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First Part.MA.Oct202010

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Adrian V. Hernandez
Adrian V. Hernandez

First part of meta-analysis lecture, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

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Meta-analysis Adrian V. Hernandez, M.D., Ph.D. Assistant Professor of Medicine Quantitative Health Sciences October 21, 2010
OUTLINE FIRST PART (40 minutes) Introduction, objectives, types of meta-analysis, definition of research question, getting information, inclusion/exclusion criteria Break 10 minutes Meta-analysis l October 10, 2012 l
OUTLINE (2) SECOND PART: 50 MINUTES Analysis (models, methods, heterogeneity, publication bias, quality, subgroup analysis) Reporting of meta-analysis (PRISMA, MOOSE guidelines) Meta-analysis l October 10, 2012 l
META-ANALYSIS: FACTS Too much information is available Many meta-analyses published lately: 1989-1993: 1301 1994-1998: 2532 1999-2003: 4917 2004-2008: 10567 Why meta-analyses? Saves money and effort Evaluates limitations of the evidence Designs future research Provides evidence for regulatory processes Meta-analysis l October 10, 2012 l
OBJECTIVES Summarize and integrate results of studies Analyze differences among studies Overcome small sample sizes Increase precision of effects Evaluate effects in subsets of patients Generate new hypotheses Meta-analysis l October 10, 2012 l
TYPES OF META-ANALYSES Randomized controlled trials (RCTs) Observational Studies Diagnostic studies Meta-analysis l October 10, 2012 l
CRITICAL ISSUES Identification and selection of studies Heterogeneity of results Analysis of data Reporting of results Interpretation of published results Meta-analysis l October 10, 2012 l
IDENTIFICATION AND SELECTION OF STUDIES The most critical step of a meta-analysis Clearly specified in protocol Phases: 1. Definition of research question 2. Literature search 3. Choice of relevant studies Meta-analysis l October 10, 2012 l
DEFINITION OF RESEARCH QUESTION Are the beneficial and harmful effects of glycoprotein IIb/IIIa receptor blockers similar between younger and older NSTE-ACS patients? What is the risk of HF with the use of rosiglitazone and pioglitazone in patients at high risk of DM and with type 2 DM? Which are the risk factors associated with hypercapnia in obese patients with OSA and without COPD? Meta-analysis l October 10, 2012 l
LITERATURE SEARCH Pubmed-Medline (www.pubmed.gov) Embase (www.embase.com) Ovid-Medline (www.ovid.com) The Web of Science (isiknowledge.com) Cochrane Library (www.cochrane.org) Scopus (www.scopus.com) Google Scholar (scholar.google.com) More on: Steinbrook R. NEJM 2006; 354:4-7. Meta-analysis l October 10, 2012 l
LITERATURE SEARCH - BIASES Publication bias Search bias Selection bias Meta-analysis l October 10, 2012 l
PUBLICATION BIAS Positive results are more likely to be published than negative results Meta-analysis l October 10, 2012 l
PUBLICATION BIAS (2) Meta-analysis l October 10, 2012 l
PUBLICATION BIAS (3) Meta-analysis l October 10, 2012 l
PUBLICATION BIAS (4) How to avoid/diminish? Identify unpublished studies (e.g. Nissen SE et al. NEJM 2007) Search registries (e.g. NIHs http://clinicaltrials.gov) Do not discard studies in other languages (e.g. German, French, Spanish) Meta-analysis l October 10, 2012 l
SEARCH BIAS How happens? Limited number of search engines Inappropriate keywords How to avoid/diminish? At least 3 search engines Use relevant keywords and show them (e.g. for RCTs: see Dickersin K et al. BMJ 1994; 309: 1286-91) Two or more researchers Meta-analysis l October 10, 2012 l
SELECTION BIAS How happens? Long list of potential articles Selection necessary (similarity, -replication) How to avoid/diminish? Define clear list of inclusion and exclusion criteria Two or more researchers Meta-analysis l October 10, 2012 l
INCLUSION/EXCLUSION CRITERIA Objective Population studied Study design-Quality of data Sample size Treatment/Intervention Controls Duration of study Calendar time Meta-analysis l October 10, 2012 l
J Gastrointest Surg (2009) 13:649656 DOI 10.1007/s11605-008-0756-8 Inclusion: phase III RCTs, Gum chewing vs. control (active/placebo) on time to flatus/LOS, elective colorectal surgery for localized disease (cancer or not), open or laparoscopic, >15 years, English, 1960-2008. Exclusion: Non-randomized studies, surgery beyond colorectal, prior colonic surgery, emergency surgery. Meta-analysis l October 10, 2012 l
COMBINATION OF STUDIES ALWAYS POSSIBLE? Enough info?, quality?, heterogeneity? Meta-analysis l October 10, 2012 l
AVAILABILITY OF INFORMATION Summary effects only (OR, RR, HR, mean [SD]). Most of the cases Limited analyses. What to do? Contact authors, Patient level data Meta-analysis l October 10, 2012 l
ALL STUDIES CAN BE COMBINED? Only reasonably well conducted RCTs? Observational studies also? Similar results between RCTs and observational? Similar results overtime? Meta-analysis l October 10, 2012 l
MA OF RCTs vs. OBSERVATIONAL 3 RCTs, n=10731 diabetic/high risk of diabetes, >12 months f-up: OR 2.1 (95% CI: 1.1-4.1) 4 Retrospective cohorts, n=67382 diabetic patients: OR 1.6 (95% CI 1.3-1.8) Meta-analysis l October 10, 2012 l
MAs OVERTIME: OBSERVATIONAL (1) 17 studies (3C, 14CC) RR for ischemic stroke: 2.8 (95%CI 2.2-3.4) Cohorts: 3.2 (2.0-5.3) Case-control: 2.8 (2.2-3.5) Meta-analysis l October 10, 2012 l
MAs OVERTIME: OBSERVATIONAL (2) 20 studies (4C, 16CC) RR for all-stroke: 1.9 (95%CI 1.4-2.6) Cohorts: 1.0 (0.5-1.8) Case-control: 2.1 (1.6-2.9) RR for ischemic stroke: 2.7 (95%CI 2.2-3.4) Meta-analysis l October 10, 2012 l

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First Part.MA.Oct202010

  • 1. Meta-analysis Adrian V. Hernandez, M.D., Ph.D. Assistant Professor of Medicine Quantitative Health Sciences October 21, 2010
  • 2. OUTLINE FIRST PART (40 minutes) Introduction, objectives, types of meta-analysis, definition of research question, getting information, inclusion/exclusion criteria Break 10 minutes Meta-analysis l October 10, 2012 l
  • 3. OUTLINE (2) SECOND PART: 50 MINUTES Analysis (models, methods, heterogeneity, publication bias, quality, subgroup analysis) Reporting of meta-analysis (PRISMA, MOOSE guidelines) Meta-analysis l October 10, 2012 l
  • 4. META-ANALYSIS: FACTS Too much information is available Many meta-analyses published lately: 1989-1993: 1301 1994-1998: 2532 1999-2003: 4917 2004-2008: 10567 Why meta-analyses? Saves money and effort Evaluates limitations of the evidence Designs future research Provides evidence for regulatory processes Meta-analysis l October 10, 2012 l
  • 5. OBJECTIVES Summarize and integrate results of studies Analyze differences among studies Overcome small sample sizes Increase precision of effects Evaluate effects in subsets of patients Generate new hypotheses Meta-analysis l October 10, 2012 l
  • 6. TYPES OF META-ANALYSES Randomized controlled trials (RCTs) Observational Studies Diagnostic studies Meta-analysis l October 10, 2012 l
  • 7. CRITICAL ISSUES Identification and selection of studies Heterogeneity of results Analysis of data Reporting of results Interpretation of published results Meta-analysis l October 10, 2012 l
  • 8. IDENTIFICATION AND SELECTION OF STUDIES The most critical step of a meta-analysis Clearly specified in protocol Phases: 1. Definition of research question 2. Literature search 3. Choice of relevant studies Meta-analysis l October 10, 2012 l
  • 9. DEFINITION OF RESEARCH QUESTION Are the beneficial and harmful effects of glycoprotein IIb/IIIa receptor blockers similar between younger and older NSTE-ACS patients? What is the risk of HF with the use of rosiglitazone and pioglitazone in patients at high risk of DM and with type 2 DM? Which are the risk factors associated with hypercapnia in obese patients with OSA and without COPD? Meta-analysis l October 10, 2012 l
  • 10. LITERATURE SEARCH Pubmed-Medline (www.pubmed.gov) Embase (www.embase.com) Ovid-Medline (www.ovid.com) The Web of Science (isiknowledge.com) Cochrane Library (www.cochrane.org) Scopus (www.scopus.com) Google Scholar (scholar.google.com) More on: Steinbrook R. NEJM 2006; 354:4-7. Meta-analysis l October 10, 2012 l
  • 11. LITERATURE SEARCH - BIASES Publication bias Search bias Selection bias Meta-analysis l October 10, 2012 l
  • 12. PUBLICATION BIAS Positive results are more likely to be published than negative results Meta-analysis l October 10, 2012 l
  • 13. PUBLICATION BIAS (2) Meta-analysis l October 10, 2012 l
  • 14. PUBLICATION BIAS (3) Meta-analysis l October 10, 2012 l
  • 15. PUBLICATION BIAS (4) How to avoid/diminish? Identify unpublished studies (e.g. Nissen SE et al. NEJM 2007) Search registries (e.g. NIHs http://clinicaltrials.gov) Do not discard studies in other languages (e.g. German, French, Spanish) Meta-analysis l October 10, 2012 l
  • 16. SEARCH BIAS How happens? Limited number of search engines Inappropriate keywords How to avoid/diminish? At least 3 search engines Use relevant keywords and show them (e.g. for RCTs: see Dickersin K et al. BMJ 1994; 309: 1286-91) Two or more researchers Meta-analysis l October 10, 2012 l
  • 17. SELECTION BIAS How happens? Long list of potential articles Selection necessary (similarity, -replication) How to avoid/diminish? Define clear list of inclusion and exclusion criteria Two or more researchers Meta-analysis l October 10, 2012 l
  • 18. INCLUSION/EXCLUSION CRITERIA Objective Population studied Study design-Quality of data Sample size Treatment/Intervention Controls Duration of study Calendar time Meta-analysis l October 10, 2012 l
  • 19. J Gastrointest Surg (2009) 13:649656 DOI 10.1007/s11605-008-0756-8 Inclusion: phase III RCTs, Gum chewing vs. control (active/placebo) on time to flatus/LOS, elective colorectal surgery for localized disease (cancer or not), open or laparoscopic, >15 years, English, 1960-2008. Exclusion: Non-randomized studies, surgery beyond colorectal, prior colonic surgery, emergency surgery. Meta-analysis l October 10, 2012 l
  • 20. COMBINATION OF STUDIES ALWAYS POSSIBLE? Enough info?, quality?, heterogeneity? Meta-analysis l October 10, 2012 l
  • 21. AVAILABILITY OF INFORMATION Summary effects only (OR, RR, HR, mean [SD]). Most of the cases Limited analyses. What to do? Contact authors, Patient level data Meta-analysis l October 10, 2012 l
  • 22. ALL STUDIES CAN BE COMBINED? Only reasonably well conducted RCTs? Observational studies also? Similar results between RCTs and observational? Similar results overtime? Meta-analysis l October 10, 2012 l
  • 23. MA OF RCTs vs. OBSERVATIONAL 3 RCTs, n=10731 diabetic/high risk of diabetes, >12 months f-up: OR 2.1 (95% CI: 1.1-4.1) 4 Retrospective cohorts, n=67382 diabetic patients: OR 1.6 (95% CI 1.3-1.8) Meta-analysis l October 10, 2012 l
  • 24. MAs OVERTIME: OBSERVATIONAL (1) 17 studies (3C, 14CC) RR for ischemic stroke: 2.8 (95%CI 2.2-3.4) Cohorts: 3.2 (2.0-5.3) Case-control: 2.8 (2.2-3.5) Meta-analysis l October 10, 2012 l
  • 25. MAs OVERTIME: OBSERVATIONAL (2) 20 studies (4C, 16CC) RR for all-stroke: 1.9 (95%CI 1.4-2.6) Cohorts: 1.0 (0.5-1.8) Case-control: 2.1 (1.6-2.9) RR for ischemic stroke: 2.7 (95%CI 2.2-3.4) Meta-analysis l October 10, 2012 l