临床试验Meta分析

1、Statistics 542Introduction to Clinical TrialsMeta Analysis1Meta-AnalysisAlternatives?OccasionallyComplementary?YesMeta-AnalysisCombination of similar studies using similar subjects and similar treatments and similar outcomes2Figure 2Odds Ratios and 95% Confidence Limits for Various Studies and a Poo

2、led Estimate3New Method of Analyzing Health Data Stirs Debate by 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

3、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.Met

4、a-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

5、 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

6、 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

7、 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, rev

8、olutionized 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 8/21/904Reference: NIH ProceedingsMethodologic Issues in Overviews of Ran

9、domized Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6, No. 3, 19875What 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 practi

10、ce guidelines6Ideal Meta AnalysisisRandomized Multi-center Control TrialSame protocolSame treatmentSame type of subjectsSame outcome measure7Issues in Meta AnalysisDifferences Across Studies in:a.Treatmentb.Control Group/Populationc.Time Span (Disease, Background Therapy)d.Outcome MeasuresPublicatio

11、n BiasCompleteness/Quality of DataAccess to Data8What Studies Should Be Included?All existing studiesAll published studiesNon-flawed trialsOther selection criteria9Meta-Analysis: When? (1)Retrospective AnalysesTest Treatment Effect When:Definitive answer not yet availableNo more studies likelyNeed t

12、o salvage available resultsDevelop Practice GuidelinesDesign New Studies10Meta-Analysis: When? (2)Prospective AnalysesNot recommendedBetter to design in advance proper multi-center trial(s)11Meta-AnalysisMethodology Not NewCombining p-values, Fisher (1948)Analysis of Variance, Fisher (1938)Combining

13、 2x2 TablesMantel-Haenszel (1959)Cochran (1954)12Odds Ratiomore explicitly OR = ad/bc13Methods of Meta-AnalysisCollapsing can be misleading if there is qualitative interaction.1.0 Collapse DataCollapsedTC2020180180OR = 1.0142.GraphicalSee Figure95% CI for each study (ad / bc) exp 1.96 (1/a + 1/b + 1

14、/c + 1/d) Methods of Meta Analysis15Apparent effects of fibrinolytic treatment on morality in the randomised trials of IV treatment of acute myocardial infarction. Stat in Med 7:890: 1988.16Comparison of meta-analysis of 12 RCTs of i.v.mixed drugs (double-blind) with i.v. metoprolol (double-blind) a

15、nd i.v. atenlol (open study). Stat in Med 6(3): 320, 1987.17Comparison 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, 1987.18Comparison of meta-analysis of 7 small RCTs of phenobarbital in

16、 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, 1987.19Odds Ratios and 95% Confidence Limits for Various Studies and

17、 a Pooled Estimate203.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 CPooled OROR = exp (O - E) / V 95% CI = exp (O - E) / V 1.96 / Methods of Meta Analysis214.Averaging P-valuesFisher (1948)Pi = P-va

18、lue for ith trialZ = -2 log (Pi) 2 with 2N df5.Averaging Test Statisticse.g. wi = niMethods of Meta Analysis22Meta-Analysis ExamplesCardiologyPost MI Treatments(e.g., beta-blockers, aspirin)Thrombolytic Therapy(e.g., streptokinase)Anticoagulants23Registries/DatabasesByar (1980) BiometricsDAmbrosia,

19、Ellenberg (1980) BiometricsStarmer et al. (1980) BiometricsMantel (1983) Statistics in Medicine24Registries/DatabasesUse Clinical Observational Series to:Describe Clinical PracticeIdentify Risk FactorsEvaluate TreatmentHistoricalConcurrent25DatabasesTreatment EvaluationComparison Requires Risk Factor ComparabilityMeasuredNot Measured or UnknownStatistical Models Usually Not AdequateAssociation vs. EstimationModel Only an ApproximationSmall Portion of Outcome Explained26Potential BiasesTime Trends (Decline in CHD Death)AscertainmentChanges in Diagnostic CriteriaAvailabil