Evidence-basedEtiology/Harm

病因研究與循證醫(yī)學(xué)實(shí)踐學(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)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)病因性研究基本概念（1）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)。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（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(duì)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)用性與病因相關(guān)的臨床問題該疾病是什么原因造成的？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？DoesexposuretoaluminumcauseAlzheimer’sdementia?Dostatinscausecancer?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,cohortstudyOR(回顧性）case-controlstudyNNH(numberneededtoharm)clinicalimportance暴露多少研究對(duì)象可導(dǎo)致1例發(fā)?。?duì)列研究）發(fā)生1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)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)系可信區(qū)間ConfidenceInterval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有關(guān)指標(biāo)的計(jì)算1.OddsRatio

2.RelativeRisk3.RiskReduction/Increase

4.NumberNeededtoTreat/Harm

證據(jù)的強(qiáng)度TheConfusionMatrix+veEvent-veEventTotalExperimentABA+ＢControlCDC+DAlsoknownasthe2x2tableEventRateEER=A/(A+B)

試驗(yàn)組事件發(fā)生率CER=C/(C+D)

對(duì)照組事件發(fā)生率+veEvent-veEventTotalExperimentABA+ＢControlCDC+DRRandORRR=EER/CER

相對(duì)危險(xiǎn)度OR=AD/BC

比值比+veEvent-veEventTotalExperimentABA+ＢControlCDC+DRelativeRiskReductionRRR=(CER-EER)/CER

=1–RR

相對(duì)危險(xiǎn)度減少率+veEvent-veEventTotalExperimentABA+ＢControlCDC+D(Absolute)RiskReductionARR=CER-EER絕對(duì)危險(xiǎn)度減少率+veEvent-veEventTotalExperimentABA+ＢControlCDC+DNumberNeededtoTreatNNT =1/ARR得到1例有利結(jié)果需要防治的病例數(shù)+veEvent-veEventTotalExperimentABA+ＢControlCDC+D舉例：

ActivatedProteinCforSevereSepsisBleedNobleedTotalAPC30820850Control17823840APC=ActivatedProteinCEfficacyandsafetyofrecombinanthumanactivatedproteinCforseveresepsis.NEnglJMed.2001Mar8;344(10):699-709EventRatesandOddsEER =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+veEvent-veEventTotalExperimentABA+ＢControlCDC+DBleedNobleedTotalAPC30820850Control17823840OR =EEO/CEO =0.037/0.021=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 =66Risk-BenefitRatioNNT =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)

反映不良反應(yīng)（越大越好）Risk-BenefitRatio =NNT/NNH =16/66 =1/4DeadNotdeadTotalAPC210640850Control259581840BleedNobleedTotalAPC30820850Control17823840怎樣解決臨床問題？

Howtosolveaclinicalproblem?臨床病案（ClinicalScenario）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臨床問題（InitialQuestion）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(duì)老年人更安全？第一步提出問題(AskClinicalQuestions)Initialquestion:Framingtheinitialquestion:answerablePatients(population)Intervention/exposureComparisonOutcomePICO轉(zhuǎn)變成可以回答的臨床問題

Framingthequestion患者類型(P)elderlypatients干預(yù)措施(I)haloperidolorperphenazine對(duì)照措施(C)olanzapine臨床結(jié)局(O)death第二步查詢證據(jù)(AcquireEvidence)PICO:keywordsTypeofquestion：harm-Bestevidence

Levelsofevidence-OptimalsourceofevidenceSearchingworthwhile?病因/不良反應(yīng)研究常用數(shù)據(jù)庫BestEvidence（ACPjournalclub,EBM)UptoDateMedlinePubMed:clinicalquery-etiologySumsearchOvid循證醫(yī)學(xué)數(shù)據(jù)庫(多庫同時(shí)檢索)ACPjournalclub,CochraneLibrary(CDSR,CCTR,DARE),Medline,EMBASE系統(tǒng)評(píng)價(jià)資料庫(CochraneDatabaseofSystematicReview,CDSR)療效評(píng)價(jià)文摘庫(DatabaseofAbstractsofReviewsofEffectiveness,DARE)臨床對(duì)照試驗(yàn)注冊(cè)資料庫(CochraneControlledTrialsRegister,CCTR)方法學(xué)數(shù)據(jù)庫(CochraneMethodologyDatabase)檢索方法選擇數(shù)據(jù)庫：ACPjournalclub（oviddatabase,bestevidence）在search中，鍵入關(guān)鍵詞olanzapine－etiology（病因?qū)W）檢索結(jié)果：1篇文獻(xiàn)（摘要）找到全文篩選結(jié)果ACPjournalClubsummary:ConventionalantipsychoticdrugsincreasedriskfordeathmorethandidatypicalantipsychoticdrugsinelderlypatientsACPJournalClub.2007;147:23.SchneeweissS,SetoguchiS,BrookhartA,DormuthC,WangPS.Riskofdeathassociatedwiththeuseofconventionalversusatypicalantipsychoticdrugsamongelderlypatients.CMAJ.2007;176:627-32研究詳情Background:Publichealthadvisorieshavewarnedthattheuseofatypicalantipsychoticmedicationsincreasestheriskofdeathamongelderlypatients.Weassessedtheshort-termmortalityinapopulation-basedcohortofelderlypeopleinBritishColumbiawhowereprescribedconventionalandatypicalantipsychoticmedications.Methods:WeusedlinkedhealthcareutilizationdataofallBCresidentstoidentifyacohortofpeopleaged65years

andolderwhobegantakingantipsychoticmedicationsbetweenJanuary1996andDecember2004andwerefreeofcancer.Wecomparedthe180-dayall-causemortalitybetweenresidentstakingconventionalantipsychoticmedicationsandthosetakingatypicalantipsychoticmedications.

Results:Of37241elderlypeopleinthestudycohort,12882wereprescribedaconventionalantipsychoticmedicationand24359anatypicalformulation.Withinthefirst180daysofuse,1822patients(14.1%)intheconventionaldruggroupdied,comparedwith2337(9.6%)intheatypicaldruggroup(mortalityratio1.47,95%confidenceinterval[CI]1.39–1.56).Multivariableadjustmentresultedina180-daymortalityratioof1.32(1.23–1.42).Incomparisonwithrisperidone（利培酮）,haloperidol（氟哌啶醇）wasassociatedwiththegreatestincreaseinmortality(mortalityratio

2.14,95%CI1.86–2.45)andloxapine（洛沙平）thelowest(mortalityratio1.29,95%CI1.19–1.40).Thegreatestincreaseinmortalityoccurredamongpeopletakinghigher(abovemedian)dosesofconventionalantipsychoticmedications(mortalityratio1.67,95%CI1.50–1.86)andduringthefirst40daysafterthestartofdrugtherapy(mortalityratio1.60,95%CI1.42–1.80).Resultswereconfirmedinpropensityscoreanalysesandinstrumentalvariableestimation,minimizingresidualconfounding.結(jié)論Interpretation:Amongelderlypatients,theriskofdeathassociatedwithconventionalantipsychoticmedicationsiscomparabletoandpossiblygreaterthantheriskofdeathassociatedwithatypicalantipsychoticmedications.Untilfurtherevidenceisavailable,physiciansshouldconsiderallantipsychoticmedicationstobeequallyriskyinelderlypatients.第三步評(píng)價(jià)證據(jù)AppraiseEvidence證據(jù)的真實(shí)性Aretheresultsvalid?證據(jù)的重要性Whataretheresults?證據(jù)的真實(shí)性

Aretheresultsvalid?1研究方法的論證強(qiáng)度

TypeofReportsonEtiology/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)？

Werethereclearlydefinedgroupsofpatients,similarinallimportantwaysotherthanexposuretothetreatmentorothercause?本研究Objective:Inelderlypatients,associationofconventionaloratypicalantipsychoticdrugs(APDs)withdeath?Design:CohortstudyParticipants:37241patients65yofageoralconventional(n=12882,meanage80y)

atypical(n=24359,meanage80y).Exclusioncriteria:canceranduseofAPDsintheyearbeforetheindexdate.2兩組結(jié)局暴露因素的測量方法是否一致？Weretreatments/exposuresandclinicaloutcomesmeasuredinthesamewaysinbothgroups?(Wastheassessmentofoutcomeseitherobjectiveorblindedtoexposure?)Weretheoutcomesandexposuresmeasuredinthesamewayinthegroupsbeingcompared?CohortStudySurveillancebias:監(jiān)測偏倚偏倚的控制－客觀指標(biāo)（Objectiveoutcome）：病死率－主觀指標(biāo)（Subjectiveoutcome）:Blinding舉例：乙型肝炎與肝癌關(guān)系的研究

3.隨訪時(shí)間及失訪率Wasthefollow-upofthestudypatientssufficientlylong(fortheoutcometooccur)andcomplete?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4病因/不良反應(yīng)研究結(jié)果是否符合病因診斷原則Dotheresultsoftheharmstudysatisfysomeofthediagnostictestsforcausation?Isitclearthattheexposureprecededtheonsetoftheoutcome?

因果效應(yīng)的先后順序－僅見于前瞻性研究Isthereadose–responsegradient?

因果效應(yīng)的相關(guān)程度，劑量依賴（吸煙與肺癌）Isthereanypositiveevidencefroma

“dechallenge–rechallenge”

study?

符合流行病學(xué)規(guī)律-危險(xiǎn)因素減弱，發(fā)病減少Istheassociationconsistentfromstudytostudy?

不同研究，結(jié)果一致（HP與胃癌）Doestheassociationmakebiologicalsense?

充分的生物學(xué)依據(jù)（CCB與癌癥，壞血病與水果蔬菜）KeyPoints1.Werethereclearlydefinedgroupsofpatients,similarinallimportantwaysotherthanexposuretothetreatmentorothercause?

研究方法的論證強(qiáng)度2.Weretreatments/exposuresandclinicaloutcomesmeasuredinthesamewaysinbothgroups?

測量方法一致3.Wasthefollow-upofthestudypatientssufficientlylong(fortheoutcometooccur)andcomplete?

隨訪時(shí)間及失訪率證據(jù)的重要性

Whataretheresults?1.因果聯(lián)系強(qiáng)度Whatisthemagnitudeoftheassociationbetweentheexposureandoutcome?Howstrongistheassociationbetweenexposureandoutcome?RR

ORNNH2.結(jié)果是否準(zhǔn)確？Whatistheprecisionoftheestimateoftheassociationbetweentheexposureandoutcome?Howpreciseistheestimateofrisk?95%CIConventionalAPDvsAtypicalAPD

Associationwithdeath第四步應(yīng)用證據(jù)

HowcanIapplytheresultstomypatient?病情相似Isourpatientsodifferentfromthoseincludedinthestudythatitsresultscannotapply?Werethestudypatientssimilartomypatient?基于納入和排除標(biāo)準(zhǔn)本研究Patients:>65yofage,60-65%womenUsed1medicalservice,andfilled1prescriptioninthetwo6-monthintervalsbeforetheindexdate.Exclusioncriteria:canceranduseofAPDsintheyearbeforetheindexdate.AtypicalAPDs:risperidone,quetiapine,olanzapine,andclozapineConventionalAPDs:loxapine,haloperidol,chlor