系統性文獻回顧及統合分析介紹 - chimei.org.t · number of publications about meta...

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系統性文獻回顧及統合分析介紹系統性文獻回顧及統合分析介紹系統性文獻回顧及統合分析介紹系統性文獻回顧及統合分析介紹

高雄榮民總醫院高雄榮民總醫院高雄榮民總醫院高雄榮民總醫院高雄榮民總醫院高雄榮民總醫院高雄榮民總醫院高雄榮民總醫院藥劑部藥劑部藥劑部藥劑部藥劑部藥劑部藥劑部藥劑部

林佩津總藥師林佩津總藥師林佩津總藥師林佩津總藥師林佩津總藥師林佩津總藥師林佩津總藥師林佩津總藥師

Outline

� 系統性文獻回顧及統合分析簡介

�� Steps for systematic reviewSteps for systematic review

�� Data analysis, present and interpret resultsData analysis, present and interpret results

� 系統性文獻回顧及統合分析之臨床重要性

� 系統性文獻回顧及統合分析之臨床應用分享

� 課程目標:� 讓學員了解系統性文獻回顧及統合分析之差異

� 讓學員了解臨床上如何利用整合分析研究

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Number of publications about metaNumber of publications about meta--analysisanalysis、、、、、、、、

systematic review or evidencesystematic review or evidence--based medicinebased medicine

�� text word text word ““systematic reviewsystematic review””

�� medical subject (MESH) heading medical subject (MESH) heading ““evidenceevidence--based medicinebased medicine””and and ““metameta--analysisanalysis as topicas topic””

�� publication type as publication type as ““metameta--analysisanalysis””

Lin PC et al. FIP 2008, Lin PC et al. FIP 2008, PIPI--PP--022022

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系統性文獻回顧及統合分析簡介系統性文獻回顧及統合分析簡介系統性文獻回顧及統合分析簡介系統性文獻回顧及統合分析簡介(systematic review and

meta-analysis)

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What is metaWhat is meta--analysis?analysis?

�� Systematic reviewSystematic review�� a clearly stated set of a clearly stated set of objectivesobjectives with with prepre--defined eligibility defined eligibility

criteria for studiescriteria for studies

�� an an explicit, explicit, reproduciblereproducible methodologymethodology

�� a a systematicsystematic searchsearch that attempts to that attempts to identify identify allall studiesstudies that that would meet the eligibility criteriawould meet the eligibility criteria

�� an an assessment of the assessment of the validityvalidity of the findings of the included of the findings of the included studies, for example through the assessment of risk of biasstudies, for example through the assessment of risk of bias

�� a a systematicsystematic presentation, and synthesispresentation, and synthesis, of the , of the characteristics and findings of the included studiescharacteristics and findings of the included studies

�� MetaMeta--analysisanalysis�� statistical procedurestatistical procedure for combining data from independent for combining data from independent

studiesstudies

Cochrane Handbook for Systematic Reviews of InterventionsCochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March Version 5.1.0 [updated March

2011]. The Cochrane Collaboration, 2011. Available from www.coch2011]. The Cochrane Collaboration, 2011. Available from www.cochranerane--handbook.org. handbook.org.

6Ann Intern Med. 2011;155:839-847.

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How to conduct a metaHow to conduct a meta--analysisanalysis

�� 1996: QUOR1996: QUOROOMM

�� quality of reporting metaquality of reporting meta--analysisanalysis

�� 2009/7: PRISMA Ann Intern Med 2009; 151(4):2642009/7: PRISMA Ann Intern Med 2009; 151(4):264--99

�� Preferred reporting items for systematic reviews and metaPreferred reporting items for systematic reviews and meta--analysisanalysis

�� Avoiding publication bias, language bias or outcome Avoiding publication bias, language bias or outcome measure etc.measure etc.

�� http://www.prismahttp://www.prisma--statement.org/ statement.org/

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QUORQUOROOMM

Lancet 1999; 354:1896-900

Potentially relevant RCTsPotentially relevant RCTs identified identified

and screened for retrieval (n= and screened for retrieval (n= ------))

RCTs retrieved for RCTs retrieved for more detailed more detailed

evaluationevaluation (n= (n= ------))

Potentially appropriate RCTsPotentially appropriate RCTs to be to be

included in the metaincluded in the meta--analysis (n= analysis (n= ----))

RCTs includedRCTs included in metain meta--analysis analysis

(n= (n= ------))

With usable informationWith usable information by by

outcome (n= outcome (n= ------))

RCTs excluded, with RCTs excluded, with

reasons (n= reasons (n= ------))

RCTs excluded, with RCTs excluded, with

reasons (n= reasons (n= ------))

RCTs excluded from metaRCTs excluded from meta--

analysis, with reasons (n= analysis, with reasons (n= ------))

RCTs withdrawn, by outcome, RCTs withdrawn, by outcome,

with reasons (n= with reasons (n= ------))

Progress through the Progress through the

stages of a metastages of a meta--

analysis for RCTsanalysis for RCTs

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HowHow to conduct a metato conduct a meta--analysisanalysis

�� Steps for systematic reviewSteps for systematic review�� Formulate review questionFormulate review question

�� Define inclusion and exclusion criteriaDefine inclusion and exclusion criteria

�� Locate studiesLocate studies

�� Select studiesSelect studies

�� Extract dataExtract data

�� Assess study qualityAssess study quality


Egger M et al. Egger M et al. Systematic Reviews in Health Care: MetaSystematic Reviews in Health Care: Meta--analysis in analysis in

context. BMJ, 2rd edition 2005context. BMJ, 2rd edition 2005

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�� Steps for systematic reviewSteps for systematic review

�� Formulate review questionFormulate review question


�� Locate studiesLocate studies�� Search strategy (reproducible)Search strategy (reproducible)

�� Key words Key words

�� MeSH termsMeSH terms

�� Databases Databases

�� PubMed or MedlinePubMed or Medline

�� EMBASEEMBASE

�� CINHALCINHAL

�� PEDroPEDro

�� Conference abstract (dependent)Conference abstract (dependent)

�� Reference lists of the identified articlesReference lists of the identified articles

�� Hand searchHand search

�� Registered centersRegistered centers

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RCT RCT 註冊平台註冊平台註冊平台註冊平台註冊平台註冊平台註冊平台註冊平台

�� International Clinical Trials Registry PlatformInternational Clinical Trials Registry Platform(ICTRP)(ICTRP) http://www.who.int/ictrp/en/http://www.who.int/ictrp/en/世界衛生組織下設的臨床試驗註冊平台，其設置的重要任務在使臨世界衛生組織下設的臨床試驗註冊平台，其設置的重要任務在使臨床試驗的進行更為透明化，並提供各權益相關人所需的有關資訊，床試驗的進行更為透明化，並提供各權益相關人所需的有關資訊，更重要是減少性質相近或相同的試驗重複投進行的浪費更重要是減少性質相近或相同的試驗重複投進行的浪費

�� ClinicalTrials.govClinicalTrials.gov http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/由美國國家衛生研究院下之國家醫學圖書館所設，專門收錄由衛生由美國國家衛生研究院下之國家醫學圖書館所設，專門收錄由衛生院、聯邦政府、地方政府及民間私立機構進行中的臨床試驗登錄資院、聯邦政府、地方政府及民間私立機構進行中的臨床試驗登錄資料料

�� James Lind Library http://www.jameslindlibrary.org/James Lind Library http://www.jameslindlibrary.org/James Lind Library James Lind Library 係由係由CochraneCochrane CollaborationCollaboration發起人之一的英國發起人之一的英國爵士爵士Iain ChalmerIain Chalmer教授所率領的編輯團隊建置，此一圖書資料建置教授所率領的編輯團隊建置，此一圖書資料建置主要的目的在呼籲重視臨床治療的公平試驗主要的目的在呼籲重視臨床治療的公平試驗((fair test)fair test)原則，以確保原則，以確保治療的真正成效，圖書資料有包括對公平試驗的解釋定義及研究設治療的真正成效，圖書資料有包括對公平試驗的解釋定義及研究設計等，並已有簡體中文版的翻譯文章可供閱讀，並收錄大部分的參計等，並已有簡體中文版的翻譯文章可供閱讀，並收錄大部分的參考文獻免費供線上瀏覽，值得有興趣者參考考文獻免費供線上瀏覽，值得有興趣者參考

國衛院實證臨床指引平台

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RCT RCT 註冊平台註冊平台註冊平台註冊平台註冊平台註冊平台註冊平台註冊平台

�� The Cochrane Central Register of Controlled Trials (Clinical The Cochrane Central Register of Controlled Trials (Clinical TrialsTrials)) http://www.mrw.interscience.wiley.com/cochrane/cochhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlrane_clcentral_articles_fs.html簡稱簡稱CENTRALCENTRAL之臨床試驗註冊資料庫，收錄詳細的臨床試驗主之臨床試驗註冊資料庫，收錄詳細的臨床試驗主題、文獻書目、摘要，不含全文，資料來源包含發表於題、文獻書目、摘要，不含全文，資料來源包含發表於MEDLINEMEDLINE、、EMBASEEMBASE及其他期刊等資料庫，以及未發表的參考及其他期刊等資料庫，以及未發表的參考文獻來源如僅於研討會發表之文獻報告，約文獻來源如僅於研討會發表之文獻報告，約3/53/5的資料由的資料由MEDLINEMEDLINE取得，其他則由包括各取得，其他則由包括各Cochrane Review GroupsCochrane Review Groups依其依其主要興趣領域所收集的臨床試驗文獻，整個收到的資料再由主要興趣領域所收集的臨床試驗文獻，整個收到的資料再由US US Cochrane CenterCochrane Center作統整再納入作統整再納入Cochrane LibraryCochrane Library

�� The Society for Clinical TrialsThe Society for Clinical Trials http://www.sctweb.org/http://www.sctweb.org/與與Clinical TrialsClinical Trials相關之研究發展、設計之國際組織相關之研究發展、設計之國際組織; ; 亦提供臨床亦提供臨床試驗摘要查詢功能試驗摘要查詢功能

�� 聯合人體試驗委員會聯合人體試驗委員會 http://www.jirb.org.tw/Default.aspxhttp://www.jirb.org.tw/Default.aspx聯合人體試驗委員會為由北榮、台大、長庚、三總、成大等五聯合人體試驗委員會為由北榮、台大、長庚、三總、成大等五家醫學中心共同成立目的為加速國內臨床試驗審查速度及提升家醫學中心共同成立目的為加速國內臨床試驗審查速度及提升臨床試驗水準。該委員會網頁上有許多臨床試驗及臨床試驗水準。該委員會網頁上有許多臨床試驗及IRBIRB審查的資審查的資訊或訓練課程講義可供下載參考訊或訓練課程講義可供下載參考國衛院實證臨床指引平台

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�� At least 2 reviewers At least 2 reviewers independentlyindependently evaluated each evaluated each

identified study and abstracted relevant characteristics identified study and abstracted relevant characteristics

�� Contact authorsContact authors for the unpublished data for the unpublished data

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�� Prepare tables comparing studies with respect to:Prepare tables comparing studies with respect to:�� Authors, YearAuthors, Year

�� PPatients (setting)atients (setting)

�� IInterventionntervention

�� CComparisonomparison

�� OOutcome (results)utcome (results)

�� Study qualityStudy quality

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Quality Quality of included studiesof included studies

�� Scale (score) approachScale (score) approach

�� Jadad scaleJadad scale

�� Chalmers TCChalmers TC

�� ------------------

�� Components approachComponents approach

�� Scales or components?Scales or components?

Health Technol Assess. 1999;3(12):i-iv, 1-98

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Study quality Study quality –– Jadad scoreJadad score

Modified from Controlled Clin Trials. 1996; 17:1-12

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BMJ. 2008 Jun 14;336(7657):1359-61

24

Aliment Pharmacol Ther 2002; 16: 1623–1632.


�� Data analysis, present and interpret resultsData analysis, present and interpret results�� Systematic review or metaSystematic review or meta--analysisanalysis

Moher D et al. Arch Pediatr Adolesc Med 1998;152:915-20



�� Systematic review or metaSystematic review or meta--analysisanalysis

�� Treatment effect (effect size)Treatment effect (effect size)

�� Continuous data: standardized (differences in means)Continuous data: standardized (differences in means)

�� Dichotomous dataDichotomous data

�� Difference scale: risk differenceDifference scale: risk difference

�� Ratio scale: odds ratio, risk ratio (hazard ratio)Ratio scale: odds ratio, risk ratio (hazard ratio)

�� Point estimate (forest plot) or cumulative forest plotPoint estimate (forest plot) or cumulative forest plot

28

Calculation of RR (relative risk, risk ratio)

��Experimental event rate (EER) = a/(a+b) Experimental event rate (EER) = a/(a+b)

�� 實驗組事件比率實驗組事件比率（發生率）（發生率）；治療組風險；治療組風險

��Control event rate (CER) = c/(c+d)Control event rate (CER) = c/(c+d)

�� 對照組事件比率對照組事件比率（發生率）（發生率）；對照組風險；對照組風險

�� RR= EER/CER= (a/a+b)/(c/c+d)RR= EER/CER= (a/a+b)/(c/c+d)

Treatment Event

Positive Negative

Exposed (experimental) a b

Not exposed c d

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Calculation of OR (odds ratio; relative odds)

�� Experimental event Odds (EEO)Experimental event Odds (EEO)

�� 實驗組中發生目標疾病的勝算實驗組中發生目標疾病的勝算

�� EEO= a/bEEO= a/b

�� Control event Odds (CEO)Control event Odds (CEO)

�� 控制組中發生目標疾病的勝算控制組中發生目標疾病的勝算

�� CEO= c/dCEO= c/d

�� OR= EEO/CEO = (a/b)/(c/d)= ad/bcOR= EEO/CEO = (a/b)/(c/d)= ad/bc

Treatment Event

Positive Negative

Exposed (experimental) a b

Not exposed c d

Forest plot for summary data (RD)

Crit Care Med 2010; 38:1197Crit Care Med 2010; 38:1197––12051205

Publication Bias in Meta-Analysis – Prevention, Assessment and Adjustments Edited by H.R. Rothstein, A.J. Sutton and M.

Borenstein

2011/9/30


�� Data analysis, present and interpret resultsData analysis, present and interpret results�� Systematic review or metaSystematic review or meta--analysisanalysis

�� Treatment effect (effect size)Treatment effect (effect size)�� Continuous data: standardized (differences in means)Continuous data: standardized (differences in means)

�� Dichotomous dataDichotomous data

�� Difference scale: risk differenceDifference scale: risk difference

�� Ratio scale: odds ratio, risk ratio (hazard ratio)Ratio scale: odds ratio, risk ratio (hazard ratio)

�� Point estimate (forest plot) or cumulative forest plotPoint estimate (forest plot) or cumulative forest plot

Crit Care Med 2010; 38:1197–1205

33

4. Perform meta4. Perform meta--analysisanalysis

Moher D et al. Arch Pediatr Adolesc Med 1998;152:915-20

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�� Software for metaSoftware for meta--analysisanalysis

�� Comprehensive metaComprehensive meta--analysis, STATA, Metaxis or analysis, STATA, Metaxis or

MetaWin MetaWin

�� Free software (Review Manager 5)Free software (Review Manager 5)BMC Medical Research Methodology BMC Medical Research Methodology 2007, 2007, 77:40:40

35


�� Data analysis and present resultsData analysis and present results




�� HeterogeneityHeterogeneity

�� VisualVisual

�� Statistical testsStatistical tests

�� ChiChi--square testsquare test for heterogeneity (Cochran Q test ) for heterogeneity (Cochran Q test )

�� II22 statisticsstatistics

�� Explore the potential risks for heterogeneityExplore the potential risks for heterogeneity

Heterogeneity-I2 test

� 0-40%: might not be important

� 30-60%: may represent moderate

heterogeneity

� 50-90%: may represent substantial

heterogeneity

� 75-100%: considerable heterogeneity

� Fixed effect model vs random effect model

Cochrane Handbook for Systematic Reviews of Interventions. 2009

37

Forest Plot & Forest Plot &

heterogeneity heterogeneity

analysisanalysis


Borenstein

2011/9/30 38

Check for heterogeneityCheck for heterogeneity

�� If significant heterogeneity is found:If significant heterogeneity is found:

�� Find out what factors might explain the Find out what factors might explain the

heterogeneityheterogeneity

�� Can decide not to combine the dataCan decide not to combine the data

�� If no heterogeneity:If no heterogeneity:

�� Can perform metaCan perform meta--analysis and generate a analysis and generate a

common, summary effect measurecommon, summary effect measure

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�� VisualVisual

�� Statistical testsStatistical tests

�� Explore the potential risks for heterogeneityExplore the potential risks for heterogeneity

�� Sensitivity analysisSensitivity analysis

�� LL’’Abbe plotAbbe plot

�� Subgroup (stratified) analysisSubgroup (stratified) analysis

�� MetaMeta--regressionregression

Supplementary File 2: Sensitivity analysis - Pooled effect estimates for stress related upper GI bleeding

Drop out

study

Risk difference [95% CI], p Heterogeneity-I2

Powell -0.05 [-0.10, 0.00], 0.07 71%

Levy -0.02 [-0.05, 0.01], 0.19 26%

Phillips -0.03 [-0.08, 0.01], 0.15 65%

Azevedo -0.03 [-0.08, 0.02], 0.18 65%

Kantorova -0.06 [-0.12, 0.01], 0.08 72%

Conrad -0.06 [-0.12, 0.00], 0.10 79%

Somberg -0.06 [-0.14, 0.01], 0.05 62%

Crit Care Med 2010; 38:1197Crit Care Med 2010; 38:1197––1205 online supplement1205 online supplement

L’Abbe plot

Crit Care Med 2010; 38:1197Crit Care Med 2010; 38:1197––1205 online supplement1205 online supplement

Crit Care Med Crit Care Med

2010; 38:11972010; 38:1197––

1205 online 1205 online

supplementsupplement

43







�� Explore the potential publication biasExplore the potential publication bias

�� Funnel plotFunnel plot

�� Begg and MazumdarBegg and Mazumdar’’s rank correlation tests rank correlation test

�� EggerEgger’’s regressions regression


Borenstein

BMC Infectious Diseases 2004, 4:6

2011/9/30 46BMC Medical Research Methodology BMC Medical Research Methodology 2007, 2007, 77:40:40

BMC Medical Research Methodology BMC Medical Research Methodology 2007, 2007, 77:40:40

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系統性文獻回顧及統合分析之臨床重要性系統性文獻回顧及統合分析之臨床重要性系統性文獻回顧及統合分析之臨床重要性系統性文獻回顧及統合分析之臨床重要性

�� 臨床執行的立場臨床執行的立場

�� Minimize the potential bias in traditional narrative Minimize the potential bias in traditional narrative

reviewsreviews

�� provide more precise estimates of the effects of provide more precise estimates of the effects of

health care from individual studieshealth care from individual studies

�� Clinical practice and decision makingClinical practice and decision making

�� 實證醫學的立場實證醫學的立場

�� Level of evidenceLevel of evidence

2011/9/30 48

The importance of metaThe importance of meta--analysisanalysis

50Circulation 2011, 123:104-123

2011/9/30 51Abstract code: PE-13The 4th Asian Conference of Pharmacoepidemiology, 2009

系統性文獻回顧及統合分析之系統性文獻回顧及統合分析之系統性文獻回顧及統合分析之系統性文獻回顧及統合分析之

臨床應用分享臨床應用分享臨床應用分享臨床應用分享

page. 57

Crit Care Med 2010; 38:1197–1205

2011/9/30 59

60N Engl J Med 2008;359:1543-54.

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�� Because of the strength of the Because of the strength of the UPLIFT data, the absence of a UPLIFT data, the absence of a strong signal related to stroke strong signal related to stroke or cardiovascular events with or cardiovascular events with tiotropium, and tiotropium, and the potential the potential methodologic limitations of the methodologic limitations of the Singh metaSingh meta--analysisanalysis, the FDA , the FDA concluded that concluded that current data do current data do not supportnot support the conclusion that the conclusion that there is an increased risk of there is an increased risk of stroke, heart attack, or death stroke, heart attack, or death associated with tiotropium associated with tiotropium HandiHaler HandiHaler

2011/9/30 62

How do you think about MAHow do you think about MA

homogeneoushomogeneous

heterogeneityheterogeneity

2011/9/30 63

How do you think about MAHow do you think about MA

�� WhyWhy a SR be performeda SR be performed

�� Disadvantages in traditional narrative reviewsDisadvantages in traditional narrative reviews

�� Clinical practice and decision makingClinical practice and decision making

�� Systematic review or metaSystematic review or meta--analysis in clinical analysis in clinical

practicepractice

�� Appropriate typeAppropriate type--ofof--study included, good quality study included, good quality

�� Apply to appropriate patient (group)Apply to appropriate patient (group)

2011/9/30 64

Thanks for your attention!!Thanks for your attention!!

Any comments or questions ??Any comments or questions ??

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