循证医学-病因学研究和循证医学实践-新-研

1、Evidence-based Etiology / Harm 病因研究与循证医学实践病因研究与循证医学实践 学习目标 n掌握评价病因性研究真实性原则(Validity ) n掌握评价病因性研究重要性原则 ( Importance ) n学会应用病因性研究证据的结果，解决 临床问题( Applying ) 病因性研究基本知识 n病因性研究基本概念 n与病因相关的临床问题 n病因性研究的主要方法 n病因/不良反应研究证据的分级 n病因性研究常用统计学指标 病因性研究基本概念（1） n病因是指引起人体发生疾病的原因。病因学是 指研究疾病病因的科学。 n病因：致病因素（直接、间接、危险因素危险因素）

2、n研究内容：用流行病学方法研究并验证危险因 素是否与疾病发生有因果关系，且评估因果联 系的强弱。例“吸烟与肺癌关系” 病因性研究基本概念（2） n不良反应的研究实质上也是病因学研究 “因”：造成不良反应的各种因素，如 各种治疗措施（药物，手术） n医疗过程中临床医师经常需要考虑某种 危险因素或治疗措施是否对患者有害。 利是否大于弊？利是否大于弊？ n用他人的研究结果来回答提出的问题 真实性真实性 重要性重要性 实用性实用性 与病因相关的临床问题 n该疾病是什么原因造成的？ n该药物或治疗措施会导致什么不良反应 吗？是否需要停药？ nDoes exposure to aluminum cause

3、 Alzheimers dementia? nDo statins cause cancer? 病因性研究的主要方法 病因性研究常用统计学指标 n因果相关性强度的指标 RR (前瞻性) RCT, cohort study OR (回顾性）case-control study nNNH (number needed to harm) clinical importance 暴露多少研究对象可导致暴露多少研究对象可导致1例发病例发病（队列研究） 发生发生1例不良反应所需治疗的病例数例不良反应所需治疗的病例数（临床研究） 因果相关性强度的指标 n当所研究疾病的发病率较低时，OR近似于RR， 故在回顾

4、性研究中可用OR估计RR,其解释与RR 同，易于统计分析 nRR 或OR愈高，则因果关系强度愈强 nRR 或OR 有多大才有意义，无一定的标准 1.2-1.5: 弱联系 1.6-2.9: 中等联系 3.0: 强联系 可信区间Confidence Interval n因果关系的强度外，评价精确度精确度 n按一定的概率一定的概率去估计总体参数所在的范 围 n95的可信区间 n循证医学 估计总体参数估计总体参数 假设检验：假设检验：RR 有关指标的计算 1. Odds Ratio 2. Relative Risk 3. Risk Reduction / Increase 4. Number Need

5、ed to Treat / Harm 證據的強度證據的強度 The Confusion Matrix +ve Event -ve Event Total ExperimentABA + ControlCDC + D Event Rate nEER = A / (A+B) 试验组事件发生率 nCER= C / (C+D) 对照组事件发生率 +ve Event -ve Event Total ExperimentABA + ControlCDC + D RR and OR nRR = EER / CER 相对危险度 nOR= AD / BC 比值比 +ve Event -ve Event Tota

6、l ExperimentABA + ControlCDC + D Relative Risk Reduction nRRR= (CER - EER) / CER = 1 RR 相对危险度减少率 +ve Event -ve Event Total ExperimentABA + ControlCDC + D (Absolute) Risk Reduction ARR = CER - EER 绝对危险度减少率 +ve Event -ve Event Total ExperimentABA + ControlCDC + D Number Needed to Treat NNT = 1 / ARR 得

7、到1例有利结果需要防治的病例数 +ve Event -ve Event Total ExperimentABA + ControlCDC + D 举例： Activated Protein C for Severe Sepsis Bleed No bleed Total APC30820850 Control17823840 Event Rates and Odds +ve Event -ve Event Total ExperimentABA + ControlCDC + D Bleed No bleed Total APC30820850 Control17823840 Risk-Bene

8、fit Ratio Dead Not dead Total APC210640850 Control259581840 Bleed No bleed Total APC30820850 Control17823840 怎样解决临床问题？ How to solve a clinical problem? 临床病案（Clinical Scenario） n84岁的男性，近期记忆力明显下降.高血压病， 高胆固醇血症。 n右眼白内障术后2天，出现易激、谵妄和性格出现易激、谵妄和性格 改变。改变。 n无感染，贫血及代谢异常的临床证据。 n心理卫生中心会诊： 抗精神病药物抗精神病药物 氟哌啶醇, halo

9、peridol , 奋乃静perphenazine, 奥氮平, olanzapine 临床问题（Initial Question） n老年患者中，用传统性抗精神病药物传统性抗精神病药物 （如氟哌啶醇, haloperidol , 奋乃静 perphenazine,）是否会增加死亡风险性？ 非典型性抗精神病药物非典型性抗精神病药物(如奥氮平, olanzapine,）是否对老年人更安全？ 第一步 提出问题(Ask Clinical Questions) nInitial question: nFraming the initial question: answerable Patients (p

10、opulation) Intervention/exposure Comparison Outcome PICO 转变成可以回答的临床问题 Framing the question n患者类型(P) elderly patients n干预措施(I) haloperidol or perphenazine n对照措施(C) olanzapine n临床结局(O) death 第二步 查询证据 (Acquire Evidence) nPICO: key words nType of question：harm - Best evidence Levels of evidence - Optima

11、l source of evidence nSearching worthwhile? 病因/不良反应研究常用数据库 nBest Evidence（ACP journal club, EBM) nUp to Date nMedline PubMed: clinical query-etiology Sumsearch Ovid循证医学数据库(多库同时检索) ACP journal club, Cochrane Library( CDSR, CCTR,DARE), Medline, EMBASE n系统评价资料库(Cochrane Database of Systematic Review,CD

12、SR) n疗效评价文摘库(Database of Abstracts of Reviews of Effectiveness, DARE) n临床对照试验注册资料库(Cochrane Controlled Trials Register,CCTR) n方法学数据库 (Cochrane Methodology Database) 检索方法 n选择数据库：ACP journal club（ovid database, best evidence） n在search 中，键入关键词 olanzapineetiology（病因学） n检索结果：1篇文献（摘要） n找到全文 筛选结果 nACP jour

13、nal Club summary: Conventional antipsychotic drugs increased risk for death more than did atypical antipsychotic drugs in elderly patients ACP Journal Club. 2007;147:23. nSchneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypica

14、l antipsychotic drugs among elderly patients. CMAJ.2007;176:627-32 研究详情 nBackground: Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients. We assessed the short-term mortality in a population-based cohort of elderl

15、y people in British Columbia who were prescribed conventional and atypical antipsychotic medications. nMethods: We used linked health care utilization data of all BC residents to identify a cohort of people aged 65 years and older who began taking antipsychotic medications between January 1996 and D

16、ecember 2004 and were free of cancer. We compared the 180-day all-cause mortality between residents taking conventional antipsychotic medications and those taking atypical antipsychotic medications. Results: nOf 37 241 elderly people in the study cohort, 12 882 were prescribed a conventional antipsy

17、chotic medication and 24 359 an atypical formulation. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% confidence interval CI 1.391.56). Multivariable adjustment resulted in a

18、180-day mortality ratio of 1.32 (1.231.42). In comparison with risperidone（利培酮利培酮）, haloperidol（氟哌啶醇氟哌啶醇） was associated with the greatest increase in mortality (mortality ratio 2.14, 95% CI 1.862.45) and loxapine（ 洛沙洛沙 平平）the lowest (mortality ratio 1.29, 95% CI 1.191.40). The greatest increase in

19、mortality occurred among people taking higher (above median) doses of conventional antipsychotic medications (mortality ratio 1.67, 95% CI 1.501.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95% CI 1.421.80). Results were confirmed in propensity score analys

20、es and instrumental variable estimation, minimizing residual confounding. 结论 nInterpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the risk of death associated with atypical antipsychotic medicatio

21、ns. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients. 第三步 评价证据 Appraise Evidence n证据的真实性真实性 Are the results valid? n证据的重要性重要性 What are the results? 证据的真实性 Are the results valid? 1 研究方法的论证强度 Type of Reports on Etiolo

22、gy/Harm n哪种研究方法？ n论证强度如何？ n是否源于真正的人体试验？ Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause? 本研究 nObjective: In elderly patients, association of conventional or atypical antipsychotic drugs (APDs) with death ? nDesign: Coho

23、rt study nParticipants: 37241 patients 65 y of age oral conventional (n = 12 882, mean age 80 y) atypical (n = 24 359, mean age 80 y). Exclusion criteria: cancer and use of APDs in the year before the index date. 2 两组结局暴露因素的测量方法是否一致？两组结局暴露因素的测量方法是否一致？ nWere treatments/exposures and clinical outcomes

24、 measured in the same ways in both groups? (Was the assessment of outcomes either objective or blinded to exposure?) nWere the outcomes and exposures measured in the same way in the groups being compared? Cohort Study nSurveillance bias: 监测偏倚 n偏倚的控制 客观指标（Objective outcome）：病死率 主观指标（Subjective outcom

25、e）: Blinding 举例：乙型肝炎与肝癌关系的研究乙型肝炎与肝癌关系的研究 3. 随访时间及失访率 nWas the follow-up of the study patients sufficiently long (for the outcome to occur) and complete? n举例：HP与胃癌：5年（无差异），10 年（显著差异） n失访超过20？-结果将失去真实性 4 病因/不良反应研究结果是否符合病因诊 断原则 nDo the results of the harm study satisfy some of the diagnostic tests for

26、causation? nIs it clear that the exposure preceded the onset of the outcome? 因果效应的先后顺序仅见于前瞻性研究 nIs there a doseresponse gradient? 因果效应的相关程度，剂量依赖（吸烟与肺癌） nIs there any positive evidence from a “dechallengerechallenge” study? 符合流行病学规律-危险因素减弱，发病减少危险因素减弱，发病减少 nIs the association consistent from study to

27、study? 不同研究，结果一致（HP与胃癌） nDoes the association make biological sense? 充分的生物学依据（CCB与癌症，坏血 病与水果蔬菜） Key Points 1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause? 研究方法的论证强度 2. Were treatments/exposures and clinical outcomes

28、 measured in the same ways in both groups? 测量方法一致 3. Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete? 随访时间及失访率 证据的重要性 What are the results? 1.因果联系强度联系强度 nWhat is the magnitude of the association between the exposure and outcome? nHow strong is the as

29、sociation between exposure and outcome? nRR OR NNH 2. 结果是否准确准确？ nWhat is the precision of the estimate of the association between the exposure and outcome? nHow precise is the estimate of risk? n95%CI Conventional APD vs Atypical APD Association with death 第四步应用证据 How can I apply the results to mypa

30、tient? 病情相似 nIs our patient so different from those included in the study that its results cannot apply? nWere the study patients similar to my patient? n基于纳入和排除标准 本研究 nPatients: 65 y of age , 60-65% women nUsed 1 medical service, and filled 1 prescription in the two 6-month intervals before the index date. nExclusion criteria: cancer and use of APDs in the year before the index date. nAtypical APDs: risperidone, quetiapine, olanzapine, and clozapine nConventional APDs: loxapine, haloperidol, chlorpromazine, trifluoperazine, thioridazine, pimozide