病因和病因推断 Cause of Disease and Causal Inference 哈尔滨医科大学流行病学教研室 Department of epidemiology ，Harbin Medical University

主要内容 (outline) 病因的概念 （concepts of causation） 因果关联的推断（inference of causal association） 病因推断的标准 (criteria of causal inference )

第一节 病因的概念 concepts of causation

一、疾病病因概念的发展 （ Development of causation in history ） 迷信阶段 水 木 火 朴素唯物主义 鬼神、上帝、天意 迷信阶段 水 木 火 朴素唯物主义 金 人 土 病因网模型 活的传染物 生物学病因的萌芽 理 生 病原物 物 机体 化 三角模式 社 会 环境 宿主 轮状模式

病因模型（causal model） 三角模型（epdemiological triad） 疾病因素轮状模型（wheel model） 病因网络模型 (web of causation)

三角模型（epidemiological triad） 环境 Environment Model of Disease 宿主 Host 病因 Agent

三角模型（epidemiological triad） 宿主 宿主 失衡 病因 环境 病因 环境 健 康（health） 疾 病（disease）

三角模型（epidemiological triad） 宿主 Host Host Agent 病因 Agent 宿主 病因 环境 Environmental 环境 Environmental

三角模型（epidemiological triad） 宿主 Host 病因 Agent 环境 Environmental

三角模型（epidemiological triad） 病因 Agent 宿主 Host 环境 Environmental

三角模型（epidemiological triad） 宿主 Host 病因 Agent 环境 Environmental

三角模型（epidemiological triad） 病因 Agent 宿主 Host 环境 Environmental

轮状模型（wheel model） Biological Environment Chemical Environment Human Organism Genetic Codes Social / Psychological Environment Chemical Environment Biological Environment Physical Environment

轮状模型（wheel model） 健康 Health 疾 病 Disease 生物环境 遗传内核 生物环境 失衡 遗传内核 宿主 宿主 理化环境 生物环境 社会环境 宿主 遗传内核 失衡 疾 病 Disease 生物环境 社会环境 遗传内核 理化环境 宿主 健康 Health

Inborn error of metabolism 生物环境 社会环境 理化环境 遗传内核 宿 主 健 康 Health 先天性代谢异常 Inborn error of metabolism

生物环境 社会环境 理化环境 遗传内核 宿 主 健 康 Health 麻疹 Measles

病因网络模型（web of causation） Morbidity and Mortality (Stroke, MI) Biological Risk Factors (Hypertension, Blood Lipids, Homocysteine) Genetic Risk Factors (Family History) Behavioral Risk Factors (Cigarette, Diet, Exercise) Environmental Factors (Socioeconomic Status, Work Environment)

病因网络模型（web of causation）

BEINGS Model Preventable causes of disease Biologic factors and Behavioral factors Environmental factors Immunologic factors Nutritional factors Genetic factors Services, Social factors, and Spiritual factors

二、病因的定义（definition of causation） A causal relationship would be recognized to exist whenever evidence indicates that the factors form part of the complex of circumstances that increases the probability of the occurrence of disease and that a diminution of one or more of these factors decreases the frequency of that disease. ----Lilienfeld (1980) Multiple definitions of cause have been offered in epidemiology. Lilienfeld AM.（1920-1984） 约翰.霍普金斯大学流行病学教授

二、病因的定义（definition of causation） 那些能使人群发病概率升高的因素，就可认为是疾病的病因；当其中某个或多个因素不存在时，人群的疾病频率就会下降。 Lilienfeld AM.（1920-1984） 约翰.霍普金斯大学流行病学教授

第二节 因果关联的推断 inference of causal association

Environmental Exposure Disease or Other Outcome Genetic Background Combination of Both Association ? Causation ? Disease or Other Outcome Suppose we determine that an exposure is associated with disease. How do we know if the observed association reflects a causal relationship?

一、因果推断的一般过程 Common process of causal inference 建立病因假设 hypothesis development 病因假设的检验和验证 test and certification of hypothesis

建立病因假设（ hypothesis development ） 密尔氏准则 Mill’s canons

密尔氏准则（Mill’s canon) 求同法 （Method of agreement） 差异法 （Method of difference） 共变法 （Method of concomitant variation） 剩余法 （Method of exclusion）

求同法（agreement canon） If events or risk factors are common to a variety of different circumstances and the events or risk factors have been positively associated with a disease, then the probability of that factor being the cause is extremely high. 钩端螺旋体病流行，共同点---下水劳动

差异法（different canon） The frequency of a disease occurrence is extremely different under different situations or conditions. If a risk factor or event can be identified in one condition and not in a second, it may be that factor, or the absence of it, that may be the cause of the disease. 察布查尔病

共变法（concomitant variations canon） The frequency or strength of an event or risk factor varies with the frequency of the disease or condition. Increased numbers of children not immunized against measles causes the incidence rate for measles to go up. 吸烟与肺癌；氟龋齿、斑釉齿

剩余法（residues canon） Subduct from any phenomenon such part as is known by previous inductions to be the effect of certain antecedents, and the residue of the phenomenon is the remaining antecedents. 乙肝病毒＋黄曲霉毒素－肝癌（藻类毒素）

病因假设的检验和验证 （test and certification of hypothesis） 病例对照研究（case-control study） 队列研究（cohort study）

二、病因推断中暴露因素与疾病关联的解释Association between exposure and disease in causal inference 统计学关联 （statistics association） 虚假关联 （spurious association） 间接关联 （indirectassociation）

Non-Causal (due to confounding) Interpreting Associations- Causal and Non-Causal Non-Causal (due to confounding) Causal Characteristic Under Study Characteristic Under Study Factor X Disease Disease

Non-Causal (due to confounding) Interpreting Associations- Causal and Non-Causal Non-Causal (due to confounding) Causal Coffee Consumption Coffee Consumption Real Association Spurious Association Smoking Real Association Pancreatic Cancer Pancreatic Cancer

统计关联到因果关联 From Epidemiological Association to Causation 暴露与疾病 有无统计学关联? exposure and disease 有无偏倚? statistical association 有时间先后否? bias temporal sequence

第三节 病因推断标准 criteria of causal inference strength consistency 关联的强度 关联的重复性 关联的时间顺序 病因与疾病分布一致 终止效应 剂量反映关系 关联的特异性 关联的生物学合理性 strength consistency temporality coherence reversibility dose-response relationship specificity biologic plausibility

因果推断标准(1)--关联的强度 关联强度越大，为因果的可能性越大 关联强度的测定 RR,OR criteria of causal inference 1--strength 关联强度越大，为因果的可能性越大 A strong association between possible cause and effect, is more likely to be causal than a weak association. 关联强度的测定 measurement of strength RR,OR

因果推断标准(1)--关联的强度 criteria of causal inference 1--strength

因果推断标准(2)－关联的重复性 不同人群、不同地区、不同时间、不同类型的研究 少数或个别研究不同甚或相反的结果并不能简单地反驳因果假设 criteria of causal inference 2--consistency 不同人群、不同地区、不同时间、不同类型的研究 少数或个别研究不同甚或相反的结果并不能简单地反驳因果假设 多数得到一致结果的研究可能遭遇共同的偏倚 研究间不同的结果可能是因为某些因素的修正作用 Consistency has the cause and effect relationship been identified by a number of different researchers? multiple studies may have common bias results may vary across studies due to modifying effects of other variables rules out associations due to factors that vary across studies

因果推断标准(3)－时间顺序 > > 前因后果：唯一必须满足的标准 criteria of causal inference 3--temporaliry 前因后果：唯一必须满足的标准 The cause must precede the effect. 采用新病例的病例对照研究 生态趋势研究 实验性研究 队列研究 > > 横断面研究 虽然闪电和雷鸣同时同处发生，但我们总是先看见闪电后听到雷鸣 This is the only absolutely essential criterion 时间 暴露 结局

Correlation between dietary fat intake and breast cancer by country 因果推断标准(4)－病因与疾病分布一致 criteria of causal inference 4--coherence 计算相关系数：是否正态分布－peason相关、spearman相关 饮食脂肪摄入与乳腺癌发病 Correlation between dietary fat intake and breast cancer by country

因果推断标准(5)－终止效应 这是强有力的反证病因关系的一种方法。 例如戒烟与肺癌的关系研究中，我们发现戒烟后，人群肺癌死亡率下降。 criteria of causal inference 5--reversibility 这是强有力的反证病因关系的一种方法。 例如戒烟与肺癌的关系研究中，我们发现戒烟后，人群肺癌死亡率下降。 When removal of a possible cause results in reduction of disease risk, the likelihood of the association being causal is strengthened For example, smokers who give up smoking have a lower risk of lung cancer than those who continue to smoke.

因果推断标准(6)－剂量反映关系 criteria of causal inference 6—dose-response relationship 如果观察到随着某因素暴露剂量的增加．人群发生某病的危险性增加，因果关联的强度增大，则称该因素与该疾病之间存在剂量反应关系。 A dose-response relationship occurs when changes in the level of a possible cause are associated with changes in the magnitude of the effect.

因果推断标准(6)－剂量反映关系 每日吸烟量与支气管肺癌的年龄调整死亡率 criteria of causal inference 6—dose-response relationship 每日吸烟量与支气管肺癌的年龄调整死亡率 Age-standardized death rates due to well-established cases of bronchogenic carcinoma

因果推断标准(7)－关联的特异性 特异性的含义就是唯一性，病因特异性就是指唯一的病因，疾病的特异性就是指唯一的疾病。 criteria of causal inference 7—specificity 特异性的含义就是唯一性，病因特异性就是指唯一的病因，疾病的特异性就是指唯一的疾病。 Specificity indicate that a single exposure is associated with only one disease.

因果推断标准(8)－关联的生物学合理性 criteria of causal inference 8—biological plausibility 当可疑因子与疾病存在统计上关联，经进一步病因假设检验（病例对照研究及队列研究）之后，还要考虑该病因假设是否与现代知识相符或相协调。 An association is plausible and thus more likely to be causal when it is consistent with other knowledge. The term coherence implies that a cause and effect interpretation for an association does not conflict with what is known of the natural history and biology of the disease Consistency of epidemiologic plausibility with existing biologic knowledge Requires knowledge of the biologic etiology of disease

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