循证医学-病因学研究和循证医学实践

1、.,1,Evidence-based Etiology / Harm病因研究与循证医学实践,.,2,学习目标,掌握评价病因性研究真实性原则(Validity ) 掌握评价病因性研究重要性原则( Importance ) 学会应用病因性研究证据的结果，解决临床问题( Applying ),.,3,病因性研究基本知识,病因性研究基本概念 与病因相关的临床问题 病因性研究的主要方法 病因/不良反应研究证据的分级 病因性研究常用统计学指标,.,4,病因性研究基本概念（1）,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。 病因：致病因素（直接、间接、危险因素） 研究内容：用流行病学方法

2、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”,.,5,病因性研究基本概念（2）,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） 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？ 用他人的研究结果来回答提出的问题 真实性 重要性 实用性,.,6,与病因相关的临床问题,该疾病是什么原因造成的？ 该药物或治疗措施会导致什么不良反应吗？是否需要停药？ Does exposure to aluminum cause Alzheimers dementia? Do statin

3、s cause cancer?,.,7,病因性研究的主要方法,.,8,病因性研究常用统计学指标,因果相关性强度的指标 RR (前瞻性) RCT, cohort study OR (回顾性）case-control study NNH (number needed to harm) clinical importance 暴露多少研究对象可导致1例发病（队列研究） 发生1例不良反应所需治疗的病例数（临床研究）,.,9,因果相关性强度的指标,当所研究疾病的发病率较低时，OR近似于RR，故在回顾性研究中可用OR估计RR,其解释与RR同，易于统计分析 RR 或OR愈高，则因果关系强度愈强 RR 或OR

4、 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,.,10,可信区间Confidence Interval,因果关系的强度外，评价精确度 按一定的概率去估计总体参数所在的范 围 95的可信区间 循证医学 估计总体参数 假设检验：RR,.,11,有关指标的计算,1. Odds Ratio,2. Relative Risk,3. Risk Reduction / Increase,4. Number Needed to Treat / Harm,.,12,.,13,證據的強度,.,14,The Confusion Matrix,Also kno

5、wn as the 2 x 2 table,.,15,Event Rate,EER = A / (A+B) 试验组事件发生率 CER= C / (C+D) 对照组事件发生率,.,16,RR and OR,RR = EER / CER 相对危险度 OR= AD / BC 比值比,.,17,Relative Risk Reduction,RRR= (CER - EER) / CER = 1 RR 相对危险度减少率,.,18,(Absolute) Risk Reduction,ARR = CER - EER 绝对危险度减少率,.,19,Number Needed to Treat,NNT = 1 /

6、 ARR 得到1例有利结果需要防治的病例数,.,20,举例：Activated Protein C for Severe Sepsis,APC = Activated Protein C Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709,.,21,Event Rates and Odds,EER= A / (A+B) = 30 / 850 = 0.035 CER= C / (C+D) = 17 / 840

7、 = 0.020 EEO = A / B = 30 / 820 = 0.037 CEO = C / D = 17 / 823 = 0.021,OR= EEO / CEO = 0.037 / 0.021 = 1.77 RR= EER / CER = 0.035 / 0.020 = 1.744,RRI= (EER CER) / CER = 0.015 / 0.020 = 0.744 = 74 % ARI= EER CER = 0.035 0.020 = 0.015 NNH= 1 / ARI = 66,.,22,Risk-Benefit Ratio,NNT = 1 / ARR = 1 / 0.06

8、= 16 (治疗16个获益1个：存活) 反映有利结果（越小越好） NNH = 1 / ARI = 1 / 0.015 = 66 (治疗66个损害1个：严重出血) 反映不良反应（越大越好） Risk-Benefit Ratio= NNT / NNH = 16 / 66 = 1 / 4,.,23,怎样解决临床问题？How to solve a clinical problem?,.,24,临床病案（Clinical Scenario）,84岁的男性，近期记忆力明显下降.高血压病，高胆固醇血症。 右眼白内障术后2天，出现易激、谵妄和性格改变。 无感染，贫血及代谢异常的临床证据。 心理卫生中心会诊：

9、抗精神病药物 氟哌啶醇, haloperidol , 奋乃静perphenazine, 奥氮平, olanzapine,.,25,临床问题（Initial Question）,老年患者中，用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(如奥氮平, olanzapine,）是否对老年人更安全？,.,26,第一步 提出问题(Ask Clinical Questions),Initial question: Framing the initial question: answerable Patients

10、(population) Intervention/exposure Comparison Outcome PICO,.,27,转变成可以回答的临床问题Framing the question,患者类型(P) elderly patients 干预措施(I) haloperidol or perphenazine 对照措施(C) olanzapine 临床结局(O) death,.,28,第二步 查询证据 (Acquire Evidence),PICO: key words Type of question：harm - Best evidence Levels of evidence - O

11、ptimal source of evidence Searching worthwhile?,.,29,病因/不良反应研究常用数据库,Best Evidence（ACP journal club, EBM) Up to Date Medline 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,.,30,系统评价资料库(Cochrane Database of Systematic

12、 Review,CDSR) 疗效评价文摘库(Database of Abstracts of Reviews of Effectiveness, DARE) 临床对照试验注册资料库(Cochrane Controlled Trials Register,CCTR) 方法学数据库 (Cochrane Methodology Database),.,31,检索方法,选择数据库：ACP journal club（ovid database, best evidence） 在search 中，键入关键词 olanzapineetiology（病因学） 检索结果：1篇文献（摘要） 找到全文,.,32,.

13、,33,.,34,筛选结果,ACP journal Club summary: Conventional antipsychotic drugs increased risk for death more than did atypical antipsychotic drugs in elderly patients ACP Journal Club. 2007;147:23. Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conven

14、tional versus atypical antipsychotic drugs among elderly patients. CMAJ.2007;176:627-32,.,35,.,36,研究详情,Background: 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 pop

15、ulation-based cohort of elderly people in British Columbia who were prescribed conventional and atypical antipsychotic medications. Methods: 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 medicatio

16、ns between January 1996 and December 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.,.,37,Results:,Of 37 241 elderly people in the study cohort, 12 882 were

17、prescribed a conventional antipsychotic 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). Multiv

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

19、 greatest increase in 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 p

20、ropensity score analyses and instrumental variable estimation, minimizing residual confounding.,.,38,结论,Interpretation: 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 atypic

21、al antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients.,.,39,第三步 评价证据 Appraise Evidence,证据的真实性 Are the results valid? 证据的重要性 What are the results?,.,40,证据的真实性Are the results valid?,.,41,1 研究方

22、法的论证强度Type of Reports on Etiology/Harm,哪种研究方法？ 论证强度如何？ 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?,.,42,本研究,Objective: In elderly patients, association of conventional or atypical antipsychotic drugs (

23、APDs) with death ? Design: Cohort study Participants: 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.,.,43,2 两组结局暴露因素的测量方法是否一致？,Were treatments/exposures and c

24、linical outcomes measured in the same ways in both groups? (Was the assessment of outcomes either objective or blinded to exposure?) Were the outcomes and exposures measured in the same way in the groups being compared?,.,44,Cohort Study,Surveillance bias: 监测偏倚 偏倚的控制 客观指标（Objective outcome）：病死率 主观指标

25、（Subjective outcome）: Blinding 举例：乙型肝炎与肝癌关系的研究,.,45,3. 随访时间及失访率,Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete? 举例：HP与胃癌：5年（无差异），10 年（显著差异） 失访超过20？-结果将失去真实性,.,46,4 病因/不良反应研究结果是否符合病因诊断原则,Do the results of the harm study satisfy some of the diagnostic

26、 tests for causation?,.,47,Is 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 Is there a doseresponse gradient? 因果效应的相关程度，剂量依赖（吸烟与肺癌） Is 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,.,48,Is the association consistent from stu

27、dy to study? 不同研究，结果一致（HP与胃癌） Does 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）,.,49,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

28、 outcomes 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,.,50,证据的重要性What are the results?,.,51,1.因果联系强度,What is the magnitude of the association between the exposure and outcome? How stro

29、ng is the association between exposure and outcome? RR OR NNH,.,52,2. 结果是否准确？,What is the precision of the estimate of the association between the exposure and outcome? How precise is the estimate of risk? 95%CI,.,53,Conventional APD vs Atypical APDAssociation with death,.,54,第四步应用证据How can I apply

30、the results to mypatient?,.,55,病情相似,Is our patient so different from those included in the study that its results cannot apply? Were the study patients similar to my patient? 基于纳入和排除标准,.,56,本研究,Patients: 65 y of age , 60-65% women Used 1 medical service, and filled 1 prescription in the two 6-month intervals before the index date. Exclusion criteria: cancer and use of APDs in the year before the index date. Atypical APDs: risperidone, quetiapine, olanzapine, and clozapine Conventional APDs: loxapine, haloperidol, chlorpromazine, trifluoperazine,