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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,542-11-#,#,542-11-#,1,Statistics 542,Introduction to Clinical TrialsMeta Analysis,542-11-#1Statistics 542Intro,542-11-#,2,Meta-Analysis,Alternatives?Occasionally,Complementary?Yes,Meta-Analysis,Combination of similar studies using similar subjects and similar treatments and similar outcomes,542-11-#2Meta-AnalysisAltern,542-11-#,3,Figure 2,Odds Ratios and 95% Confidence Limits for Various Studies and a Pooled Estimate,542-11-#3Figure 2Odds Ratios,542-11-#,4,New Method of Analyzing Health Data Stirs Debate by Lawrence K. Altman,Increasing use of a controversial statistical method to evaluate medical therapies and surgical procedures is beginning to affect profoundly the care of pregnant women and patients with cancer, heart disease and many other common conditions.,The method, known as meta-analysis promises to plan an increasingly important role in determining health risks, environmental hazards and national policy on payment for medical care.,Backers say technique can draw big, reliable conclusions from small, inconsistent findings.,Meta-analysis is a term derived from the Greek meaning an analysis that is more comprehensive. The larger numbers obtained by combining studies provide a greater statistical power than any of the individual studies. Researchers are often able to draw more reliable inferences or new conclusions from the combined results than from the smaller studies that may be inconclusive individually.,In earlier applications of meta-analysis, researchers evaluated intelligence quotients, government social welfare programs and many other topics. Meta-analysis has come to medicine late, but “it is now undergoing a boom in popularity,” said Dr. Thomas C. Chalmers, a distinguished physician of the Department of Veterans Affairs in Boston and a pioneer in methodology.,The method involves an analysis of previous analyses. It combines the results of a wide range of existing smaller studies and then applies one of several statistical techniques to discover more precisely what is known from previous research. It may also produce a unified result from diverse, apparently contradictory studies.,The technique has already shed new light on the effectiveness of medical therapies. Although it has not, in itself, revolutionized any medical treatment it has helped clear away the confusion caused by studies with scattered and apparently conflicting findings and has strengthen and confirmed findings from traditional clinical trials.,NY Times,8/21/90,542-11-#4New Method of Analyzi,542-11-#,5,Reference: NIH Proceedings,Methodologic Issues in Overviews,of Randomized Clinical Trials,NIH Conference,May 1986,Statistics in Medicine,Vol 6, No. 3, 1987,542-11-#5Reference: NIH Procee,542-11-#,6,What is the Purpose?,a.Testing for a treatment effect (rejecting the null hypothesis),b.Evaluating a safety issue (rare events),c.Estimating size of treatment effect in subgroups,d.Design of new studies,e.Develop practice guidelines,542-11-#6What is the Purpose?a,542-11-#,7,Ideal Meta Analysis,is,Randomized Multi-center Control Trial,Same protocol,Same treatment,Same type of subjects,Same outcome measure,542-11-#7,542-11-#,8,Issues in Meta Analysis,Differences Across Studies in:,a.Treatment,b.Control Group/Population,c.Time Span (Disease, Background Therapy),d.Outcome Measures,Publication Bias,Completeness/Quality of Data,Access to Data,542-11-#8Issues in Meta Analys,542-11-#,9,What Studies Should Be Included?,All existing studies,All published studies,Non-flawed trials,Other selection criteria,542-11-#9What Studies Should B,542-11-#,10,Meta-Analysis: When? (1),Retrospective,Analyses,Test Treatment Effect When:,Definitive answer not yet available,No more studies likely,Need to salvage available results,Develop Practice Guidelines,Design New Studies,542-11-#10Meta-Analysis: When?,542-11-#,11,Meta-Analysis: When? (2),Prospective,Analyses,Not recommended,Better to design in advance proper multi-center trial(s),542-11-#11Meta-Analysis: When?,542-11-#,12,Meta-Analysis,Methodology Not New,Combining p-values, Fisher (1948),Analysis of Variance, Fisher (1938),Combining 2x2 Tables,Mantel-Haenszel (1959),Cochran (1954),542-11-#12Meta-AnalysisMethodo,542-11-#,13,Odds Ratio,more explicitly,OR = ad/bc,T,C,S,a,b,a + b,F,c,d,c + d,a + c,b + d,542-11-#13Odds Ratiomore expli,542-11-#,14,Methods of Meta-Analysis,Collapsing can be misleading if there is,qualitative,interaction.,1.0 Collapse Data,RCT-1,T,C,S,15,5,F,85,95,OR = 3.35,RCT-2,T,C,S,5,15,F,95,85,OR = 0.30,Collapsed,T,C,20,20,180,180,OR = 1.0,542-11-#14Methods of Meta-Anal,542-11-#,15,2.Graphical,See Figure,95% CI for each study,(ad / bc) exp 1.96 (1/a + 1/b + 1/c + 1/d) ,Methods of Meta Analysis,542-11-#152.GraphicalMethods,542-11-#,16,Apparent effects of fibrinolytic treatment on morality in the randomised trials of IV treatment of acute myocardial infarction.,Stat in Med,7:890: 1988.,542-11-#16Apparent effects of,542-11-#,17,Comparison of meta-analysis of 12 RCTs of i.v.mixed drugs (double-blind) with i.v. metoprolol (double-blind) and i.v. atenlol (open study).,Stat in Med,6(3): 320, 1987.,542-11-#17Comparison of meta-a,542-11-#,18,Comparison of meta-analysis of mortality in 11 RCTs and reinfarction rates in 10 RCTs of i.v. streptokinase with large co-operative study (GISSI).,Stat in Med,6(3): 320, 1987.,542-11-#18Comparison of meta-a,542-11-#,19,Comparison of meta-analysis of 7 small RCTs of phenobarbital in the treatment of neonatal intra-cranial haemmorrhage with one large co-operative study (3 institutions). Endpoints are total infants with haemmorrhage and totals with severe haemorrhage (Grades III-IV) only.,Stat in Med,6(3): 321, 1987.,542-11-#19Comparison of meta-a,542-11-#,20,Odds Ratios and 95% Confidence Limits for Various Studies and a Pooled Estimate,542-11-#20Odds Ratios and 95%,542-11-#,21,3.Blocking (Peto-MH),Overall Estimate,Let O =,a,i,E =,E,i,E,i,=,(a,i,+ c,i,)(a,i,+ b,i,),n,i,V =,V,i,V,i,=,(a,i,+ c,i,) )(b,i,+ d,i,)(c,i,+ d,i,)(a,i,+ b,i,n,i,2,(n,i,- 1),Z =,O - E,C,Pooled OR,OR = exp (O - E) / V ,95% CI = exp (O - E) / V 1.96 / ,Methods of Meta Analysis,542-11-#213.Blocking (Peto-MH,542-11-#,22,4.Averaging P-valuesFisher (1948),P,i,= P-value for i,th,trial,Z = -2,log (P,i,) ,2,with 2N df,5.Averaging Test Statistics,e.g.,w,i,= n,i,Methods of Meta Analysis,542-11-#224.Averaging P-value,542-11-#,23,Meta-Analysis Examples,Cardiology,Post MI Treatments,(e.g., beta-blockers, aspirin),Thrombolytic Therapy,(e.g., streptokinase),Anticoagulants,542-11-#23Meta-Analysis Exampl,542-11-#,24,Registries/Databases,Byar (1980),Biometrics,DAmbrosia, Ellenberg (1980),Biometrics,Starmer et al. (1980),Biometrics,Mantel (1983),Statistics in Medicine,542-11-#24Registries/Databases,542-11-#,25,Registries/Databases,Use Clinical Observational Series to:,Describe Clinical Practice,Identify Risk Factors,Evaluate Treatment,Historical,Concurrent,542-11-#25Registries/Databases,542-11-#,26,Databases,Treatment Evaluation,Comparison Requires Risk Factor Comparability,Measured,Not Measured or Unknown,Statistical Models Usually Not Adequate,Association vs. Estimation,Model Only an Approximation,Small Portion of Outcome Explained,542-11-#26DatabasesTreatment E,542-11-#,27,Potential Biases,Time Trends (Decline in CHD Death),Ascertainment,Changes in Diagnostic Criteria,Availability of Technology,Selection Bias,542-11-#27Potential BiasesTime,542-11-#,28,Compliance “Adjustment”,ComplianceClofibratePlacebo, 80%15.0%15.1%,All18.2%19.4%,Coronary Drug Project (NEJM, 1980),5 Year Mortality,542-11-#28Compliance “Adjustme,542-11-#,29,Registries,Bias in Treatment Effect,(Peto,Biomedicine, 1978),Trials of Anticoagulant Therapy,DesignStudiesPatients Effect,Historical1890050% Reduction,Concurrent8300050% Reduction,RCT6300020% Reduction,542-11-#29RegistriesBias in Tr,542-11-#,30,PTCA,PTCA Registry,Tracked and compared usage,Lead to further trials,No PTCA vs. placebo,TIMI-II,Compared immediate vs. delayed PTCA,BARI,Compares PTCA vs. CABG,542-11-#30PTCAPTCA Registry,542-11-#,31,CABG,CASS RCT (,Circulation, 1983),Comparison of immediate vs. delayed CABG,CASS Registry (,J Clin Inv, 1983),Prognostic value of Angiography,542-11-#31CABGCASS RCT (Circul,542-11-#,32,Arboretum,542-11-#32Arboretum,
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