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Galton.uchicago.edu
Meta-Analysis (or Overview) Clinical Scenario
• Mrs BW 64 y.o. • Hysterectomy • Dx of osteoporosis (Spinal BMD < 2SD below Dx of osteoporosis (Spinal BMD < 2SD below
• ? aminobisphosphonate (etidronate, ? aminobisphosphonate (etidronate, alendronate)
• Pt concern: cost Osteoporosis
• Affects 30-40% of postmenopausal women • 1.5M fractures annually • Vertebral fractures most common • Nonvertebral fractures (esp. hip) major causes Nonvertebral fractures (esp. hip) major causes of morbidity, mortality, cost
• Risk of hip fracture (50yo white woman): 1/6 • Risk of wrist fracture (50yo white woman): 1/6 Postmenopausal Postmenopausal osteoporosis
• Imbalance of bone formation and resorption • Progressive decline in bone mass, + risk of Progressive decline in bone mass, + risk of fracture
• Aminobisphosphonates: potent, specific Aminobisphosphonates: potent, specific inhibitor of osteoclast-mediated bone inhibitor of osteoclast-mediated bone resorption
• Eg: etidronate, alendronate Alendronate
• + Bone mineral density
• —But is new bone weaker? —But is new bone weaker?
• Mineralization unaffected at therapeutic does
• —But is there a clinical effect? —But is there a clinical effect?
• - Vertebral fracture incidence
• —But most morbidity from hip, wrist —But most morbidity from hip, wrist
• Does it reduce nonvertebral fractures? Meta-Analysis is
• A formal method for research synthesis • A quantitative and potentially more objective A quantitative and potentially more objective alternative to the expert review paper. Aspirin and MI
• How strong is the effect of aspirin in reducing How strong is the effect of aspirin in reducing post-MI mortality?
• Answer: about 10% reduction • How do we know? • Many studies “inconclusive” Finding small effects Small effects can be important A 10% reduction is hard to find (reducing 20% mortality to 18%) —Without a long, huge (thus expensive) study How large a study? Need to have 95% CI narrower than roughly Need to have 95% CI narrower than roughly 0.20 ± 0.02 This gives 50-50 chance of detection Thus, need se(difference) < 0.01 SE(difference of two proportions) = 0.8 x 0.2 x Setting this equal to 0.01 and solving for n we Setting this equal to 0.01 and solving for n we have n 800 in each group Combine evidence Combine evidence from many studies
• Assess whether there really is any effect • Estimate the size of the effect Reasons for doing Reasons for doing meta-analysis
• Increase power by increasing sample size Increase power by increasing sample size (pooling)
• Resolve conflicting reports (consensus) • Improve estimates of effect size • Answer new questions Meta-analysis
• Combines features of multicenter trials and Combines features of multicenter trials and retrospective studies
• Multicenter trials similarities—we are Multicenter trials similarities—we are combining studies with
• Common questions Common questions
• Similar study designs Similar study designs
• Simultaneous controls within each study unit Simultaneous controls within each study unit
• Similarities to retrospective studies
• Investigators choose which studies to include and exclude Investigators choose which studies to include and exclude
• Susceptible to selection biases Susceptible to selection biases
• Susceptible to ascertainment biases (Are “negative”
• Susceptible to ascertainment biases (Are “negative” studies as likely to be published?) studies as likely to be published?) Alendronate Alendronate meta-analysis
• Karpf, et al, JAMA (April 9, 1997) • Five studies
• RCT • Placebo controlled • >2 yr duration Meta-analysis Issues
• Were criteria for including and excluding Were criteria for including and excluding studies clearly defined in advance?
• Were criteria for evaluating the results from Were criteria for evaluating the results from studies clearly defined in advance?
• Does the overview use patient-level data?
➔ • How objective was the review? ➔ • Does the overview assess heterogeneity? How objective was the How objective was the
• Review by more than one reader • Procedures for resolving disagreements Procedures for resolving disagreements between readers
• Blinded review • Use of prepared data-extraction forms Does the overview Does the overview assess heterogeneity?
• Variation in the validity of the studies being Variation in the validity of the studies being
• Homogeneity of the studies regarding study Homogeneity of the studies regarding study
• Homogeneity of the studies with respect to the Homogeneity of the studies with respect to the size of measured effects?
• Possible factors accounting for heterogeneity? Reader's Guide: All articles
• Are the results valid? • What were the results? • Will the results help me in caring for my Will the results help me in caring for my patients? Are the results valid?
• Did the review address a focused clinical Did the review address a focused clinical question?
• Were the criteria used to select articles for Were the criteria used to select articles for inclusion appropriate?
• Secondary guides
• Is it unlikely that important, relevant studies were missed? Is it unlikely that important, relevant studies were missed?
• Was the validity of the included studies appraised? Was the validity of the included studies appraised?
• Were assessments of studies reproducible? Were assessments of studies reproducible?
• Were the results similar from study to study? Were the results similar from study to study? What are the results?
• What are the overall results of the review? • How precise were the results? Will the results help me in Will the results help me in caring for my patients?
• Can the results be applied in my patient care? • Were all clinically important outcomes Were all clinically important outcomes considered?
• Are the benefits worth the harms and costs?
Leitlinien der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Halschirurgie Otorhinolaryngol Nova 2002–03;12:161–174Erhalten: 13. Juni 2003Angenommen: 27. Juni 2003 Antibiotikatherapie der Infektionen an Kopf und Hals (Konsensusbericht)1, 2 Im Auftrag des Präsidiums herausgegeben von P. Federspil, Homburg/Saar Mitglieder der Konsensuskonferenz:3 P. Federspil, Hom
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Will the results help me in