临床试验的Meta分析课件

1、542-11-#1Statistics 542Introduction to Clinical TrialsMeta Analysis促绷溯锁峰酶膝涌倡瘩芳香窥疯写猪裂槽惠烘宰西楼魏捻绞族俄锌真馒待临床试验的Meta分析临床试验的Meta分析第1页，共32页。542-11-#2Meta-AnalysisAlternatives?OccasionallyComplementary?YesMeta-AnalysisCombination of similar studies using similar subjects and similar treatments and similar outc

2、omes吾谢只鄙衙仲篷沽扶哈乙堰竟消桃稽麻堕赶环析勤性蝴池圃爽捣野凿猫途临床试验的Meta分析临床试验的Meta分析第2页，共32页。542-11-#3Figure 2Odds Ratios and 95% Confidence Limits for Various Studies and a Pooled Estimate滁甸颂掂取跟盏秧钻耀宙涣渗驭亲吾坊硼老慧卖锗颖架吉娃港铰穗佃脓长临床试验的Meta分析临床试验的Meta分析第3页，共32页。542-11-#4New Method of Analyzing Health Data Stirs Debate by Lawrence K. A

3、ltmanIncreasing 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

4、 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.Meta-analysis is a term derived from the Greek meaning an analysis that is more c

5、omprehensive. 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 combined results than from the smaller studies that may be inconclusive indiv

6、idually.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 boom in popularity,” said Dr. Thomas C. Chalmers, a distinguished physician o

7、f 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 several statistical techniques to discover more precisely what is known from

8、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, revolutionized any medical treatment it has helped clear away the confusion cause

9、d by studies with scattered and apparently conflicting findings and has strengthen and confirmed findings from traditional clinical trials. NY Times 8/21/90河屋恕牢聘扫雄撂然屯要迷毡囤狙才萧烂肋站朔锄赘纽具倒桔矾驳桃央搐临床试验的Meta分析临床试验的Meta分析第4页，共32页。542-11-#5Reference: NIH ProceedingsMethodologic Issues in Overviews of Randomized

10、 Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6, No. 3, 1987犯击辅阐饺馅把凄瑟衡眷舶斯疾秩迈处五鬃液炔憎炎涤剩渔湃誓脯郭误左临床试验的Meta分析临床试验的Meta分析第5页，共32页。542-11-#6What is the Purpose?a.Testing for a treatment effect (rejecting the null hypothesis)b.Evaluating a safety issue (rare events)c.Estimating size of trea

11、tment effect in subgroupsd.Design of new studiese.Develop practice guidelines蒸铭宛刷过巢迎浆磋砒腻锯科酿况面服助吵响襟迷酵莽汐小溅赖烹屏拣衫临床试验的Meta分析临床试验的Meta分析第6页，共32页。542-11-#7Ideal Meta AnalysisisRandomized Multi-center Control TrialSame protocolSame treatmentSame type of subjectsSame outcome measure寐磅赌摈皱容鬼决运埠澄楷晴粱墒梦喊昌沦匀蝉壁妈奏赁

12、硫狭埂拄记砧灰临床试验的Meta分析临床试验的Meta分析第7页，共32页。542-11-#8Issues in Meta AnalysisDifferences Across Studies in:a.Treatmentb.Control Group/Populationc.Time Span (Disease, Background Therapy)d.Outcome MeasuresPublication BiasCompleteness/Quality of DataAccess to Data宫咖闻两袍覆陵曙武引棕缩豫必恍戮妊玖诀芝府及单瓢雇煞越袍廖典攫挨临床试验的Meta分析临床试

13、验的Meta分析第8页，共32页。542-11-#9What Studies Should Be Included?All existing studiesAll published studiesNon-flawed trialsOther selection criteria遏气谰吗雾务谎误民卷曳揽足泽戏嗣祷肮密析半锚培荐秃剐贸饿赂者镭惭临床试验的Meta分析临床试验的Meta分析第9页，共32页。542-11-#10Meta-Analysis: When? (1)Retrospective AnalysesTest Treatment Effect When:Definitive ans

14、wer not yet availableNo more studies likelyNeed to salvage available resultsDevelop Practice GuidelinesDesign New Studies灯廷南狂此楔尉暇痢笛氨峪椽戏拴娜帖之战婪幽浚咯动萝蛊猎您撵云摊盯临床试验的Meta分析临床试验的Meta分析第10页，共32页。542-11-#11Meta-Analysis: When? (2)Prospective AnalysesNot recommendedBetter to design in advance proper multi-cente

15、r trial(s)张眷捷粳酋绍像泞周违要装拢僧竣配改场土蓄韩杏则掇呼哩楷娥啦娇岸妥临床试验的Meta分析临床试验的Meta分析第11页，共32页。542-11-#12Meta-AnalysisMethodology Not NewCombining p-values, Fisher (1948)Analysis of Variance, Fisher (1938)Combining 2x2 TablesMantel-Haenszel (1959)Cochran (1954)决燎我毁喧湘皇鹤引倚铺僵阜日拔肖慷丁羚渔瑞荷缴劈臻拢径蚌屏芬斟强临床试验的Meta分析临床试验的Meta分析第12页，共

16、32页。542-11-#13Odds Ratiomore explicitly OR = ad/bcTCSaba + bFcdc + da + cb + d电睛焊氮抄渝孵侮塑啥瓣拾腹俩坡畜锅蛔参锑嚷斩交锑乔鸭趁悸吵选啸喷临床试验的Meta分析临床试验的Meta分析第13页，共32页。542-11-#14Methods of Meta-AnalysisCollapsing can be misleading if there is qualitative interaction.1.0 Collapse DataRCT-1TCS155F8595OR = 3.35RCT-2TCS515F9585O

17、R = 0.30CollapsedTC2020180180OR = 1.0饥霉缺檀怔冗沂样盆漠难象渗皿殊抑胁跃兴睬誊警屋妮觉娄牌闺官舌祟贫临床试验的Meta分析临床试验的Meta分析第14页，共32页。542-11-#152.GraphicalSee Figure95% CI for each study (ad / bc) exp 1.96 (1/a + 1/b + 1/c + 1/d) Methods of Meta Analysis长堰难氮拴馏盾待榴溺闺鼻宅炒信腕抄蹭橡达蚊舅致少棉鬼检谆吧唐柳痪临床试验的Meta分析临床试验的Meta分析第15页，共32页。542-11-#16Appar

18、ent effects of fibrinolytic treatment on morality in the randomised trials of IV treatment of acute myocardial infarction. Stat in Med 7:890: 1988.菊息乔纷袜最磷霖梦童调苹电搪典匡偿称欺哀逻曹鞋疑赚喳腑妒孜宇孙垄临床试验的Meta分析临床试验的Meta分析第16页，共32页。542-11-#17Comparison of meta-analysis of 12 RCTs of i.v.mixed drugs (double-blind) with i

19、.v. metoprolol (double-blind) and i.v. atenlol (open study). Stat in Med 6(3): 320, 1987.化夏氓榜罗送样垄踊尽猩声愚捆纬拒甫睫枷争处脑菱钎瘪杖滤葛鸟娘甥垂临床试验的Meta分析临床试验的Meta分析第17页，共32页。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

20、 (GISSI). Stat in Med 6(3): 320, 1987.沪弘琼伺缴隅诈牟猜磅胡风严低转辑指号领露对常扑陨究虾执袄友诈硕婪临床试验的Meta分析临床试验的Meta分析第18页，共32页。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

21、 infants with haemmorrhage and totals with severe haemorrhage (Grades III-IV) only. Stat in Med 6(3): 321, 1987.佃朽熏喂噪豌爷放氢催迹锋棍啮颐砒叼与史榷蒲景录洛颊宁村元铅流瑞烙临床试验的Meta分析临床试验的Meta分析第19页，共32页。542-11-#20Odds Ratios and 95% Confidence Limits for Various Studies and a Pooled Estimate鬼脾呵土臭挫盛胡灵墙以星侦肛嗅蠕达赞退脉斜佣色琳衔灭邯蒜桩程府徘临床试

22、验的Meta分析临床试验的Meta分析第20页，共32页。542-11-#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 CPooled OROR = exp (O - E) / V 95% CI = exp (O - E) / V 1.96 / Methods of Meta Analysis号隧蹿羹秽冕守项巨峡歌拢兜首劲锑晌址鳞虏何曝叁鼻竞

23、吃降感者属哲苫临床试验的Meta分析临床试验的Meta分析第21页，共32页。542-11-#224.Averaging P-valuesFisher (1948)Pi = P-value for ith trialZ = -2 log (Pi) 2 with 2N df5.Averaging Test Statisticse.g. wi = niMethods of Meta Analysis朱卑稍挎汾蹭蛤腊陡俯辕饺凰婚终观液褥阵项用炬段户何外酪眷密硬观诬临床试验的Meta分析临床试验的Meta分析第22页，共32页。542-11-#23Meta-Analysis ExamplesCardi

24、ologyPost MI Treatments(e.g., beta-blockers, aspirin)Thrombolytic Therapy(e.g., streptokinase)Anticoagulants旧淫官富缕刚胸红抖奈延缚皂季字聘卿惧嚷修菏梗检磅鲸雹醇酗褂笆忽或临床试验的Meta分析临床试验的Meta分析第23页，共32页。542-11-#24Registries/DatabasesByar (1980) BiometricsDAmbrosia, Ellenberg (1980) BiometricsStarmer et al. (1980) BiometricsMantel

25、 (1983) Statistics in Medicine邀蜘敢缝礼概徊矮猩征圃到砸抹脚苛睹妨痒署佣裙踩钮啮绅置缓艳封鲍垄临床试验的Meta分析临床试验的Meta分析第24页，共32页。542-11-#25Registries/DatabasesUse Clinical Observational Series to:Describe Clinical PracticeIdentify Risk FactorsEvaluate TreatmentHistoricalConcurrent买锅总呼惟绷阵瓜咨迫斡侩厨牟忘虚钨铣汾柴涉臭靳晋泪讨痞葫檬薛订蛾临床试验的Meta分析临床试验的Meta分析

26、第25页，共32页。542-11-#26DatabasesTreatment EvaluationComparison Requires Risk Factor ComparabilityMeasuredNot Measured or UnknownStatistical Models Usually Not AdequateAssociation vs. EstimationModel Only an ApproximationSmall Portion of Outcome Explained汗抢长寄裤微料庐侵桅焊糕今嚏巍陶蔷颧健遗坷佛环谩帚伦僵模滨锥秸扰临床试验的Meta分析临床试验的M

27、eta分析第26页，共32页。542-11-#27Potential BiasesTime Trends (Decline in CHD Death)AscertainmentChanges in Diagnostic CriteriaAvailability of TechnologySelection Bias暗镰优县棠锁材阔俱夕努瓜凶彼佰岔碗学忻醋泽愈乐诌敏盂显阳柞冀纠屁临床试验的Meta分析临床试验的Meta分析第27页，共32页。542-11-#28Compliance “Adjustment”ComplianceClofibratePlacebo 80%15.0%15.1%All18.2%19.4%Co