1、临床试验的Meta分析1Alternatives?OccasionallyComplementary?YesMeta-Analysis Combination of similar studies using similar subjects and similar treatments and similar outcomes临床试验的Meta分析2临床试验的Meta分析3Increasing use of a controversial statistical method to evaluate medical therapies and surgical procedures is b
2、eginning 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 medi
3、cal 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 individ
4、ual 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 pro
5、grams 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
6、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 ne
7、w 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.
8、NY Times 8/21/90临床试验的Meta分析4Methodologic Issues in Overviews of Randomized Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6,No.3,1987临床试验的Meta分析5a.Testing for a treatment effect(rejecting the null hypothesis)b.Evaluating a safety issue(rare events)c.Estimating size of treatment effec
9、t in subgroupsd.Design of new studiese.Develop practice guidelines临床试验的Meta分析6Ideal Meta AnalysisisRandomized Multi-center Control Trial Same protocol Same treatment Same type of subjects Same outcome measure临床试验的Meta分析7 Differences Across Studies in:a.Treatmentb.Control Group/Populationc.Time Span(
10、Disease,Background Therapy)d.Outcome Measures Publication Bias Completeness/Quality of Data Access to Data临床试验的Meta分析8 All existing studies All published studies Non-flawed trials Other selection criteria临床试验的Meta分析9Retrospective Analyses Test Treatment Effect When:Definitive answer not yet availabl
11、e No more studies likely Need to salvage available results Develop Practice Guidelines Design New Studies临床试验的Meta分析10Prospective Analyses Not recommended Better to design in advance proper multi-center trial(s)临床试验的Meta分析11Methodology Not New Combining p-values,Fisher(1948)Analysis of Variance,Fish
12、er(1938)Combining 2x2 Tables Mantel-Haenszel(1959)Cochran(1954)临床试验的Meta分析12more explicitly bcaddbcadbddbbcaccaaOR/)/()/()/()/(OR=ad/bcTCSaba+bFcdc+da+cb+d临床试验的Meta分析13Collapsing can be misleading if there is qualitative interaction.1.0 Collapse DataRCT-1TCS155F8595OR=3.35RCT-2TCS515F9585OR=0.30Coll
13、apsedTC2020180180OR=1.0临床试验的Meta分析142.GraphicalSee Figure95%CI for each study (ad/bc)exp 1.96 (1/a+1/b+1/c+1/d)临床试验的Meta分析15Apparent 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16Comparison of
14、 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 of mortality in 11 RCTs and reinfarction rates in 10 RCTs of i.v.streptokinase with large co-operative study(GISSI
15、).Stat in Med 6(3):320,1987.临床试验的Meta分析18Comparison 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-
16、IV)only.Stat in Med 6(3):321,1987.临床试验的Meta分析19临床试验的Meta分析203.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/VV临床试验的Meta分析214.Averaging P-valuesFisher(1948)Pi=P-value for ith trialZ=-2
17、log(Pi)2 with 2N df5.Averaging Test Statisticse.g.wi=niN(0,1)212/iiiiwZwZ临床试验的Meta分析22Cardiology Post MI Treatments(e.g.,beta-blockers,aspirin)Thrombolytic Therapy(e.g.,streptokinase)Anticoagulants临床试验的Meta分析23 Byar(1980)Biometrics DAmbrosia,Ellenberg(1980)Biometrics Starmer et al.(1980)Biometrics M
18、antel(1983)Statistics in Medicine临床试验的Meta分析24Use Clinical Observational Series to:Describe Clinical Practice Identify Risk Factors Evaluate Treatment Historical Concurrent临床试验的Meta分析25Treatment Evaluation Comparison Requires Risk Factor Comparability Measured Not Measured or Unknown Statistical Mod
19、els Usually Not Adequate Association vs.Estimation Model Only an Approximation Small Portion of Outcome Explained临床试验的Meta分析26 Time Trends(Decline in CHD Death)Ascertainment Changes in Diagnostic Criteria Availability of Technology Selection Bias临床试验的Meta分析27ComplianceClofibratePlacebo 80%15.0%15.1%
20、All18.2%19.4%Coronary Drug Project(NEJM,1980)5 Year Mortality临床试验的Meta分析28Bias in Treatment Effect(Peto,Biomedicine,1978)Trials of Anticoagulant Therapy DesignStudiesPatients EffectHistorical1890050%ReductionConcurrent8300050%ReductionRCT6300020%Reduction临床试验的Meta分析29 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临床试验的Meta分析30 CASS RCT(Circulation,1983)Comparison of immediate vs.delayed CABG CASS Registry(J Clin Inv,1983)Prognostic value of Angiography临床试验的Meta分析31临床试验的Meta分析32
