循證醫(yī)學EBM介紹課件

何謂實證醫(yī)學臺大內(nèi)科張家勳

MD,MScinClinicalEpidemiologyE-mailaddress:

OurGoals…觀念澄清什麼是“實證醫(yī)學”?

為什麼要推動實證醫(yī)學教學?

實證醫(yī)學教學和一般教科書上談的知識有什麼不一樣?平常醫(yī)師是如何去診斷、治療患者?

臨床上面臨的問題有許多不確定性,這種不確定性是以機率來表示機率的估計可以來自個人以往的經(jīng)驗,但免不了有某種程度的偏差沒有任何一位臨床醫(yī)師擁有完全足夠的臨床經(jīng)驗,可辨識大部分慢性病之間細微又長期的互動關係53位COPDAE患者接受吸入性支氣管擴張劑及一種實驗藥物治療,六個小時後,患者的癥狀有顯著改善;甚至有1/4的患者PEFR改善40%以上

BullardMJ,etal.AmJEmergMed1996;141:139-43你相信你的觀察嗎-猜猜看他們接受什麼治療?DoSomethingisBetterthan

DoNothing?“依據(jù)我的經(jīng)驗:肝硬化合併門脈高壓的患者,接受分流手術治療(Portal-SystemicShunting)者比未接受手術治療者,發(fā)生食道靜脈出血的機率要來得少腹水比較容易控制因此也活得比較久…”降血脂藥物Clofibrate是否能降低

高血脂合併心臟病患者之死亡率?

NEJM1980;303:1038-41服用Clofibrate人數(shù)死亡率乖乖吃藥的人70815%不乖乖吃藥的人35725%總計110320%服用安慰劑人數(shù)死亡率181315%88228%278921%Clinicaloutcomesdependon:SeverityofillnessCo-morbidityOtherprognosticfactors(knownandunknown)

Drugcompliance,healthawareness,socialsupport…

Treatment生理學與病理學是瞭解疾病機轉及治療患者的基礎，然而…醫(yī)學理論往往繁多而不一致看似合理的治療原則有時對病人反而有害-以心肌梗塞後病人的心律不整為例瞭解疾病的病理生理學是必要的，但是單是如此對於臨床執(zhí)業(yè)來說仍是不夠的。所以英國醫(yī)師ArchieCochrane大力提倡隨機對照試驗的重要性，並指出醫(yī)療資源應運用於經(jīng)嚴謹研究證實有效的治療才能提供合理的服務。

我們?yōu)槭颤N要學(教)“實證醫(yī)學”?我們?yōu)槭颤N要提倡實證醫(yī)學?提供獨立思考終生學習的模式及技巧同時提升臨床研究及醫(yī)療照護之品質(zhì)參考以嚴謹科學原則為依據(jù)的觀察作為臨床決策的指引提供最佳的臨床照護減少不必要的支出有多少醫(yī)師在醫(yī)學院唸書的時候有聽過PET、EBCT、脈衝光以及各式各樣新的診療方式?您是如何去學習、評估、應用新的醫(yī)療科技?有人說現(xiàn)代醫(yī)學本來就是以實證為基礎的；我們現(xiàn)在要談的實證醫(yī)學教學和一般教科書上談的知識有什麼不一樣?ConstantlyquestioningattitudeLifelonglearningChangelearners’behavior(literaturesearching,reading,practicing)Betterpatientcareandoutcomes有什麼系統(tǒng)性的方式能讓學生容易養(yǎng)成終生學習、獨立思考的習慣和技巧?教授實證醫(yī)學時需要特別提醒大家的…

初步的研究報告結果仍需要進一步的驗證目前沒有充分證據(jù)支持的治療並非一定無效參考國外臨床研究的結果應用於國內(nèi)病患的照顧需要考慮人種、環(huán)境、醫(yī)療制度等種種之間的差異除了強調(diào)實證外在診治療病患時仍應尊重病患的選擇(preference)如何明確的分析

臨床問題

臺大內(nèi)科

張家勳MD,MScinclinicalepidemiology實證醫(yī)學的五大步驟Step1:如何明確的分析我們所面臨的臨床問題?Step2:證據(jù)在哪裡?如何有效率的搜尋文獻Step3:臨床研究的結果可信嗎?Step4:其臨床意義為何?Step5:我該如何利用臨床研究的結果照顧個別病人?Clinicalscenario(I)林先生,a60y/ocook,visitedERduetoincreasedproductivecoughanddyspneafor3daysCOPDdiagnosedfor3years;FEV165%predicted;neverbeenhospitalizedSmoking:1PPDfor30yrs,quittedfor1+yearRx:Atrovent2puffbid,Mucosolvon1#tid.PE:160/90mmHg,36.8℃,110,24;diffusewheezingWBC9800,CxR:nodefinitepneumonicpatchSymptomsnotrespondedtoBricanylIHq30minX2…Howtoaskameaningfulquestion?“學長,這個病人要不要用類固醇?”“老師,我們要不要開類固醇給這個病人?”有什麼好處?Beableto:RelievesymptomsImprovelungfunction/airflowobstruction(FEV1orPEFR)Reducetreatmentfailure(death,intubations,readmission,orintensificationofdrugtherapy)Shortenlengthofhospitalstay?療效是不是大於副作用?Beableto:RelievesymptomsImprovelungfunction/airflowobstruction(FEV1orPEFR)Reducetreatmentfailure(death,intubations,readmission,orintensificationofdrugtherapy)Shortenlengthofhospitalstay?Not↑riskofinfection,hyperglycemia,orGIbleeding?Clinicalscenario(II)王太太?70歲?

有慢性關節(jié)炎的病史?長期服用NSAID。這次因吐咖啡渣、解黑糞前來急診?經(jīng)內(nèi)視鏡檢查為胃潰瘍合併出血?並住院接受治療。三天後發(fā)生咳嗽、發(fā)燒、氣促等癥狀…

WBC:14000/mm3

CxR:↑infiltrateover

bilaterallowerlungSputumGramstain:G(+)cocciwithphagocytosisSputumAcid-faststain:fewacid-fastbacilli??Howtoaskameaningfulquestion?“學長,我們是不是直接就要開始讓病人接受抗結合藥物的治療,還是先安排她做痰液的TB-PCR檢查?”Thespecific,answerableclinicalquestion:PatientsInterventionvs.ComparisonOutcomesThespecific,answerableclinicalquestion:在懷疑肺結核的患者成人尚未接受治療HIV陰性PPDtest陽性…痰液檢體的Nucleicacidamplification/TB-PCRtestMycobacteriumtuberculosisDirect(MTD)testAMPLICORIn-houseThespecific,answerableclinicalquestion:與下列常用的檢查相較臨床診斷(clinicalsymptoms+riskfactors+CxR)痰液acid-fastbacilliAFBstain痰液TBculture在下列各方面孰優(yōu)孰劣?準確度(accuracy;i.e.,sensitivityandspecificity)安全性所需時間花費國際間常用的實證醫(yī)學評估報告資料庫CochranedatabaseofsystematicreviewGuidelineclearinghouse:ov美國AHRQwebsite:英國NICEwebsite:加拿大CCOHTAwebsite:蘇格蘭SIGNwebsite:

紐西蘭NZGGwebsite:

案例一71歲女性，有慢性支氣管性炎、心房纖維顫動、慢性退化性關節(jié)炎等疾病，曾分別於民國88至90年間接受兩次超音波跟骨骨質(zhì)密度測定檢查，檢查結果分別呈示T-score＜－3.6及＜－3.7，經(jīng)診斷為骨質(zhì)疏鬆癥第四度，故接受CalciumCitrate950mg1#BID的治療。審查專家認為病人接受骨密度檢查之方式和部位並不適宜

Thespecific,answerableclinicalquestion:Patients:停經(jīng)後的婦女Intervention:以超音波測量跟骨所得的骨密度Comparison:以DXA測量脊椎或髖骨的骨密度Outcomes:準確預測未來骨折的發(fā)生花費方便性…案例二病患為24歲女性，因頭痛、嘔吐至急診就醫(yī)，就診時意識及理學檢查均正常但於藥物治療後頭痛、嘔吐癥狀並無緩解，醫(yī)師懷疑有蜘蛛膜下腔出血，安排頭部CT(無顯影劑)，其檢查報告為：腦皮質(zhì)髓質(zhì)接合處變不清晰、腦室變小、皮質(zhì)溝閉塞，顯示有腦腫脹；疑為不明原因之腦水腫，可能為假性腦瘤或創(chuàng)傷導致。健保局認為該醫(yī)師未進行詳細神經(jīng)學檢查，且在此案例中CT為非必要之檢查。Thespecific,answerableclinicalquestion:蜘蛛膜下腔出血的患者中，有多少百分比在一開始的理學/神經(jīng)學檢查均為正常?在頭痛急性發(fā)作雖經(jīng)藥物治療後癥狀並未緩解的患者中，罹患蜘蛛膜下腔出血的可能性有多高?案例三50歲女性，因持續(xù)有胃酸逆流、心灼熱之癥狀，經(jīng)診斷為逆流性食道炎，胃鏡檢查結果為糜爛性食道炎，gradeB，醫(yī)師依氫離子幫浦阻斷劑(PPI)相關藥品給付規(guī)定向健保局提出事前審查申請。審查醫(yī)師認定為「非治療必需」，而應考慮手術治療，故不予同意使用。Thespecific,answerableclinicalquestion:Patients:罹患中等程度逆流性食道炎的患者在接受急性期(6-8週)PPI治療後Intervention:降低逆流的手術Comparison:長期PPI維持療法Outcomes:患者癥狀、生活品質(zhì)食道炎復發(fā)率併發(fā)癥(食道狹窄、食道癌)醫(yī)療成本…案例四63歲女性，有糖尿病、高血壓、肝硬化等病史，於住院檢查時發(fā)現(xiàn)肝右葉有一顆肝細胞癌，進而分別接受二次無線頻率電熱消除療法（radiofrequencyablation,RFA）

（目前支付標準無此項申報項目）。申請人以「肝腫瘤內(nèi)酒精注射PEIT」申報費用，初核時以「與事實不符」為由不予給付，申請人以「病人接受RFA若以一般PEIT計價才作2次，比一般PEIT作4-6次更便宜..」申複，又以「PEIT之治療乃以針穿刺打藥，而與RFA雷同，在其他各科給付項目亦有健保項目不周全而以類似項目取代者，且病人追蹤後腫瘤縮小，可見其效果?！篂橛?，向本會提起爭議審議。

Thespecific,answerableclinicalquestion:Patients:肝硬化合併小型肝癌但無法開刀的患者Intervention:電燒法

Comparison:酒精注射Outcomes:患者存活率

反應率併發(fā)癥，包括腹痛、發(fā)燒等不適住院天數(shù)經(jīng)濟效益…

案例五67歲男性，有定向感及記憶力差等癥狀，診斷為Alzheimer’sdisease，以Aricept1＃QD治療，使用六個月後評估CDR為1級，MMSE為11分，故以Aricept繼續(xù)治療，因之後評估CDR降為2級，故醫(yī)師以Aricept治療效果不佳為由，擬改以另一藥物Exelone治療。健保局以同類型藥物，非治療所需，不予同意。

案例六31歲女性，因反復下腹疼痛及經(jīng)痛就診，經(jīng)口服藥物治療無效，近日因癥狀加劇，疑似子宮內(nèi)膜異位癥，安排住院而接受腹腔鏡手術治療。經(jīng)腹腔鏡檢查，發(fā)現(xiàn)子宮有瘤狀突起(1cm)及多囊性卵巢，認為其為引起疼痛及排卵功能不足之原因，故以腹腔鏡取掉兩處腫瘤。其病理組織切片檢查報告顯示為adenomyosis與endometriosis。醫(yī)師認為前者的腫瘤較難拿掉，所花的時間比切除肌瘤的時間更多，故以myomectomy同等給付應屬合理。審查醫(yī)師認為病患僅有腹部疼痛，且病理報告不符子宮肌瘤切除術論病例計酬案件之要件，改以子宮肌瘤切除術一般案件給付(健保尚無腹腔鏡子宮肌瘤切除術之支付標準)。

案例七林先生,30歲銀行行員,這次來門診的主述為三週來不典型胸痛、心悸、以及有一次近乎暈厥急診部醫(yī)師臆斷:過度換氣癥候群

HolterECG:sinustachycardia心臟超音波檢查:二尖瓣脫垂合併輕度逆流“我會不會有立即的生命危險呢?”其它常用的網(wǎng)路資源ClinicalEvidence:Bandolier:專科醫(yī)學會網(wǎng)站AHA:AASLD:ACG:ACCP:K/DOQI:AAN:HowShouldIUseArticles

aboutTherapy/Prevention?

Examplesforevidence-basedpractice臺大內(nèi)科

張家勳/楊泮池教授Howtoaskameaningfulquestion?

“給寶寶喝LGG優(yōu)酪乳對身體有沒有好處?”Thespecific,answerableclinicalquestion:PatientsInterventionvs.ComparisonOutcomes什麼樣的人…小朋友開發(fā)中國家營養(yǎng)不良的小朋友上托兒所的小朋友生病住院的小朋友健康的小朋友成人健康人旅行的人使用抗生素的人…用什麼治療,比較什麼治療…Intervention:“益生菌”(Probiotics)“乳酸菌”(Lactobacilli)

“LGG”(LactobacillusrhamnosusstrainGG)Comparison:不飲用PlaceboL.acidophillusBifidobacteriumbifidum有什麼好處?預防…感染性腹瀉(細菌引起的,病毒引起的…)使用抗生素引起的腹瀉(特別是Clostridiumdifficile所引起的)呼吸道感染,泌尿道感染,其它方面的感染…

治療腹瀉:減輕腹瀉嚴重度減少腹瀉次數(shù)縮短腹瀉天數(shù)…該如何證明LGG的療效呢?小明五歲前體弱多病,自從飲用LGG牛奶以後,就很少感冒了…隔壁阿媽給他的孫子喝LGG牛奶,比我家阿明的抵抗力好得多…該如何證明LGG的療效呢?根據(jù)某家醫(yī)學中心的研究LGG可改善腸道內(nèi)生態(tài)平衡,使壞菌不容易滋長,同時並增加人體腸道製造抗體的能力…某觀察性研究顯示:服用LGG優(yōu)酪乳越多的人,發(fā)生腸胃道、泌尿道、以及呼吸道感染的情況越少…Users’GuidestotheMedicalLiterature

UsingElectronicHealthInformationresourcesClinicalEvidence:

CochraneLibraryCochraneDatabaseofSystematicReviewsBandolier:Nationalguidelineclearinghouse:JAMA2000;283:1875-9

ACPJournalClubMEDLINESearch:

HierarchyandMethodologicalFilterMeta-analysis/Systematicreview:Meta-analysisinpublicationtype(useLIMIT)Systematicreview(searchfield:Textword)RandomizedControlledTrialinpublicationtypeControlledClinicalTrialinpublicationtype健康的小朋友長期飲用LGG牛乳能將

感染性腹瀉的危險性降低多少?將問題分解為數(shù)個層面(並不是全部都需要用於搜尋)病人族群

健康的小朋友介入方法

LGG結果

感染性腹瀉研究設計系統(tǒng)性文獻回顧或

隨機對照試驗找出每個層面的同義字、變異的拼法、及subjectheadings:以LGG為例,可考慮下列字彙:LGG,Lactobacillus,Lactobacilli,ProbioticsWhatwehavenow…LactobacillusGGreduceddiarrheaincidenceinchildrentreatedwithantibiotics-ACPJclub2000;133(1):24;JPediatr.1999;135:564-8Lactobacillustherapyforacuteinfectiousdiarrheainchildren:Ameta-analysis-Pediatrics2002;109:678-84Probioticsinpreventionofantibioticassociateddiarrhea:meta-analysis-BMJ2002;324:1-6Probioticsinthetreatmentandpreventionofacuteinfectiousdiarrheaininfantsandchildren:asystematicreview-Cochranedatabaseofsystematicreviews,Issue3,2002EffectofLongTermConsumptionofProbioticMilkonInfectionsinChildrenDesign:Randomized,doubleblind,placebo-controlledtriallasted7monthsoverthewinterSetting:18daycarecentersinsimilarsocioeconomicareasinHelsinki,FinlandPatients:571healthychildrenaged1-6yearsExcludedchildrenwithallergytocow’smilklactoseintoleranceseverefoodallergy,andotherseverechronicdiseaseBMJ2001;322:1-5EffectofLongTermConsumptionofProbioticMilkonInfectionsinChildrenIntervention:TheLactobacillusmilk(1%fat,5-10x105cfu/mlofLGG)Thecontrolmilk(samecomponentbutwithoutLGG)Theaimwasadailyconsumptionof200ml;otherproductscontainingprobioticbacteriawereforbiddenMainoutcome:#ofdayswithrespiratoryandGIsymptoms(fromsymptomdiaryrecordedbyparents)Absencesfromdaycarecenterduetoillness#ofchildrenwithURIwithotitismedia,sinusitis,acutebronchitis,pneumoniaasdiagnosedbyadoctorAntibiotictreatmentsduringthesevenmonthinterventionAretheresultsofthestudyvalid(I)?Wastheassignmentofpatientstotreatmentsrandomized?Wastherandomizationlistconcealed?Werethegroupssimilaratthestartofthetrial?

JAMA1993;270(21):2598-2601CharacteristicLGG(n=282)Control(n=289)Age(years),mean,SD4.6(1.3-6.8)4.4(1.3–6.7)16%6%212%13%315%23%422%16%523%28%622%14%Siblings1.1(0–4)1.0(0–4)Durationofbreastfeeding(months)6.8(0–32)7.1(0–30)Smokinginhousehold32%34%Respiratoryinfectionsinpast12months0–250%47%3–436%30%≧514%23%Aretheresultsofthestudyvalid(II)?Werepatients,healthworkers,andstudypersonnel“blind”totreatment?Asidefromtheexperimentalintervention,werethegroupstreatedequally?Wasfollow-upcomplete?Werepatientsanalyzedinthegroupstowhichtheywererandomized(intention-to-treatanalysis)?JAMA1993;270(21):2598-2601另一篇主題類似的研究有什麼弱點?某家醫(yī)院將100位年齡0.5~5歲腹瀉小於5天的小朋友,隨機分配至治療組(AB菌)及對照組(靜脈注射補充水分),觀察益生菌的療效,由護士小姐觀察小朋友之後腹瀉時間的長短(定義為至最後一次水瀉出現(xiàn)的時間),以Student’sttest及2test作分析統(tǒng)計,

發(fā)現(xiàn)治療組的小朋友在入院後第一天及第二天的腹瀉次數(shù)有顯著的減少,在整個腹瀉時間上也有明顯的減少(3.1vs.3.6days,p<0.01)…ActaPaediatrTw2001;42:301-5ClinicalcharacteristicsofstudyandcontrolgroupsStudygroup(n=50)Controlgroup(n=50)pAge,mean,SD(m/o)17.2(11.5)14.5(10)0.16Durationofdiarrheaathome(day)1.6(0.9)1.66(0.6)0.51Dehydration4.3%4.0%0.32OutcomeoftherapyStudygroupControlgrouppDiarrheafrequencyDay06.7(2.6)6.8(3.1)0.64Day12.9(2.0)4.0(1.3)<0.01Day21.9(1.9)3.7(2.4)<0.01Durationofdiarrheainhospital(day)3.1(0.7)3.6(0.8)<0.01Recoveryrateonthe2ndday52%18%<0.01Whatweretheresults?LGG(n=252)Control(n=261)pAnyillness(days)25(22–28)27(24–30)0.22Respiratorysymptoms(days)21(18–24)23(20–26)0.28GIsymptoms(days)2.9(2.6–3.2)3.0(2.7–3.4)0.57Absenceduetoillness(days)4.9(4.4–5.5)5.8(5.3–6.4)0.03Acuteotitismedia31%39%0.08Sinusitis3%4%0.69Acutebronchitis6%7%0.43Pneumonia1%2%1.00Allinfectiontogether39%47%0.05Antibiotictreatment44%54%0.03研究的結果可有不同的方式表達OutcomeLGGControlpARR(95%C.I.)NNTAllrespiratoryinfection39%47%0.05-8.6%(-17.2~-0.1)12Antibiotictreatment44%54%0.03-9.6%(-18.2~-1.0)10Absoluteriskreduction(ARR):47%-39%=8%Relativeriskreduction(RRR):(47%-39%)/47%=17%假設有100位小朋友在冬天的七個月內(nèi)其中有47位會得到嚴重的呼吸道感染;如果這100位小朋友均飲用LGG牛奶,其中僅39位會得到嚴重的呼吸道感染;故長期飲用LGG牛奶,每100位可避免其中8位得到嚴重的呼吸道感染換言之,每治療12位,可拯救其中1人:Numberneededtotreattopreventonefailure(NNT)=12=1/ARRWhyuseNNT?假設有下列三種情況:Situation:LGGControlRRRNNT#1本研究中的患者39%47%17%12#2患者病情輕微3.9%4.7%17%125#3患者病情嚴重78%94%17%6雖然LGG

在三類患者療效(RRR)

相同,但在抵抗力較差的小朋友飲用LGG,只要治療較少的小朋友,即可多拯救一人(NNT較小),故可知治療應考慮患者的baselinerisk;越容易發(fā)生疾病相關併發(fā)癥的患者,越容易從治療中獲益

NNT

的臨床意義較直覺雖說每治療12人可防止1

人罹患嚴重的呼吸道感染,但我們不知是哪一位患者可因此獲益,此為治療之不確定性(uncertainty)一篇研究的結果是不是就可以確定治療一定有效?系統(tǒng)性文獻回顧和傳統(tǒng)的文獻回顧有什麼不同?其他有關益生菌是否能預防

小兒腹瀉的研究結果如何?TrialYearLocationAgerange(month)ProbioticTypeofdiarrheaIRRSaavedra1994USA:long-termcarefacility5–24B.BifidumNosocomial0.23(0.02–1.18)Szajewska2001Poland:pediatrichospital1–36LGGNosocomial0.17(0.03-0.65)Oberhelman1999Peru:urbantown1–30LGGCommunityacquired0.97(0.85-1.10)OxfordCenterforEvidence-basedMedicineLevelsofEvidence(May2001)LevelTherapy1a系統(tǒng)性回顧Systematicreview(分析數(shù)個隨機臨床對照試驗,其結果均類似)1b設計良好,結果精確之隨機臨床對照試驗1cAllornone2a系統(tǒng)性回顧(分析數(shù)個世代研究,其結果均類似)2b世代研究Cohortstudy;設計粗糙之隨機臨床對照試驗2c"Outcomes"Research;Ecologicalstudies3a系統(tǒng)性回顧(分析數(shù)個病例-對照研究,其結果均類似)3b病例-對照研究Case-controlstudy4某家醫(yī)院的十年經(jīng)驗;設計不良之世代研究及病例-對照研究5未經(jīng)考證之專家個人意見,基礎研究,細胞實驗,生理實驗,動物實驗…的結果

HowShouldIUseArticles

aboutDiagnosis?

Examplesforevidence-basedpractice臺大內(nèi)科

張家勳/楊泮池教授Physicianshavealwayshadtheirfavoritestrategiesforthediagnosticmanagementofmostproblems.Butasnewtestsbecomeavailable,strategieshavechanged,arechanging,andwillcontinuetochange…

PaulCutlerMD.Clinicalscenario王太太?70歲?

有慢性關節(jié)炎的病史?長期服用NSAID。這次因吐咖啡渣、解黑糞前來急診?經(jīng)內(nèi)視鏡檢查為胃潰瘍合併出血?並住院接受治療。三天後發(fā)生咳嗽、發(fā)燒、氣促等癥狀…

WBC:14000/mm3

CxR:↑infiltrateover

bilaterallowerlungSputumGramstain:G(+)cocciwithphagocytosisSputumAcid-faststain:fewacid-fastbacilli??臨床診斷常犯的錯誤以為檢查結果為陽性就能100%的確定患者有病忽視了患者罹患該疾病的基本可能性(priorprobability)不了解診斷工具本身的特性(敏感度、特異度)重複地選擇不會影響患者處置的檢查Whatwewilllearntoday…Step1:如何明確的分析我們所面臨的臨床問題?Step2:證據(jù)在哪裡?如何有效率的搜尋文獻Step3:臨床研究的結果可信嗎?Step4:其臨床意義為何?Step5:我該如何利用臨床研究的結果照顧我的病人?Howtoaskameaningfulquestion?“學長,我們是不是直接就要開始讓病人接受抗結合藥物的治療,還是先安排她做痰液的TB-PCR檢查?”Step1:如何明確的分析我們所面臨的臨床問題?Thespecific,answerableclinicalquestion:PatientsInterventionvs.ComparisonOutcomesStep2:證據(jù)在哪裡?如何有效率的搜尋文獻TheroleofclinicalsuspicioninevaluatinganewdiagnostictestforactivetuberculosisDesign:ProspectivecohortstudySetting:6medicalcentersand1publichealthTBclinicbetweenFebandDec1996.Participants:425patientssuspectedofhavingactivepulmonaryTBbasedonsymptoms,riskfactors,PPTtest,CxRfindings.IdentifiedbychestorIDspecialist.Noteligibleiftheyreceivedmulti-drugtreatmentforTBfor≧7daysduringthepast3months.JAMA2000;283:639-45TheroleofclinicalsuspicioninevaluatinganewdiagnostictestforactivetuberculosisDescriptionoftest:EnhancedMTD.Sitephysicianestimatedtheprobability(0%~100%)thatthepatienthadTB,basedonclinicaljudgment;physicianswereblindedtotheresultsofE-MTD.Allotherlabresults(mightincludeAFBsmears)wereavailable.Referencestandard:DefiniteactiveTB:highclinicalsuspicion(>80%)and≧2positiveculturesDefiniteabsenceofactiveTB:lowclinicalsuspicion(<10%)withoutanypositivecultureOtherwise,thecaseswerereviewedbytheindependentexpertpanel:atleast2ofthe3membershadtoconsiderthepatienttohaveortobefreeofTBJAMA2000;283:639-45Step3:這篇臨床研究的結果可信嗎?Aretheresultsofthestudyvalid?Didthepatientsampleincludeanappropriatespectrumofpatients?Wasthereanindependent,blindcomparisonwithareferencestandard?Didtheresultsofthetestinfluencethedecisiontoperformthereferencestandard?Werethemethodsforperformingthetestdescribedinsufficientdetailtopermitreplication?JAMA1994;271:389-91試比較不同研究患者納入方式

對研究可信度的影響AlmedaJetal.收集238位肺結核患者檢體,與46位健康醫(yī)學院學生及47位未感染肺結核COPD患者所收集到的檢體相比較,發(fā)現(xiàn):TB-PCR在診斷肺結核的敏感度為62%,特異度為100%…EurJClinMicrobiolInfectDis2000;19:859-867Whatis“SpectrumofPatients”?

Therangeoffeaturesfoundinpatientsusedtochallengeatest’ssensitivityandspecificitytodistinguishpeoplewithorwithoutdiseaseForbothdiseasedandcomparativegroups,consider…PathologicspectrumClinicalspectrumCo-morbidspectrumNEnglJMed1978;299:926-930試比較不同研究黃金標準的選擇

對研究可信度的影響在一項前瞻性研究中,BodmerTetal.收集了621個懷疑罹患肺結核患者的呼吸道檢體,以結合菌培養(yǎng)當作診斷的黃金標準,發(fā)現(xiàn)TB-PCR的敏感度74%,特異度為99%…JClinMicrobiol1994;32:1483-1487BiasinAssociatingtheTestResults

andtheDiseaseDiagnostic-reviewbiasThetestresultaffectsthesubjectivereviewofthedatathatestablishthediagnosisValuesofDopplerultrasoundindiagnosisofclinicallysuspecteddeepveinthrombosis.BMJ1975;4:552-4

Test-reviewbiasAtestthatisinterpretedsubjectivelycanbebiasedbytheknowledgeofthediagnosisValueofinfarct-specificisotope(99mTc-labeledstannouspyrophosphate)inmyocardialscanning.BMJ1975;3:517-20.BiasinAssociatingtheTestResults

andtheDiseaseIncorporationbiasThetestresultisactuallyincorporatedintotheevidencetodiagnosethediseaseAtestforpatencyofthecysticductinacutecholecystitisAnnInternMed1975;82:13-17Work-upbiasTheresultofthetestmayaffectthesubsequentclinicalwork-upneededtoestablishthediagnosis…VerificationBiasorWork-upBiasTestReferencestandardsTotalReferencestandardsTotalDzNoDzDzNoDzPos8010018080100180Neg2090092029092Total1001000110082190272Sensitivity=80%Specificity=90%Sensitivity=80/82=98%Specificity=90/190=47%OxfordCenterforEBMLevelsofEvidenceLevelDiagnosis1aSR(withhomogeneity)ofLevelIdiagnosticstudies

1bValidatingcohortstudywithgoodreferencestandards

1cAbsoluteSpPinsandSnNouts2aSR(withhomogeneity)ofLevelIIdiagnosticstudies

2bExploratorycohortstudywithgoodreferencestandards3aSR(withhomogeneity)of3bandbetterstudies

3bNon-consecutivestudy;orwithoutconsistentlyappliedreferencestandards

4Case-controlstudies,poorornon-independentreferencestandard

5Expertopinionwithoutexplicitcriticalappraisal,orbasedonphysiology,benchresearchor"firstprinciples"

Step4:其臨床意義為何?Whataretheresults?Arelikelihoodratiosforthetestresultspresentedordatanecessaryfortheircalculationprovided?JAMA1994;271:703-707Predictivevalueshavemore

explicitclinicalmeanings…Foratestwithsensitivity=80%andspecificity=90%DiseaseNodiseasePositive801090Negative2090110Total100100Positivepredictivevalue=80/90=89%Negativepredictivevalue=90/110=82%ButwillchangewhileprevalencechangesForatestwithsensitivity=80%andspecificity=90%DiseaseNodiseasePositive80100180Negative20900920Total1001000Positivepredictivevalue=80/180=44%↓Negativepredictvalue=900/920=98%

↑Asinglecut-offvaluetoindicateabnormalityisNOTenough!!Irondeficiencyanemia(IDA)NoIDAFerritin<30acFerritin≧30bdSensitivity=a/a+bSpecificity=d/c+dAsinglecut-offvaluetoindicateabnormalityisNOTenough!!Serumferritin(mg/dl)SpecificitySensitivity≦15??15-24??25-34??35-44??45-100??≧100??LR:aricherwaytointerpretthetestswithmultiplelevelsofpositiveSerumferritin(mg/dl)LR≦1551.815-248.825-342.535-441.845-1000.5≧1000.08Whyuselikelihoodratio(LR)?TestClinicalvalueMeaningStabilitywithchangingprevalenceCanusemultiplelevelsofatestresultSensitivitySpecificityNoYesNoPredictivevalueYesNoNoWhyuselikelihoodratio(LR)?TestClinicalvalueMeaningStabilitywithchangingprevalenceCanusemultiplelevelsofatestresultSensitivitySpecificityNoYesNoPredictivevalueYesNoNoLikelihoodratioYesYesYesHowtocalculateandusepositiveandnegativelikelihoodratio?

Post-testodds=pre-testoddsxLRPositiveLR(LR+)=sensitivity/(1-specificity)NegativeLR(LR-)=(1-sensitivity)/specificity註Odds=p/1-p;probability=odds/1+odds例如:和信鯨贏球的機率為80%,則鯨隊贏球的勝算為4:1=4LR=probabilitythatfindingispresentinpatientswithdiseaseprobabilitythatfindingispresentinpatientswithoutdisease診斷的過程是一連串機率的改變…一位68歲女性,在最近一週來發(fā)生咳嗽有痰的情形,您認為她罹患肺結核的可能性有多高?診斷的過程是一連串機率的改變…0%100%95%以往有肺結核的病史咳痰僅一週午間發(fā)燒夜間盜汗體重沒有減輕胸部X光顯示:右上葉肺炎浸潤痰液AFBsmear顯示AFB(+)

P5xLR5=P6Whatweretheresults?Oftotal338patientswithcompletestudyforms,validlabresults,andsufficientinformationforfinaldiagnoses,72(21%)wereconsideredtohaveactiveTB.E-MTDtestAFBsmearClinicalSuspicionLevelClinicalSuspicionLevelLowIntermediateHighLowIntermediateHighN2246846N2246846LR+28150174LR+1.12.510LR-3LR-7HowtoInterpretalikelihoodratio:LikelihoodratioInterpretation>10Strongevidencetoruleindisease5–10Moderateevidencetoruleindisease2–5Weakevidencetoruleindisease0.5–2.0Nosignificantchangeinthelikelihood0.2–0.5Weakevidencetoruleoutdisease0.1–0.2Moderateevidencetoruleoutdisease<0.1Strongevidencetoruleoutdisease020406080100PositivepredictiveValue,%PositivepredictiveValue

EnhancedMycobacteriumtuberculosisAcid-FastBacilliSmear020406080100NegativepredictiveValue,%NegativepredictiveValueClinicalSuspicionofTuberculosisLowIntermediatehighoverallLowIntermediatehighoverallOtherimportantresultsinthisstudyForthelowclinicalsuspiciongroup,bothtestswereusefulforrulingoutdisease;Neitherprovedconvincingevidenceforrulingindisease.Forhighsuspiciongroup,bothtestswereusefulforrulingindisease;However,thePV-ofAFBsmearwasonly37%,comparedwith91%fortheE-MTD.E-MTDoffersgreatestutilityintheintermediatesuspiciongroup:TheTBandnon-TBcaseswereequallylikelytohaveapositiveAFBsmearTheprevalenceofthesuggestiveCxR,coughandweightlosswerealsosimilarMycobacteriaotherthanTBwereculturedmorecommonlyStep5:我該如何利用臨床研究的結果照顧我的病人?Willtheresultshelpmeincaringformypatients?Willthereproducibilityofthetestresultanditsinterpretationbesatisfactoryinmysetting?PoorreproducibilityareduetoProblemsofthetestitselfEx.RIAkitsforhormonelevelsExpertiseisrequiredinperformingorinterpretingthetestEx.Cardiacecho,abdominalsono,V/Qscan.Aretheresultsapplicabletomypatients?Testpropertiesmaychangeindifferentsub-populationsPracticeinasimilarsettingMeetalltheinclusioncriteriaNotviolateanyoftheexclusioncriteriaAretherecompellingreasonsthattheresultsshouldnotbeapplied?SeverityofdiseasesMixofcompellingconditionsTheissueofgeneralizabilitymayberesolvedifyoucanfindanoverviewthatpoolstheresultsofanumberofstudiesWillpatientsbebetterasaresultofthetest?TheusefulnessofadiagnostictestdependsonWhetheritaddsinformationbeyondthatotherwiseavailableWhetherthisinformationleadstoachangeinmanagementthatisultimatelybeneficialInsomesituation,testsmaybeaccurate,managementmayevenchange,buttheirimpactonpatientoutcomemaybefarlesscertain.Ex.Rightheartcatheterizationforcriticallyillpatients試著思考下列問題:參加研究，轉介納入病人的均為對診治肺結核很有經(jīng)驗的胸腔科或感染科醫(yī)師；將本研究的結果應用在我們平常臨床照護上有什麼該注意的呢？Turningbacktoourpatient…由以上可知:在臨床上懷疑罹患肺結核可能性較低的族群中,痰液AFB染色陽性者其罹患肺結核的機率不到40%;

這時有什麼辦法來幫助我們提高肺結核的診斷率??多重試驗(平行試驗或序列試驗)在此時有幫助嗎?若TB-PCR的結果為陰性(或陽性),對我們的處理有什麼影響?Evidenceisneverenough…利用CSFTB-PCR檢查快速診斷結核性腦膜炎JClinMicrobiol1998;36:1251-1254JClinMicrobiol2000;38:3150–3155利用TB-PCR檢查診斷結核性肋膜炎及其他肺外結核Chest1998;113:1190-1194Chest2001;119:1737-1741HowToUseArticlesabout

ClinicalPredicationRules

Examplesforevidence-basedpracticing臺大內(nèi)科

張家勳/楊泮池教授E-mail:Clinicalscenario林同學,20歲男性,這次來急診的主述為三天來持續(xù)發(fā)燒,同時合併咳嗽有黃痰和氣促10天前開始輕微發(fā)熱、喉嚨痛、及流鼻水除過敏性鼻炎外無其他重大疾病否認在過去二週內(nèi)曾出國旅遊理學檢查:130/85mmHg,38℃,100,20;nowheezingWBC18000;CxR:pneumonicpatchoverR’tlowerlung要不要安排林同學住院呢?實際上常面臨的情況經(jīng)驗有限…沒有一致地、完整地追蹤病人過於強調(diào)特殊的案例不容易了解個別特徵(即預後因子)與其他特徵間的相互關係難以評估個別因子以及與其他因子相互作用下對病人預後的整體影響Whatwewilllearntoday…Step1:如何明確的分析我們所面臨的臨床問題?Step2:證據(jù)在哪裡?如何有效率的搜尋文獻Step3:臨床研究的結果可信嗎?Step4:其臨床意義為何?Step5:我該如何利用臨床研究的結果照顧我的病人?Step1:如何明確的分析我們所面臨的臨床問題?TheSpecific,AnswerableClinicalQuestion:Patients:罹患社區(qū)性肺炎的病人Intervention:WBC高的患者(eg,>15,000)Comparison:WBC不高的患者Outcomes:死亡率是否顯著高了許多…TheSpecific,AnswerableClinicalQuestion:Patients:罹患社區(qū)性肺炎的病人Intervention:ClinicalpredictionruleComparison:醫(yī)師的經(jīng)驗或直覺Outcomes:準確預測住院期間發(fā)生mortality&morbidity減少不必要的住院但是不會降低照護的品質(zhì)…

WhatAreClinicalPredictionorClinicalDecisionRules(CPR;CDR)Toolsthatquantifytheindividualcontributionsthatvariouscomponentsofhistory,physicalexamination,andbasiclabresultsmaketowardthediagnosis,prognosis,orlikelyresponsetotreatmentinapatientAttempttoformallytest,simplify,andincreasetheaccuracyofclinicians’diagnosticandprognosticassessmentsMostlikelytobeusefulwheredecisionmakingiscomplex,orthereareopportunitiestoachievecostsavingswithoutcompromisingpatientcareJAMA,2000;284:79~84Step2:證據(jù)在哪裡?如何有效率的搜尋文獻ThreeStepsforPuttingCDRintoClinicalPractice…Step1.

DerivationIdentificationoffactorswithpredictivepowerStep2.

ValidationEvidenceofreproducibleaccuracyNarrowValidationApplicationofruleinasimilarclinicalsettingandpopulationasinStep1BroadValidationApplicationofruleinMultipleclinicalsettingswithvaryingprevalenceandoutcomesofdiseaseLevelofEvidence

4