patient admitted to the hospital for treatment of heart failure.

2. How well does the use of N terminal Pro B type Natriuretic peptide as a guide to therapy.
3. Improve the length of hospital stay and the rate Of subsequent readmission for heart failure ?

How to Acquire evidence ?

In laboratory medicine an alternative to Clinical trail is Diagnostic accuracy studies.

The best design for diagnostic accuracy Studies is a prospective cohort study with a

Blinded comparison of the performance of

Experimental test and that of an appropriate Gold standard test in a spectrum of patients Suspected to having the disease in question.

An important goal of studies of diagnostics test is to Determine whether the new test adds information to that known from patient observation or other investigations

How to start a search ?

How to seek evidence-based information

Computer system

Clinical Evidence or PIER (UpToDate)

ACP Journal Club, InfoPOEMS, Dynamed

Cochrane Library, PubMED Clinical Queries, BMJUpdates, guidelines

Original Studies

OR SUMsearch or TRIP

Choosing Resources
Background
Rare

Foreground
Unfiltered Database (e.g. MEDLINE) Filtered/ Pre-appraised Evidence

Common

Textbooks

Where to search ?

It is best to start the search with looking for External evidence based guidelines that can be Adapted. The search for evidence usually starts in databases Such as the Cochrane Library which contains high quality Systematic reviews or meta analysis.

If a search is not successful in the secondary Literature one can look for primary reports in the Medline. Use Pub Med for the search of Medline.
The best single search term for laboratory test Is sensitivity . However the word diagnostic test, Diagnosis Diagnostic use combined with the corresponding Clinical condition ( eg: Chronic renal failure)and Finally the name of the test ( eg: Soluble transferrin Receptor.

Determine the level of evidence of the primary Studies and reviews.

The highest level of evidence is a good quality well Conducted systematic review or meta analysis of RCT for testing patient related outcomes. ( PSA for Screening Prostate cancer ) Prospective cohort studies for Diagnostic accuracy studies. ( Total PSA Vs the free PSA / Total PSA in the diagnosis Of prostate cancer )

What and Why do we choose a systemic review?

Systematic Searching Systematic Reviews

Definitions
Review articles A broad overview of a topic, similar to a textbook chapter.

Often covers multiple, background aspects of a disease such as natural history, etiology, epidemiology, signs & symptoms, diagnosis, treatment, and prognosis. The article summarizes the results from many other primary studies. The studies to summarize are chosen at the discretion of the author.

Definitions
Review articles A broad overview of a topic, similar to a textbook chapter. Systematic Review A type of review article that focuses on a focused clinical question
Studies are chosen using a standardized protocol to minimize selection bias.

Definitions
Review articles A broad overview of a topic, similar to a textbook chapter. Systematic Review A type of review article that focuses on a focused clinical question

Meta-analysis A type of systematic review in which the numerical results from individual studies are mathematically combined to give a single, overall estimate of treatment effect.

Definitions
Review articles Systematic Review Meta-analysis

A systematic review can be thought of as a research project done on the medical literature itself. Instead of human beings acting as subjects, the subjects of a systematic review are individual RCTs

Finding Systematic Reviews

Produces high quality systematic reviews

Managed by the Cochrane Collaboration

A not-for-profit international organization and one of the initial developers of systematic reviews Available through the HSLIC web site.

Finding Systematic Reviews

Pub Med Clinical Queries They are accessed from the "Clinical Queries" link on the blue side bar of the PubMed home page.

How to critically appraise an Evidence?

Essential Concepts
Three concepts are essential to understanding the critical appraisal of systematic reviews. These are:

Publication bias. Publication bias is one of the factors that systematic reviews attempt to avoid by selecting studies in a systematic way.
Heterogeneity. Heterogeneity is a statistical measure of the difference between the results from different studies. The less heterogeneous results are, the easier it becomes to estimate overall effect.

HOW TO DETECT HETEROGENICITY?

Forrest Plots

Effect of probiotics on the risk of antibiotic associated diarrhoea

D'Souza, A. L et al. BMJ 2002;324:1361

Forest plots. These graphical displays show study data in a way that makes it easy to see similarities and differences between studies.

Look at the title of the forest plot, the intervention, outcome effect measure of the investigation and the scale

The label tells you what the comparison and outcome of interest are

Effect of probiotics on the risk of antibiotic associated diarrhoea

Scale measuring treatment effect. Take care when reading labels!

Effect of probiotics on the risk of antibiotic associated diarrhoea

The names on the left are the authors of the primary studies included in the MA

Each study has an ID (author)

Effect of probiotics on the risk of antibiotic associated diarrhoea

Treatment effect sizes for each study (plus 95% CI)

Effect of probiotics on the risk of antibiotic associated diarrhoea

The small squares represent the results of the individual trial results The size of each square represents the weight given to each study in the meta-analysis

Horizontal lines are confidence intervals Diamond shape is pooled effect Horizontal width of diamond is confidence interval
Effect of probiotics on the risk of antibiotic associated diarrhoea

The vertical line represents the line of no effect, i.e. where there is no statistically significant difference between the treatment/intervention

group and the control group

The vertical line in middle is the line of no effect For ratios this is 1, for means this is 0
Effect of probiotics on the risk of antibiotic associated diarrhoea

Pooled Se = 0.71 Heterogeneity p<0.001

Pooled Sp = 0.95 Heterogeneity p<0.001

Pai M, et al. Comparison of diagnostic accuracy of commercial and in-house nucleic acid amplification tests for tuberculous meningitis: a meta-analysis. Poster presented at the American Society for Microbiology, 2003

Average men having an average meal

How to detect Bias?

Funnel plots
A funnel plot is a scatter plot of treatment effect against a measure of study size.

64

Funnel Plots
attempt to detect bias in study selection results of each study plotted against sample size what should we expect?

65

Why Funnel?
precision in the estimation of the true treatment effect increases as the sample size increases. Small studies scatter more widely at the bottom of the graph
In the absence of bias the plot should resemble a symmetrical inverted funnel

66

Funnel Plot

Favors Treatment

Favors Control

Odds Ratio

67

Funnel Plot

Favors Treatment

Favors Control

Odds Ratio

68

Funnel Plot

Favors Treatment

Favors Control

Odds Ratio

69

Funnel Plot

Favors Treatment

Favors Control

Odds Ratio

70

71

72

Publication Bias
Asymmetrical appearance of the funnel plot with a gap in a bottom corner of the graph

73

Drawbacks to systematic reviews/meta-analyses

Can be done badly
2 systematic reviews on same topic can have different conclusions

Inappropriate aggregation of studies A meta-analysis is only as good as the papers included Tend to look at broad questions that may not be immediately applicable to individual patients

How to rate or grade the evidence?

Quality of primary studies and reviews

Rating of the level of evidence of individual articles 1a

Meta analysis or systematic review based on at least several level 1b studies

1b

Diagnostic trial or outcome study of good quality

Diagnostic trial or outcome study of medium quality Insufficient patients or other trials ( Case control or other designs) Descriptive studies , case reports etc Statement of committees, opinion of experts, not systematic

II

III

IV

Rating of the strength of the evidence supporting Guidelines recommendations

A

Supported by at least by two independent Studies of level 1b or one review of 1a

Supported by at least two independent studies of level II Not supported by sufficient studies of level I of II Advices of experts

Compile an evidence table

1.Publication details of the individual studies.

2. Study design
3.Spectrum of patient and patient setting.

4.Prevalence of the condition.

5.Diagnostic test used of compared.

6.Out come measured.

7.Effects measured including measures of diagnostic accuracy.

8. Comments on specific issues raised by the study. ( biases) 9.Quality rating and level of evidence of the study.

Make the judgment based on:

1.Quality of the evidence :

The extent to which the studys design, conduct, And analysis have minimized selection, measurement and Confounding bias. 2.Quantity of evidence:
The number of studies that have evaluated the given Topic and the sample size of each study. 3. Consistency of the evidence.

Meta-analysis Software
Free RevMan [Review Manager] Meta-Analyst Epi Meta Easy MA Meta-Test Meta-Stat Commercial Comprehensive Metaanalysis Meta-Win WEasy MA General stats packages Stata SAS S-Plus http://www.prw.le.ac.uk/epidemio/personal/ajs22/meta/

Diagnostic accuracy studies allow the

calculation of various statistics that provide an indication of "test performance" how good the index test is At detecting the target condition.

Whiting et al. in: BMC Medical Research Methodology 2003 http://www.biomedcentral.com/14712288/3/25

Do we need a detailed statistical and epidemiological skills To practice EBLM ?

No

Then what is needed ? Critical appraisal skill Competent understanding of the strengths and weakness of systemic Reviews and meta analysis

The laboratory personnel must direct more effect to demonstrate the impact of laboratory tests on a greater variety of clinical outcomes.

Are the Results of This Diagnostic Study Valid?

Was there an independent, blind comparison with a reference (gold) standard of diagnosis? Was the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom it would be used in practice)? Was the reference standard applied regardless of the diagnostic test result? Was the test (or cluster of tests) validated in a second, independent group of patients?

DIAGNOSIS WORKSHEET

Can We Apply This Valid, Important Evidence About a Diagnostic Test in Caring for Our Patient?
Is the diagnostic test available, affordable, accurate, and precise in our setting?
Can we generate a clinically sensible estimate of our patients pre-test probability (from personal experience, prevalence statistics, practice databases, or primary studies)? Will the resulting post-test probabilities affect our management and help our patient? *Could it move acrosis a test-treatment threshold? *Would our patient be a willing partner in carrying it out? Would the consequences of the test help our patient?

Introduction Probands

STARD (Standards for reporting diagnostic accuracy) - a checklist

Diagnostic accuracy between tests or across patient groups Demographic description, inclusion and exclusion criteria, symptoms, data collection criteria. Time frame, number and group of probands, time of measurements, treatment of probands Description of standard and rationale for comparison. Technical, analytical specifications (linearity, cutoff levels, uncertainty, bias, etc) Methods for reporting diagnostic validities, comparisons between groups, test reproducibility Cross tabulaton of results (reference, test), analytical and diagnostic acuracy between groups of probands, ROC-curves, Box-Whiskers plot.

Study design Reference standard Test method Statistical methods Results

Conclusion

Clinical application

P. M. Bossuyt et al. 2003

Evidence of performance designed to facilitate decision making

Decisions Cost effectiveness Organizational impact
Clinical impact

Diagnostic Therapeutic Outcome

Diagnostic performance Technical performance

How to act and Modify ?

Test

Question

Result

Action

Outcome

Troponin I

Has the patient 7.2g/L Decide to admit, had a MI Intensive care Is this breathless patient suffering from Heart failure 56ng/L Seek alternative diagnostic method

Decreased morbidity & mortality Avoid incorrect diagnosis & treatment

BNP

HbA1C

Is this patient complying with treatment protocol

10.6% ( No change in a year

Consider changing Treatment, closer monitoring and freq visit

Persistently high value has increased risk of complications

Promises of EBLM
It ties clinical practices to scientific standards of evidence Able to draw upon the objective experience of many researchers working with accepted scientific standards of evidence EBLM should also promote greater uniformity

Evaluate implementing cost cutting measures

EBM should provide a scientific basis for the construction of public policy

Critics
Standard guidelines Disincentives of individual innovation Becomes more like cook book medicine

Lower standards by deskilling practitioners

Instead to clinical judgment practitioners will be encouraged to Use protocols Incapable of operating effectively in diverse situation

Is the highest level of evidence always the strongest

Recommendation ?

NO

Highest level of evidence may not provide the Strongest recommendations in some local contest. The evidence must be supplemented with considered Judgment of the potential clinical benefits and harms Patients preferences

The organizational and economic impact of testing.

In patients presenting with complaints with symptoms Of tongue and mouth the prevalence of Vit B12 Deficiency in only 8%. The relatively low cost of Testing for B12 deficiency And availability of effective treatment may counter Balance the low probability of this cause. Might lead to recommendation of B12 testing in One community . But not so in another community because the relative Costs may be different.

An example where patients choices are considered Is the triple test used for antenatal screening of Downs screening. The consequences of positive screening test is Amniocentesis which may harm the fetus. And in positive cases an abortion may be required.

BUT
Good professionals should treat guidelines more as options. As True standards and professional organizations do not enforce adherence. Change in health care is possible with guidelines. Its creation and Implementation reflects the collaborative nature of health care.

Future
Establish a culture of EBLM

How ?
Change the pattern of Journal Club start from the Residents

Evaluating a systemic review or Even journal can be even a part Of MD evaluation.

Critical appraisal checklists

CASP (Critical Skills Appraisal Programme)
http://www.phru.nhs.uk/casp/critical_appraisal_tools.htm

JAMA Users Guides to the Medical Literature

http://www.cche.net/usersguides/main.asp

Crombie I (1996) The Pocket Guide to Critical Appraisal, BMJ Books, London
Greenhalgh T (2001) How to Read a Paper, BMJ Books, London BestBETs CA database
http://www.bestbets.org/cgi-bin/browse.pl?~show=appraisal

There are different checklists for different study Designs at:

1.The centre for Evidence Based Medicine ( WWW.cebm.net)

2.Casp International network ( WWW.caspinternational.org.uk ) 3. Centre for Health Evidence ( WWW.cche.net )

Impact of EBLM

THANK YOU For your patient listening