EVIDENCE BASED

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EVIDENCE BASED LABORATORY MEDICINE
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• By
• Dr.R.Ramesh MD
• Professor Of Biochemistry,
• Manakula Vinayagar Medical college,
• Pondicherry

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"THE THREE MAIN TASKS OF THE CLINICIAN
AREDIAGNOSIS, PROGNOSIS, AND 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
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What I will be sharing with you Today?
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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.
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What is Evidence based Medicine ?
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EBLM
Conscientious explicit and judicious use of
current best evidence in Laboratory medicine
for making well informed decision
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COMPONENTS OF EBLM
Best external evidence
Individual expertise
EBLM
Patients values expectation
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Why evidence based Medicine?
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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
aspects
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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
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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
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How to practice ?
ASK

1. Identification of question
   
2. Track down the best evidence
3. Critical assessment of the best evidence.
4. Implementation of best practice.
5. Evaluate
   

Acquire
Appraise
ACT
AUDIT
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Elements of EBLM
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The First Step of EBLM

• Convert a clinical situation into a searchable,
  (and hopefully answerable) question using
• PICO
• PATIENT
• INTERVENTION
• COMPARISON
• OUTCOME

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PICO
P
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
I
ntervention
C
omparison
O
utcome
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PICO
P
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
I
ntervention
C
omparison
O
utcome
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PICO
P
atient or Problem
Comparison refers to the benchmark against
which the intervention is measured. Often it
refers to another treatment, no treatment, or a
placebo.
I
ntervention
C
omparison
O
utcome
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PICO
P
atient or Problem
I
ntervention
Outcome refers to the anticipated result of the
intervention.
C
omparison
O
utcome
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How to apply this for EBLM?
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QUESTIONS 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 ?
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Types of question
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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
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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 ?
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How to Acquire evidence ?
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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.
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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
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How to start a search ?
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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
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Choosing Resources
Foreground
Background
Unfiltered Database (e.g. MEDLINE)
Textbooks
Rare
Filtered/ Pre-appraised Evidence
Common
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Where to search ?
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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.
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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.
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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 )
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What and Why do we choose a systemic review?
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Systematic Searching Systematic Reviews
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Definitions
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.

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

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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.

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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.

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How to critically appraise an Evidence?
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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.

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HOW TO DETECT HETEROGENICITY?
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Forrest Plots
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Effect of probiotics on the risk of antibiotic
associated diarrhoea
D'Souza, A. L et al. BMJ 20023241361
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Forest plots. These graphical displays show
study data in a way that makes it easy to see
similarities and differences between studies.
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Look at the title of the forest plot, the
intervention, outcome effect measure of the
investigation and the scale
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The label tells you what the comparison and
outcome of interest are
Effect of probiotics on the risk of antibiotic
associated diarrhoea
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Scale measuring treatment effect. Take care when
reading labels!
Effect of probiotics on the risk of antibiotic
associated diarrhoea
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The names on the left are the authors of the
primary studies included in the MA
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Each study has an ID (author)
Effect of probiotics on the risk of antibiotic
associated diarrhoea
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Treatment effect sizes for each study (plus 95
CI)
Effect of probiotics on the risk of antibiotic
associated diarrhoea
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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
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Horizontal lines are confidence intervals
Diamond shape is pooled effectHorizontal width
of diamond is confidence interval
Effect of probiotics on the risk of antibiotic
associated diarrhoea
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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
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The vertical line in middle is the line of no
effectFor ratios this is 1, for means this is 0
Effect of probiotics on the risk of antibiotic
associated diarrhoea
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Pooled Se 0.71 Heterogeneity plt0.001
Pooled Sp 0.95 Heterogeneity plt0.001
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
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Average men having an average meal
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How to detect Bias?
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Funnel plots

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

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Funnel Plots

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

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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

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Funnel Plot
Sample size
Favors Treatment Favors Control
Odds Ratio
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Funnel Plot
Sample size
Favors Treatment Favors Control
Odds Ratio
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Funnel Plot
Sample size
Favors Treatment Favors Control
Odds Ratio
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Funnel Plot
Sample size
Favors Treatment Favors Control
Odds Ratio
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Publication Bias
Asymmetrical appearance of the funnel plot with a
gap in a bottom corner of the graph
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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

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How to rate or grade the evidence?
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Quality of primary studies and reviews
Rating of the level of evidence of individual
articles
Meta analysis or systematic review based on at
least several level 1b studies
1a
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)
II
III
Descriptive studies , case reports etc
Statement of committees, opinion of experts, not
systematic
IV
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Rating of the strength of the evidence supporting
Guidelines recommendations
Supported by at least by two independent Studies
of level 1b or one review of 1a
A
B
Supported by at least two independent studies of
level II
C
Not supported by sufficient studies of level I
of II
Advices of experts
D
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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.Diagno
stic test used of compared. 6.Out come
measured. 7.Effects measured including measures
of diagnostic accuracy.
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8. Comments on specific issues raised by the
study. ( biases) 9.Quality rating and level
of evidence of the study.
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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.
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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/me
ta/
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• 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/1471-2288/3/25

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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.
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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?
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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?
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STARD (Standards for reporting diagnostic
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
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Evidence of performance designed to facilitate
decision making
Decisions
Cost effectiveness
Organizational impact
Clinical impact
Diagnostic Therapeutic Outcome
Diagnostic performance
Technical performance
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How to act and Modify ?
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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 changing Treatment, closer monitoring and freq visit Persistently high value has increased risk of complications
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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
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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
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Is the highest level of evidence always the
strongest Recommendation ?
NO
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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.
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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.
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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.
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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.
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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.
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Critical appraisal checklists

• CASP (Critical Skills Appraisal Programme)
• http//www.phru.nhs.uk/casp/critical_appraisal_too
  ls.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?showap
  praisal

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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.o
rg.uk ) 3. Centre for Health Evidence (
WWW.cche.net )
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Impact of EBLM
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THANK YOU For your patient listening