循證醫(yī)學(xué)-病因?qū)W研究和循證醫(yī)學(xué)實(shí)踐-新-研課件

1、Evidence-based Etiology / Harm病因研究與循證醫(yī)學(xué)實(shí)踐Evidence-based Etiology / Harm學(xué)習(xí)目標(biāo)掌握評(píng)價(jià)病因性研究真實(shí)性原則(Validity )掌握評(píng)價(jià)病因性研究重要性原則( Importance )學(xué)會(huì)應(yīng)用病因性研究證據(jù)的結(jié)果，解決臨床問題( Applying )學(xué)習(xí)目標(biāo)掌握評(píng)價(jià)病因性研究真實(shí)性原則(Validity )病因性研究基本知識(shí)病因性研究基本概念與病因相關(guān)的臨床問題病因性研究的主要方法病因/不良反應(yīng)研究證據(jù)的分級(jí)病因性研究常用統(tǒng)計(jì)學(xué)指標(biāo)病因性研究基本知識(shí)病因性研究基本概念病因性研究基本概念（1）病因是指引起人體發(fā)生疾病的原因。

2、病因?qū)W是 指研究疾病病因的科學(xué)。病因：致病因素（直接、間接、危險(xiǎn)因素）研究內(nèi)容：用流行病學(xué)方法研究并驗(yàn)證危險(xiǎn)因 素是否與疾病發(fā)生有因果關(guān)系，且評(píng)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（1）病因是指引起人體發(fā)生疾病的原因。病因病因性研究基本概念（2）不良反應(yīng)的研究實(shí)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)）醫(yī)療過程中臨床醫(yī)師經(jīng)常需要考慮某種危險(xiǎn)因素或治療措施是否對患者有害。利是否大于弊？用他人的研究結(jié)果來回答提出的問題 真實(shí)性 重要性 實(shí)用性病因性研究基本概念（2）不良反應(yīng)的研究實(shí)質(zhì)上也是病因?qū)W研究與病因相關(guān)的臨床問題該疾病是什么原因造成

3、的？該藥物或治療措施會(huì)導(dǎo)致什么不良反應(yīng)嗎？是否需要停藥？Does exposure to aluminum cause Alzheimers dementia?Do statins cause cancer?與病因相關(guān)的臨床問題該疾病是什么原因造成的？病因性研究的主要方法病因性研究的主要方法病因性研究常用統(tǒng)計(jì)學(xué)指標(biāo)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 studyNNH (number needed to harm)clinical importance暴露多少研究對象可導(dǎo)致1例發(fā)病（隊(duì)列研究）發(fā)生1例不良反應(yīng)所需治療的

4、病例數(shù)（臨床研究）病因性研究常用統(tǒng)計(jì)學(xué)指標(biāo)因果相關(guān)性強(qiáng)度的指標(biāo)因果相關(guān)性強(qiáng)度的指標(biāo)當(dāng)所研究疾病的發(fā)病率較低時(shí)，OR近似于RR，故在回顧性研究中可用OR估計(jì)RR,其解釋與RR同，易于統(tǒng)計(jì)分析RR 或OR愈高，則因果關(guān)系強(qiáng)度愈強(qiáng)RR 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)系因果相關(guān)性強(qiáng)度的指標(biāo)當(dāng)所研究疾病的發(fā)病率較低時(shí)，OR近似于R可信區(qū)間Confidence Interval因果關(guān)系的強(qiáng)度外，評(píng)價(jià)精確度按一定的概率去估計(jì)總體參數(shù)所在的范 圍95的可信區(qū)間循證醫(yī)學(xué)估計(jì)總體參數(shù)假設(shè)檢驗(yàn)：RR可信區(qū)間Confidence Interval

5、因果關(guān)系的強(qiáng)度有關(guān)指標(biāo)的計(jì)算1. Odds Ratio 2. Relative Risk3. Risk Reduction / Increase 4. Number Needed to Treat / Harm 有關(guān)指標(biāo)的計(jì)算1. Odds Ratio 2. Relati循證醫(yī)學(xué)-病因?qū)W研究和循證醫(yī)學(xué)實(shí)踐-新-研課件證據(jù)的強(qiáng)度證據(jù)的強(qiáng)度The Confusion Matrix+ve Event-ve EventTotalExperimentABA + ControlCDC + DAlso known as the 2 x 2 tableThe Confusion Matrix+ve Event

6、-Event RateEER = A / (A+B) 試驗(yàn)組事件發(fā)生率CER= C / (C+D) 對照組事件發(fā)生率+ve Event-ve EventTotalExperimentABA + ControlCDC + DEvent RateEER = A / (A+B)+ve ERR and ORRR = EER / CER 相對危險(xiǎn)度OR= AD / BC 比值比+ve Event-ve EventTotalExperimentABA + ControlCDC + DRR and ORRR = EER / CER+ve EveRelative Risk ReductionRRR= (CER

7、 - EER) / CER = 1 RR 相對危險(xiǎn)度減少率+ve Event-ve EventTotalExperimentABA + ControlCDC + DRelative Risk ReductionRRR= (C(Absolute) Risk ReductionARR = CER - EER絕對危險(xiǎn)度減少率+ve Event-ve EventTotalExperimentABA + ControlCDC + D(Absolute) Risk ReductionARR =Number Needed to TreatNNT = 1 / ARR得到1例有利結(jié)果需要防治的病例數(shù)+ve Ev

8、ent-ve EventTotalExperimentABA + ControlCDC + DNumber Needed to TreatNNT = 1舉例：Activated Protein C for Severe SepsisBleedNo bleedTotalAPC30820850Control17823840APC = Activated Protein CEfficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):69

9、9-709舉例：Activated Protein C for SeEvent Rates and OddsEER= A / (A+B)= 30 / 850 = 0.035CER= C / (C+D)= 17 / 840 = 0.020EEO = A / B= 30 / 820 = 0.037CEO = C / D= 17 / 823 = 0.021+ve Event-ve EventTotalExperimentABA + ControlCDC + DBleedNo bleedTotalAPC30820850Control17823840OR= EEO / CEO= 0.037 / 0.02

10、1 = 1.77RR= EER / CER = 0.035 / 0.020 = 1.744RRI= (EER CER) / CER= 0.015 / 0.020 = 0.744 = 74 %ARI= EER CER= 0.035 0.020 = 0.015 NNH= 1 / ARI= 66Event Rates and OddsEER= A / Risk-Benefit RatioNNT = 1 / ARR = 1 / 0.06= 16 (治療16個(gè)獲益1個(gè)：存活) 反映有利結(jié)果（越小越好）NNH = 1 / ARI = 1 / 0.015= 66 (治療66個(gè)損害1個(gè)：嚴(yán)重出血) 反映不良反

11、應(yīng)（越大越好）Risk-Benefit Ratio= NNT / NNH= 16 / 66= 1 / 4DeadNot deadTotalAPC210640850Control259581840BleedNo bleedTotalAPC30820850Control17823840Risk-Benefit RatioNNT = 1 / A怎樣解決臨床問題？How to solve a clinical problem?怎樣解決臨床問題？How to solve a clini臨床病案（Clinical Scenario）84歲的男性，近期記憶力明顯下降.高血壓病，高膽固醇血癥。右眼白內(nèi)障術(shù)后2

12、天，出現(xiàn)易激、譫妄和性格改變。無感染，貧血及代謝異常的臨床證據(jù)。心理衛(wèi)生中心會(huì)診：抗精神病藥物氟哌啶醇, haloperidol , 奮乃靜perphenazine, 奧氮平, olanzapine臨床病案（Clinical Scenario）84歲的男性，臨床問題（Initial Question）老年患者中，用傳統(tǒng)性抗精神病藥物（如氟哌啶醇, haloperidol , 奮乃靜perphenazine,）是否會(huì)增加死亡風(fēng)險(xiǎn)性？非典型性抗精神病藥物(如奧氮平, olanzapine,）是否對老年人更安全？臨床問題（Initial Question）老年患者中，用傳第一步 提出問題(Ask C

13、linical Questions)Initial question:Framing the initial question: answerablePatients (population)Intervention/exposureComparisonOutcomePICO第一步 提出問題(Ask Clinical Question轉(zhuǎn)變成可以回答的臨床問題Framing the question患者類型(P) elderly patients干預(yù)措施(I) haloperidol or perphenazine對照措施(C) olanzapine臨床結(jié)局(O) death轉(zhuǎn)變成可以回答的臨床

14、問題Framing the quest第二步 查詢證據(jù) (Acquire Evidence)PICO: key wordsType of question：harm - Best evidence Levels of evidence - Optimal source of evidenceSearching worthwhile?第二步 查詢證據(jù) (Acquire Evidence)PIC病因/不良反應(yīng)研究常用數(shù)據(jù)庫Best Evidence（ACP journal club, EBM)Up to DateMedlinePubMed: clinical query-etiologySumse

15、archOvid循證醫(yī)學(xué)數(shù)據(jù)庫(多庫同時(shí)檢索)ACP journal club, Cochrane Library( CDSR, CCTR,DARE), Medline, EMBASE病因/不良反應(yīng)研究常用數(shù)據(jù)庫Best Evidence（AC系統(tǒng)評(píng)價(jià)資料庫(Cochrane Database of Systematic Review,CDSR)療效評(píng)價(jià)文摘庫(Database of Abstracts of Reviews of Effectiveness, DARE)臨床對照試驗(yàn)注冊資料庫(Cochrane Controlled Trials Register,CCTR)方法學(xué)數(shù)據(jù)庫 (C

16、ochrane Methodology Database)系統(tǒng)評(píng)價(jià)資料庫(Cochrane Database of S檢索方法選擇數(shù)據(jù)庫：ACP journal club（oviddatabase, best evidence）在search 中，鍵入關(guān)鍵詞olanzapineetiology（病因?qū)W）檢索結(jié)果：1篇文獻(xiàn)（摘要）找到全文檢索方法選擇數(shù)據(jù)庫：ACP journal club（ovi循證醫(yī)學(xué)-病因?qū)W研究和循證醫(yī)學(xué)實(shí)踐-新-研課件循證醫(yī)學(xué)-病因?qū)W研究和循證醫(yī)學(xué)實(shí)踐-新-研課件篩選結(jié)果ACP journal Club summary: Conventional antipsychoti

17、c 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 conventional versus atypical antipsychotic drugs among elderly patients.

18、 CMAJ.2007;176:627-32篩選結(jié)果ACP journal Club summary: 循證醫(yī)學(xué)-病因?qū)W研究和循證醫(yī)學(xué)實(shí)踐-新-研課件研究詳情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 population-based cohort of e

19、lderly 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 medications between January 1996 a

20、nd 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. 研究詳情Background: Public health Results:Of 37 241 elderly people in the study cohort, 12 882 were p

21、rescribed 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). Multiva

22、riable 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

23、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 pr

24、opensity score analyses and instrumental variable estimation, minimizing residual confounding. Results:Of 37 241 elderly peop結(jié)論Interpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the risk of death

25、 associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients. 結(jié)論Interpretation: Among elderl第三步 評(píng)價(jià)證據(jù) Appraise Evidence證據(jù)的真實(shí)性Are the results valid?證據(jù)的重要性What are the results?第

26、三步 評(píng)價(jià)證據(jù) Appraise Evidence證據(jù)的真證據(jù)的真實(shí)性Are the results valid?證據(jù)的真實(shí)性Are the results valid?1 研究方法的論證強(qiáng)度Type of Reports on Etiology/Harm哪種研究方法？論證強(qiáng)度如何？是否源于真正的人體試驗(yàn)？ Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?1 研究方法的論證強(qiáng)度Type

27、of Reports on本研究Objective: In elderly patients, association of conventional or atypical antipsychotic drugs (APDs) with death ?Design: Cohort studyParticipants: 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 a

28、nd use of APDs in the year before the index date.本研究Objective: In elderly patie2 兩組結(jié)局暴露因素的測量方法是否一致？Were treatments/exposures and clinical 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 measur

29、ed in the same way in the groups being compared?2 兩組結(jié)局暴露因素的測量方法是否一致？Were treatCohort StudySurveillance bias: 監(jiān)測偏倚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 Cohort StudySurveillance bias:3. 隨訪時(shí)間及失訪率Was the follow-up of the study patients sufficiently long (for t

30、he outcome to occur) and complete?舉例：HP與胃癌：5年（無差異），10 年（顯著差異）失訪超過20？-結(jié)果將失去真實(shí)性3. 隨訪時(shí)間及失訪率Was the follow-up o4 病因/不良反應(yīng)研究結(jié)果是否符合病因診斷原則Do the results of the harm study satisfy some of the diagnostic tests for causation?4 病因/不良反應(yīng)研究結(jié)果是否符合病因診斷原則Do the Is it clear that the exposure preceded the onset of the

31、outcome? 因果效應(yīng)的先后順序僅見于前瞻性研究Is there a doseresponse gradient? 因果效應(yīng)的相關(guān)程度，劑量依賴（吸煙與肺癌）Is there any positive evidence from a “dechallengerechallenge” study? 符合流行病學(xué)規(guī)律-危險(xiǎn)因素減弱，發(fā)病減少Is it clear that the exposure Is the association consistent from study to study? 不同研究，結(jié)果一致（HP與胃癌）Does the association make biolog

32、ical sense? 充分的生物學(xué)依據(jù)（CCB與癌癥，壞血病與水果蔬菜）Is the association consistent Key Points1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause? 研究方法的論證強(qiáng)度2. Were treatments/exposures and clinical outcomes measured in the same ways in b

33、oth 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(shí)間及失訪率Key Points1. Were there clearl證據(jù)的重要性What are the results?證據(jù)的重要性What are the results?1.因果聯(lián)系強(qiáng)度What is the magnitude of the association between the exposure and outcome?How st

34、rong is the association between exposure and outcome?RR OR NNH1.因果聯(lián)系強(qiáng)度What is the magnitude 2. 結(jié)果是否準(zhǔn)確？What is the precision of the estimate of the association between the exposure and outcome?How precise is the estimate of risk?95%CI2. 結(jié)果是否準(zhǔn)確？What is the precisioConventional APD vs Atypical APDAssoc

35、iation with deathConventional APD vs Atypical A第四步應(yīng)用證據(jù)How can I apply the results to mypatient?第四步應(yīng)用證據(jù)How can I apply the re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?基于納入和排除標(biāo)準(zhǔn)病情相似Is our patient so diff

36、eren本研究Patients: 65 y of age , 60-65% womenUsed 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 clozapineConventional APDs: loxapine,