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Systematic Review/Meta-analysis
Siti Rizny F. Saldi, Indah S. Widyahening,
Respati W. Ranakusma
Acknowledgements
Paul Glasziou, Steve McDonald, Elaine Beller
Bond University Australia
Cochrane Training
Compiled by Miranda Cumpston, based on materials by
Georgia Salanti, Julian Higgins, Steff Lewis, the Cochrane
Statistical Methods Group, the Australasian Cochrane
Centre, and the Dutch Cochrane Centre
Level of evidence
SR-MA
RCTs
Cohort studies
Case-controlled studies
Case series/reports
Background information/
expert opinion
MEDLINE 2010
2,000 articles / day
Approximately
75 new trials
published every
day
Bastian H, Glasziou P, Chalmers I. Seventy-five trials and eleven systematic reviews a day: how will we ever keep up?. PLoS Med. 2010;7(9)
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Traditional approach
Expert opinion
Narrative review articles
Consensus statements
(group expert opinion)
New approach
(Systematic reviews)
Explicit quantitative
synthesis of ALL the
evidence
Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
evidence for clinical decisions. AnnDr.Intern
RSUPN Med. 1997;126(5):376-80.
Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
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Systematic review
“The application of strategies that limit bias in the
assembly, critical appraisal, and synthesis of all
relevant studies on a specific topic.”
Oxford Centre of Evidence Based Medicine (OCEBM) Levels Table
Two types:
Qualitative (non-statistical)
Quantitative (statistical) or meta-analysis
Review article
Systematic review
Meta-analysis
Review article
Systematic review
Meta-analysis
What is meta-analysis?
Statistical methods (meta-analysis) may or may not be used to
analyze and summarize the results of the included studies.
Meta-analysis = quantitative approach for systematically
combining results of previous research to arrive at conclusions
about the body of research
What does it mean?
Quantitative → numbers
Systematic → methodical
Combining → putting together
Previous research → what’s already done
Conclusions → new knowledge
Why meta-analysis?
To quantitatively summarize estimate from
previous studies (i.e. resolve controversies)
Helps guide for further research
Increase statistical power
Improves generalizability
3. Plan methods
How to search?
▪ Sources
▪ Find published relevant articles:
▪ Major bibliographic databases: PubMed/MEDLINE, EMBASE, CENTRAL.
▪ Textbooks, printed journals, reference lists
▪ Unpublished materials:
▪ Theses, dissertations, trial registries, contact with experts/personal
communication (peer group), etc.
▪ Search strategies:
▪ Database: MeSH terms and text words
▪ Others: hand-searching → a manual page-by-page
examination of the entire contents, to identify all eligible
reports
▪ No limitation on years and languages
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
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1
Standard Error
3
0.1 0.33 0.6 1 3 10
Source: Matthias Egger & Jonathan Sterne Effect
Asymmetrical funnel plot
0
1
Standard Error
Small study
effect
2
3
0.1 0.33 0.6 1 3 10
Source: Matthias Egger & Jonathan Sterne Effect
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Domains to address
random sequence generation
allocation concealment
blinding of participants and personnel
blinding of outcome assessment
incomplete outcome data
selective reporting
other bias
Blinding of outcome
Detection
assessment Outcome Outcome
assessment assessment
Attrition Incomplete outcome data
Effect measure
Trial 1
Trial 2
Trial 3
Trial 4
Many similar trials
Trial 5
Trial 6
Trial 7
Trial 1+2+3
+4+5+6+7
RR
RR =
= ??
??
Relative Risk
Relative Risk of Death
(RR)
(RR) of death
Favours Point
steroid Favours placebo
estimate
Trial Deaths
Babies Steroid Placebo "best guess at truth"
#1 1070 6.8% 11.2%
Relative
Relative
Risk
Risk (RR)
(RR) of Death
of death
Favours steroid Favours placebo
Trial Deaths
Babies Steroid Placebo "Cumulative Meta-analysis"
#1 1070 6.8% 11.2%
Total 2486
Relative
Relative
Risk
Risk (RR)
(RR) of Death
of death
Forest plot
The data for each trial are here, divided into experimental and
control groups
Forest plot
• This is the % weight given to each study in the pooled analysis
• For the mean difference: SDs are used together with the sample
sizes to compute the weight given to each study.
Forest plot
The label above the graph tells you which statistic has been
used
Forest plot
• Mid point of the box shows point effect estimate of each study
• The size of the block for each study is proportional to the % weight.
• The horizontal line represents the confidence interval.
Forest plot
• Take care to read the labels
• Things to the left do not always mean the treatment is
better than the control
Forest plot
• The pooled analysis is given a diamond shape
• The widest bit is located on the point estimate, and the horizontal width in the
confidence interval.
• Does the confidence interval cross the line of no effect?
Overall effect
estimate
Forest plot
1
2
3
4
5
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Study I 1992
Study II 1994
Study III 1995
Study IV 1995
Study V 1996
Study VI 1997
Study VII 1999
Study VIII 2000
Combined
0.1 10
OR = 1
Favor drug Favor placebo
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective
Study I 1992
Study II 1994
Study III 1995
Study IV 1995
Study V 1996
Study VI 1997
Study VII 1999
Study VIII 2000
Combined
-0.3 +0.3
Favor drug Xe- Xc= 0 Favor placebo
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective
Issues in meta-analysis
Choosing a model -- heterogeneity
Fixed effects model or random effects?
Bias in meta analysis
poor quality of trials
publication bias
Quality control in meta analysis
PRISMA guidelines
Statistical Software for meta analysis
What is heterogeneity
Variation or Differences
between the true intervention effects underlying
the different studies
Clinical diversity/heterogeneity
Participants
e.g. condition, age, gender, location, study eligibility
criteria
Interventions
intensity/dose, duration, delivery, additional
components, experience of practitioners, control
(placebo, none, standard care)
Outcomes
follow-up duration, ways of measuring, definition of an
event, cut-off points
Methodological diversity/heterogeneity
Design
e.g. randomised vs non-randomised
Conduct
e.g. risk of bias (allocation concealment, blinding, etc.),
approach to analysis
Identifying heterogeneity
Visual inspection (eyeball test) of forest plots
Chi-squared (χ2) test (Q test)
I2 statistic to quantify heterogeneity
Analysis
Many techniques
Focus on variability
Fixed effects model
Only intra-study, ignore inter-study variability
Narrower CI
Random effects model
Considers also inter-study variability
Broader CI
Bayesian statisticians (less popular)
Prior probability
Even broader CI
Unless the studies are very heterogeneous → fixed and
random model usually similar
Random (sampling)
error • assumes all studies are
measuring the same treatment
effect
• estimates that one effect
• if not for random (sampling)
error, all results would be
identical
Study
result
Common
Source: Julian Higgins true effect
Random-effects model
Random
error • assumes the treatment effect
varies between studies
• estimates the mean of the
distribution of effects
• weighted for both
within-study and between-study
variation (tau2, 2)
Study-
specific
effect
Mean of true
Source: Julian Higgins effects
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Adapted from Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm
and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3.
Some heterogeneity
Fixed Random
Adapted from Adams CE, Awad G, Rathbone J, Thornley B. Chlorpromazine versus placebo for schizophrenia.
Cochrane Database of Systematic Reviews 2007, Issue 2.
Small study effects
Fixed Random
Adapted from Li J, Zhang Q, Zhang M, Egger M. Intravenous magnesium for acute myocardial infarction.
Cochrane Database of Systematic Reviews 2007, Issue 2.
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Evidence in context
assess the quality of (confidence in) the body of
evidence:
when your analysis is complete
for each outcome
always report results in the context of these findings
informs your Results, Discussion and Conclusions
report consistently throughout the review
Advantages:
▪ Combined effect size: more definitive
▪ Enables subgroup analysis
▪ Background for further studies
Disadvantages:
▪ Statistical controversies
▪ Publication bias
▪ Disadvantages of secondary data
▪ Technical limitations: Details of studies rarely identical
Thank you