EVIDENCE BASED LABORATORY MEDICINE

By Dr.R.Ramesh MD Professor Of Biochemistry, Manakula Vinayagar Medical college, Pondicherry

"THE THREE MAIN TASKS OF THE CLINICIAN ARE

DIAGNOSIS, PROGNOSIS, AND DIAGNOSIS, PROGNOSIS, AND TREATMENT.TREATMENT.

OF THESE DIAGNOSIS IS BY FAR THE MOST IMPORTANT, FOR UPON IT THE

SUCCESS OF THE OTHER TWO DEPENDS."

RYLE J.A. The natural history of disease 2nd ed. Oxford University Press, 1948

What I will be sharing with you What I will be sharing with you Today?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 What is Evidence based Medicine ?Medicine ?

EBLM

Conscientious explicit and judiciousexplicit and judicious use of current best

evidence in Laboratory medicine for making well

informed decision

Individual expertiseIndividual expertiseBest external evidenceBest external evidence

Patients values Patients values & & expectationexpectation

EBLM

COMPONENTS OF EBLMCOMPONENTS OF EBLM

Why evidence basedWhy evidence basedMedicine?Medicine?

Increased innovation New technologies

Greater knowledge New treatments & Diagnostics

Increased workload More patient visits

More spending Salary and other costs

Patient expectation More knowledge from internet

Legal aspectsLegal 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

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

What is particular to laboratory medicine?

How to practice ?

1. Identification of question

2. Track down the best evidence

3. Critical assessment of the best evidence.

4. Implementation of best practice.

5. Evaluate

ASK

Acquire

Appraise

ACT

AUDIT

Elements of EBLMElements of EBLM

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

PICOPICO•PATIENT

•INTERVENTION

•COMPARISON

•OUTCOME

atient or atient or ProblemProblemnterventionomparison

utcome

“Patient” refers to the person presenting with the problem, or more simply, to the problem itself. Both concepts are important in searching.

atient or Problem

nterventionntervention

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 Problemntervention

omparisomparisonon

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

utcomeutcome

“Outcome” refers to the anticipated result of the intervention.

How to apply this for EBLM?

QUESTIONS TO BE ASKEDQUESTIONS TO BE ASKED

CARO QUESTIONS

C: Case What are the patient characteristics, conditions, symptoms, demographics ?

A: Assay Which procedure or strategy is considered ?

R: Reference

What is the standard procedure, the comparator ?

O: Outcome

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

Types of questionTypes of question

Type I : Regarding diagnostic accuracy of the testType 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 improvingType II : Related to the value of test in improvingPatients outcomes.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 ?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 ?

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

How to seek evidence-based information

Choosing Resources

ForegroundBackground

Rar

eC

om

mon

UnfilteredDatabase

(e.g. MEDLINE)

Filtered/Pre-appraised

Evidence

Textbooks

Where to search ?Where to search ?

It is best to start the search with looking forExternal evidence based guidelines that can be Adapted.

The search for evidence usually starts in databasesSuch as the Cochrane Library which contains high qualitySystematic reviews or meta analysis.

If a search is not successful in the secondary Literature one can look for primary reports in theMedline.

Use Pub Med for the search of Medline.

The best single search term for laboratory testIs “ sensitivity “.

However the word “diagnostic test”, “Diagnosis” “Diagnostic use” combined with the correspondingClinical condition ( eg: Chronic renal failure)andFinally the name of the test ( eg: Soluble transferrinReceptor.

Determine the level of evidence of the primaryStudies and reviews.

The highest level of evidence is a good quality wellConducted systematic review or meta analysis of RCTfor 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

DefinitionsReview articlesA 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.

DefinitionsReview articlesA broad overview of a topic, similar to a textbook chapter.

Studies are chosen using a standardized protocol to minimize selection bias.

Systematic Review

A type of review article that focuses on a focused clinical question

Definitions

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

Meta-analysisA 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 anHow to critically appraise anEvidence?Evidence?

Essential ConceptsThree 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 HOW TO DETECT HETEROGENICITY?HETEROGENICITY?

Forrest Plots

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

Effect of probiotics on the risk of antibiotic associated diarrhoea

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


Scale measuring treatment effect. Take care when reading labels!


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

Each study has an ID (author)


Treatment effect sizes for each study

(plus 95% CI)


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 effectHorizontal width of diamond is confidence interval


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


Pooled Se = 0.71Heterogeneity p<0.001

Pooled Sp = 0.95Heterogeneity 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?How to detect Bias?

65

Funnel plots Funnel plots

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

66

Funnel PlotsFunnel Plots

• attempt to detect bias in study selection

• results of each study plotted against sample size

• what should we expect?

67

Why Funnel?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

68

Funnel PlotSam

ple

si z

e

Favors Treatment Favors Control

Odds Ratio

69

Funnel PlotSam

ple

si z

e


Odds Ratio

70

Funnel PlotSam

ple

si z

e


Odds Ratio

71

Funnel PlotSam

ple

si z

e


Odds Ratio

72

73

74

Publication Bias

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

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 gradeHow to rate or gradethe evidence?the evidence?

Quality of primary studies and reviewsRating of the level of evidence of individual articles

1a

1b

II

III

IV

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

Diagnostic trial or outcome study of good quality

Diagnostic trial or outcome study of medium qualityInsufficient patients or other trials( Case control or other designs)

Descriptive studies , case reports etc

Statement of committees, opinion of experts, not systematic

Rating of the strength of the evidence supporting Guidelines recommendations

A

B

C

D

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

Supported by at least two independent studiesof 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 study’s design, conduct,And analysis have minimized selection, measurement andConfounding bias.

2.Quantity of evidence:

The number of studies that have evaluated the givenTopic 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 Meta-

analysis– 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 2003http://www.biomedcentral.com/1471-2288/3/25

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.

DIAGNOSIS WORKSHEETAre 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?

Can We Apply This Valid, Important Can We Apply This Valid, Important Evidence About a Diagnostic Test in Caring Evidence About a Diagnostic Test in Caring

for Our Patient? for Our Patient? Is the diagnostic test available, affordable,

accurate, and precise in our setting?

Can we generate a clinically sensible estimate of our patient’s 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?

STARD (Standards for reporting STARD (Standards for reporting diagnostic accuracy) - a checklistdiagnostic accuracy) - a checklist

Introduction Diagnostic accuracy between tests or across patient groups

Probands Demographic description, inclusion and exclusion criteria, symptoms, data collection criteria.

Study design Time frame, number and group of probands, time of measurements, treatment of probands

Reference standard

Description of standard and rationale for comparison.

Test method Technical, analytical specifications (linearity, cut-off levels, uncertainty, bias, etc)

Statistical methods

Methods for reporting diagnostic validities, comparisons between groups, test reproducibility

Results Cross tabulaton of results (reference, test), analytical and diagnostic acuracy between groups of probands, ROC-curves, Box-Whiskers plot.

Conclusion Clinical application

P. M. Bossuyt et al. 2003

Decisions

Cost effectiveness

Organizational impact

Clinical impact

Diagnostic TherapeuticOutcome

Diagnostic performance

Technical performance

Evidence of performance designed to facilitate decision making

How to act and Modify ?How to act and Modify ?

Test Question Result Action Outcome

Troponin I

Has the patient had a MI

7.2µg/L

Decide to admit,Intensive care

Decreased morbidity & mortality

BNP Is this breathless patient suffering from Heart failure

56ng/L Seek alternative diagnostic method

Avoid incorrect diagnosis & treatment

HbA1C Is this patient complying with treatment protocol

10.6%( No change in a year

Consider changingTreatment, closer monitoring and freq visit

Persistently high value has increased risk of complications

Promises of EBLMPromises of EBLMIt 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 constructionof public policy

CriticsCritics

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 consideredJudgment of the potential clinical benefits and harms

Patients preferences

The organizational and economic impact of testing.

In patients presenting with complaints with symptomsOf tongue and mouth the prevalence of Vit B12Deficiency in only 8%.

The relatively low cost of Testing for B12 deficiencyAnd availability of effective treatment may counterBalance the low probability of this cause.

Might lead to recommendation of B12 testing in One community .

But not so in another community because the relativeCosts may be different.

An example where patients choices are consideredIs the triple test used for antenatal screening ofDowns 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.

FutureFutureEstablish a culture of EBLM

How ?

Change the pattern of JournalClub – start from the Residents

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

Critical appraisal checklistsCritical 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

http://www.phru.nhs.uk/casp/critical_appraisal_tools.htm

http://www.phru.nhs.uk/casp/critical_appraisal_tools.htm

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

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

http://www.bestbets.org/cgi-bin/browse.pl?~show=appraisal

http://www.bestbets.org/cgi-bin/browse.pl?~show=appraisal

There are different checklists for different studyDesigns 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 )

http://www.cebm.net/

http://www.caspinternational.org.uk/

http://www.cche.net/

Impact of EBLMImpact of EBLM

THANK YOUTHANK YOU

For your patient listeningFor your patient listening

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EVIDENCE BASED LABORATORY MEDICINE