临床试验的Meta分析课件

1、Statistics 542Introduction to Clinical TrialsMeta Analysis临床试验的Meta分析1Statistics 542Introduction tMeta-AnalysisAlternatives?OccasionallyComplementary?YesMeta-AnalysisCombination of similar studies using similar subjects and similar treatments and similar outcomes临床试验的Meta分析2Meta-AnalysisAlternatives

2、?Figure 2Odds Ratios and 95% Confidence Limits for Various Studies and a Pooled Estimate临床试验的Meta分析3Figure 2Odds Ratios and 95% CNew Method of Analyzing Health Data Stirs Debate by Lawrence K. AltmanIncreasing use of a controversial statistical method to evaluate medical therapies and surgical proce

3、dures 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 pay

4、ment 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 an

5、y 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

6、 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 analys

7、is 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

8、 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

9、from traditional clinical trials. NY Times 8/21/90临床试验的Meta分析4New Method of Analyzing HealthReference: NIH ProceedingsMethodologic Issues in Overviews of Randomized Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6, No. 3, 1987临床试验的Meta分析5Reference: NIH ProceedingsMethWhat is the Purp

10、ose?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 guidelines临床试验的Meta分析6What is the Purpose?a.TestingIdeal Meta AnalysisisRandomized Multi-center Con

11、trol TrialSame protocolSame treatmentSame type of subjectsSame outcome measure临床试验的Meta分析7临床试验的Meta分析7Issues in Meta AnalysisDifferences Across Studies in:a.Treatmentb.Control Group/Populationc.Time Span (Disease, Background Therapy)d.Outcome MeasuresPublication BiasCompleteness/Quality of DataAcces

12、s to Data临床试验的Meta分析8Issues in Meta AnalysisDiffereWhat Studies Should Be Included?All existing studiesAll published studiesNon-flawed trialsOther selection criteria临床试验的Meta分析9What Studies Should Be IncludeMeta-Analysis: When? (1)Retrospective AnalysesTest Treatment Effect When:Definitive answer no

13、t yet availableNo more studies likelyNeed to salvage available resultsDevelop Practice GuidelinesDesign New Studies临床试验的Meta分析10Meta-Analysis: When? (1)RetroMeta-Analysis: When? (2)Prospective AnalysesNot recommendedBetter to design in advance proper multi-center trial(s)临床试验的Meta分析11Meta-Analysis:

14、When? (2)ProspeMeta-AnalysisMethodology Not NewCombining p-values, Fisher (1948)Analysis of Variance, Fisher (1938)Combining 2x2 TablesMantel-Haenszel (1959)Cochran (1954)临床试验的Meta分析12Meta-AnalysisMethodology Not NOdds Ratiomore explicitly OR = ad/bcTCSaba + bFcdc + da + cb + d临床试验的Meta分析13Odds Rati

15、omore explicitlyOR = Methods of Meta-AnalysisCollapsing can be misleading if there is qualitative interaction.1.0 Collapse DataRCT-1TCS155F8595OR = 3.35RCT-2TCS515F9585OR = 0.30CollapsedTC2020180180OR = 1.0临床试验的Meta分析14Methods of Meta-AnalysisCollap2.GraphicalSee Figure95% CI for each study (ad / bc

16、) exp 1.96 (1/a + 1/b + 1/c + 1/d) Methods of Meta Analysis临床试验的Meta分析152.GraphicalMethods of Meta AnApparent effects of fibrinolytic treatment on morality in the randomised trials of IV treatment of acute myocardial infarction. Stat in Med 7:890: 1988.临床试验的Meta分析16Apparent effects of fibrinolytComp

17、arison 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.临床试验的Meta分析17Comparison of meta-analysis ofComparison of meta-analysis of mortality in 11 RCTs and reinfarction rates in 10 RCTs of i.v.

18、 streptokinase with large co-operative study (GISSI). Stat in Med 6(3): 320, 1987.临床试验的Meta分析18Comparison of meta-analysis ofComparison 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). Endpoi

19、nts are total infants with haemmorrhage and totals with severe haemorrhage (Grades III-IV) only. Stat in Med 6(3): 321, 1987.临床试验的Meta分析19Comparison of meta-analysis ofOdds Ratios and 95% Confidence Limits for Various Studies and a Pooled Estimate临床试验的Meta分析20Odds Ratios and 95% Confidence3.Blocking

20、 (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 Analysis临床试验的Meta分析213.Blocking (Peto-MH)Methods o4.Averaging P-valuesFisher (1948

21、)Pi = P-value for ith trialZ = -2 log (Pi) 2 with 2N df5.Averaging Test Statisticse.g. wi = niMethods of Meta Analysis临床试验的Meta分析224.Averaging P-valuesFisher (Meta-Analysis ExamplesCardiologyPost MI Treatments(e.g., beta-blockers, aspirin)Thrombolytic Therapy(e.g., streptokinase)Anticoagulants临床试验的M

22、eta分析23Meta-Analysis ExamplesCardioloRegistries/DatabasesByar (1980) BiometricsDAmbrosia, Ellenberg (1980) BiometricsStarmer et al. (1980) BiometricsMantel (1983) Statistics in Medicine临床试验的Meta分析24Registries/DatabasesByar (1980Registries/DatabasesUse Clinical Observational Series to:Describe Clinic

23、al PracticeIdentify Risk FactorsEvaluate TreatmentHistoricalConcurrent临床试验的Meta分析25Registries/DatabasesUse ClinicDatabasesTreatment EvaluationComparison Requires Risk Factor ComparabilityMeasuredNot Measured or UnknownStatistical Models Usually Not AdequateAssociation vs. EstimationModel Only an ApproximationSmall Portion of Outcome Explained临床试验的Meta分析26DatabasesTreatment Evaluation临Potential BiasesTime Trends (Decline in CHD Death)AscertainmentChanges in Diagnostic CriteriaAvailability of TechnologySelection Bias临床试验的Meta分析27Potential BiasesTime Trends (DCompliance “Adjustment”Compl