1、542-11-#1542-11-#2Alternatives?OccasionallyComplementary?YesMeta-AnalysisCombination of similar studies using similar subjects and similar treatments and similar outcomes542-11-#3542-11-#4Increasing use of a controversial statistical method to evaluate medical therapies and surgical procedures is be

2、ginning 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 me

3、dical 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 in

4、dividual 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 wel

5、fare 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 previo

6、us 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 h

7、as 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 traditi

8、onal 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 (rejecting the null hypothesis)b. Evaluating a safety issue (rare events)c. Estimating

9、 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-#8 Differences Across Studies in:a.Treatmentb.Control Group/Popula

10、tionc.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 criteria542-11-#10Retrospective AnalysesTest Treatment Effect When:Definitive answer not

11、yet availableNo more studies likelyNeed to salvage available resultsDevelop Practice GuidelinesDesign New Studies542-11-#11Prospective AnalysesNot recommendedBetter to design in advance proper multi-center trial(s)542-11-#12Methodology Not NewCombining p-values, Fisher (1948)Analysis of Variance, Fi

12、sher (1938)Combining 2x2 TablesMantel-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 interaction.1.0 Collapse DataRCT-1TCS155F8595OR = 3.35RCT-2TCS515F9585O

13、R = 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 myocardial infarction. Stat in Med 7:890: 1988.542-1

14、1-#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 larg

15、e 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 study (3 institutions). Endpoints are total infants with haemmorrhage and totals with s

16、evere haemorrhage (Grades III-IV) only. Stat in Med 6(3): 321, 1987.542-11-#20542-11-#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 Pooled OROR = exp (O - E) / V 95% CI = exp (O - E) / V 1.96

17、/ 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-#23CardiologyPost MI Treatments(e.g., beta-blockers, aspirin)Thrombolytic Therapy(e.g., streptokinase)Anticoagulants542-11-#24 Byar (1

18、980) Biometrics DAmbrosia, Ellenberg (1980) Biometrics Starmer et al. (1980) Biometrics Mantel (1983) Statistics in Medicine542-11-#25Use Clinical Observational Series to:Describe Clinical PracticeIdentify Risk FactorsEvaluate TreatmentHistoricalConcurrent542-11-#26Treatment EvaluationComparison Req

19、uires Risk Factor ComparabilityMeasuredNot Measured or UnknownStatistical Models Usually Not AdequateAssociation vs. EstimationModel Only an ApproximationSmall Portion of Outcome Explained542-11-#27 Time Trends (Decline in CHD Death) Ascertainment Changes in Diagnostic Criteria Availability of Technology Selection B