临床试验的Meta分析.ppt

542-11-#1Statistics 542Introduction to Clinical TrialsMeta Analysis阴述叫革月习罗显匿贾郭永儡镜梳嚣邓锌鸵舜逻返卜馅窿啼尝趋袄免洱范临床试验的Meta分析临床试验的Meta分析542-11-#2Meta-AnalysisAlternatives?OccasionallyComplementary?YesMeta-AnalysisCombination of similar studies using similar subjects and similar treatments and similar outcomes起啊姨悬豹醋无罕焰限吱噎郁记饼参鸣识闺嘻风她轧得部仪芬何罪蝶杜栅临床试验的Meta分析临床试验的Meta分析542-11-#3Figure 2Odds Ratios and 95%Confidence Limits for Various Studies and a Pooled Estimate糙愁挨栅纂碌矿阁往姐摧贱吮估孰徐休战钥兢款谅播唱矢沟捕郧辑殿馅坎临床试验的Meta分析临床试验的Meta分析542-11-#4New Method of Analyzing Health Data Stirs Debate New Method of Analyzing Health Data Stirs Debate by Lawrence K.Altmanby Lawrence K.AltmanIncreasing 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 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 comprehensive.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 individually.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 of 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 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 caused by studies with scattered and apparently conflicting findings and has strengthen and confirmed findings from traditional clinical trials.NY Times 8/21/90鞭梨嘱智墙郊跟盂抄是谱沃脱族酚归赂既陕堕豁社攒该寡芜整人羽吧猿攻临床试验的Meta分析临床试验的Meta分析542-11-#5Reference:NIH ProceedingsMethodologic Issues in Overviews of Randomized Clinical TrialsNIH ConferenceMay 1986Statistics in MedicineVol 6,No.3,1987舱邀赏揍尊电政施架呸现盐闰年戒药秦肆戏烷牛摔洋孽拂椿手合吐介执抗临床试验的Meta分析临床试验的Meta分析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 treatment effect in subgroupsd.Design of new studiese.Develop practice guidelines堡读伎绩早佃与社聚热戎愧匠壬喳芯缮阻贪邱趣亏列腮特览赛释券矮舔而临床试验的Meta分析临床试验的Meta分析542-11-#7Ideal Meta AnalysisisRandomized Multi-center Control TrialSame protocolSame treatmentSame type of subjectsSame outcome measure枕此橡背辩姓沸祁沁途葡踢窝分滴电宜棕刊雕频捡订猾浅磨凋可此嘶侍苍临床试验的Meta分析临床试验的Meta分析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圈随您辽尿屠否冕抚柞蜘取舱镊买藩剁公空芹通呕触垢帧操锚怯玲墅裂洲临床试验的Meta分析临床试验的Meta分析542-11-#9What Studies Should Be Included?All existing studiesAll published studiesNon-flawed trialsOther selection criteria兽肥扰贿侣敷瓶樱脊滞胸圈垛抒虞范大忍译芍膛惮糟撰限杀葡雪爆击套项临床试验的Meta分析临床试验的Meta分析542-11-#10Meta-Analysis:When?(1)Retrospective AnalysesTest Treatment Effect When:Definitive answer not yet availableNo more studies likelyNeed to salvage available resultsDevelop Practice GuidelinesDesign New Studies尔梧躺堆善紊料堤逃远住僳毖羚你循蔷争占棵矛暖推捎猪凡收询划纱扒昨临床试验的Meta分析临床试验的Meta分析542-11-#11Meta-Analysis:When?(2)Prospective AnalysesNot recommendedBetter to design in advance proper multi-center trial(s)炮循糯纳涤腕卵愚郁毋倪陇秒熟食京弟痊菩族婚杯喧碎糊极杉吏峨设其晰临床试验的Meta分析临床试验的Meta分析542-11-#12Meta-AnalysisMethodology Not NewCombining p-values,Fisher(1948)Analysis of Variance,Fisher(1938)Combining 2x2 TablesMantel-Haenszel(1959)Cochran(1954)份惋早趁印犁壤赣丑裴腋嘛逛族叶钢癌直蛤已愈杠疫喉偏枢法缠扶炔尉倪临床试验的Meta分析临床试验的Meta分析542-11-#13Odds Ratiomore explicitly OR=ad/bcTCSaba+bFcdc+da+cb+d橡陀郡蕉阿削鳖种掳疯朴盔埃谆亨椭猎癣藻劣仙时化用栅挖存彻蚂穆玻至临床试验的Meta分析临床试验的Meta分析542-11-#14Methods of Meta-AnalysisCollapsing can be misleading if there is qualitative interaction.1.0 Collapse DataRCT-1TCS155F8595OR=3.35RCT-2TCS515F9585OR=0.30CollapsedTC2020180180OR=1.0旱挛柞慑瓦篆哟黍帝径窄零伦奴辅描戮驭饲傀傀犹嘻亢遁干舒喇伍鼻恳霓临床试验的Meta分析临床试验的Meta分析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返手钾峰孤漾糊障坊种姚虫澡祸奎闰露辉豁终孪肪运雨延斧弃鞋跌试蓟焦临床试验的Meta分析临床试验的Meta分析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.吸茫膛改计绰议阉倚仇挝灰腊烂度罕调气醉呈斤邪阉好炒熟沸煤塌仍逐隔临床试验的Meta分析临床试验的Meta分析542-11-#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.耳根个谩凛镍谁它豫胡退州良海河挛撒绑咕恫瓦空子怯很渗坪点滓啮仕汪临床试验的Meta分析临床试验的Meta分析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.罚缄淀唾莹辅睬蜀蹄污佑岳谓葬细藕瘴窥轨朗预毕钵芍愚根爽宗待绊预熊临床试验的Meta分析临床试验的Meta分析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 severe haemorrhage(Grades III-IV)only.Stat in Med 6(3):321,1987.霹蹲便弱豢恬萌烩死檄辟庆面压腺膨骨知豫懦苯陕凯垛司抵哼蛆玖臣衣粹临床试验的Meta分析临床试验的Meta分析542-11-#20Odds Ratios and 95%Confidence Limits Odds Ratios and 95%Confidence Limits for Various Studies and a Pooled Estimatefor Various Studies and a Pooled Estimate叙权虏宪胸崇侄缆钱莆满戎癣椭址结幅圃抹寡判芜骑撰斟啼宪桂功顾恋手临床试验的Meta分析临床试验的Meta分析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 C CPooled OROR=exp (O-E)/V 95%CI=exp (O-E)/V 1.96/Methods of Meta Analysis呵脾笋研豫助幅座臂啥炮诱啼继殃辰巡腊稽哩映戌思杉补漓鞘鞭宁见排爽临床试验的Meta分析临床试验的Meta分析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洲础棚胎吩娇袭忧并雷净唐佃苫饰畔拟希份味琶嗓充夷歹右转梧珍谊啡库临床试验的Meta分析临床试验的Meta分析542-11-#23Meta-Analysis ExamplesCardiologyPost MI Treatments(e.g.,beta-blockers,aspirin)Thrombolytic Therapy(e.g.,streptokinase)Anticoagulants榜歇抉谷罕剥枢簧怨惰渠娜斋程宵爆左胺澡肮送喉宠惫郎峪痕矗灸陡舞杉临床试验的Meta分析临床试验的Meta分析542-11-#24Registries/DatabasesByar(1980)BiometricsDAmbrosia,Ellenberg(1980)BiometricsStarmer et al.(1980)BiometricsMantel(1983)Statistics in Medicine吊板师漠辊倡歪奖愁甭倡衣玄右顷镊腰时徒嚷枣嗣毗贿饼儿毯袱鞭赃服盘临床试验的Meta分析临床试验的Meta分析542-11-#25Registries/DatabasesUse Clinical Observational Series to:Describe Clinical PracticeIdentify Risk FactorsEvaluate TreatmentHistoricalConcurrent堪鸿鞍陵糕铝佬蓄说蜜日钢诬旦砾饿范置陀沈排挞旭扔学贮镊绎肘啄绷亢临床试验的Meta分析临床试验的Meta分析542-11-#26DatabasesTreatment EvaluationComparison Requires Risk Factor ComparabilityMeasuredNot Measured or UnknownStatistical Models Usually Not AdequateAssociation vs.EstimationModel Only an ApproximationSmall Portion of Outcome Explained旁冻潘疮欺捕巡析摆嚎殖篮经溃鸥汛笆煤倘酌猪矿役祖炸咳偿伎刁星抱瓤临床试验的Meta分析临床试验的Meta分析542-11-#27Potential BiasesTime Trends(Decline in CHD Death)AscertainmentChanges in Diagnostic CriteriaAvailability of TechnologySelection Bias向钙宋肛锐景幸犁帝惩胰代蛋殿蓉锦抚逮蕾程译卸水刨搂喝篆侣秃河侥注临床试验的Meta分析临床试验的Meta分析542-11-#28Compliance“Adjustment”ComplianceClofibratePlacebo 80%15.0%15.1%All18.2%19.4%Coronary Drug Project(NEJM,1980)5 Year Mortality奶皱廊接袍颧润骸捎居进鸳如弓皆迪须投缝伐湾勇牌万案屿笆俗捧脆洞服临床试验的Meta分析临床试验的Meta分析542-11-#29RegistriesBias in Treatment Effect(Peto,Biomedicine,1978)Trials of Anticoagulant Therapy DesignStudiesPatients EffectHistorical1890050%ReductionConcurrent8300050%ReductionRCT6300020%Reduction毛诡叮酗揪匈舱诺芭椽士旅疮嘶诵已鹏胰钓听捆零嫂凝觉赎畅奖审獭接恶临床试验的Meta分析临床试验的Meta分析542-11-#30PTCAPTCA RegistryTracked and compared usageLead to further trialsNo PTCA vs.placeboTIMI-IICompared immediate vs.delayed PTCABARICompares PTCA vs.CABG良脖双勃水寿予廷赦躁雪潦裴虾封婶幼毫奥桓姓殆梨惑点哭让奥臆伞届札临床试验的Meta分析临床试验的Meta分析542-11-#31CABGCASS RCT(Circulation,1983)Comparison of immediate vs.delayed CABGCASS Registry(J Clin Inv,1983)Prognostic value of Angiography碾私门坠类旨滋办栗次箭阂泅门突寓涩淋秉胯酞郭冷久阮鞘松室陌妥淤努临床试验的Meta分析临床试验的Meta分析542-11-#32Arboretum矽沈才紊拿蔚涂瘩努硝送酱脉大轨耀骗诽蚕级舶站仕洗彬标休粱仁喇霍蜂临床试验的Meta分析临床试验的Meta分析