1、1队列研究队列研究 Cohort study2队列研究队列研究 Cohort study Incidence studies Longitudinal studies Follow-up studies Prospective studies发病率研究纵向研究随访研究前瞻性研究3Epidemiology is the study of the distribution and determinants of disease and health related status in a specify population and the application of this study to
2、 control of health problems.A Dictionary of Epidemiology, 2nd ed.A Dictionary of Epidemiology, 2nd ed.by Last, J.M198819884Descriptive EpidemiologyHypothesisAnalytical EpidemiologyJudging CausalityPrevention StrategiesConcept MapCase-ControlCohort studyExperimental Epidemiology c.s.Ecologyscre5Descr
3、iptive Epidemiologic Process WHO was affected? WHERE were they affected?WHEN were they affected?HOW and WHY?6Descriptive Studies: UsesHypothesis generatingSuggesting associationsEvaluating intervention effectStudying health situation of population7Analytical Epidemiologic ProcessHOW the way?WHY reas
4、on?Causal inference8An important causal inference criteria Temporality refers to the necessity for a cause to precede an effect in time. What kind of study satisfies the logistic order? Cohort study!9 Outline Example Design and implement Data sort and analysis Bias and control Advantage，limitation概述
5、实例研究设计与实施资料的整理与分析偏倚及控制优点和局限性队列研究 Cohort Study10 简简 史史 概概 念念 原原 理理 特特 点点 目目 的的 类类 型型 Brief history Concept Principle Features Purpose Types第一节第一节 概述概述 Outline11 简简 史史 Brief history起源 OriginsGraunt (17世纪) 用横断面死亡资料，用寿命表方法构建生命史Graunt (17th century) used cross-sectional mortality data to reconstruct life
6、 history using life-table methodsFarr（19 世纪）将寿命表方法发展为人群健康的指标Farr (19th century) advanced the use of life-table methods a an indicator of population health保险业研究1870 1899 Insurance industry study 1870 1899 12结核（结核（2020世纪世纪） Tuberculosis (20th century)WH Frost 在有结核的132个家庭的队列开展第一个回顾性队列研究（1933）WH Frost p
7、erformed the first retrospective cohort study in a cohort of 132 homes with tuberculosis（1933）用人年来估计罹患率Used person-years to estimate attack rates 简简 史史 History13Framingham study of cardiovascular disease, 1948-Japanese atomic bomb survivors, 1946-British physician study, 1950s-Nurses Health study, 1
8、976-Aniline-dye occupational cohort, 1954Asbestos exposure and lung cancer mortality 1965Retrospective cohort studiesProspective cohort studies14 是将人群按是否暴露某可疑因素及其暴露程度分为是将人群按是否暴露某可疑因素及其暴露程度分为不同亚组，追踪其各自结局，比较不同亚组结局率的的不同亚组，追踪其各自结局，比较不同亚组结局率的的差异，从而判定暴露与结局间有无因果关联及关联大小差异，从而判定暴露与结局间有无因果关联及关联大小的一种观察性研究方法。的一种
9、观察性研究方法。 An epidemiologic design in which the incidence of a disease (or condition) is compared among exposed and unexposed individuals，to judge if there is causal relationship between exposure and outcome. 概念概念 Whats the cohort study15Cohort Study Key Point: Presence or absence of risk factor is de
10、termined before outcome occurs.16队列 What is a cohort? Cohort - Latin word for one of 10 divisions of a Roman legionA group of individuals sharing same experience followed up for a specified period of timebirth cohortoccupational cohort队列 拉丁语原意是指古罗马军团中的一个分队一组人群 有共同经历 随访一特定时间 出生队列 职业队列1718暴露 指接触过某种物质、
11、具备某种特征或处于某种状态。Exposure c o n t a c t i n g s o m e materials，with some features or being in some status. 19危险因素 泛指能引起某特定不良结局,或使其发生的概率增加的因子，包括个人行为、生活方式、环境和遗传等多方面的因素.Risk factor refer elements associated with an increased risk of mal-outcomes, including behavior, life style, environmental and genetic
12、factor and so on.20 Principle of a Cohort StudyBegin with disease-free personsClassify subjects as exposed/unexposedFollow up and record outcomes in both groupsCompare outcomes with relative riskAnalysis association between exposure and outcome从没有疾病人群开始 将研究对象分为暴露与非暴露组随访并记录两组结局相对危险度比较结果分析暴露与结局关系21Sou
13、rce: partially adapted from WHO, 1993R1R0A1A0Incidence rate among exposed IR1 = A1 (no. exposed cases) / R1 (total person-time exposed) Incidence rate among unexposed IR0 = A0 (no. unexposed cases) / R0 (total person-time unexposed)Incidence rate ratio (exposed vs. unexposed) = IR1 / IR0 = (A1/A0) /
14、 (R1/R0) Principle of a Cohort Study22 Features 特点特点ObservationalSet up control From cause to outcome, appreciate temporality Confirm the casual relationship between exposure and outcome观察性研究设立对照由因到果，符合时间顺序能确证暴露与结局间因果关系23Verify the hypothesis of cause of diseaseEvaluate the effect of prevention and
15、control Study the natural history of diseaseSurveillance post market of new drug检验病因假设 评价预防效果 研究疾病的自然史新药的上市后监测 目目 的的 Purpose24Framingham study of cardiovascular diseaseIndividuals 30 62 years old in community at risk for diseaseFramingham, MA, 1948 to presentExamples of cohort study25Goal to elucida
16、te the natural history of HIV/AIDS5000 gay men, volunteers5 cities in US1984 Extensive evaluations Questionnaire Physical examination Laboratory testingMulti-Centered AIDS Cohort Study26 类型 TypesBased on recruit time of study subjects Prospective v.s. RetrospectiveBased on the type of cohort Fixed v
17、.s. Dynamic依据研究对象召集的时间 前瞻性 VS 回顾性依据队列的类型 固定 VS 动态 27 类型 TypesCombined with case-control study Nested case-control study Case-cohort study与病例对照研究结合 巢式病例对照研究 病例队列研究 28 Prospective Cohort studyIdentify cohort concurrentCategory based on exposure s t a t u s o r p o s s i b l e explanatory/ prognostic f
18、actors of subject in the present 队列的确定是现在根据研究对象现在的暴露状态或可能暴露/预后因素分组 依据研究对象召集的时间分类29Follow-up Outcome will occur sometime in future随访结局在将来某时刻出现 Prospective Cohort study依据研究对象召集的时间分类30Prospective cohort studytimeExposureStudy startsDiseaseoccurrence依据研究对象召集的时间分类31Prospective Cohort： Question Question:
19、Are non- s t e r o i d a l a n t i -inflammatory drugs a risk factor for GI bleeds?问题: 非甾体固醇抗炎药是否为胃肠道出血的危险因素?依据研究对象召集的时间分类32Identify cohort: new diagnoses of rheumatoid arthritis Oct. 2002 to Oct. 2003Determine exposure status: identify patients prescribed NSAIDs and those who are not确定队列: 2002.10-2
20、003.10诊断的类风湿关节炎患者确定暴露状态: 确定开与未开NSAIDs药物处方的病人Prospective Cohort： Question依据研究对象召集的时间分类33Determine outcomes: follow-up all patients for 1 year identify how many GI bleeds there are in each sub-cohort or exposure group确定结局: 随访所有的病人1年 - 确定在暴露及非暴露组出现多少胃肠道出血的病人。Prospective Cohort： Question依据研究对象召集的时间分类34P
21、rospective Cohort StudiesAdvantageStrengthens temporality in inference cause more accurately measuring risk factors (not need to reconstruct past exposures) more accurately measuring confounding优点 因果推断的时间顺序强危险因素测量更准确 (不需要构建过去的 暴露)更准确的测量混杂因素依据研究对象召集的时间分类35Limitation:expensive and time consuming (ince
22、ption and follow-up) large numbers required to study rare outcomes difficult to study chronic diseases with long latency局限性:昂贵, 费时间 (启动及随访)研究罕见结局是需大样本难于研究慢性潜伏期长的疾病Prospective Cohort Studies36 Historical (Retrospective) Cohort StudyIdentify cohort in the past E.g., through records or administrative d
23、atabasesDetermine exposure or prognostic factors in the past Again, records or databasesIdentify outcome Outcome can be identified in past or present Outcome must be after previous two steps37Retrospective cohort studytimeExposureStudy startsDiseaseoccurrence38Historical Cohort ExampleQuestion: Are
24、non-s t e r o i d a l a n t i -inflammatory drugs a risk factor for GI bleeds?问题: 非甾体固醇抗炎药是否为胃肠道出血的危险因素?39Historical Cohort ExampleIdentify cohort e.g., people diagnosed with rheumatoid arthritis between January and December 1992 Determine exposure status. Which of these patients were prescribed NSA
25、IDs?Determine outcome. Did patient develop gastrointestinal tract bleeds during the five years after inception into cohort? (follow-up lasted until December 1997)40Historical (Retrospective) Cohort Studies Advantage:Cohort easier to assemble (inception period in past) Baseline measurements already a
26、vailable Follow-up already taken place Less costly and time- consuming优点:队列易召集(在过去起始)基线测量已经可以利用已经随访耗费少,省时间41Limitation:no way to control the q u a l i t y o f p a s t measurements incomplete data setsconfounder may be incompletely control 局限性无法控制过去暴露的质量资料不全混杂因素控制不全Historical (Retrospective) Cohort S
27、tudies42 双向性队列研究 Mixed (Ambispective) Cohort Study研究队列的确定是过去 Identify cohort in the past根据研究对象过去某时刻的暴露情况分组 Category the subjects to groups based on exposure situation in the past需要随访 need follow up部分结局可能已出现 Some outcome may have already occurred 第一节第一节 概概 述述43Mixed Cohort ExampleQuestion: Are non-st
28、eroidal anti-inflammatory drugs a risk factor for GI bleeds?Identify cohort (patients who were diagnosed with rheumatoid arthritis between October 2000 and September 2001)Which of these patients are prescribed NSAIDs?How many of these patients will experience GI bleeds during next five years? 44时间顺序
29、时间顺序 过去过去 现在现在 将来将来 历史性队列历史性队列双向性队列双向性队列前瞻性队列前瞻性队列前瞻性收集资料前瞻性收集资料依据研究对象召集的时间分类45timeExposureStudy startsDiseaseoccurrenceDiseaseoccurrencetimeStudy startsExposuretimeDiseaseoccurrenceStudy starts历史性队列历史性队列双向性队列双向性队列前瞻性队列前瞻性队列Exposure依据研究对象召集的时间分类46前瞻性队列研究明确的检验假设所研究疾病的发生率较高,一般不低于5明确规定暴露因素和结局变量可靠的测量手段足
30、够的观察人群和暴露情况能完成随访的人群足够的人、财、物力不同类型研究选用的原则47Cohort Study Design TypeslFixed Cohort A group of individuals recruited and enrolled at a uniform point or in a periodCohort does not take on new members after it is assembledExamplesPatients admitted to the ER with acute MISurvivors of Hiroshima bombingsChil
31、dren born to HIV-infected mothers依据队列的类型48历史性队列研究前瞻性队列研究1-5足够数量、完整、有关研究对象暴露和结局档案材料不同类型研究选用的原则双向性队列研究历史性队列条件继续随访需前瞻性队列研究条件49l 固定队列固定队列 fixed cohort研究开始研究开始 start研究结束研究结束end出现结局出现结局outcome occurred未出现结局未出现结局Without outcome依据队列的类型50TypeslDynamic cohortA group of individuals recruited and enrolled throu
32、gh a mechanism that allows for in and out migration of peopleDynamic population ExamplesFramingham StudyKaiser Permanente 51l 动态队列动态队列 Dynamic Cohort第一节第一节 概概 述述出现结局出现结局Outcome occurred失访失访Lost follow-up依据队列的类型研究开始研究开始 start研究结束研究结束end52二硫化碳长期低剂量的暴露与冠心病的关系 第二节第二节 研究实例研究实例53二硫化碳（二硫化碳（CSCS2 2）神经系统毒物，抑
33、制酶的活性，影响脂蛋白代神经系统毒物，抑制酶的活性，影响脂蛋白代 谢，谢， 造成心血管疾病造成心血管疾病长期接触低浓度长期接触低浓度CSCS2 2可引起慢性中毒和动脉粥可引起慢性中毒和动脉粥 样硬化样硬化短时间接触高浓度的短时间接触高浓度的CSCS2 2蒸气可急性中毒蒸气可急性中毒54研究因素 长期低剂量的CS2暴露定 义 在有CS2暴露但不至引起急性中毒的车间 工作5年2020世纪世纪6060年代芬兰职业卫生研究所年代芬兰职业卫生研究所Hernberg和和Tolonen教授做的前瞻性队列研究教授做的前瞻性队列研究55二、确定研究结局二、确定研究结局 心肌梗死血压变化 心电图的改变 心绞痛发作
34、56三、确定研究现场和人群三、确定研究现场和人群 暴露组 19421967年某粘纤厂25至64岁， 343名男性工人有5年以上CS2暴露史对照组 年龄3岁 出生地区相同 工种的体力消耗相当 在同一城市的造纸厂随机选择的343名男性工人 57四、资料收集四、资料收集 查阅档案记录 用药情况、既往车间CS2的浓度等询问 姓名、性别、年龄、工种及工作年限、吸烟、业余时间的体力活动情况实验室检查 血糖、血脂、血清胆固醇水平、血压、心电图、心脏大小、体重及车间CS2浓度的动态变化 58五、资料分析五、资料分析表4-1 暴露组和对照组的心肌梗死发生率及RRCSCS2 2暴露组发生心肌梗死的暴露组发生心肌梗
35、死的RRRR为为3.573.57，两组致死性心肌梗，两组致死性心肌梗死发生率和总的心肌梗死发生率差异有显著性死发生率和总的心肌梗死发生率差异有显著性59 CS2在不同临床类型冠心病的发生中作用程度不同临床类型RRAR心肌梗塞3.575.25致死性心肌梗塞4.693.21非致死性心肌梗塞2.742.04心绞痛1.8911.6心电图冠心样改变1.4 6.1表4-2 CS2与不同临床类型冠心病的RR和AR比较60六、结六、结 论论 长期低剂量CS2暴露与冠心病发病和死亡存在因果关系 CS2所致的冠心病，以致死性心肌梗死为主措施 芬兰当局已于1972年把CS2的车间最高容许浓度从20ppm降至10pp
36、m61PurposeIdentify exposuresIdefine outcomesI d e n t i f y s t u d y f i e l d a n d population Sample size Data collectioan and follow-up Quality control 明确目的明确目的确定研究因素确定研究因素确定研究结局确定研究结局确定研究现场与人群确定研究现场与人群确定样本量确定样本量资料的收集与随访资料的收集与随访质量控制质量控制第三节第三节 设计和实施设计和实施 Design and Implement62 明确目的 Clarify Purpos
37、e 在现况调查或病例对照研究的基础上，提出可疑的暴露于疾病的关系 Based on the results of descriptive study and case-control study，to generate hypothesis of the association between suspected exposure and disease 63 确定研究因素 Identify ExposureMain exposures Based on purpose according to descriptive study and case-control study F a c t
38、o r m a y e f f e c t outcome confounder, demography features 主要暴露因素 在描述性研究和病例对照研究的基础上，根据研究目的确定可能影响结局的因素 混杂因素 人口学特征等64 暴露测量 Measuring ExposureContent - Nature of the exposure; biologic mechanismsl Quality uPeriodic - e.g., cigarettes, sexual contactsuSingular - e.g., nuclear exposurel Quantity uCont
39、inuous and periodic exposures must be quantifieduDose-response relationship65 暴露测量 Measuring ExposureMethods of Measuringl Interviewl Medical exam Blood tests or other specimens, Biomarkers, Other laboratory testsl Records, medical recordsl Sample storagel Environment surveillance data66 Measuring E
40、xposureMeasuring exposure is one of the fundamental activities of a cohort studyExposure measurement must be comparable for all members of the cohortCarefully defined in advance of studySpecific attention should be given to the accuracy and precision of proposed measurements -Pilot studies often nee
41、ded67 确定研究结局 Determine Outcome发病或死亡血清指标分子标志的变化定性或定量Morbidity or mortalityIndicator of serumChange of molecular biomarkerQuantity or quality 结局是研究队列中预期结果事件 outcome are expected event of follow-up 68Examples of Outcomes or Diseases Lung Cancer Heart Disease Motor vehicle injury HIV infection Diabetes
42、Diphtheria69 一次研究可有多个结局One study may have several outcome吸烟吸烟慢性支气管炎慢性支气管炎Chronicbronchitis冠心病冠心病CHD 结局的测量 采用国际或国内通用的标准Using existed international or nation standard70 研究研究现场现场 study field 有足够符合条件的研究对象有足够符合条件的研究对象 There are enough suitable subjects 领导重视、群众支持领导重视、群众支持 Government pay attention，mass sup
43、port 确定研究现场与研究人群确定研究现场与研究人群 Identify Study Field and Population第三节第三节 设计与实施设计与实施71 研究现场 Study Field发病率较高 High incidence医疗条件好， 交通便利 High medical facility， transportation有代表性 Nice representatives72 研究人群 Study Population 从目标人群中抽出的具有代表性的人 Sampling the representative subjects from target population 未患所研究
44、疾病 Disease free 分为暴露人群和非暴露人群 Categories as exposed and non-exposed population 确定人群纳入标准 Define Population at risk using inclusion criteria第三节第三节 设计与实施设计与实施73 暴露人群选择Selection of Exposed PopulationSpecial occupational exposure group (uranium miners or asbestos workers. Cooperation, good record, regu. E
45、xam, easy follow-up)Special exposure groups ( smokers, X-ray workersThe general population ( the outcome of interest has a high incidence rate)74Special resource groups (e.g., physicians, nurses, insured)Geographically or facility-defined groups (hospitals with specialized maternity care) 暴露人群选择Sele
46、ction of Exposed Population75非暴露人群选择 Selection of Non-exposed Group 内对照 (internal controls) 一群研究对象内部 Controls is selected with a one-sample (population -based) cohort of exposure, Example: a.Select the cohort (such as all residents of a given neighborhood) b.All members of the cohort are then given
47、first round questionnaires, and/or clinical examinations, and/or testing to determine exposurec.The cohort is then divided into exposure categories based on those results第三节第三节 设计与实施设计与实施76外对照 (External controls) 一群研究对象外部-If everyone in a cohort is exposed (such as workers in an industry), a separat
48、e cohort as similar as possible to the exposed in terms of income, education, geography, and age should be sought非暴露人群选择 Selection of Non-exposed Group77总人口对照 (total population controls) 整个地区现成的发病或死亡资料 多重对照 (multiple controls) 两种或以上的对照形式 非暴露人群选择 Selection of Non-exposed Group78 Study Populations Exa
49、mplesFramingham study of cardiovascular disease Individuals 30 62 years old in community at risk for disease Framingham, MA, 1948 to present79Table 4-3 Framingham Study Cohort AssemblyNo. MenNo. WomenTotal Random Sample3,0743,4336,507Respondents2,0242,4454,469Volunteers312428740Respondents free of C
50、HD19752,4184,393Volunteers free of CHD 307427734Total free of CHD2,2822,8455,12780Study Populations MACSMulti-Centered AIDS Cohort Study Goal to elucidate the natural history of HIV/AIDS 5000 gay men, volunteers 5 cities in US 1984 1999 Extensive evaluationsQuestionnairePhysical examinationLaborator
