临床研究方法病因学方

1、病因学研究北京协和医院普通内科方病因学研究前言基本概念研究方法测量指标评价原则前言流行病学 实验性研究（experimental research） 随机 非随机 观察性研究（observational research） 描述性研究(descriptive epidemiology) 分析性研究(analytic epidemiology)前言病因学研究的重要性 治疗 预防基本概念(cause)a cause is that which produces an effect的分类必要条件(necessary cause)充分条件(sufficient cause)基本概念病因(cause)

2、病因是导致疾病发生的因素病因的分类充分，且必要21三体唐氏综合症充分，但不必要放射线白血病必要，但不充分宫颈癌HPV既不充分，也不必要高血压冠心病充分，且必要疾病X因素A充分，但不必要或或因素C疾病X因素A因素B必要，但不充分疾病X 因素B + 因素A + 因素C 既不充分，也不必要 因素E +或 因素D +或 因素F +因素C疾病X因素A因素B病因的分类直接病因（近因） 引起疾病的直接因素间接病因（远因） 与发病有间接因素直接病因与间接病因 因素A 疾病X 因素C因素B疾病X因素A(risk factor)流行病学层次的“病因”使疾病发生概率(风险)增高的因素 因素(factor)人群疾病发

3、生的概率(risk) 因素(factor)消失人群疾病发生的概率(risk)Abraham Liliendeld病因模型学模型疾病因素模型病因模型充分病因集合模型（Rothmans pie）影响健康的因素遗传政治生物物理医疗政策行为化学环境种族学模型生物环境环境宿主宿主遗传内核致病因子环境理化环境轮状模型流行病学三角疾病因素模型因素生物学因素环境因素医学生物学因素疾病心理行为因素卫生因素远因近因病因模型Rothmans pieBerkman. Soc Sci Med. 2000 Sep;51(6):843-57Glass & McAtee. Soc Sci Med 2006;62:16

4、50Healthy People 2010Association is NOT Cause机遇Chance (random error)偏倚Bias (systematic error)Confounding因果推断的逻辑方法：Mill准则求异法（Method of difference）求同法（Method of agreement）共变法（Method of concomitant variation ） 类推法（Method of analogy）排除法（Method of exclusion）因果推断标准单病因致病假说(Koch, 1882)患者体内均能检出引起该病的病原体(必要病因)

5、其他疾病患者中不能检出该病原体(效应特异性)该病原体能够从患者体内分离培养，接种易感动物能病(充分病因)该能从患病动物体内分离到相同病原体Robert Koch多病因致病推断标准(Bradford-Hill Criteria)时间顺序(temporality) Did the exposure precede the disease?关联强度(strength of association) How strongly associated is the putative risk with the outcome of interest?一致性(consistency across inves

6、tigations) Have the results been replicated by different studies, in different settings, by different investigators, and under different conditions?推断标准(Bradford-Hill Criteria)剂量-效应关系(biological gradient) Are increasing exposures (i.e., dose and duration) associated with increasing risks of disease?

7、试验证据(experimental evidence) Is there evidence from true experiments in humans?生物可能性(biological plausibility) Is there a credible biological or physical mechanism that can explain the association?推断标准(Bradford-Hill Criteria)符合性(coherence) Is the association consistent with the natural history and epi

8、demiology of the disease?特异性(specificity) Is the exposure associated with a very specific disease rather than a wide range of diseases?类比性(Analogy) The effect of similar factors may be considered推断标准(Bradford-Hill Criteria)"None of my nine viewpoints can bringindisputable evidence for or agains

9、t the cause- and-effect hypothesis and none can berequired sine qua non”-HillHill, Austin Bradford (1965). “The environment and disease: association or causation?” Proceedings of the Royal Society of Medicine 58: 295300.推断标准(Bradford-Hill Criteria)常用Strength Consistency TemporalityBiological gradien

10、t不常用Coherence Experiment Analogy SpecificityPlausibility误差(error)研究结果与客观实际不符合的地方误差的分类 随机误差(random error)：机遇(chance) 随机抽样/测量时随机出现的变异 没有固定的大小和方向，一般呈正态分布 系统误差(systematic error)：偏倚(bias) 对象选取/测量/分析时的方法学缺陷 有固定的大小和方向偏倚选择偏倚(selection bias) 在选取研究对象的过程中，由于选取方式不当导致入选对象与未入选对象之间系统差异 如：志愿者，方便样本，研究对象不同意/失访信息偏倚(in

11、formation bias) 由于测量、观察或资料收集过程中方法问题，使获得的资料 如：回忆偏倚，系统误差者偏倚混杂(Confounding)因素与疾病发生的关联程度受其他因素的干扰ExposureOutcomeConfoundingExposureOutcomeFACTORWhat is this?Directed Acyclic Graphs (DAGs)“DAGs are a set of arrows drawn along atimeline, characterizing causal and temporal relationships between variables. T

12、here can never be a cycle (hence acyclic) because we can never go back in time.”CommuDent Oral Epidemiol 2002;30:399-404.DAGsDirected 沿时间轴走行的一组箭头 箭头代表“可能导致” 无箭头代表相互之间“没有因果关系”Acyclic 某因素不能导致自身的出现Graphs 图示各种因间的关系DAGs的作用与结局之间的因果关系与结局之间的关系间的因果关系用图代表 有效组织 找出因 找出混杂因素 找出中介因素分析时可避免过度调整Causation of Bias: The

13、 EpiscopeFIGURE 1 . “The Episcope.” A user of epidemiologic evidence sees a “known” RD (kRD) that results from informationtransmitted, like light rays through a telescope, from a causal (“aetiologic”) RD (aRD) in a target population, through layers of “lenses” and “filters.” Each layer is a distinct

14、 domain where certain types of biases operate, potentially adding additional distortions to the association of interest. Domains a through k are illustrated in Figures 2-10.Epidemiology. 2001,12(1):114-122.A. The original cause of the image transmitted through the episcope is theassociation (if it e

15、xists) between the causal agent and morbidity.B. Other background factors cloud the association randomly.C. In the source population, the association of interest can be further distorted by correlated causes.None of the above phenomena is observable without diagnoses and exposure measurements, which

16、 are produced as follows:D. Morbidity is a contributing cause of diagnoses, which are recorded in medicalcharts or deaths, as well as self-reported on questionnaires. Thesediagnoses and recordings have varying sensitivities and specificities.E. The occurrence of the causal agent is a contributing ca

17、use of the occurrence of evidence of exposure, which is recorded via interviews, self-administered questionnaires, administrative forms, and other instruments with varying sensitivities and specificities.F. Data on diagnoses and exposures are collated by various means into files anddatabases, usuall

18、y for administrative purposes and sometimes specifically for epidemiologic studies.G. In a descriptive study, the selection usually involves grouping subjects into various exposure levels and examining disease rates. For a cohort study, the database may be used for choosing specific exposure groups

19、to follow.H. Then comes the harvesting of new cases in a cohort study or, analogously, the selection of cases and controls for a case-control study.I. The investigators do many data analyses but submit only their best for publication.J. The journal judges the submitted paper and may decide not to pu

20、blish it.K. Knowledge brokers, such as Cochrane Collaboration meta-analysts, guideline committees, or local experts, help decision makers use the published papers.病因学研究前言基本概念研究方法（设计方案）测量指标评价原则研究方法描述性研究(descriptive study) 个案报告(case report) 病例系列(case series)发现线索提出病因假设分析性研究(analytic study)初步验证病因假设证实病因病

21、例对照研究(case-control study)横断面研究(cross-sectional study)队列研究(cohort study)干预性研究(interventional study)进一步验证病因随机(randomization)盲法 (blinded)对照(controlled)综合确定因果关系研究方法causeSilicone Breast ImplantsRheumatologic DiseasesRCTRexposed= a/(a + b)RR (Relative Risk) =Runexposedc/(c + d )RCT优点 Randomized Strongest

22、design establishing cause and effect relationship （interventional study）缺点 ethical Time consuming Expensive队列研究Cohort StudyTimeonset of studyDiseaseNo DiseaseDiseaseEligible SubjectsNo DiseaseDirection of InquiryUnexposedExposed队列研究Cohort StudyRexposed= a/(a + b)RR (Relative Risk) =Runexposedc/(c +

23、d )队列研究Cohort Study优点 Direct calculation risk ratio (relative risk) Clear temporal relationship between exposure and disease Minimize bias Strongest observational design establishing cause and effect relationship队列研究Cohort Study缺点 Time consuming Often requires a large sample size Expensive Not effic

24、ient for study of rare diseases Losses to follow-up may diminish validity Changes over time in diagnostic methods may lead to biased results病例对照研究Case-Control StudyTimeonset of studyExposedCasesUnexposedExposedControlsUnexposedDirection of Inquiry病例对照研究Case-Control StudyOddscasea/cOR (Odds Ratio) =O

25、ddscontrolb/d病例对照研究Case-Control Study优点 Efficient for study of rare diseases Efficient for study of chronic diseases Tend to require smaller sample size Less expensive May be completed more rapidly病例对照研究Case-Control Study缺点 Risk of disease cannot be estimated directly Not efficient for study of rare

26、 exposures More susceptible to selection bias Information on exposure may be less accurate病因学研究前言基本概念研究方法（设计方案）测量指标评价原则Incidence RateIncidence RateCumulative Incidence (Risk)Prevalence (Rate?)RatioIRR = Incidence Rate RatioRR = Relative Risk= Risk Ratio= Cumulative Incidence Ratio OR = Odds RatioPR

27、= Prevalence RatioPOR = Prevalence Odds RatioDifferenceIRD = Incidence Rate DifferenceRD = Cumulative Incidence Difference (Risk Difference)PD = Prevalence Difference队列研究Cohort StudyTimeonset of studyDiseaseNo DiseaseDiseaseEligible SubjectsNo DiseaseDirection of InquiryUnexposedExposed测量指标队列研究(Coho

28、rt Study): RRs with outcomeRisk =度AllsOutcomeExposedUnexposedTotalDiseaseABNo DiseaseCDA+BC+DTotalA+CB+DA+B+C+D测量指标队列研究(Cohort Study)Riskexposed = Exposeds with outcome =AA + CAll exposedsRiskunexposed= Unexposeds with outcome =BB+ DAll unexposedsRexposed= A/(A + C)RR(Relative Risk) =RunexposedB/(B

29、+ D)相对度测量指标队列研究(Cohort Study)Attributable Risk = Rexposed- Runexposed= A/(A + C) - B/(B + D)归因度Attributable Risk Percent = Rexposed- Runexposed = A/(A + C) - B/(B + D)A/(A + C)Rexposed归因比测量指标队列研究(Cohort Study)Outcome吸烟不吸烟Total肺癌24915无肺癌531393194526485084Total533883196085348测量指标队列研究(Cohort Study)吸烟发生

30、肺癌的为0.47%A249Risk吸烟组 = 0.47%A + C249 + 53139不吸烟发生肺癌的为0.05%B15Risk不吸烟组 = 0.05%B+ D15 + 31945吸烟发生肺癌的是不吸烟的9.94倍Rexposed= 0.47% = 9.94度(RR) =相对Runexposed0.05%测量指标队列研究(Cohort Study)度(AR) = Rexposed- Runexposed= 0.47% - 0.05%0.42%归因为0.42%吸烟导致肺癌发生的绝对比(ARP) = Rexposed- Runexposed = 0.47% - 0.05%0.89归因Rexpos

31、ed0.4789%的肺癌归因于吸烟测量指标节育器和输卵管炎？2000女性队列Rexpose？Runexpose？RR？Outcome用IUD不用IUDTotalyes4515no955985601940Total100010002000的女性 1200有一个RR？的女性 800有超过一个RR？Outcome用IUD不用IUDTotalyes426no6589448752Total700100800Outcome用IUD不用IUDTotalyes39no297891121188Total3009001200设计方案病例对照研究(Case-Control Study)Timeonset of studyExposedCasesUnexposedExposedControlsUnexposedDirection of Inquiry测量指标病例对照研究