1、循证医学循证医学Evidence-BasedMedicine目录 循证医学介绍(slide 1-42)及教學應用 提出临床问题(PICO)提升文献搜索技能(cite references)严格文献评读 实例练习病紀引用引用考文獻考文獻 (PubMed or UpToDate)Medical Education in the New Century Bioinformatics Ethics Humanities Patient-centered care Problem-based learning Evidence-based medicine 定义定义：Use of current bes
2、t evidence in making decisions about the care of individual patients.EBM(EBN,EBP)is the integration of best research evidence with clinical expertise and patients unique biology,values andcircumstances(patients expectation).(Evidence-based Practice)(Sackett&Straus)Evidence-BasedEvidence-Based Medici
3、neMedicineDrPtEvDecision Making in Health CareSearching bibliographic databasesClinical practice guideline(CPG)Evidence-based journal abstracts“Do no harm”What you learned during your professional trainingBrowse journalsTextbooksAsk colleaguesChart record cite reference 病紀引用文獻引用文獻1.Formulate an answ
4、erable question.Ask(PICO)提問:由個案的床資提出可回答的床問題2.Track down the best evidence.Acquire(Cite paper)尋找最佳的實證文獻各種文獻資庫，包括發表及未發表的資3.Critically appraise the evidence for validity,impact,and applicability.Appraisal(VIP)評估最佳實證醫學文獻的可信、床重要性、以及可應用性4.Integrate with our clinical expertise and patient values.整合並應用於實際患者
5、的治決策 床應用告知 Apply(3 E)5.Evaluate our effectiveness and efficacy.效果評估 Audit溝通用簡單且病人可以聽懂的語言，告知各種處置之可能與風險實證醫學的五大進實證醫學的五大進步驟步驟Five Steps to Practice EBM(5 As)床問題床問題型型診斷診斷 (Diagnosis)(Diagnosis)Sensitivity,specificity敏感、特Predictive value(PPV,NPV)陽性預測值、陰性預測值ROC curve,Likelihood ratio(LR+,LR-)概似比治治 (Therapy
6、)(Therapy)Clinical trial(Randomized Controlled Trial,RCT,RR)預後預後 (Prognosis)(Prognosis)Prediction model(Survival analysis,HR 風險比)危險因子探討危險因子探討 (Risk(Risk factor)factor)Cohort study(Relative Risk,RR 相對風險比)Case-control study(Odds Ratio,OR 勝算比)Step 1.Converting the need for information(about prevention,
7、diagnosis,prognosis,therapy,causation,etc.)into an answerable question.(Ask)-PICOStep 2.Searching the best evidence with which to answer that question.(Acquire)Step 3.Critically appraising the evidence for its validity (closeness to the truth),impact(size of the effect),and applicability(usefulness
8、in our clinical practice).(AApppprraaiissaall)-VIPStep 4.Integrating the evidence with our clinical expertise and patients unique biology,values and circumstances.(Apply)-3 EStep 5.Evaluating our effectiveness and efficiency in executing steps 1-4 and seeking ways to improve them for next time.(Audi
9、t)實證醫學的五大進實證醫學的五大進步驟步驟Five Steps to Practice EBM(5 Ass)I 隨機控制對照研究Meta-analysisII 世代研究世代研究III 病病對照研究對照研究IV 病病報告及系報告及系V 個人意個人意、動物及試管研究、動物及試管研究Animal,test tube research統計方法統計方法 Meta-analysis 統合分析 圖示結果 Forest plot研研 究究 設設 計計 與與 證證 據據 強強 (Bias,Robust)Hierarchy of evidence:arranges study designs by their
10、susceptibility to bias.(Robust)Randomized ControlledTrials(RCT)I研究設計與證據強研究設計與證據強The Evidence PyramidLevel of EvidenceLevel of Evidence IVIVDouble Blinded RCTModify from:Oxford Center for EBMGrade of RecommendationLevel of EvidenceTherapyAFrom:Oxford Center for EBM1aSystematic review(with homogeneity
11、)of RCTs1bSingle RCT(randomized controlled trial)1cAll-or-noneB研究設計與證據的強研究設計與證據的強Evidence-Based Medicine:How to Practice and Teach EBM.2nd ed.David L.Sackett,Sharon E.Straus,W.Scott Richardson,William Rosenberg,R.Brian Haynes.Churchill Levingstone.2000,p173-177Guideline 證據等級（證據等級（Levels of Evidence）
12、:床指引(Guideline)建議的形成是根據文獻的證據等級 而，建議強與證據等級有關，但建議強並非表示建議的重要2aSystematic review of cohort studies2bCohort study or poor RCT2cOutcomes research3aSystematic review of case-control studies3bCase-control study性。C4Case seriesD5Expert opinion,physiology,bench researchUS Preventive Services Task Force Rating
13、System of Quality of Scientific EvidenceI:Evidence obtained from at least 1 properly designed,randomized controlled trialII-1:Evidence obtained from well-designedcontrolled trials without randomizationII-2:Evidence obtained from well-designed cohort or case-control analytic studies,preferentially fr
14、om more than 1 center or groupII-3:Evidence obtained from multiple time series with or without the intervention,or dramatic results in uncontrolled experiments(such as the results of the introduction of penicillin treatment in the 1940s)III:Opinions of respected authorities,based on clinical experie
15、nce,descriptive studies,or reports of expert committees實證醫學沿革實證醫學沿革1972英國床病學者Archie Cochrane提出實證醫學的概。所有醫為應有嚴謹研究且證實為有效的根 據，才能將醫資源做最有效的運用，並強調 Randomized controlled trials 的重要性。*無效果 之檢驗或治要做1992英國國家衛生部成實證醫學中 心，並以Archie Cochrane之名命名，進 而促使1993Cochrane Collaboration的設。(Iain Chalmers,David Sackett)Lancet 曾把
16、Cochrane Collaboration比作床醫學的人基因組計劃1.1.分配：分配：Experimental study 實驗性實驗性研究研究 vs.觀察性觀察性研究研究 Observational study2.2.時間時間：Longitudinal(prospective or retrospective)vs.Cross-sectional studyStudy DesignStudy DesignStudy DesignStudy Design研究開始研究開始問題問題 (用途)研究種研究種時間性時間性過去過去現在現在未未Cross-sectional(prevalence)橫斷性
17、觀察7收集資7Case&non-Case盛盛、診斷、診斷Cohort(longitudinal)縱向性(前瞻)定義世代並評 估危險因子觀察結果Y*N發生發生、病程預、病程預 後、病因後、病因Clinical Trial(experimental)縱向性(前瞻)作治治 組與對照組觀察結果Y*N藥物藥物效評估效評估Case control(retrospective)縱向性(回溯)評估危險因子Exposure:Y*N界定病組 與非病組病因病因尤其罕尤其罕 病病Repeated cross-sectional橫斷性 觀察收集資7重複收集77隨時間改變隨時間改變Calculation of RR,OR
18、Risk factor(Treatment)Event(Disease)PositiveDiseasedNegativeNon-diseasedExposed (Experimental gr.)A=1B=29Not exposed (Control group)C=9D=21EER,experimental event rate=a/a+b=0.033(Cohort study,RCT)CER,control event rate=c/c+d=0.301.Relative Risk=Risk ratio=EER/CER=(a/a+b)/(c/c+d)=0.11風險指標指標:Relative
19、Risk(ratio)=EER/CER vs.Absolute Risk(difference)=EERCERvs.NNT=1/ARR(Case-control study)*Experimental event Odds=a/b=0.034*Control event Odds=c/d=0.432.*Relative Odds=*Odds Ratio=(a/b)/(c/d)=ad/bc=0.08In rare event(盛10%),ORRR Odds:a ratio of events to non-events=p/(1-p)vs.Probability=event/(event+non
20、-event)Treatment of Class III-IV Lupus NephritisMeta-Analysis (pooling studies)Treatment of diffuse proliferative lupus nephritis:A meta-analysis ofrandomized controlled trialsAm J Kidney Dis.2004 Feb;43(2):197-208.Cochrane Renal Group Cochrane Database of SystematicReviews.1,2004.2004 AJKDAm J Kidn
21、ey Dis.2004;43:197-208.Cochrane Renal Group Cochrane Database of Systematic Reviews 2004.0 Summary effect:Diamond-shaped symbols represent the summary estimator of overall effect pooling the weighted effect of individual RCTs.4 Null Hypothesis(虛無假設虛無假設 RR,OR,or HR=1,mean difference,effect size=0):a
22、vertical line at 1.0 representing equivalence in risk for an outcome with experimental and control treatment.Values of RR less than 1 indicate a reduction in risk for the outcome with the experimental treatment.Conversely,values of RR more than 1 indicate an increase in risk.O Point estimate and 95%
23、CI(點估計與區間估計):The RR for each outcome and its 95%CI are indicated by a solid square and a line.The 95%CIs are a measure of variability in the precision of the RR estimate and its statistical significance.The size of the solid square represents the contribution(weight)of the trial to the analysis.Hete
24、rogeneity(non-combinability if p 12,000http:/www.library.nhs.uk/Default.aspxNZGG-New Zealand Guidelines Group http:/www.nzgg.org.nz/National Health and Medical Research Council http:/www.nhmrc.gov.au/Center for Evidence-based Medicine,Oxford http:/ Infobase(Canadian Medical Association)http:/mdm.ca/
25、cpgsnew/cpgs/index.asp 台灣實證床診指引平台(建置中)http:/ebpg.nhri.org.tw/Resource Centers for Guidelines學習目標學習目標“Learning by Doing”Five steps in practicing EBMFormulate clinical question PICO principleSearch databaseCochrane database,CCTR,DARE,ACP journal clubUpToDatePubMed-Clinical queries(high quality filter)
26、etc.Micromedex,CINHALJudge level of evidence(Judge level of evidence(研究設計),critical ),critical appraisal appraisal(VIP principle,RAMbo,Critical appraisal sheet,CASP)Calculate NNT,NNHnumber needed to treat(NNT=1/ARR)number needed to harm(NNH=1/ARI)Read Read forest plotforest plot (meta-analysis)(meta
27、-analysis)Practice主動積極 自我學習 Attitude and behavior changeapply to patient care and chart record(cite reference!).我家我家大有氣喘，如果我吃益生菌，大有氣喘，如果我吃益生菌，可以預防第可以預防第2 2胎新生兒氣喘的發生嗎？胎新生兒氣喘的發生嗎？實實習習Scenario 床情境床情境28歲懷孕三個月的母親，帶著2歲有氣喘的兒童，到婦兒科門診，問優乳可可以預防或減少未 新生兒過敏病(氣喘)的發生？Q&A:益生菌(probiotics)、優乳可可以預防或減少過敏氣喘病發生或嚴重程？電視、報紙
28、、PubMed上、許博士：喝優乳增加腸道益生菌減少氣喘等效果。益生菌(Probiotics)就是對身體友好處的好菌，是一種可改善宿主腸內菌相平衡，有益宿主健 康之活微生物體。如一般人熟悉的A、B菌，被認為具有保健效益，主要為乳酸菌和部分酵母菌。益菌生（Prebiotics，又稱為益生源）又是麼？它是指可以激腸道裏的好菌生長的食物，這的物質如我們常聽到的膳食纖維和果寡就是。益菌生物質能夠被有益菌用而產生有機 酸，激腸蠕動，並且能促進有益菌生長，抑制壞菌，使腸道健康。科學家發現，人體免疫樞地位的細胞T巴球，由所分的細胞素同而分成二型（簡稱Th1,Th2），者間具有動態的平衡關係，影響免疫系統對抗原
29、的反應，如Th2反應太強，就會出現過敏症 。初生嬰兒的免疫機制偏向造成過敏的Th2，益生菌有助新生兒建平衡的Th1Th2免疫機制。1.Formulate an answerable question.(Ask:PPIICCOO*)由個案的床資形成可回答的床問題*(PICO)2.Track down the best evidence.(Acquire:cite ref.)尋找最佳的實證各種文獻及資庫，包括發表及未發表的資3.CCrriittiiccaallllyy aapppprraaiissee the eevviiddeennccee for vvaalliiddiittyy,impact
30、,and applicability.(Appraisal:VIP)評估各種醫學報告的可信、床重要性，以及可應用性4.Integrate with our clinical expertise and patient values.整合並應用於實際患者的治決策床應用(Apply:3 E)5.Evaluate our effectiveness and efficacy.(Audit)效果評估 告知以病人可以聽懂的語言，告知各種處置之可能與風險(%)實證醫學的五大進實證醫學的五大進步驟步驟Five Steps to Practice EBM(5 As)1.Asking Answerable Cl
31、inical Questions(PICO)Well-built Clinical Question“Background”questionAsk general knowledge about a disorderHave two essential components:A question root(who,what,why,when,how,why,where)with a verbA disorder,or an aspect of a disorder“Foreground”questionAsk for specific knowledge about managing pati
32、ents with a disorderHave four(or three)essential components(PICO):1.Patient/Problem:Who is the patient or what is the problem being addressed?(病人族群與特徵)2.Intervention:What is the intervention(treatment)?(A 處置或檢驗處置或檢驗)3.Comparison intervention:What are the alternatives?(B 處置或檢驗處置或檢驗)4.Outcomes:What ar
33、e the outcomes?(重要的重要的床結果、指標床結果、指標)Patient Who is the patient or what is the problem being addressed?病人問題病人問題Intervention What is the intervention?(A)介入處置介入處置 或或 檢驗檢驗Comparison What are the alternatives?(B)對照的處置對照的處置 或或 檢驗檢驗 (其它的選擇其它的選擇)Outcome What are the outcomes?重要的床結果、指標床結果、指標There Are Four Ele
34、ments of a Well-formulated Question use PPIICCOO format 1.Asking Answerable Clinical Question(PICO)Patient/Problem病人問題病人問題孕婦(有氣喘家族史)Intervention介入處置介入處置 (檢查檢查)吃益生菌(probiotics)Comparison對照的處置對照的處置吃益生菌Outcomes床結果床結果減少新生嬰兒氣喘的 發生Step 1.提出問題的要點:*As specific asAs specific as possible!possible!Scenario 床情境
35、床情境:Ask PICOPatientInterventionComparisonOutcomePassengerStockingNo stockingDVTPopulationInfluenza vac.No vaccineURI%SLE nephritisEndoxan/steroidSteroidMortality/ESRDOsteoporosisHormoneNo hormoneCancerBells palsyAcute coronaryAnti-virus/SteroidTroponin IObservationCPK-MBComplicationDiagnosisKawasaki
36、High dose aspirinLow dose aspirinaneurysm2.Searching The Best Evidence尋找最佳實證資直接使用次級醫學資庫(secondarysecondary journalsjournals or or databasesdatabases)ACP journal club,Cochrane database,CINAHL(Cumulative Index to Nursing and Allied Health Literature),Micromedex同時同時尋找原始研究文資庫(primary(primary journalsjou
37、rnals or or databases)databases)如 Medline,NEJM,Lancet原則：搜尋與病人問題相同或似且證據等級(level of evidence 由上往下 top down)較高之文獻，再謹慎嚴 格評與評估此文章的證據在此問題的適用性。1.Cochrane library,CCTR*,ACP journal club,DARE2.UUppTTooDDaattee,MD consult3.PPuubbMMeedd,Medline,CINAHLMeta-analysisSystematic reviewCochrane(keyword 關鍵字關鍵字)Clinic
38、al queries*(高品質高品質)Clinical evidenceBest evidenceGuidelines Clearinghouse(Evidence is never enough)Clinical queriesFree:http:/ the Best Evidence5S EBM Resources(非關證據強弱!)Model from:Haynes,R.B.(2006).Of studies,syntheses,synopses,summaries,and systems:the 5S evolution of information services for evide
39、nce-based health care decisions.ACP Journal Club,145(3),A8.整合證據提供特定臨床問題之概述與建議整合證據提供特定臨床問題之概述與建議ACP PIERBMJ Clinical EvidenceDynaMed MDconsult UpToDate對單篇研究或回顧性文獻作摘要評述對單篇研究或回顧性文獻作摘要評述ACP Journal Club,Evidence-Based Medicine (PubMed,Ovid Medline)特定臨床問題的系統性評論文獻特定臨床問題的系統性評論文獻Cochrane Database of Systema
40、tic ReviewsDatabase of Abstracts of Reviews of Effects (PubMed,Ovid Medline):Systematic Reviews結個別病的床知與支援決策系統原始文獻原始文獻 original studies(PubMed,Ovid Medline,CINAHL,EMBASE Cochrane CENTRAL,Google Scholar CEPS中文電子期刊,中文期刊篇目索引)3.Synopses4.Syntheses5.Studies1.Systems2.SummariesPre-filteredSecondaryPrimaryL
41、evel of Evidence IVI 隨機控制對照研究Double Blinded RCTMeta-analysisIV 病病報告及系報告及系統計方法統計方法 Meta-analysis 圖示結果 Forest plotV 個人意個人意、動物試管研究、動物試管研究研研 究究 設設 計計 與與 證證 據據 強強 (Bias,Robust)Hierarchy of evidence:arranges study designs by their susceptibility to bias.(Robust)Randomized ControlledTrials(RCT)I研究設計與證據強研究設
42、計與證據強II 世代研究世代研究III 病病對照研究對照研究Current Best EvidenceThe Best Evidence Depends on the Type of QuestionWhat are the phenomena/problems?ObservationWhat is frequency of the problem?(Frequency)Random(or consecutive)sampleDoes this person have the problem?(Diagnosis)Random(or consecutive)sample with gold s
43、tandardWho will get the problem?(Prognosis)Follow-up of inception cohortHow can we alleviate the problem?(Therapy)Randomized controlled trial(RCT)Thank you!以下以下slide 43-79為為考附件考附件Q&ABoolean AND,OR,NOTTruncation:$*Combine textwords/keywords/MeSH with ORTextwords/keywords 的部分，最好能善用的部分，最好能善用 truncation
44、 的功能的功能要找有關要找有關 Salmonella 的資的資，但，但文中有時以文中有時以 Salmonellosis 表示，表示，這時你可以用這時你可以用 Salmonell$or Salmonell*代表所有代表所有 Salmonell 開頭開頭 的字的字！MeSH(Medical Subject Heading)in PubMedFree text searching,limit function將將 P/I/C/O 分別轉換成分別轉換成同的字同的字關鍵字關鍵字MeSH 再搜尋再搜尋Kawasaki Aspirinmucocutaneous lymph node syndrome sal
45、icylic acidsalicyl*Coronary aneurysmSearch Strategy搜尋策Scenario 床情境床情境Patient and/or problem:A 3-y-o Kawasaki disease children with high fever for 5 days.Intervention:IVIG and High dose aspirin(30-100 mg/kg/d)(treatment A)anti-inflammation doseComparison intervention:IVIG and Low dose aspirin(3-5 mg/
46、kg/d)(treatment B)anti-platelet doseOutcomes:Coronary artery aneurysm(%)重要結果 outcomeKeywords:xxx and xxx and(Cochrane or meta-analysis or Systematic review)Dr.YuMeSH高品質過資使用Clinical Queries加加 速得到高等級實證醫學證據速得到高等級實證醫學證據CClliinniiccaall QQuueerriieess使用Clinical Queries加加速得到高等級證據速得到高等級證據Q&A:哪一篇是 Best evid
47、ence?嚴格評文章 2009.061.2.3.4.5.6.7.Osborn DA.Probiotics in infants for prevention of allergicdisease and food hypersensitivity.Cochrane Database Systematic Review 2007;CD006475Kopp MV.Randomized,double-blind,placebo-controlled trial of probiotics for primary prevention:no clinical effects of Lactobacil
48、lus GG supplementation.Pediatrics 2008;121:e850-6Kalliomki M.Probiotics in primary prevention of atopic disease:a randomised placebo-controlled trial.Lancet 2001;357:1076-9Blumer N.Perinatal maternal application of Lactobacillus rhamnosus GG suppresses allergic airway inflammation in mouse offspring
49、.Clin Exp Allergy 2007;37:348-57乳酸菌達人 氣喘過敏兒的實驗報告 台灣氣喘衛教學會事長徐世達 醫師 過敏氣喘照護的新觀：益生菌的功能Vliagoftis H,et al.Probiotics for the treatment of allergic rhinitis and asthma:systematic review of randomized controlled trials.Ann Allergy Asthma Immunol 2008;101:570-9Kuitunen M,et al.Probiotics prevent IgE-associa
50、ted allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol 2009;123:335-413.如如 何何 評評 文文V-I-P principle(RAMbo,CAT,CASP,Gate frame.)Yes No?UnclearHow do I apply the results to the care of my patients?Both 1&2(V-I-P)1.Are Are the result the result Va
