临床试验的Meta分析.pptx

542-11-#1Statistics 542Introduction to Clinical TrialsMeta Analysis542-11-#2Meta-AnalysisAlternatives?OccasionallyComplementary?YesMeta-AnalysisCombination of similar studies using similar subjects and similar treatments and similar outcomes542-11-#3Figure 2Odds Ratios and 95%Confidence Limits for Various Studies and a Pooled Estimate542-11-#4New Method of Analyzing Health Data Stirs Debate New Method of Analyzing Health Data Stirs Debate by Lawrence K.Altmanby Lawrence K.AltmanIncreasing 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 8/21/90542-11-#5Reference:NIH ProceedingsMethodologic Issues in Overviews of Randomized Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6,No.3,1987542-11-#6What 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 subgroupsd.Design of new studiese.Develop practice guidelines542-11-#7Ideal Meta AnalysisisRandomized Multi-center Control TrialSame protocolSame treatmentSame type of subjectsSame outcome measure542-11-#8Issues in Meta AnalysisDifferences Across Studies in:a.Treatmentb.Control Group/Populationc.Time Span(Disease,Background Therapy)d.Outcome MeasuresPublication BiasCompleteness/Quality of DataAccess to Data542-11-#9What Studies Should Be Included?All existing studiesAll published studiesNon-flawed trialsOther selection criteria542-11-#10Meta-Analysis:When?1)Retrospective AnalysesTest Treatment Effect When:Definitive answer not yet availableNo more studies likelyNeed to salvage available resultsDevelop Practice GuidelinesDesign New Studies542-11-#11Meta-Analysis:When?(2)Prospective AnalysesNot recommendedBetter to design in advance proper multi-center trial(s)542-11-#12Meta-AnalysisMethodology Not NewCombining p-values,Fisher(1948)Analysis of Variance,Fisher(1938)Combining 2x2 TablesMantel-Haenszel(1959)Cochran(1954)542-11-#13Odds Ratiomore explicitly OR=ad/bcTCSaba+bFcdc+da+cb+d542-11-#14Methods of Meta-AnalysisCollapsing can be misleading if there is qualitative interaction.1.0 Collapse DataRCT-1TCS155F8595OR=3.35RCT-2TCS515F9585OR=0.30CollapsedTC2020180180OR=1.0542-11-#152.GraphicalSee Figure95%CI for each study (ad/bc)exp 1.96 (1/a+1/b+1/c+1/d)Methods of Meta Analysis542-11-#16Apparent 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-#17Comparison 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-#18Comparison 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-#19Comparison of meta-analysis of 7 small RCTs of phenobarbital in the treatment of neonatal intra-cranial haemmorrhage with one large co-operative study3 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-#20Odds Ratios and 95%Confidence Limits Odds Ratios and 95%Confidence Limits for Various Studies and a Pooled Estimatefor Various Studies and a Pooled Estimate542-11-#213.Blocking(Peto-MH)Overall EstimateLet O=aiE=EiEi=(ai+ci)(ai+bi)niV=ViVi=(ai+ci)(bi+di)(ci+di)(ai+bi ni2(ni-1)Z=O-E C CPooled OROR=exp (O-E)/V 95%CI=exp (O-E)/V 1.96/Methods of Meta Analysis542-11-#224.Averaging P-valuesFisher(1948)Pi=P-value for ith trialZ=-2 log(Pi)2 with 2N df5Averaging Test Statisticse.g.wi=niMethods of Meta Analysis542-11-#23Meta-Analysis ExamplesCardiologyPost MI Treatments(e.g.,beta-blockers,aspirin)Thrombolytic Therapy(e.g.,streptokinase)Anticoagulants542-11-#24Registries/DatabasesByar(1980)BiometricsDAmbrosia,Ellenberg(1980)BiometricsStarmer et al.1980)BiometricsMantel(1983)Statistics in Medicine542-11-#25Registries/DatabasesUse Clinical Observational Series to:Describe Clinical PracticeIdentify Risk FactorsEvaluate TreatmentHistoricalConcurrent542-11-#26DatabasesTreatment EvaluationComparison Requires Risk Factor ComparabilityMeasuredNot Measured or UnknownStatistical Models Usually Not AdequateAssociation vs.EstimationModel Only an ApproximationSmall Portion of Outcome Explained542-11-#27Potential BiasesTime Trends(Decline in CHD Death)AscertainmentChanges in Diagnostic CriteriaAvailability of TechnologySelection Bias542-11-#28Compliance“Adjustment”ComplianceClofibratePlacebo 80%15.0%15.1%All18.2%19.4%Coronary Drug Project(NEJM,1980)5 Year Mortality542-11-#29RegistriesBias in Treatment Effect(Peto,Biomedicine,1978)Trials of Anticoagulant Therapy DesignStudiesPatients EffectHistorical1890050%ReductionConcurrent8300050%ReductionRCT6300020%Reduction542-11-#30PTCAPTCA RegistryTracked and compared usageLead to further trialsNo PTCA vs.placeboTIMI-IICompared immediate vs.delayed PTCABARICompares PTCA vs.CABG542-11-#31CABGCASS RCT(Circulation,1983)Comparison of immediate vs.delayed CABGCASS Registry(J Clin Inv,1983)Prognostic value of Angiography542-11-#32Arboretum