1、臨床研究設計方法北京協(xié)和醫(yī)院普通內(nèi)科方衛(wèi)綱聯(lián)系方式Email：fangwg辦公室：北京協(xié)和醫(yī)院（西院區(qū)）普通內(nèi)科電話：6915-8312Epidemiology. 2001,12(1):114-122.Causation of Bias: The EpiscopeFIGURE 1 . “The Episcope.” A user of epidemiologic evidence sees a “known” RD (kRD) that results from information transmitted, like light rays through a telescope, from

2、 a causal (“aetiologic”) RD (aRD) in a target population, through layers of “l(fā)enses” and “filters.” Each layer is a distinct 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.A.

3、The original cause of the image transmitted through the episcope is the association (if it exists) 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.

4、 None of the above phenomena is observable without diagnoses and exposure measurements, which are produced as follows:D. Morbidity is a contributing cause of diagnoses, which are recorded in medical charts or death certificates, as well as self-reported on questionnaires. These diagnoses and recordi

5、ngs have varying sensitivities and specificities.E. The occurrence of the causal agent is a contributing cause of the occurrence of evidence of exposure, which is recorded via interviews, self-administered questionnaires, administrative forms, and other instruments with varying sensitivities and spe

6、cificities.F. Data on diagnoses and exposures are collated by various means into files and databases, usually 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

7、examining disease rates. For a cohort study, the database may be used for choosing specific exposure groups 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 b

8、ut submit only their best for publication.J. The journal judges the submitted paper and may decide not to publish it.K. Knowledge brokers, such as Cochrane Collaboration meta-analysts, guideline committees, or local experts, help decision makers use the published papers.發(fā)現(xiàn)臨床問題形成研究假設實施研究項目分析研究數(shù)據(jù)合理解釋結

9、果解決臨床問題臨床研究的步驟發(fā)現(xiàn)臨床問題形成研究假設 研究設計設計研究方案實施研究項目分析研究數(shù)據(jù)理解研究局限，合理解釋結果應用研究結果，解決臨床問題臨床研究的要素研究問題研究方法研究對象研究參數(shù)樣本量統(tǒng)計方法醫(yī)學倫理 PICO Patient Intervention Comparison Outcome研究問題什么問題是好問題？Feasible | 可行性InterestingNovel | 創(chuàng)新性EthicalRelevant | 重要性在“研究背景”中，陳述這個問題重要嗎？哪些已經(jīng)清楚，哪些還不清楚？早前研究有什么不足？搞清楚到底有什么用？新的科學知識？改變臨床實踐？指定新的政策？臨床

10、研究的要素研究問題研究方法研究對象研究參數(shù)樣本量統(tǒng)計方法醫(yī)學倫理 研究方法觀察性研究描述性研究分析性研究干預性研究臨床試驗觀察性研究被動觀察“事件”在“研究對象”中的分布/發(fā)生描述性研究疾病在人群中的分布分析性研究隊列研究橫斷面研究病例-對照研究干預性研究主動對“研究對象”施以“干預”，觀察它對“事件”發(fā)生的影響臨床試驗隨機盲法非隨機開放性時間框架日歷時間年齡研究開始的時間時間軸以日歷時間為軸以年齡為軸以日歷時間為軸以研究開始的時間為軸隨機對照試驗Designing Clinical Research, 3rd edition. 定義RANDOMIZED CONTROLLED TRIAL (R

11、CT) An epidemiological experiment in which subjects in a population are randomly allocated into groups, usually called study and control groups, to receive or not to receive an experimental preventive or therapeutic procedure, maneuver, or intervention.The results are assessed by rigorous comparison

12、 of rates of disease, death, recovery, or other appropriate outcome in the study and control groups.A Dictionary of Epidemiology, 5th edition. 評價RANDOMIZED CONTROLLED TRIAL (RCT) RCTs are generally regarded as the most scientifically rigorous method of hypothesis testing available in epidemiology an

13、d medicine.Nonetheless, they may suffer serious lack of generalizability, due, for example, to the non-representativeness of patients who are ethically and practically eligible, chosen, or consent to participate.A Dictionary of Epidemiology, 5th edition. 特殊形式的隨機對照試驗CROSSOVER CLINICAL TRIALA method o

14、f comparing two (or more) treatments or interventions in which subjects, upon completion of one treatment, are switched to the other.In the case of two treatments, A and B, half the patients are randomly allocated to receive these in the order “A first, then B,” and half to receive them in the order

15、 “B first, then A.”The outcomes cannot be permanent changes (e.g., they can be symptoms, functional capacity).A Dictionary of Epidemiology, 5th edition. A “washout” phase is often needed before beginning the second treatment.The analysis will have to check whether a carryover effect was present.A Di

16、ctionary of Epidemiology, 5th edition. 示意圖評價CROSSOVER CLINICAL TRIALIf the biological and clinical bases of the trial are coherent, the results will be unbiased and the design will help reduce “noise” and sample size requirements.A Dictionary of Epidemiology, 5th edition. 示意圖隊列研究Designing Clinical R

17、esearch, 3rd edition. 定義COHORT STUDYThe analytic epidemiological study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the occurrence of a

18、given disease or other outcome.A Dictionary of Epidemiology, 5th edition. 評價COHORT STUDYThe main feature of cohort study is observation of large numbers over a long period (commonly years), with comparison of incidence rates in groups that differ in exposure levels.The essential feature of the metho

19、d is observation of the population for a sufficient number of person-years to generate reliable incidence or mortality rates in the population subsets.A Dictionary of Epidemiology, 5th edition. 回顧性隊列研究HISTORICAL COHORT STUDYA cohort study conducted by reconstructing data about persons at a time or t

20、imes in the past.This method uses existing records about the health or other relevant aspects of a population as it was at some time in the past and determines the current (or subsequent) status of members of this population with respect to the condition of interest.Different levels of past exposure

21、 to risk factor(s) of interest must be identifiable for subsets of the population.A Dictionary of Epidemiology, 5th edition. 示意圖現(xiàn)在過去將來建立隊列回顧性隊列研究前瞻性隊列研究隨機對照試驗與前瞻隊列研究病例-對照研究Designing Clinical Research, 3rd edition. 定義CASE-CONTROL STUDYThe observational epidemiological study of persons with the diseas

22、e (or another outcome) of interest and a suitable control group of persons without the disease (comparison group).The potential relationship of a suspected risk factor or an attribute to the disease is examined by comparing the diseased and nondiseased subjects with regard to how frequently the fact

23、or or attribute is present (or, if quantitative, the levels of the attribute) in each of the groups (diseased and nondiseased).A Dictionary of Epidemiology, 5th edition. 示意圖巢式病例-對照研究NESTED CASE-CONTROL STUDYAn important type of case-control study in which cases and controls are drawn from the popula

24、tion in a fully enumerated cohort. A set of controls is selected from subjects (i.e., noncases) at risk of developing the outcome of interest at the time of occurrence of each case that arises in the cohort.A Dictionary of Epidemiology, 5th edition. 示意圖橫斷面研究Designing Clinical Research, 3rd edition.

25、定義CROSS-SECTIONAL A study that examines the relationship between diseases (or other health-related characteristics) and other variables of interest as they exist in a defined population at one particular time.The presence or absence of disease and the presence or absence of the other variables (or,

26、if they are quantitative, their level) are determined in each member of the study population or in a representative sample at one particular time.A Dictionary of Epidemiology, 5th edition. The relationship between a variable and the disease can be examined (1) in terms of the prevalence of disease i

27、n different population subgroups defined according to the presence or absence (or level) of the variables and (2) in terms of the presence or absence (or level) of the variables in the diseased versus the nondiseased. Disease prevalence rather than incidence is normally recorded in a cross-sectional

28、 study.The temporal sequence of cause and effect cannot necessarily be determined in a cross-sectional study.A Dictionary of Epidemiology, 5th edition. 示意圖這是一個什么研究？這是一個什么研究？生態(tài)學研究ECOLOGICAL STUDYA study in which the units of analysis are populations or groups of people rather than individuals.An exam

29、ple is the study of the relationship between the distribution of income and mortality rates in states or provinces. A Dictionary of Epidemiology, 5th edition. 評價ECOLOGICAL STUDYConclusions of ecological studies may not apply to individuals; thus caution is needed to avoid the ecological fallacy.Ecol

30、ogical studies can reach valid causal inferences on causal relationships at the ecological level (e.g., group level or among groups).Ecological studies are necessary for decisions that affect entire groups (e.g., for public and private policies that are developed across an entire state, country, or

31、region).A Dictionary of Epidemiology, 5th edition. 哪種研究設計最好？沒有永遠的最好，合適就好科學性證據(jù)級別局限性可行性成本倫理研究方法的選擇Essentials of Epidemiology in Public Health, 2nd edition. 臨床研究的要素研究問題研究方法研究對象研究參數(shù)樣本量統(tǒng)計方法醫(yī)學倫理 什么是“人群”“人群”是一組特定的人人物性別、年齡、民族、社會經(jīng)濟狀況地點省、市、區(qū)時間日歷、壽命舉例北京市民臨床研究生住院患者舉例北京市民2010年第6次人口普查期間具有北京市城鎮(zhèn)戶口的居民臨床研究生北京協(xié)和醫(yī)學院201

32、2年入學臨床型碩士研究生住院患者2012年9月3日在北京協(xié)和醫(yī)院住院的所有患者目標人群來源人群研究人群目標人群有可能發(fā)生某種情況或疾病的人來源人群符合研究入選條件的人研究人群最終參加研究的人舉例人乳頭狀瘤病毒（HPV）疫苗預防子宮頸癌的有效性研究目標人群全世界可能發(fā)生子宮頸癌的人來源人群2012年北京市符合入選 條件的人研究人群2012年在北京市各研究 單位最終參加研究的人研究對象的選擇選擇最適合回答“研究問題”的人群目標人群來源人群納入標準排除標準臨床特征人口學特征時間特征地點特征影響隨診數(shù)據(jù)質(zhì)量治療順應性安全性等盡量少研究對象研究人群抽樣簡單隨機分層隨機整群隨機隨機抽樣順序入組系統(tǒng)抽樣非隨

33、機抽樣代表性（無應答/失訪）臨床研究的要素研究問題研究方法研究對象研究參數(shù)樣本量統(tǒng)計方法醫(yī)學倫理 研究參數(shù)的選擇觀察性研究描述性研究率分析性研究預測變量結局變量干預性研究干預變量結局變量研究參數(shù)的類別連續(xù)變量身高、體重、血壓、血糖分類變量名義變量種族、職業(yè)等級變量高血壓分級、腫瘤分期二分變量性別、冠心?。ㄓ?無）舉例研究參數(shù)的測量精確性與準確性研究參數(shù)的精確性定義Relative lack of random error測量可重復的程度 隨機誤差的對立面A Dictionary of Epidemiology, 5th edition. 精確性的評價指標連續(xù)變量A measure of precision is the inverse of the variance of a measurement or estimate. A measure of imprecision is the standard error of measurement.分類變量一致比KappaA Dictionary of Epidemiology, 5th edition. 影響精確性的因素觀察者觀察對象測量工具提高精確性的策略培訓并考核觀察者改進測量工具標化