introduction to systematic reviews and meta-analyses craig a umscheid, md, msce, facp assistant...
TRANSCRIPT
Introduction to Systematic Reviews and Meta-Analyses
Craig A Umscheid, MD, MSCE, FACP
Assistant Professor of Medicine and Epidemiology
Director, Penn Center for Evidence-based Practice
Senior Associate Director, ECRI-Penn AHRQ EPC
TEACH Level II Workshop 4
NYAM
August 8th, 2013
PENN CENTER FOR EVIDENCE-BASED PRACTICE
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Outline
The CaseDefinitionsSteps to Consider when Performing or
Appraising a SR/MAReporting ToolConclusions
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The Case
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Setting the Stage: Images of the H1N1 Influenza Epidemic
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2009 H1N1 Cases Seen in One Mexican Hospital
JAMA. 2009;302(17):1880-1887
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The Case
You’re the CMO of a moderate sized hospital in Upstate NY, 100s of miles from a quarternary care hospital, and you hear about the below patient from the Director of your MICU:
38 yo physician admitted to your hospital with fever, cough, SOB, and muscle aches worsening over three days
PMH of high cholesterol and seasonal allergies, on a statin for cholesterol SH of 1 drink per day, no tobacco or illicits, 2 kids (3y and 1y), wife, and 2
cats VS: BP 110/70 HR 115 RR 28 O2 sat 90% Multilobar pneumonia on CXR, lab tests diagnostic for H1N1 Admitted to the ICU for hypoxemia Despite intubation and the use of salvage therapies, hypoxemia persists
and patient deteriorates Within first week of his ICU stay, patient codes and despite heroic efforts
by his team he is pronounced dead
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Demographics of H1N1 Patients in Critical Care
JAMA. 2009;302(17):1880-1887
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Demographics of Hospitalized Pts with H1N1
Demographics of Hospitalized Patients with H1N1
Study Age (mean)
Co-Morbidities (mean N) Time Course (median days)
Symptoms to hospital
Hospital to ICU
Hospital to Death Mortality
JAMA (Mexico) 44 years 2 6 days 1 day 10 days 41% (60d)
JAMA (Canada) 32 years 2 4 days 1 day 14 days 17% (90d)
JAMA. 2009;302(17):1880-1887
JAMA. 2009;302(17):1872-1879
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Extra Corporeal Membrane Oxygenation (ECMO)
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The Case (continued)
Should our moderate-sized hospital invest in an ECMO program?
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Should our moderate-sized hospital invest in an ECMO program?
A. Yes
B. No
C. Don’t know, need more information
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Definitions
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“Narrative review”
Traditional review by content expertMost common method of summarizing a fieldLimitations:
• Lack systematic methods to identify, appraise, and synthesize information
• Potential for selective inclusion and exclusion of studies to support a position
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“Original research study”
Well designed, well conducted studies can provide unbiased information
Limitations:• False negative results • False positive results • Weak external validity
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“Systematic reviews” vs. “Meta-analyses”
Systematic review • Literature review
prepared using a systematic approach to minimize bias and random error in identification of information
• May or may not include a meta-analysis
Meta-analysis • Statistical pooling of the
results of individual studies
• Aims to produce a single estimate of treatment effect
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Systematic Review/Meta-analysis
Address limitations of narrative reviews:• Uses prespecified, explicit methods to:
– reduce bias– allow for replication– reveal areas of uncertainty or in need of further research
Address limitations of original research studies:• Pools data across studies to:
– give more precise estimates of effect– reduce false positive or false negative results– improve generalizability – explore between-study differences in results
BMJ. Volume 315. November 22, 1997.
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Meta-analysis Medline publications
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5000
10000
15000
20000
25000
Year
No.
Pub
licat
ions
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Steps to Consider when Performing or Appraising a SR/MA
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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1. Define the question Questions most commonly address therapeutic
interventions, harms, and diagnostic tests
Type of question can point to type of studies to seek
Type of question Study Design
Therapy Randomized controlled trial
Harm RCT, cohort study, case-control study
Diagnostic test Cross-sectional
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1. Define the question (cont)
Population• age range, gender, race, diagnosis, severity class
Intervention or exposure • specific drug or device, doses, frequencies, IV, PO,
inpatient, outpatient, management strategiesComparison group
• placebo, usual care, active comparatorOutcomes
• process measures, clinical outcomes, cost
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PICO for ECMO SR
Patients• Adults• Acute respiratory failure from H1N1 pneumonia• Any critical care unit in the world
Intervention• ECMO
Comparator• Standard Care
Outcomes• Mortality
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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2. Establish eligibility criteria
Study designs • RCT, cohort, case-control, cross-sectional
Publication status• Peer-reviewed publications only• Also include abstracts?
Language• English, other languages?
Other• Publication year• Study size• Minimum follow-up
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A Note on Publication Bias
Bias can be introduced in a SR by not including relevant studies:• Unpublished (Gray Literature)• Published in non-English language• Published only in meeting proceedings or as abstracts• Published but not identified
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Cumulative Publication Rate for RCTs
Scherer. CDSR. 2007.
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Submission and Publication Time
Ioannidis. JAMA. 1998.
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Funnel Plots: Assessing Publication Bias
No Publication Bias Publication Bias
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Funnel Plot of Effects of Homeopathy
Linde, Lancet, 1997
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Funnel Plot following Trim and Fill
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Eligibility criteria for ECMO SR
Only included published studiesStudies were retrieved if:
1. reported on the use of ECMO in patients with influenza OR
2. any controlled trial reporting comparisons between those managed with and without ECMO
Studies had to report mortality ratesMinimum of ten patients in each groupNo language restrictions
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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3. Search literature
Use librarians to help devise search strategy, and filters to limit your search
Identify information resources to search • Electronic literature databases• Reference lists of key papers and review articles • Hand searches of high value journals• Discussion with experts in the field• Contact pharmaceutical or device manufacturers• Trial registries
Use sampling of resources to increase yield
Screen titles, abstracts and full text• Single versus two independent reviewers?• Automatation?
– Abstrckr. Available at: http://tuftscaes.org/citation_screening/
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Search Filters
Umscheid. CID. 2013.
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Electronic Literature Databases
Medline (Medical Literature Analysis and Retrieval System Online) • Premier database of medical research• PubMed interface is free• Ovid interface supported thru institutional accounts, and allows for more
complex searching
Embase (Excerpta Medica Database) • Large European database similar in scope and content to Medline• Includes many conference proceedings• Up to 70% citations in Embase not in Medline
Cochrane Controlled Trials Registry• Fastest, most reliable method for determining if a controlled trial has been
published on any topic
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Search Strategy for ECMO SR
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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4. Extract Data
Set priorities for data to extract• Anticipate structure and content of final evidence tables• Resist temptation to extract everything
Establish quality control• Dual extraction vs. solo extraction with random checks
Consider free electronic resources to help• Systematic Review Data Repository. Agency for Healthcare Research
and Quality. 2013. Available at: http://srdr.ahrq.gov/.
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Data extraction for ECMO SR
Pulmonary
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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5. Evaluate individual study quality
A study’s quality is a measure of its internal validity
Biased studies lead to erroneous findings in systematic reviews
Decide on how to evaluate quality• Use established scales (e.g. Jadad scale for RCTs)• Select components most likely to distinguish studies with higher risks of bias
from those with lower risks
Components versus scales• Scales have advantage of providing single summary measure of quality • Multiple scales exist, few are validated, and there are differences in items
included and weighting of items across scales• Component analysis has advantage of assessing specific aspects of quality
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Quality scales
Moher et al. Control Clin Trials. 1995.
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Evaluating quality of ECMO RCTs
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Study quality (continued)
Decide how quality evaluation will be used• To determine eligibility of study for SR• To weight studies• For subgroup analyses
Subgroup analyses based on quality scales or criteria can help determine effect of bias in studies
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Examining Effect of LWMH on Risk of DVT Stratified by Study Quality
Nurmohamed. Lancet. 1992.
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Quality of RCTs in ECMO SR
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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6. Synthesize data Qualitative synthesis using evidence
tables and written evidence summaries
Quantitative synthesis using meta-analysis• RevMan. Cochrane. 2012. Available at:
http://ims.cochrane.org/revman. • OpenMeta[Analyst]. 2012. Available at:
http://www.cebm.brown.edu/open_meta.
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Evidence table for ECMO SR
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Meta-analysis Estimate a summary measure and its
variance for each study Weight each study according to its sample
size - Studies with more “events” get greater weight
Statistically combine or pool results from each study to obtain a weighted average
- Not just a simple average Assess for statistical heterogeneity
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Forest plot of effect of ECMO on mortality in ARF
2009
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Assessing heterogeneity
Heterogeneity• Are differences in study-specific estimates statistically significant?
Assessment• Visual examination of Forest Plot• Statistical tests
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Efficacy of BCG Vaccination
Colditz, JAMA, 1994
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Statistical tests of heterogeneity Assess whether study-specific estimates are statistically different
from one another
Q test (i.e. chi squared test)• Most common test used• Power is generally low with small number of studies • Excessive power with large number of studies
I squared• Percentage of variation across studies that is due to heterogeneity
between studies and not chance• 0 to 100%
– >50% is considered moderate to high
Importantly, heterogeneity can exist even in absence of statistical significance
BMJ VOLUME 327 6 SEPTEMBER 2003 p557-60
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Forest plot of effect of ECMO on mortality in ARF
2009
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Fixed effects vs. Random effects Analyses
Fixed Effects• Assumes there is one underlying effect of intervention which all
individual studies are measuring• Assumes any differences between individual study results is a
consequence of sampling variation (i.e. chance)
Random Effects• Assumes any differences between individual study results is a
consequence of chance as well as real differences in the effects of the intervention across different studies
• Offers a more conservative (less precise) pooled estimate• If there is significant heterogeneity, should analyze using random
effects
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Forest plot of effect of ECMO on mortality in ARF
2009
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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7. Explore heterogeneity between studies
Differences in study design, populations, intervention, comparator, outcome definitions and conduct of trials can lead to differing results between studies
Examination of differences can help one understand the conditions most likely to yield positive or negative effects from an intervention
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Meta-analysis of AZT on Mortality
Search identified 8 studies
7 studies: no effect1 study: large effect
Why do you think 1 study was not pooled with the others?
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Forest plot of effect of ECMO on mortality in ARF
2009
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Study heterogeneity
If studies are heterogenous:• “Don’t ignore, instead explore!”
Exploration of heterogeneity is a critical objective of meta-analysis
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Seven Key Steps for SR/MA
1. Define the question2. Establish eligibility criteria3. Search literature4. Extract data5. Evaluate individual study quality6. Synthesize data qualitatively and/or
quantitatively (MA)7. Explore heterogeneity
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Reporting Tool for a SR and MA
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Back to Our Case
Should our moderate-sized hospital invest in an ECMO program?
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Should our moderate-sized hospital invest in an ECMO program?
A. Yes
B. No
C. Don’t know, need more information
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Conclusions
SR/MA is scientifically rigorous process of identifying the available evidence on a particular topic
SR are both qualitative and quantitative (MA)
MA involves statistical pooling of available data that results in weighted average
Exploration of heterogeneity in MA is critical
Potential limitations of SR/MA include poor quality of identified studies, publication bias, and heterogeneity
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References
General Systematic Review Resources Umscheid CA. A primer on performing systematic reviews and meta-analyses. Clinical Infectious Diseases. 2013. Egger M, Davey Smith G, Altman D (eds). Systematic Reviews in Health Care. Meta-analysis in Context. London:
BMJ Books, 2001.
Resources for Systematic Reviews Examining Harm Chou R, Helfand M. Challenges in systematic reviews that assess treatment harms. Annals of Internal Medicine.
2005: 142(12): 1090-1099. Loke YK, Price D, Herxheimer A. Systematic reviews of adverse effects: framework for a structured approach. BMC
Medical Research Methodology. 2007. 7:32. Hammad TA, Pinheiro SP, Neyarapally GA. Secondary use of RCTs to evaluate drug safety: a review of
methodologic considerations. Clinical Trials. 2011.
Resource for Systematic Reviews Examining Diagnostic Tests Smetana GW, Umscheid CA, Chang S, Matchar DB. Methods guide for authors of systematic reviews of medical
tests: a collaboration between the Agency for Healthcare Research and Quality and the Journal of General Internal Medicine. J Gen Intern Med. 2012;27: Suppl 1:S1-3.