在流行病调查中形成假设 Forming Hypotheses During Epidemic Investigations

1. 在流行病调查中形成假设Forming Hypotheses During Epidemic Investigations Robert E. Fontaine, MD MScResident Advisor to CFETP Division of Global Public Health Capacity DevelopmentCoordinating Office for Global HealthCenters for Disease Control and Prevention

2. 本次讲座的目的Objectives of the presentation 探讨生成假设的重要性 Discuss the importance of hypothesis generation 描述假设生成的途径 Describe approaches to generating hypotheses 按照系统途径形成假设 Develop hypotheses following a systematic approach

3. 假设是从事实、数据和信息中产生的可测试的推断 A hypothesis is a testable proposition developed from facts, data, and information. 假设的质量取决于数据的宽度和准确性 The quality of the hypothesis depends upon the breadth and accuracy of the data 调查的成功取决于假设的质量 The success of the investigation depends upon the quality of the hypotheses

4. 完美假设应该包括哪些内容?What should the perfect hypothesis include? • 人口 Population • 原因和并存因素 Causes and co-factors • 预期结果 Expected effect • 剂量反应关系 Dose-response • 时间效应关系 Time-response relationship 在X镇，2004年1到四月军团病的暴发是由于较年长的购物者（40岁以上）暴露于杂货店A蔬菜部的一个造雾仪而发生的。In county X, the legionnaires disease outbreak from January to May 2004 resulted from Exposure of older (> 40y) shoppers in grocery A to a mist machine in the vegetable department.

5. 提出假设Develop a hypothesis Time 准备现场工作Prepare for field work 证实暴发存在 Establish existence of an outbreak Verify the diagnosis 验证诊断 Define, count, and interview cases 定义，计数，采访病例 确定人、地点和时间特征 Characterize person, place and time Develop a hypothesis 提出假设 Develop analytic study to test hypothesis 通过分析研究验证假说 Reconsider, refine, retest hypothesis 再推敲，修正和再检验假说 实施控制措施 Implement Control 将调查结果进行交流 Communicate Findings

6. 假设生成循环图Hypothesis generation cycle 数据和事实 Data and facts Adapted from Mausner & Bahn

7. 假设可包括并存因素并导向新的暴露源Hypotheses can cover co-factors and direct new exposures 并存因素Co-factors 直接暴露Direct exposures 环境 Environmental 宿主既有因素 Existing host factors 危险行为 Risky Behaviors 暴露 Exposure 进入体内 Entry to body 进入细胞 Entry to cells 病中暴露 Exposures During Illness 近因 Proximal 细胞损伤 Cell damage 疾病 Disease 诱因 Triggers 器官衰竭 Organ failure 死亡 Death

8. 流行病学假设形成Forming a hypothesis in epidemiology 疾病Disease + 时间Time + 地点Place + 人群Person + 暴露Exposures + 推论Analogy

9. 疾病和病因The disease and the agent

10. Use the scientific/public health literature

11. 确定与疾病和病因相关的已知事实 Determine known facts about the disease and the agent. • 感染史 Natural history of infection • 微生物学 Microbiology • 生物体的生态小环境 Ecological niche of the organism • 毒素的物理和化学性质 Physical and chemical properties of a toxin • 中毒可能引发的疾病 Expected disease from poisoning • 同种病因先前曾引发的暴发 Previous outbreaks from the same agent

12. 霍乱的一些信息 Facts about cholera • 必须有高感染剂量>1,000,000 Requires high infectious dose > 1,000,000 • 在水中自由生存 Free-living in water • 适应盐水环境 Tolerates salt • 能够消化甲壳质 Can digest chitin • 对酸高度敏感 Highly sensitive to acid • 在食物中成倍繁殖 Multiplies in food • 早先由食物或水引发的暴发 Previous outbreaks from food or water

13. 硫化氢的一些事实Facts about hydrogen sulfide gas • 低剂量就可以产生：Low dose produces • 对眼睛和喉咙的刺激性 （相关其他气体也有同样效果） Irritation of eyes and throat (also from related gasses). • 异味Bad smell • 高剂量Higher doses • 无味No smell • 击倒 （突然意识丧失）knockdown (sudden unconsciousness) • 突然死亡Sudden death • 比空气密度大－向下漂移Denser than air – flows to low areas • 从水中蒸发Evaporates from water • 粪肥、腐烂的鱼、气和油井，造纸及火山活动都可以产生硫化氢 Produced by manure, rotting fish, gas and oil wells, paper production, volcanic activity

14. 未知病因的疾病Diseases with an unknown agent 海湾战争综合症 Gulf War Syndrome 慢性疲乏综合症 Chronic Fatigue Syndrome 云南猝死 Yunnan Sudden Death 群体性臆症 Mass Hysteria Guillian–Barre氏综合征 Guillian Barre Syndrome Brainerd 腹泻 Brainerd diarrhea

15. 如果这些暴露以前就存在，为什么暴发没有早些发生？如果这些暴露以前就存在，为什么暴发没有早些发生？ If these exposures were previously present, why did the outbreak not appear earlier? 时间模式Patterns in time暴露发生在病发前Exposure precedes onset!

16. 一所城镇中的E肝暴发－你能从中看出什么？Hepatitis E in a town – What can you learn? 水每天氯化 Water chlorinated daily 水只在周一氯化 Water chlorinated on Monday only 总水管修好 Water main repaired 黄疸病例 Jaundice cases 总水管损坏 Water main broken 选举宴会Election banquets 6月June 7月July 8月Aug 9月Sept 10月Oct 11月Nov 周截止日Week ending on

17. 下图所示模式显示出一个车间内肺炎传播的哪些信息？What does this pattern tell us about transmission of pneumonia in a workshop?

18. 哪些因素在空间上接近被感染的人群？ What factors are close in space to the affected persons 哪些因素在空间上与感染人群和非感染人群相仿？ What factors are not or are no closer to affected than to unaffected persons 地点分布，为什么会是这里而非其他地方Distribution by place, Why here? Why not there?

19. 哪些因素在空间上接近被感染的人群？What factors are close in space to the affected persons 住宅 Residence 商业 Business

20. 按发病时间排列的病例 Cases ordered by onset 3 无明确发病时间的病例 Cases with unknown onset ? 首发病例 First case 1 卫生所 Health Center + 和其他地理特点的关系可能十分重要Relationships to other geographic features may be important N 风向 Wind direction *J Heukelbach et.al. Trop Med Internat Health, 6:635-42, 2001

21. 这一人群做的哪些事是其他人群没有做的？ What did this group do that other groups did not? 人群分布Distribution by Person为什么发生在这一人群中Why in this group of people?

22. 通过副伤寒的人群分布我们可以有哪些推论？What can we learn from the distribution of paratyphoid by person? Step 5

23. 在根据假设进行的访谈中发现的哪些暴露能够提供最好的解释？What exposures from “hypothesis generating interviews” give the best explanation? 询问采访对象潜伏期内的暴露Ask individuals about exposures during the incubation period 询问采访对象的日常行为和习惯 Ask individuals about their general behaviors and habits 找出社区里环境、社会和行政方面的特殊情况 Find out about specific environmental conditions, social and administrative situation of the community 有哪些异常或特殊事件发生？ What unusual or special occurances happened?

24. 可以通过关键的现象找出暴露因素Exposures may be detected through key observations Schools’ well 0.2M 1.5M Village well

25. Note the water dripping from a leak in the pipe joint

26. 暴露因素应包括环境数据 Exposures will include data about the environment 20 天 20 days rainfall cases 病例cases 雨量 rainfall 160 80 有一例实验室确诊病例的暴发An outbreak with one lab confirmed case 60 120 暑假 Summer holiday 40 80 20 天20days 20 40 0 0 1 10 20 1 10 20 1 10 20 1 10 20 1 10 20 1 10 20 7月Jul 8月Aug 9月Sep 10月Oct 11月Nov 12月Dec

27. 推论 Analogy 疾病的分布（时间、地点和人物）与某种已知疾病相似。The distribution of disease (time place and person) is similar to another disease that has been explained.

28. 评定调查发现的重要性 Assessing the importance of a finding 数据的质量Quality of the data 数据密度Data density 内在精确性Inherent precision 发现或模式的特异性Specificity of the finding or pattern

29. 复杂调查中制定假设矩阵 Develop a hypothesis matrix for difficult investigations

30. 其他需要考虑的因素 Other considerations 特殊病例或单个病例The “outlier” or isolated case 明显冲突的现象Apparently conflicting observations 应出现而没出现的情况What should be present, but it is missing.

31. 什么是对暴发的最佳阐释？What best explains the outbreak? 任何暴发都会有多于一种似乎合理的假设。哪一个是最合理的？Any outbreak produces > 1 plausible hypothesis. Which is most plausible? 两种或更多变量间的关联通常大于一种 Association of two or more variables lessens the individual association 和某种因素的关联可能因其于真实病因更加接近而更加重要 Associations with some factors may be more important because they have a more probable relation to the actual cause

32. 一个简单的例子 A simple example • 共有258人参加婚礼 Among 258 persons attending a wedding • 来自9个村庄的23名妇女在就餐时出现头痛、恶心、头晕和晕厥症状 23 women from 9 villages develop headache, nausea, dizziness, syncope while eating dinner at a wedding party. • 140名妇女在帐篷中吃的晚餐 140 women ate dinner in a tent • 118名男士在外面吃的晚餐118 men ate dinner outside • 婚礼于11月的乡村举办，人们通过燃烧木炭取暖Held in the countryside in November charcoal fires used to keep warm • 医院诊断为“食物中毒”Hospital diagnoses “food poisoning”

33. 我们可以得出什么假设? What hypothesis can we form? 参加婚宴的妇女由于暴露帐篷内燃烧的炭火所产生的一氧化炭致病。 Illness among women attending the wedding party resulted from exposure to carbon monoxide generated from charcoal fires in the enclosed tent.

34. Najaran溶血性尿毒症综合症Hemolytic Uremic Syndrome in Najaran • 疾病信息 The disease • 毒素由Ⅰ型痢疾志贺菌引起 Toxin from Shigella dysenteriae type 1 • 抗药性 Amplicillin, cotrimoxizole resistance • 急性肾衰竭 Acute renal failure • 社区内有800名痢疾病例 800 cases dysentery in community • 40个痢疾病例住院治疗 40 cases dysentery admitted to hospital • 痢疾病人中有10例溶血性尿毒症综合症 10 cases of HUS in dysentery patients

35. 10例溶血性尿毒症综合症数据－可以看出哪些情况？Data for 10 HUS cases – What do you notice?

36. Do you notice anything special after sorting the data?

37. 住院后溶血性尿毒症综合症的发病有2－5天的延迟 2-5 day delay of HUS after hospital admission

38. 溶血性尿毒症综合症的假设是什么？What is the hypothesis for HUS 用以治疗痢疾或腹泻的某种抗生素（痢疾志贺菌对其有抗药性）导致Najaran的儿童患溶血性尿毒症综合症 Treatment of dysentery or diarrhea with specific antibiotics to which Shigella dysenteriae was resistant caused HUS in children of Najaran.

39. 假设并不一定要和所有观测到的现象一致Not necessary to be consistent with all observations • 一次暴发或一种疾病可能有多种原因 Multiple causes for an outbreak or disease • 疾病归类的缺陷 Imperfect disease classification • 所观测到的不一致的现象可能会通过更深入的调查中得到解释 Observations that appear inconsistent may actually explain on deeper investigation.

40. 认为一个假设是正确的信念、信服度或是经验的多少和假设是否正确无关 The intensity of the belief, conviction or experience that a hypothesis is true has no bearing on whether it is true or not. 认为一个假设是错误的信念、信服度或是经验的多少和假设是否错误无关 The intensity of the belief, conviction or experience that a hypothesis is false has no bearing on whether it is false or not.

41. 我们所观察到的关联性很可能对科学或医学来讲都是新的。我们一定不能仅仅因为他们太离奇就轻易地将他们排除 The association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. “Sir Austin Bradford Hill” “当你把所有不可能的情况都排除以后，剩下的，无论看起来多么不可信，一定是事实的真相。”“When you have eliminated the impossible, whatever remains, however improbable, must be the truth.” Sherlock Holmes (Arthur Conan Doyle)

42. 问题和评论？ Questions and comments?