广药选修药物流行病学实验流行病学

实验流行病学ExperimentalEpidemiology第五章

广东药学院姚振江Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.学习目的实验流行病学的定义实验流行病学的特点实验流行病学的分类实验流行病学的设计实验流行病学的强势与弱势Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.推荐参考文献吴涛,詹思延,李立明.流行病学实验研究发展历史.中华流行病学杂志2004;25(7):633-636.…5第五章实验流行病学研究(experimentalstudy)历史发展Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.

1747年

苏格兰医师JamesLind首次对比研究了用桔子、柠檬及其他干预治疗坏血病的疗效5第五章实验流行病学研究Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.

OnMay20,1747heisreadytobeginthefirstclinicalnutritionexperiment.Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.group1drankonequartofcideradaygroup2gargledwithsulfuricacid

group3hadtwospoonfulsofvinegar,3timesadaygroup4drank1/2-pintseawateradaygroup5drankbarleywater

group6atetwoorangesand1lemonadayHowdidheconducthisexperiment?

Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.Whathappened?Onlysailorswhoatetheorangesandlemonfeltbetter.Infact,inonlysixdaystheyfeltgreatandwereabletostartworkingagain.Theothersailorsintheexperimentfeltworse.

Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.1816年

法国Hamilton医师首次报道了爱丁堡的一项大型对照实验，评价放血疗法的效果，这是迄今为止有关采用交替法产生对照的最早记载之一。‘Ithadbeensoarranged,thatthisnumberwasadmitted,alternately,insuchamannerthateachofushadonethirdofthewhole.Thesickwereindiscriminatelyreceived,andwereattendedasnearlyaspossiblewiththesamecareandaccommodatedwiththesamecomforts.Onethirdofthewholeweresoldiersofthe61stRegiment,theremainderofmyown(the42nd)Regiment.NeitherMrAndersonnorIeveronceemployedthelancet.Helosttwo,Ifourcases;whilstoutoftheotherthird[treatedwithbloodlettingbythethirdsurgeon]thirtyfivepatientsdied."Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.1898年丹麦医师Fibiger通过半随机对照实验验证血清治疗白喉的效果。8outof239

patientsintheserumtreatedgroupand30

outof245

inthecontrolgroupdied.Noformalstatisticalanalysiswasperformedbut"noobjectioncanberaisedagainstthestatisticalsignificanceofthenumbers,"whichweredeemedcorrectbyaninspectorofthesickbenefitassociation(in1900

Pearsoninventedthe2test,10whichwouldhaveshownP=0.0003).Therateofserumsicknesswashighat60%.

Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.Tables-2-by-2unstratified11:44:19,2011-4-22 |+-|Total -------+-------------+------- +|8231|239 -|30215|245 -------+-------------+------- Total|38446|484TestsofsignificanceFisherexacttest(onetailed):0.000187Fisherexacttest(twotailed):0.000289Uncorrectedchi-square:13.24p-value:0.000275YatescorrectedChi-square:12.04p-value:0.000522Measuresofexposureeffect[95%CI]Riskratio:0.27[0.13,0.58]Oddsratio:0.25[0.11,0.55]Riskdifference:-0.09[-0.14,-0.04]Proportionalattributablerisk:-2.66[-6.82,-0.71]Populationproportionalattr.risk:-0.56[-0.76,-0.26]Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.1948年英国医学研究委员会领导开展了世界第一个临床随机对照实验（RandomizedcontroledTrial，RCT），由英国统计学家Hill评估了链霉素治疗肺结核的疗效。Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.First“modern”RCT-1948TheherowasAustinBradfordHillEvaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.FrancisTM,NapierJA,VoightRBetal

Evaluationofthe1954fieldtrialofpoliomyelitisvaccine

FinalReportAnnArborUniversityMichigan1957Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.1954fieldtrialofpoliomyelitisvaccineEvaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.ResultsofvaccinetrialsTherandomized,controlledexperimentSizeRate(per100,000)Treatment200,00028Control200,00071Noconsent350,00046TheObservedControlstudySizeRate(per100,000)Grade2(vaccine)225,00025Grade1,3(control)725,00054Grade2(noconsent)125,00044Source:ThomasFrancis,Jr.,“Anevaluationofthe1954Poliomyelitisvaccinetrials---summaryreport,”AmericanJournalofPublicHealthvol45(1955)pp.1-63.Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.

实验流行病学(experimentalepidemiology)

以人群为研究对象的实验研究

:

又称：

流行病学实验（epidemiologicalexperiment）

干预研究（interventionstudy

）Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学(experimentalepidemiology)

将来自同一总体的研究人群随机分为实验组和对照组，研究者对实验组人群施加某种干预措施后，随访并比较两组人群的发病(死亡)情况或健康状况有无差别及差别大小，从而判断干预措施效果的一种前瞻性、实验性研究方法。Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.随访观察结局事件不发生结局事件发生结局事件不发生随机分组

实验流行病学研究原理示意图结局－结局+实验组（干预措施）对照组（对照措施）样本目标人群结局+结局－Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学主要特点对照前瞻干预随机Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学对照前瞻干预随机与观察性研究进行比较描述性研究分析性研究队列研究病例对照研究为什么要设立对照?因果性实验中的对照法则设立对照Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.对照前瞻干预随机为什么要设立对照?影响实验流行病学研究效应的主要因素不能预知的结局霍桑效应(Hawthorneeffect)安慰剂效应(placeboeffect)潜在的未知因素的影响设立对照的方式标准方法对照安慰剂对照自身对照交叉对照Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学随访结局指标前因后果对照前瞻干预随机与观察性研究进行比较描述性研究分析性研究队列研究病例对照研究Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学暴露研究者施加对照前瞻干预随机与观察性研究进行比较描述性研究分析性研究队列研究病例对照研究Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.盲法

(blinding)减少研究对象和研究者主观因素的影响(信息偏倚)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.Justkidding：双盲实验

患者家属：医生,流行病学家采用的双盲试验是这个意思吗？？？医生患者护士Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.单盲(singleblind)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.双盲(doubleblind)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.三盲(tripleblind)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.开放试验(opentrial)不可能实现盲法外科手术锻炼饮食教育……Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.即使是药物也很难完全做到盲法药物的气味、味觉、感觉副作用检验结果对药物进行化验Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.来自总体的随机抽样人群随机分配到实验组和对照组5第五章实验流行病学对照前瞻干预随机与观察性研究进行比较描述性研究分析性研究队列研究病例对照研究Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.控制混杂的方法研究设计阶段随机化限制匹配资料分析阶段分层分析多变量分析Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.对照前瞻干预随机可比的对照有效的对照组间非处理因素可比组间效应测量可比随机分配盲法保证基线组间平衡保证随访过程中组间平衡Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学真实验(trueexperiment)对照前瞻干预随机描述性研究

-分析性研究队列研究++

病例对照研究(/)

+随机抽样检验假设能力+++Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学真实验(trueexperiment)对照前瞻干预随机类实验(quasi-experiment)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学类实验(quasi-experiment)真实验(trueexperiment)对照前瞻干预随机Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.自身前后比较比较干预前测量干预干预后测量已知结果Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究对象试验组(干预组)对照组有效无效有效无效发病时序工作时序5第五章实验流行病学随机分配Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.资料的收集数据分析研究设计结果解释实验流行病学研究的实施Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究设计明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法暴露疾病干预措施结局Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究设计明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法对干预措施有效的人群预期发病率较高的人群干预对其无害的人群能将实验坚持到底的人群依从性好的人群排除(exclusions)减少结果偏倚(保证内部真实性)影响结果外推(影响外部真实性)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究设计明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法相对稳定、足够的数量较高、稳定的发病率疫苗：近期未发生该病流行较好的医疗卫生条件领导重视、群众配合Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究设计明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法有效对照安慰剂对照交叉对照……Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究设计明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法干预前结局指标，样本量干预措施实施前后的变化，样本量，样本量(1-)，样本量单侧检验或双侧检验研究对象分组数量Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学研究实例计数资料假设对照组的发病率为40%，通过干预措施发病率下降到20%才有推广使用价值，规定=0.01（双侧），=0.05，问两组要观察多少人？

干预措施实施前后的变化(1-)单侧检验或双侧检验研究对象分组数量Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.EpiCalc2000Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.EpiCalc2000Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.5第五章实验流行病学研究实例计量资料假设对照组血清胆固醇水平为215mg/dl，合理膳食可以使干预组较对照组降低15mg/dl，已知从其他资料获得胆固醇标准差为25mg/dl，规定=0.05（双侧），=0.05，计算各组样本数？Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.EpiCalc2000Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.EpiCalc2000Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.研究设计明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法简单随机分组分层随机分组整群随机分组Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.简单随机分组EpiCalc2000Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.分层随机分组总体层层层可按年龄、性别、种族、教育水平等分层在各层内再进行前述的简单随机分组Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.整群随机分组以家庭、学校、医院、村庄或居民区等为单位随机分组要保证组间可比性(群间变异越小越好)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.明确研究目的选择研究对象确定实验现场设立对照确定样本大小随机化分组应用盲法研究设计单盲双盲三盲Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.数据分析资料整理表结局指标频率指标计量指标效应指标Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.数据分析频率指标治疗措施有效率治愈率病死率生存率复发率…预防措施抗体阳性率发病率感染率…资料整理表结局指标频率指标计量指标效应指标计量指标治疗措施血压胆固醇…预防措施抗体几何平均滴度…Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.数据分析资料整理表结局指标频率指标计量指标效应指标组间差异的统计学检验Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.数据分析保护率效果指数…资料整理表结局指标频率指标计量指标效应指标Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.保护率

(protectiverate,PR)保护功效

(protectiveefficacy,PE)归因保护/预防比例

(attributableprotectiveproportion)指标涵义对照组如果接受干预措施，则会减少的发病或死亡的比例试验组中归因于干预措施而减少的发病或死亡的比例Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.效果指数

(indexofeffectiveness,IE)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.偏倚问题偏倚(bias)

使实验流行病学研究的结果系统的偏离真相，即低估或高估某干预措施的效果。Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.偏倚问题选择偏倚信息偏倚混杂偏倚研究初期严格、正确地执行随机化分配及盲法(隐藏分组情况)，可以最大限度地减少实验流行病学研究中的选择偏倚反之，实验流行病学研究同样不能幸免选择偏倚Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.偏倚问题选择偏倚信息偏倚混杂偏倚随机分配后实验流行病学研究中涉及的选择偏倚主要来自于随机分配后的“退出”(withdrawal)不合格(ineligibility)不依从(noncompliance)失访(losstofollow-up)降低效率易引入选择偏倚Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.偏倚问题选择偏倚信息偏倚混杂偏倚随机分配后“退出”引起偏倚的原因退出者发生结局事件的概率不同于继续随访者(信息截尾)信息截尾的程度在不同干预组间不同意向性分析(intentiontotreatanalysis)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.RCT’s–BasicAnalysisDichotomous(DiseaseYes/No)OutcomeNRandomizeRt=a/n1Rc=c/n0RR=Rt/RcandARR=Rc-RtEvaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.MeasuresofEffectusedinRCT’sEER

=30/100=30%CER

=40/100=40%EER=Experimental(ortreatment)eventrateCER=Control(orbaseline)eventrateRR=EER/CER=30/40=75%RRR=1–RR=25%ARR=CER-EER

=40–30=10%NNT=1/ARR=1/0.10=10Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.StatisticalAnalyses-ITTIntention-to-TreatAnalysis

GoldStandardComparesoutcomesbasedonoriginalrandomizationschemeregardlessofeligibility,non-compliance,cross-overs,andlost-to-follow-upPerProtocol(PP)Analysis

Comparesoutcomesbasedonactualtreatmentreceivedamongthosewhowerecompliant(analysisdropsnon-compliant)AskswhetherthetreatmentworksamongonlythosethatcomplyAsTreated(AT)AnalysisComparesoutcomesbasedonactualtreatmentreceivedregardlessoforiginalassignment.Equivalenttoanalyzingthedataasacohortstudy!Askswhetherthetreatmentworksamongthosethattookit.BothPPandATapproachesignoreoriginalrandomizationandarethereforesubjecttoBIAS!!!Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.ITTvs.Per-Protocolvs.AsTreatedEvaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.

EffectofITTvs.PPvs.ATanalysesonanRCTofcoronaryarterybypasssurgeryversusmedicaltreatmentin767menwithstableangina.(Lancet1979;i:889-93).

Allocated(vs.actual)treatmentMedical(medical)Medical(surgical)Surgical(surgical)Surgical(medical)ARR(95%CI)Subjects3235036826Deaths272156Mortality8.4%4.0%4.1%23.1%ITTanalysis7.8%(29/373)5.3%(21/394)2.4%(-1.0,6.1)PPanalysis8.4%(27/323)4.1%(15/368)4.3%(0.7,8.2)ATanalysis9.5%(33/349)4.1%(17/418)5.4%(1.9,9.3)Evaluationonly.CreatedwithAspose.Slidesfor.NET3.5ClientProfile.Copyright2004-2011AsposePtyLtd.偏倚问题选择偏倚信息偏倚混杂偏倚确定偏倚(ascertainmentbias)施加干预的人被干预的人判断结局的人分析数据的人(安慰剂)+Evaluationonly.CreatedwithAspose.Slidesfor