1、临床试验的Meta分析幻灯片 本课件本课件PPT仅供大家学习使用仅供大家学习使用 学习完请自行删除，谢谢！学习完请自行删除，谢谢！本课件本课件PPT仅供大家学习使用仅供大家学习使用 学习完请自行删除，谢谢！学习完请自行删除，谢谢！542-11-#2Alternatives?OccasionallyComplementary?YesMeta-Analysis Combination of similar studies using similar subjects and similar treatments and similar outcomes542-11-#3542-11-#4Incre
2、asing 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 increasingl
3、y 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.Th
4、e 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 earlie
5、r 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 Vetera
6、ns 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 als
7、o 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 a
8、pparently conflicting findings and has strengthen and confirmed findings from traditional clinical trials.NY Times 8/21/90542-11-#5Methodologic Issues in Overviews of Randomized Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6,No.3,1987542-11-#6a.Testing for a treatment effect(reject
9、ing 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 Trial Same protocol Same treatment Same type of subjects Same outcome me
10、asure542-11-#8 Differences Across Studies in:a.Treatmentb.Control Group/Populationc.Time Span(Disease,Background Therapy)d.Outcome Measures Publication Bias Completeness/Quality of Data Access to Data542-11-#9 All existing studies All published studies Non-flawed trials Other selection criteria542-1
11、1-#10Retrospective Analyses Test Treatment Effect When:Definitive answer not yet available No more studies likely Need to salvage available results Develop Practice Guidelines Design New Studies542-11-#11Prospective Analyses Not recommended Better to design in advance proper multi-center trial(s)542
12、-11-#12Methodology Not New Combining p-values,Fisher(1948)Analysis of Variance,Fisher(1938)Combining 2x2 Tables Mantel-Haenszel(1959)Cochran(1954)542-11-#13more explicitly bcaddbcadbddbbcaccaaOR/)/()/()/()/(OR=ad/bcTCSaba+bFcdc+da+cb+d542-11-#14Collapsing can be misleading if there is qualitative in
13、teraction.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)542-11-#16Apparent effects of fibrinolytic treatment on morality in the randomised trials of IV treatment of acute
14、myocardial infarction.Stat in Med 7:890:1988.542-11-#17Stat 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 o
15、f 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-#20542-11-#213.Blocking(Peto-
16、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/VV542-11-#224.Averaging P-valuesFisher(1948)Pi=P-value for ith trialZ=-2 log(Pi)2 with 2N df5.Averaging Test Statisticse.g.wi=niN(0,1)212/iiiiwZwZ542-11
17、-#23Cardiology Post MI Treatments(e.g.,beta-blockers,aspirin)Thrombolytic Therapy(e.g.,streptokinase)Anticoagulants542-11-#24 Byar(1980)Biometrics DAmbrosia,Ellenberg(1980)Biometrics Starmer et al.(1980)Biometrics Mantel(1983)Statistics in Medicine542-11-#25Use Clinical Observational Series to:Descr
18、ibe Clinical Practice Identify Risk Factors Evaluate Treatment Historical Concurrent542-11-#26Treatment Evaluation Comparison Requires Risk Factor Comparability Measured Not Measured or Unknown Statistical Models Usually Not Adequate Association vs.Estimation Model Only an Approximation Small Portio
19、n of Outcome Explained542-11-#27 Time Trends(Decline in CHD Death)Ascertainment Changes in Diagnostic Criteria Availability of Technology Selection Bias542-11-#28ComplianceClofibratePlacebo 80%15.0%15.1%All18.2%19.4%Coronary Drug Project(NEJM,1980)5 Year Mortality542-11-#29Bias in Treatment Effect(P
20、eto,Biomedicine,1978)Trials of Anticoagulant Therapy DesignStudiesPatients EffectHistorical1890050%ReductionConcurrent8300050%ReductionRCT6300020%Reduction542-11-#30 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.CABG542-11-#31 CASS RCT(Circulation,1983)Comparison of immediate vs.delayed CABG CASS Registry(J Clin Inv,1983)Prognostic value of Angiography542-11-#32
