How to design a studyData managementKuan-Fu Chen MD,PhDAlison Su-Hsun Liu MD, PhDDec 27, 2012 Howtodesignastudy&Datamanagemen2 Formalfellowship 3 Howtodesignastudy&Datamanagemen4 SASEnterpriseGuide(EG) Biosignatureproject CMRP 5 Howtodesignastudy&Datamanagemen6Purposedcourses "HowtodesignastudyDatamanagement" "Univariatesta>s>csSamplesizecalcula>on" "Mul>variablesta>s>csBivariatesta>s>cs" "Studiesofdiagnos>candprognos>ctests;Sta>s>csandcausality"7Otherop>ons?Fellowcourse8 1 101/8/14(W) 2 101/9/6(W)3 101/10/4(W)4 101/11/1(W)5 101/12/6(W) Proposal6 102/1/3(W) 7 102/2/7(W) () 8 102/3/7(W) () 9 102/4/4(W) () ()10 102/5/2(W) () ()11 102/6/6(W) () 12 102/7/4(W) paper paperreference 13 102/8/1(W) (1)(2)(3)1027abstract1.(1)(2) 2.:10:00~12:00; 10:00~12:009,},, [zvz} [z(; ,|;(z|z; |zp;z z|z|;z,|| |,;z [_ |;z,(z|;z z[ |;z,||;,|;z, ___|;z,|| |,;z [_ |-|z,| ___|;z,|| |,;z [_ j{]_ ___|;z,|| |,;z [_ ,(V, ___|;z,|| |,;z [_ z-[;qz|;;z ___|;z,|| |,;z [_ ,|z_z;;z} ,| }y,;, ___|;z,|| |,;z [_ ,z;;z}|;z }y,;, ___|;z,|| |,;z [_ ,|z_z;;z} ,| }y,;, ___|;z,|| |,;z [_ [;z; [z_;z,,;z ___|;z,|| |,;z [_ ,z;;z}|;z }y,;, ___|;z,|| |,;z 3 [_ [z_;,|;z [z_;z,,;z ___|;z,|| |,;z [_ $(;v;v} }y,;, ___|;z,|| |,;z [_ z|-}y,;, ___[p; |,;z ___ _[|, [p;,zq;z}z_y [;;qz;[p; |,;z ___ __"", ,;zz, z[ qz;|;,;|y[p; |,;z ___ _"", ,;zz, z[ qz;|};|y[p; |,;z ___ (_, |jz |(;} j;,|z;y z[ ,;,z,z[p; |,;z ___ jQ____, V};,;|y z[ ,;_z,|;z , ,z;zz;_ |z,|,[p; |,;z ___ jQ____, [z};|;};|y z[ ,;_z,|;z , ,z;zz;_ |z,|,[p; |,;z ___ [_(-) j__, [,zq;,z, |;;},[p; |,;z ___ [_() jj[, ,zjz;| $|(,;z,[p; |,;z ___ [_()__Qj__[, ,,z-zz|;z} , ,;z,,-,zz|;z} $|(,;z,[p; |,;z ___ [,|;q|;_ ;;,| z[ ,;,z,z (,;_ zp;,zq;z}z_;z ,|[p; |,;z ___ |z;p;z|;_ ,| [;zq zp;,zq;z}z_;z ,|(,;z,[p; ,,vzz, [_ ,};;z} [;z,;z|;z [(}z[p; ,,vzz, [_ ,zqp;|;vz [[[zz|;vzz,, [z,z;zj[p; ,,vzz, [_ [zz;,;z ,}y,;,[;z|;z} |,;z [_ [_____[;z|;z} ,,vzz, 4 __ ___]]|___[;z|;z} ,,vzz, __ [__[;z|;z} ,,vzz, __ _[;z|;z} ,,vzz, ___ __[;z|;z} |,;z 4 [_ |_,zzz,,, $Q[ ___[| |,;z 3 [_ [| wz;|,jzp ___[| ,,vzz, [_ [zw |z |zzj [| ; [ ___[;z|;z} |,;z _ [___Q_[;z|;z} |,;z [ j]_[_[__0,0,; _Otherop>ons?JHUGTPCI10Otherop>ons?JHUGTPCI11Otherop>ons?JHUGTPCI12De#iningresearchquestionsSearchingtheliteratureMeasurementofratesandrisksGathering&questionnairedevelopmentManagingyourowndataStatistics:Describingdata&makinginferencesPrecision&con#idenceintervalsComparingmeans(Z&ttests)ProportionsSamplesizeSurvivalanalysisMultivariateanalysisHowtochoosetheappropriatestatisticalmethodPrediction/prognosticsmodelsStudydesign:CasereportsandcaseseriesCross-sectionalstudiesCase-controlstudiesProspectivestudiesClinicaltrialsEvaluationofdiagnostictestsandscreeningSystematicreviews/meta-analysisPhasesofdrugdevelopmentEthicalissuesClinicaltrialsIRBMentoringResearchfunding&careerdevelopmentAnatomyofapaperDealingwithmedicaljournalsGCRC Howtodesignastudy&Datamanagemen13OK,letsgetstartedRa>onale Whydoresearch? Whydoclinicalresearch? Whynotbenchresearch? Howtotranslatefrombenchtobedside?15Objec>ves Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs16Deningresearchques>onsPICO(S)inEBMPopula>on(pa>ent):HowwouldIdescribeagroupofpa>entssimilartomine?Interven>on(therapy):Whichmain/newinterven>onamIconsidering?Comparison:Whatisthealterna>vetocomparewiththeinterven>on?placebo,standardofcare,etc.Outcome:WhatcanIhopetoaccomplish,measure,improve,oraect?StudydesignWhatstudydesignwouldprovidethebestlevelofevidenceforthisques>on?17Deningresearchques>onsPICO(S)indiagnos>c/prognos>cstudyPopula>onWhatarethecharacteris>csofthepa>ents/cohort?Whatisthecondi>onthatmaybepresent?Interven>on(diagnos>ctest/predictor[s])Whichdiagnos>ctestamIconsidering?ComparisonWhatisthediagnos>cgoldstandard?OutcomeHowlikelyisthetesttopredict/ruleoutthiscondi>on?StudydesignWhatstudydesignwouldprovidethebestlevelofevidenceforthisques>on?18Pickingaresearchques>onNEJM1994I.AnCcipatetheResultsbeforeDoingFirstStudyII.PickanAreaonBasisofInterestofOutcomeIII.LookforanUnderoccupiedNicheHasPotenCalIV.GotoTalks&ReadPapersoutsideAreaofInterestV.BuildonaTheme19Pickingaresearchques>onNEJM1994VI.FindaBalancebtwLow-Risk&High-RiskVII.BePreparedtoPursuetoAnyDepthVIII.DierenCateYourselffromYourMentorIX.DonotAssumeClinicalResearchIsEasierX.Focus,Focus,Focus20Outstandingproposal NIHCri>queFINER Feasibility InteresCng Novel Ethical Relevant21Outstandingproposal Feasibility TechnicalexperCsetodowhatproposingtodo. PaCentrecruitment demonstratethatyouhaveenoughpa>ents. Manageableinscope. Reasonable>meandmoney. Interes>ng Towhom? ShouldbefascinaCngtoothers.22Outstandingproposal Novel Notalwaysmeanabsolutelynew&undonebefore. Notrepea>ngsomethingalreadyknown. Canuseknownmethods. Eveniftwoprevioustrialsshowedconic>ngresults toresolvetheresults Goesfartherthanapreviousstudy extentwhatwasshownbefore Newapproach,newtechnique,newparadigm (e.g.genomics,proteomics) ojenawardedonnoveltythanfeasibility/likelihood23Outstandingproposal Ethical Relevant ScienCcclinicaloutcome Ifthislackinknowledgeimportanttotheeld? Clinicaloutcomesorclinicaldeliveryoutcomes? Furtheringimportantnewdiscoveriesintheeld?24Outline Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs25Howdoyousearch? Whynotjustlookinatextbook? Whynotjustreadafewpapers? Doesdoingagoodsearchmaker? Whatdatabasesareavailable? Howdoesonesearch? Noteasy!Dontunderes>mate Obstacle:Notfoundorpublished.26Wheredoyousearch? Primary,secondaryvs.Publicdatabase PubMED/MEDLINEdatabase CochraneCentralRegisterofControlledTrials Othermedicalandhealthcaredatabases EMBASE,ScienceCitaConIndex,,CINAHL,Psychlit Non-Englishlanguageliterature27Wheredoyousearch? Greyliterature (theses,industryles,internalreports) Referencesofprimarysources (andreferencesofreferences) Otherunpublishedsourcesknowntoexperts (seekbypersonalcommunicaCon) Rawdatafrompublishedstudies (seekbypersonalcommunicaCon)28Outline Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs29HillsCriteriaforcausa>on Temporalrela>onship:anabsoluteone Strength Dose-responserela>onship Consistency Plausibility Considera>onofalternateexplana>ons Experiment Coherence Specicity:weakestone30Causaldiagram31Causaldiagram32Viral LoadSeverityVaccinationAntiviral+S&SBCPTime since onset+Demographics Causaldiagram33ThreattoCausalinference Lackofprecision Lackofinternalvalidity(accuracy) Confoundingbias SelecConbias InformaCon,measurementbias MisclassicaConbias Lackofexternalvalidity(generalizability) Incorrectassessmentofdirec>onofcausality34Illustra>onofPrecisionvs.Accuracy35http://www.yorku.ca/psycho/en/postscript.asp36http://upload.wikimedia.org/wikipedia/commons/3/38/Accuracy_and_precision.svg

Illustra>onofPrecisionvs.AccuracySimpsonsParadox373839Causaldiagram(again)40Selec>onbiasincohort41Selec>onbiasincohort42Berksons(Selec>on)biasincasecontrol43Diagnos>c(Selec>on)biasincasecontrol44Outline Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs45EBMPyramid46Lancet 2002; 359: 57-61 4748Typeofclinicalstudies Epidemiologicalstudy Clinicaltrials Evalua>onofdiagnos>ctestsandscreening Systema>creviews/meta-analysis Predic>on/prognos>csmodels Compara>veeec>veresearch/DecisionanalysisEpidemiologicalstudy Cross-sec>onalstudies Case-controlstudies Cohortstudies Nestedstudies Gene>cepidemiologicalstudies Molecularepidemiologicalstudies49Studydesign:CohortstudyEpidemiologic Methods 7521November 20, 2006Lecture 8Lecture 8Nested case-control and case-cohort designs2Lecture objectives Describe design features of nested case-control and case-cohort studies Understand the impetus for nesting case-control and case-cohort studies in cohort studies Describe sampling schemes for each design Contrast timing of exposure assessments in nested case-control and case-cohort studies3Cohort study3 events or cases occur among 8 people, of whom 5 are ever exposed Exposed are solid lines, unexposed are dashed Dots are eventsTimePersons4Limitations of cohort study Breadth of the study may limit measuring exposure on everyone Often number who develop outcome veMoreexpensive EcientEvaluatemul>pleoutcome EvaluatesingleoutcomeRepeatedmeasurement OnlyonemeasurementNeedlongtermfollowup Pronetoselec>onbias,ascertainmentbias,diagnos>csurveillancebias53Cohortstudyvs.SurveystudyCohortStudy Survey/cross-sec9onalStudyPurpose Causalinference SurveyExample Framingham NHAMCSSampling Convenient Systema>cGeneralizability Narrow BroadPower/samplesize Common DependonsamplingmethodFeasibility/dicultyCohortretainmentNonresponsebias/samplingerror5455Clinicaltrials-phase56Conven9onal Descrip9ve0 Transla>onalITreatmentmechanismI Dose-nding IDose-rangingIIa Safety&ac>vityIIb-III Compara>veIV Post-marking(expandedsafety)Clinicaltrials-phase57585960Clinicaltrials-structure61CONSORT (Consolidated Standards of Reporting Trials)Clinicaltrials-structure62Clinicaltrials-structure63Clinicaltrials-structure64Clinicaltrials-type Randomized Openlabel Blinded/masked:single,double,triple Placebo/comparatercontrolled Non-inferiority/equivalent Factorial:interac>on Cross-over:comparetooneself65Evalua>onofdiagnos>ctestsandscreening Bias:verica>on,spectrum Goldstandardissue Discrimina>onvs.Calibra>on ROC,goodness-of-t Performanceissue SensiCvity,specicityvs.PPV,NPV LikelihoodraCo,thresholdmodel662x2nightmareDiseased HealthyTest(+) A CTest(-) B DPerformance DetailSensi>vitySpecicityPPVNPVLR(+)LR(-)672x2tableDiseased HealthyTest(+) A CTest(-) B DPerformance DetailSensi>vity A/A+BSpecicity D/C+DPosi>vePredic>veValue A/A+CNega>vePredic>veValue D/B+DPosi>veLikelihoodra>o Sensi>vity/(1-Specicity)Nega>veLikelihoodra>o (1-Sensi>vity)/Specicity68PrevalentperiodDiseased HealthyTest(+) A CTest(-) B DPerformance DetailSensi>vityA/A+BSpecicity D/C+DPosi>vePredic>veValueA/A+C~100%Nega>vePredic>veValueD/B+D~0%69Non-PrevalentperiodDiseased HealthyTest(+) ACTest(-) BDPerformance DetailSensi>vity A/A+BSpecicityD/C+DPosi>vePredic>veValueA/A+C~0%Nega>vePredic>veValueD/B+D~100%70Inter-observeragreement Probabilityagreement Kappasta>s>cs Correla>oncoecient Intra-classcorrela>oncoecient Limitofagreement(Bland-Altmanplot) KrippendorsAlpha71Examplegallopheartsound72Examplegallopheartsound73Examplegallopheartsound74Examplegallopheartsound75Examplegallopheartsound76ExamplesNACPR77ExamplesNACPR7879ClinicalPredic>onRules WhatisCPR? WhyisitimportantforustodoCPRstudies DevelopmentofCPR Valida>onofCPR Implementa>onofCPR ProgressinEMOutline Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs81Measurement Ques>onnaire DevelopmentandvalidaCon Retrospec>vedatabase HIS+SAS+SQLinCGMH>NHIRD Specimens&Assay:valida>on Informa>onbias:recallbias Followup:censoringissue(missingness)82Outline Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs83MicrosojAccessasthetool84MicrosojAccessasthetool85MicrosojAccessasthetool86MicrosojAccessasthetool87SASEG@CGMH88SASEG@CGMH89SASEG@CGMH90SASEG@CGMH91Outline Deningresearchques>ons Searchingliterature Causalinference Studydesigninclinicalresearch Measurement Databasemanagement Somebiosta>s>cs92Sta>s>calinference9394h"p://www.intuitor.com/sta2s2cs//CentralLim.html795Samplesizecalcula>onFreesojwarePS:PowerandSampleSizeCalcula>onhttp://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSizeG*Powerhttp://www.psycho.uni-duesseldorf.de/abteilungen/aap/gpower3/UiowaJAVAhttp://www.cs.uiowa.edu/~rlenth/Power/FreewebsiteOpenEpihttp://www.sph.emory.edu/~cdckms/sample%20size%202%20grps%20cohort.htmRaosojforsurveystudyhttp://www.raosoft.com/samplesize.htmlUBCCAhttp://stat.ubc.ca/~rollin/stats/ssize/b2.htmlSamplesizecalcula>on96Samplesizecalcula>on97Ques>ons?kfchen@cgmh.org.tw98