循證醫(yī)學(xué)-病因?qū)W研究和循證醫(yī)學(xué)實踐-新-研

1、Evidence-based Etiology / Harm病因研究與循證醫(yī)學(xué)實踐病因研究與循證醫(yī)學(xué)實踐學(xué)習(xí)目標(biāo)n掌握評價病因性研究真實性原則(Validity )n掌握評價病因性研究重要性原則( Importance )n學(xué)會應(yīng)用病因性研究證據(jù)的結(jié)果，解決臨床問題( Applying )病因性研究基本知識n病因性研究基本概念n與病因相關(guān)的臨床問題n病因性研究的主要方法n病因/不良反應(yīng)研究證據(jù)的分級n病因性研究常用統(tǒng)計學(xué)指標(biāo)病因性研究基本概念（1）n病因是指引起人體發(fā)生疾病的原因。病因?qū)W是 指研究疾病病因的科學(xué)。n病因：致病因素（直接、間接、危險因素危險因素）n研究內(nèi)容：用流行病學(xué)方法研究并驗

2、證危險因 素是否與疾病發(fā)生有因果關(guān)系，且評估因果聯(lián) 系的強(qiáng)弱。例“吸煙與肺癌關(guān)系”病因性研究基本概念（2）n不良反應(yīng)的研究實質(zhì)上也是病因?qū)W研究 “因”：造成不良反應(yīng)的各種因素，如各種治療措施（藥物，手術(shù)）n醫(yī)療過程中臨床醫(yī)師經(jīng)常需要考慮某種危險因素或治療措施是否對患者有害。利是否大于弊？利是否大于弊？n用他人的研究結(jié)果來回答提出的問題 真實性真實性 重要性重要性 實用性實用性與病因相關(guān)的臨床問題n該疾病是什么原因造成的？n該藥物或治療措施會導(dǎo)致什么不良反應(yīng)嗎？是否需要停藥？nDoes exposure to aluminum cause Alzheimers dementia?nDo stat

3、ins cause cancer?病因性研究的主要方法病因性研究常用統(tǒng)計學(xué)指標(biāo)n因果相關(guān)性強(qiáng)度的指標(biāo)RR (前瞻性) RCT, cohort studyOR (回顧性）case-control studynNNH (number needed to harm)clinical importance暴露多少研究對象可導(dǎo)致暴露多少研究對象可導(dǎo)致1例發(fā)病例發(fā)?。犃醒芯浚┌l(fā)生發(fā)生1例不良反應(yīng)所需治療的病例數(shù)例不良反應(yīng)所需治療的病例數(shù)（臨床研究）因果相關(guān)性強(qiáng)度的指標(biāo)n當(dāng)所研究疾病的發(fā)病率較低時，OR近似于RR，故在回顧性研究中可用OR估計RR,其解釋與RR同，易于統(tǒng)計分析nRR 或OR愈高，則因果關(guān)系

4、強(qiáng)度愈強(qiáng)nRR 或OR 有多大才有意義，無一定的標(biāo)準(zhǔn)1.2-1.5: 弱聯(lián)系1.6-2.9: 中等聯(lián)系 3.0: 強(qiáng)聯(lián)系可信區(qū)間Confidence Intervaln因果關(guān)系的強(qiáng)度外，評價精確度精確度n按一定的概率一定的概率去估計總體參數(shù)所在的范 圍n95的可信區(qū)間n循證醫(yī)學(xué)估計總體參數(shù)估計總體參數(shù)假設(shè)檢驗：假設(shè)檢驗：RR有關(guān)指標(biāo)的計算1. Odds Ratio 2. Relative Risk3. Risk Reduction / Increase 4. Number Needed to Treat / Harm 證據(jù)的強(qiáng)度證據(jù)的強(qiáng)度The Confusion Matrix+ve Even

5、t-ve EventTotalExperimentABA + ControlCDC + DEvent RatenEER = A / (A+B) 試驗組事件發(fā)生率nCER= C / (C+D) 對照組事件發(fā)生率+ve Event-ve EventTotalExperimentABA + ControlCDC + DRR and ORnRR = EER / CER 相對危險度nOR= AD / BC 比值比+ve Event-ve EventTotalExperimentABA + ControlCDC + DRelative Risk ReductionnRRR= (CER - EER) / C

6、ER = 1 RR 相對危險度減少率+ve Event-ve EventTotalExperimentABA + ControlCDC + D(Absolute) Risk ReductionARR = CER - EER絕對危險度減少率+ve Event-ve EventTotalExperimentABA + ControlCDC + DNumber Needed to TreatNNT = 1 / ARR得到1例有利結(jié)果需要防治的病例數(shù)+ve Event-ve EventTotalExperimentABA + ControlCDC + D舉例：Activated Protein C f

7、or Severe SepsisBleedNo bleedTotalAPC30820850Control17823840Event Rates and Odds+ve Event-ve EventTotalExperimentABA + ControlCDC + DBleedNo bleedTotalAPC30820850Control17823840Risk-Benefit RatioDeadNot deadTotalAPC210640850Control259581840BleedNo bleedTotalAPC30820850Control17823840怎樣解決臨床問題？How to

8、solve a clinical problem?臨床病案（Clinical Scenario）n84歲的男性，近期記憶力明顯下降.高血壓病，高膽固醇血癥。n右眼白內(nèi)障術(shù)后2天，出現(xiàn)易激、譫妄和性格出現(xiàn)易激、譫妄和性格改變。改變。n無感染，貧血及代謝異常的臨床證據(jù)。n心理衛(wèi)生中心會診：抗精神病藥物抗精神病藥物氟哌啶醇, haloperidol , 奮乃靜perphenazine, 奧氮平, olanzapine臨床問題（Initial Question）n老年患者中，用傳統(tǒng)性抗精神病藥物傳統(tǒng)性抗精神病藥物（如氟哌啶醇, haloperidol , 奮乃靜perphenazine,）是否會增加死

9、亡風(fēng)險性？非典型性抗精神病藥物非典型性抗精神病藥物(如奧氮平, olanzapine,）是否對老年人更安全？第一步 提出問題(Ask Clinical Questions)nInitial question:nFraming the initial question: answerablePatients (population)Intervention/exposureComparisonOutcomePICO轉(zhuǎn)變成可以回答的臨床問題Framing the questionn患者類型(P) elderly patientsn干預(yù)措施(I) haloperidol or perphenazin

10、en對照措施(C) olanzapinen臨床結(jié)局(O) death第二步 查詢證據(jù) (Acquire Evidence)nPICO: key wordsnType of question：harm - Best evidence Levels of evidence - Optimal source of evidencenSearching worthwhile?病因/不良反應(yīng)研究常用數(shù)據(jù)庫nBest Evidence（ACP journal club, EBM)nUp to DatenMedlinePubMed: clinical query-etiologySumsearchOvid循

11、證醫(yī)學(xué)數(shù)據(jù)庫(多庫同時檢索)ACP journal club, Cochrane Library( CDSR, CCTR,DARE), Medline, EMBASEn系統(tǒng)評價資料庫(Cochrane Database of Systematic Review,CDSR)n療效評價文摘庫(Database of Abstracts of Reviews of Effectiveness, DARE)n臨床對照試驗注冊資料庫(Cochrane Controlled Trials Register,CCTR)n方法學(xué)數(shù)據(jù)庫 (Cochrane Methodology Database)檢索方法n選

12、擇數(shù)據(jù)庫：ACP journal club（oviddatabase, best evidence）n在search 中，鍵入關(guān)鍵詞olanzapineetiology（病因?qū)W）n檢索結(jié)果：1篇文獻(xiàn)（摘要）n找到全文篩選結(jié)果nACP 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.nSchneewei

13、ss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ.2007;176:627-32研究詳情nBackground: Public health advisories have warned that the use of atypical antipsychotic medications increases

14、 the risk of death among elderly patients. We assessed the short-term mortality in a population-based cohort of elderly 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 ide

15、ntify a cohort of people aged 65 years and older who began taking antipsychotic medications 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 antipsycho

16、tic medications. Results:nOf 37 241 elderly people in the study cohort, 12 882 were 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 aty

17、pical drug group (mortality ratio 1.47, 95% confidence interval CI 1.391.56). Multivariable adjustment resulted in a 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,

18、 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 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

19、the start of drug therapy (mortality ratio 1.60, 95% CI 1.421.80). Results were confirmed in propensity score analyses and instrumental variable estimation, minimizing residual confounding. 結(jié)論nInterpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medica

20、tions is comparable to and possibly greater than the risk of death associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients. 第三步 評價證據(jù) Appraise Evidencen證據(jù)的真實性真實性Are the re

21、sults valid?n證據(jù)的重要性重要性What are the results?證據(jù)的真實性Are the results valid?1 研究方法的論證強(qiáng)度Type of Reports on Etiology/Harmn哪種研究方法？n論證強(qiáng)度如何？n是否源于真正的人體試驗？ 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 p

22、atients, association of conventional or atypical antipsychotic drugs (APDs) with death ?nDesign: Cohort studynParticipants: 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

23、 index date.2 兩組結(jié)局暴露因素的測量方法是否一致？兩組結(jié)局暴露因素的測量方法是否一致？nWere treatments/exposures and clinical outcomes 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

24、?Cohort StudynSurveillance bias: 監(jiān)測偏倚n偏倚的控制客觀指標(biāo)（Objective outcome）：病死率主觀指標(biāo)（Subjective outcome）: Blinding舉例：乙型肝炎與肝癌關(guān)系的研究乙型肝炎與肝癌關(guān)系的研究 3. 隨訪時間及失訪率nWas the follow-up of the study patients sufficiently long (for the outcome to occur) and complete?n舉例：HP與胃癌：5年（無差異），10 年（顯著差異）n失訪超過20？-結(jié)果將失去真實性4 病因/不良反應(yīng)研究結(jié)果

25、是否符合病因診斷原則nDo the results of the harm study satisfy some of the diagnostic tests for causation?nIs it clear that the exposure preceded the onset of the outcome? 因果效應(yīng)的先后順序僅見于前瞻性研究nIs there a doseresponse gradient? 因果效應(yīng)的相關(guān)程度，劑量依賴（吸煙與肺癌）nIs there any positive evidence from a “dechallengerechallenge” st

26、udy? 符合流行病學(xué)規(guī)律-危險因素減弱，發(fā)病減少危險因素減弱，發(fā)病減少nIs the association consistent from study to study? 不同研究，結(jié)果一致（HP與胃癌）nDoes the association make biological sense? 充分的生物學(xué)依據(jù)（CCB與癌癥，壞血病與水果蔬菜）Key Points1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment

27、 or other cause? 研究方法的論證強(qiáng)度2. Were treatments/exposures and clinical outcomes measured in the same ways in both groups? 測量方法一致3. Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete? 隨訪時間及失訪率證據(jù)的重要性What are the results?1.因果聯(lián)系強(qiáng)度聯(lián)系強(qiáng)度nWhat is the magnitude of

28、the association between the exposure and outcome?nHow strong is the association between exposure and outcome?nRR OR NNH2. 結(jié)果是否準(zhǔn)確準(zhǔn)確？nWhat is the precision of the estimate of the association between the exposure and outcome?nHow precise is the estimate of risk?n95%CIConventional APD vs Atypical APDAss

29、ociation with death第四步應(yīng)用證據(jù)How can I apply the results to mypatient?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基于納入和排除標(biāo)準(zhǔn)本研究nPatients: 65 y of age , 60-65% womennUsed 1 medical service, and filled 1 pr

30、escription 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 clozapinenConventional APDs: loxapine, haloperidol, chlorpromazine, trifluoperazine, thioridazine, pimozide,