TwoIntroductoryObservations

Alittleknowledgeisadangerousthing,

ApplyingthePrinciplesof EpidemiologytoClinicalResearch
ThomasR.Vetter,M.D.,M.P.H. MauriceS.AlbinProfessorofAnesthesiology ViceChairandDirector,DivisionofPainMedicine DepartmentofAnesthesiology UABSchoolofMedicine Birmingham,Alabama
2011ThomasR.Vetter

butalittlewantofknowledgeisalsoa dangerousthing.
SamuelButler(18351902)

Forsome,epidemiology id i l i istoosimple i l to warrantseriousconsideration,andforothers itistooconvolutedtounderstand.Ihopeto demonstratetothereaderthatneitherview iscorrect.

KennethJ.Rothman Epidemiology:AnIntroduction, 2002

MyPresentationObjectives
Toreviewthebasicsofclinicalepidemiology Tofosteranappreciationofthefundamental

ThreeExcellentIntroductoryResources
Epidemiology: AnIntroduction 1st Edition,2002 Rothman Epidemiologyand Biostatistics 1st Edition,2009 Kestenbaum EpidemiologyKept Simple nd 2 Edition,2003 Gerstman

epidemiologicalunderpinningsofmostclinicalresearch
Toraiseawarenessofthesourcesofbiasinstudydesign Toexploretheconceptofconfoundinginstudydesign Todiscussthevariousmethodsandspecificstepsto

identifyandtocontrolforbiasandconfounding,including regressionmodelingandpropensityscores
Toidentifythereadilyavailableepidemiologysoftware

optionsfortheclinicalresearcher

ThreeExcellentIntermediateResources
ModernEpidemiology 3rd Edition,2008 Rothman, Greenland,&Lash Epidemiology: StudyDesign andDataAnalysis 2nd Edition,2004 Woodward Epidemiology: BeyondtheBasics 2nd Edition,2007 Szklo &Nieto

Sometimesitseemslike

U Penn Center for Clinical Epidemiology and Biostatistics (CCEB): www.cceb.upenn.edu/pages/localio/EPI521

Exposure to general anesthetics early in life can cause learning disabilities later in childhoodMAYBE.

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ThoughtsonClinicalTrialstoAddressthe EffectsofAnesthesiaontheDevelopingBrain

ThreeCurrentClinicalTrialstoAddressthe EffectofAnesthesiaontheDevelopingBrain
Retrospectivecohortstudyofchildrenwhohadanesthetic

exposurebeforeage3yrs,theperiodofsynaptogenesisin humans,withprospectivefollowupanddirectassessment
SunLS,LiG,DiMaggioC,ByrneM,RauhV,BrooksGunJ,KakavouliA,WoodA,Coinvestigatorsofthe
Lena S. Sun, M.D., Guohua Li, M.D., Dr.P.H., Charles DiMaggio, Ph.D., M.P.H., Mary Byrne, Ph.D., M.P.H., Virginia Rauh, Sc.D.,M.S.W., Jeanne Brooks-Gunn, Ph.D., Ed.M.,Athina Kakavouli, M.D., Alastair Wood, M.D., Coinvestigators of the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Research Network

PediatricAnesthesiaNeurodevelopmentAssessment(PANDA)ResearchNetwork:Anesthesiaand neurodevelopmentinchildren:Timeforananswer.Anesthesiology2008;109:75761

Prospectiverandomizedcontrolledtrialofhealthyinfants

undergoinginguinalherniorraphyreceivingeitherspinalor generalanesthesia,withanNof598andIQatage5yrs
DavidsonAJ,McCannME,MortonNS,MylesPS:Anesthesiaandoutcomeafterneonatalsurgery:
Andrew J. Davidson, M.B., B.S., M.D., Mary Ellen McCann, M.D., M.P.H., Neil S. Morton, M.B., Ch.B., Paul S. Myles, M.D., M.P.H.

Theroleforrandomizedtrials.Anesthesiology2008;109:9414

CasecontrolstudyusingverylargeDenmarknationaland

Rochester(OlmsteadCounty),MNpopulationdatabases,with identificationandcontrolforanumberofconfounders
HansenTG,fortheDanishRegistryStudyGroup,FlickR:Anestheticeffectsonthedevelopingbrain:
Tom G. Hansen, M.D., Ph.D., for the Danish Registry Study Group, Randall Flick, M.D., M.P.H.

Insightsfromepidemiology.Anesthesiology2009;110:13

PublicHealthEpidemiology
Thestudyofthedistributionofdiseasesinpopulations

BradfordHillsAttributesofCausation
Strength:strongertheassociation,lesslikelyduetobias Consistency:persons,places,circumstancesandtimes Specificity:onediseaseandoneexposurerelationship Temporality:whichisthecartandwhichisthehorse? Biological i l i lgradient di :presenceof fad doseresponsecurve Biologicalplausibility:makessensegivenwhatweknow Coherence:congruentwiththenaturalhistoryofdisease Experimentation:evidencederivedfromclinicaltrials Analogy:similarrelationshipsshownwithotherE D
A.B. Hill, The Environment and Disease: Association or Causation? Proceedings of the Royal Society of Medicine, 58 (1965), 295-300.

andthefactorsthatinfluencetheoccurrenceofdisease
Epidemiologyattemptstodeterminewho ismostprone

toaparticulardiseaseoroutcome;where theriskofthe diseaseoroutcomeishighest;when thediseaseor outcomeismostlikelytooccur;howmuch theriskis increasedthroughexposure;andhowmany casesofthe diseasecouldbeavoidedbyeliminatingtheexposure

TargetPopulation StudyPopulation StudySample Awebofcausationisalmostalwayspresent.
BMJ:EpidemiologyfortheUninitiated http://www.bmj.com/epidem/epid.html

ClinicalEpidemiology
Applicationofepidemiologicalprinciplesandmethodsto

Efficacy,Effectivenessversus Efficiency
Theevaluationofaneworexistinghealthcareintervention

questionsregardingdiagnosis,prognosis,andtherapy Randomizedclinicaltrialistheprimeexample Pharmacoepidemiology

Drugbenefitsversusadverseeffects innatelyvery

ortreatmentinvolvesoneormoreofthreesteps:
Achievingitsstatedclinicalgoal

Efficacy
Demonstratedunderoptimal circumstancesinaprospectiverandomized

controlledtrial(RCT) but theresultsarelimitedtothestudysubjects

applicabletoanesthesiology&painmedicine Oftenconductedafter thedrughasbeenmarketed

ClinicalOutcomesandComparativeEffectivenessResearch
Epidemiologicmethodsplusclinicaldecisionanalysisandan economicevaluation todetermineoptimaltreatment Patientreportedoutcomeofhealthrelatedqualityoflife Phase2TranslationalorImplementationResearch(NIH/AHRQ)

Effectiveness
Producinggreaterbenefitthanharm Assessedunderordinary circumstancesinthemoregeneralpopulation

oftenbywayofanobservationalyetanalyticlongitudinalcohortstudy

Efficiency
Healthstatusimprovementforagivenamountofresources($)expended Determinedviaacosteffectivenessanalysisorcostutilityanalysis
Robinson & Vetter (2009): Healthcare Economic Evaluation of Chronic Pain

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PrevalenceversusIncidence
Incidence =#ofnew outcomesorcasesofthedisease Prevalence =#ofexisting outcomesorcasesofthedisease
Proportion rangesfrom0%to100% Pointprevalence ataspecificpoint intime Periodprevalence overamoresustainedtimeperiod

CumulativeIncidence
Cumulativeincidenceisthemostcommonwayto

estimaterisk inthesourcepopulationofinterest
Cumulativeincidence(CI)=quotientof

#ofnew casesobservedduringthefollowupperiod #ofdiseasefree subjects s bjectsatstartoffollo followup pperiod

Afewexamples:
Postoperativeemergence deliriumwithsevoflurane Persistentincisionalpain3monthsafterthoracotomy 3yearIQafterreceivinganeonatalanesthestic 5yearmortalityafteraprotininversustranexamicaciduse 10yearmyocardialinfarctionwithHDL<40mg/dL

Thelongertheduration ofaconditionordisease,

intuitively,thegreatertheprevalenceofthedisease Prevalence IncidenceXAverageDurationofDisease Commoncoldhasahighincidence but ashortduration lowpointprevalence TypeIIDMhasalowerincidence but alongduration higherpointprevalence

BasicStudyDesignSchematic
Crosssectional studies

HierarchyofRiskEstimationStudies

Observational

Cohortstudies

Comparative Studies

Casecontrol studies Individually randomized controlledtrials Cluster randomized controlledtrials

RCTisconsideredthegold standardandproverbialholy grailinclinicalresearch. research

Experimental

ClinicalTrials

www.gfmer.ch/PGC_RH_2005/pdf/Cluster_Randomized_Trials.pdf

Modified from Kraemer, Lowe & Kupfer, To Your Health: How to Understand What Research Tells Us About Risk (2005), pg. 107

WhatsWrongwithanRCT?

1. CrossSectionalStudy
Examinestherelationshipbetweenpotentialriskfactors

andoutcomesduringashortperiodoftime(snapshot)
Potentialriskfactorsoroutcomesarenotlikelytochange

duringthedurationortimeframeofthestudy.
Highlyrestrictedstudysubjecteligibilitybaseduponwelldefinedinclusion

andexclusioncriteria canmakestudyenrollmentprotracted
EthicalandlogisticalconstraintsprecludeusinganRCTdesigntoanswer

Crosssectionalstudyestimatesthepointprevalence. Valuableaspilotstudytoestablishtentativeassociation Generatehypothesesformorerigorousstudies Examples:Coexistingdepressionamongpatients

certainquestions oftenmorecomplex,realworldchallenges.
Minoritiesandbothageextremes pediatricandgeriatricpatients are

conventionallyexcludeddespiteequalorgreaterclinicalneed. TheresultsofanRCToftenlackexternalvalidityandcannotbegeneralizedto themorediversepopulation withcoexistingdiseases. Simplerandomizationmaynotsufficientlycontrolforconfoundingvariables.

Rochon et al., BMJ 2005;330:895-897

presentingtoachronicpainmedicineclinic;positive pregnancytestamongpediatricsurgicaloutpatients

Vetter: Epidemiology and Clinical Research

2. CohortStudy
LongitudinalstudyofE Drisk relationship(forward) Singleexposurewithmultiplesubsequentoutcomes Attheoutsetofstudyall participantsareoutcomefree Naturalorselfselectionintoriskcategories Duringfollowupperiodparticipantsarereassessedasto

WhatisRisk?
Risk:Theprobability ofanoutcomewithinapopulation Likelihoodapersoninapopulationwillhavetheoutcome Riskisanumberbetween0%and100%or 0and1.0 Thespecifiedhealthoutcomeisbinary(+/oryes/no). Thestudypopulationmustbeclearlydefined defined. Whilewelldefined,thispopulationcannotbeknown:

whethertheoutcomehasoccurred.
Timeconsumingandcostlytoperformifprospective Losstofollowupanddifferentialattritioncanleadtobias

thusarepresentativestudysampleisselectedandan estimatedriskinthisstudysampleisdetermined.
Riskestimateisforaspecificand logicalrisktimeperiod,

(systematicerror)andthusvalidityissues.
AnRCT representsanexperimental formofcohortstudy.

e.g.,24hourspostoperatively,5yearfollowup.
Efficacy=(riskcontrol riskintervention)/(riskcontrol)=RRR

WhatisaRiskRatio?
Aratioisthequotientoftwonumbers Riskratio=RiskingroupA RiskinGroupB Riskratiorangesfrom0toinfinity()with1=nullvalue InmostepidemiologicalstudiesGroupAandGroupB

2X2Table
Drug X Outcome (+) Outcome () Total A C A+C Drug Y B D B+D Total A+B C+D A + B + C+ D

differbywayofaselfselectedornaturalseriesofevents
Whereasinarandomizedcontrolledtrial(RCT)GroupA

andGroupBdifferinarandomizedyetverycontrolled mannerwitheachgroupreceivingaspecifictreatment
Riskratioallowsforacomparison oftheriskofthe

diseaseoroutcomeinGroupAversusGroupB.
Moreappropriateforhighincidenceconditions

Frequency or Proportion for Drug X = A/(A+C) and Frequency or Proportion for Drug Y = B/(B+D) Risk for Drug X = A/(A+C) and Risk for Drug Y = B/(B+D) Risk Ratio = [A/(A+C)] [B/(B+D)]

NurseControlledAnalgesia
Neonate Serious Adverse Event (+) Serious Adverse Event () Total 13 497 510 Older 1 Month 26 9543 9569 Total 39 10049 10079

HypothesisTesting
InanRCTversus inaprospectivecohortstudy RCT Ho:P1 P0 =0andHa:P1 P0 0
P =proportionofthestudygroupwiththeoutcome

CohortStudyHo:RR=CI1/CI0 =1andHa:RR=CI1/CI0 1
RR =riskratio CI =cumulativeincidenceofthediseaseoroutcomeincohort

Risk for Neonate = 13/510 = 0.025 or 2.5% Risk for Older 1 Month = 26/9569 = 0.0027 or 0.27% Risk Ratio or Relative Risk = 0.025/0.0027 = 9.4 (4.8,18.2)
Howard et al., Nurse-Controlled Analgesia (NCA) Following Major Surgery in 10000 Patients in a Childrens Hospital, Pediatric Anesthesia 2010:20:126-134

AcohortstudyandanRCTareessentiallyaskingthesame

questions:whatistheeffectoftheexposure(treatment) onthedisease(outcome)and isitsignificant?

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RiskDifferenceandthe NumberNeededtoTreat
RiskDifference orCumulativeIncidenceDifference(CID)=

PostoperativeNausea&Vomiting
Clonidine Caudal (2 mcg/kg) (+) PONV () PONV Total PONV Risk 10 (50% incidence) 10 20 10 20 = 0.5 Hydromorphone Caudal (10 mcg/kg) 18 (90% incidence) 2 20 18 20 = 0.9

CI1 CI0 with1=thoseexposedand0=unexposed

AbsoluteRiskReduction(ARR)inclinicalepidemiology NumberNeededtoTreat (NNT)=1/(CI1 CI0)=1/ARR NumberNeededtoHarm (NNH)inthecaseofan

untowardevent(stroke,MI,death)oranadverseside effect(respiratorydepression,persistentparesthesia)
Farmoregermanethanasimplepvalue

Fishers exact test P = 0.014 (because a cell size < 5) Risk ratio (RR) = 0.9 0.5 = 1.8 PONV 1.8 times as likely Absolute risk reduction (ARR) = 0.9 0.5 = 0.4 or 40% Number needed to treat (NNT) = 1 0.4 = 2.5 patients

KetamineandHallucinations
Incidenceandriskofhallucinationsinawakeorsedated

3. CaseControlStudy
Istheobservedoutcomerelatedtotheexposure? Outcomeordiseaseisobservedfirst:E D(backward) Singleoutcomewithmultiplepreviousexposures Casesaresubjectswith theoutcomeofinterest Controlsaresubjectswithout theoutcomeofinterest Controlssampledfromthesamesourcepopulationbut

patientsnot receivingabenzodiazepinewashigh:
Riskof10.43%versusriskof5.70% 4.73%riskdifference Riskratioof2.32 (95%CI,1.09 4.92) Numberneededtoharm =1 (0.1043 (0 10430.057) 0 057)=21

Inanesthetizedpatientstheincidenceofhallucinationswas

lowandindependentofbenzodiazepineadministration:
Riskof0.76%versusriskof0.41% 0.35%riskdifference Riskratioof1.49 butnot significant(95%CI,0.18 12.6) Numberneededtoharm =1 (0.0035)=286
Elia & Tramer, Pain 2005;113:61-70

mustbesampledindependentlyoftheirexposurestatus
Lesscostlyandlesstimeconsumingthancohortstudy Efficientforrare outcomes Cannot generateanoverallriskorrateestimatebut

insteadanoddsratio isdeterminedandnot ariskratio

ProbabilityversusOdds
Probability(P)
Numberoftimesanoutcomeoccursoutofthetotal#of

2X2TableRevisited
Outcome (+) Cases with Disease Exposure (+) Exposure () A C Outcome () Controls w/o Disease B D

attempts
Rangesfrom0to1 EpiBeautywon30of50races Pofwinning gis30/50 / =0.60

Odds
P (1P)=probabilityofwinning probabilityoflosing Rangesfrom0toinfinity() Horserace: Oddsofwinning=0.6/(10.6)=0.6/0.4=1.5to1

OddsRatio
Ratiooftheoddsofthediseaseorclinicaloutcomewith

theexposureversus withouttheexposure

A and C are selected based on disease (outcome) status We cannot calculate the rate or risk of getting the disease (outcome) because we do not know the denominator (size of study population) Odds = number of cases with disease number of non-cases of disease Odds with exposure = (A/B) and odds without exposure = (C/D) Odds ratio with versus without exposure = (A/B) (C/D) = AD/BC

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PerioperativeQuestionsThatCouldBe AddressedbyaCaseControlStudy
Rareoutcomeswithseveralpossibleexposureriskfactors Whataretheriskfactorsformalignanthyperthermia? Isepiduralcatheterplacementundergeneralanesthesia

PatientControlledAnalgesiabyProxy
ThresholdEvent(TE)=O2saturation, bradypnea,&oversedation TE(+) PCAProxy y PCAw/oProxy 21 37 TE() 124 120 Total 145 157
Exposure odds ratio = (21 X 120) (124 X 37) = 0.54 (0.30 0.99) 2 test P < 0.015 versus 2 test P = 0 0.045 045 act actual al

ariskfactorforpostoperativeparaplegia?
Doesp pulseoximetry y and/or / endtidalcapnography p g p y

decreasetheriskofperioperative brainanoxia?
Doesneonatalanesthesiacauselatercognitivedeficits? Isnurseorparentproxypatientcontrolledanalgesia

RescueEvent(RE)=naloxone,airway intervention,&escalationofcare(toICU) PCAProxy PCAw/oProxy RE(+) 11 1 RE() 134 156 Total 145 157

(PCA)ariskfactorforrespiratorydepressionorarrest? Examplesoffertilegroundforcasecontrolstudies:
ASAClosedClaimsProject PediatricPerioperativeCardiacArrest(POCA)Registry MulticenterPerioperativeOutcomesGroup(MPOG)

Exposure odds ratio = (11 X 156) (134 X 1) = 12.8 (1.6 100.0) 2 test P < 0.015 2 test P = 0.005 actual

Voepel-Lewis et al., The Prevalence of Risk Factors for Adverse Events in Children Receiving Patient-Controlled Analgesia by Proxy or Patient-Controlled Analgesia after Surgery Anesthesia & Analgesia 2008;107:7-75

TwoOtherTypesofStudyDesign
Nestedcasecontrolstudy
Acasecontrolstudythatissetornestedwithinanexisting

SourcesofErrorinStudyDesign
RandomError:simplevariabilityinthesampledata SystematicError or Bias:3basictypes

cohortstudyorevenaninterventionstudylikeanRCT Greatestadvantageofnestedstudyisthatcasesandcontrols comefromthesamepopulation,whichavoidsselectionbias.

Clusterrandomizedtrial
Studysubjectsinaninterventionstudynaturallyoccurin

separategroupsorclusters(e.g.,geographiclocation)
Ratherthanrandomizeindividualstotreatment,randomize

basedupontheclusters(e.g.,hospital,surgicalservice)
Oftenappliedforconvenienceoroutofnecessity Deceptivelysimpletoconstructanddataanalysisiscomplex

SelectionBias Individualshavedifferentprobabilitiesofbeinginthestudy samplebaseduponrelevantcharacteristics(EandD) Differential Diff ti lloss l to t follow f ll up including i l di in i anRCT InformationBias Misclassificationofexposureand/ordisease(outcome)status, validityofdiagnosisasmeasuredbysensitivityandspecificity Observerbiasismitigatedviablinding(masking)inanRCT Confounding Effectoftheexposureofinterestismixedtogetherwithand confusedbytheeffectofoneormoreothervariables

RandomErrorversus SystematicError
Estimate (variable) = parameter + random error + systematic error

ExampleofConfounding
CADPresent VitaminE Supplement (+) VitaminE Supplement () 50 66 CADAbsent 500 384

As N increases, the SEM decreases and thus 95% CI becomes narrower

Rothman, Epidemiology: An Introduction (2002), pg. 95

1000subjects,age5055years,followedfor15years: RiskwithvitaminEsupplementuse=50/550=0.09(9%) Riskw/ovitaminEsupplementuse=66/450=0.15(15%) Riskratio=0.09/0.15=0.62;P=0.008 Riskoddsratio(crude)=(50X384) (500X66)=0.58 VitaminEappearscardioprotectivebutisitreally?

Fitzmaurice, Confused by Confounding? Nutrition 2003; 19:189-191

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ExampleofConfounding(Contd)
Smokers
CADPresent VitaminE Supplement (+) VitaminE Supplement () 10 50 CADAbsent 40 P = 0.85 200 There is no association between vitamin E supplement and CAD after controlling for the effects of smoking. Stratum risk odds ratio = (40 X 184) (460 X 16) = 1.0 P = 0.88 Stratum-specific odds ratios are similar in magnitude Stratum risk odds ratio = (10 X 200) (40 X 50) = 1.0

Interactionversus Confounding
Confounding (fromtheLatinconfundere meaningtomix

NonSmokers
CADPresent VitaminE Supplement (+) VitaminE Supplement () 40 16 CADAbsent 460 184

together):anundesirabledistortionoftheassociation betweenanexposure(E)anddisease(D)broughtaboutby extraneousfactors (C1,C2,etc). Interaction:effectmodificationwherebytheeffecton theresponse p (y)ofoneexplanatory p yvariable(x) ( )depends p onthelevelofoneormoreotherexplanatoryvariables Twowayortwofactormodel:y=b0+b1x1 +b2x2+b3x1x2
Thejointeffectoftwoormoreexplanatoryvariablesislarger

orsmallerthanthesumoftheparts.
b3x1x2 =interactiontermtestedwithH0:b3 =0

Synergism (fromtheGreeksunergos meaningworking

Fitzmaurice, Confused by Confounding? Nutrition 2003;19:189-191

together)isatypeofbiological interaction.

Interactionversus Confounding
Interaction
Smoking(C)amplifies the

Confounding
Smoking(C)confuses the

PotentialConfounder
Foravariabletobeconsideredaconfounderofan

riskofthromboembolic disease(D)withoral contraceptiveuse(E). Interactionexistsbetween theinterdependentrisk factorsofsmoking(C)and oralcontraceptiveuse(E). Thiseffectmodificationis biologicalsynergism.

relationshipbetween alcoholconsumption(E) andlungcancer(D). Sincealcoholandsmoking arerelated,and smoking(C) isanindependentrisk factorforlungcancer(D). Thisextraneousfactor resultsinconfounding.

association,itmustsatisfythreebasicconditions:
1. Thepotentialconfoundermustbeassociatedwith

thediseaseoroutcomeofinterest.
2 Thepotentialconfoundermustbeassociatedwith 2.

theexposureofinterest.
3. Thepotentialconfoundermustnot bean

intermediatevariableinthecasualrelation betweentheexposureanddiseaseoroutcome (i.e.,itisnotpartofthewebofcausation).

Fitzmaurice, Confused by Confounding? Nutrition 2003;19:189-191

Woodward, Epidemiology: Study Design and Data Analysis (2005) Rothman, Greenland, & Lash, Modern Epidemiology (2008)

BasicWaystoReduceConfounding
Randomization Restriction Matching Weighting Stratification St tifi ti Regression Propensityscores Instrumentalvariables Analysisofcovariance(ANCOVA)
Wunsch, Linde-Zwirble & Angus, Journal of Critical Care 2006;21:1-7

TechniquestoAdjustforConfounding inObservationalStudies

Wunsch, Linde-Zwirble & Angus, Journal of Critical Care 2006;21:1-7

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Randomization
Randomizationisonlyapplicableinanexperimental

Restriction
Oftenappliedinadditiontorandomization Studyinclusion andevenmoresostudyexclusion

studyinwhichexposureisassignedorcontrolled. Withalargeenoughsamplesize(N),randomization producestwoormorestudygroupswithnearlythe samedistributionofthestudysubject(patient) characteristicsthatareplausibleconfoundingvariables. Randomizationalsoreducesconfoundingbyanyother unidentified factorsorvariables. Butrandomizationisnotalwaysfeasibleorethical, especiallyinretrospectivestudiesorlongitudinal observationalstudies.

criteriacontrolfortheidentified confounders.
Tradeoffisthatstudyfindingsareassuredlyvalid

onlyfortherestrictedstudypopulationfromwhich thestudysampleisdrawn. Thisexternalvalidityissuemustbeconsideredin generalizingfindingstoamorediversepopulation. Oneofthechallengesofapplyingevidencebased medicineinonesdailypractice:Arethesestudy findingsapplicabletomygivenpatient?

Matching
Individualsfromthetwostudygroupsarepaired

AssessingforConfoundinginRCTI

baseduponthepresumedconfoundingvariables.
Allowsforevendistributionofpotentialconfounders Mostoftenappliedincasecontrolstudies Age, A sex,racearecommonmatching t hi variables. i bl Expensiveandtimeconsuming Reducesthepowerofthestudybecausenotallstudy

Inalmostallclinicaltrials,thestudygroupsarecompared usingparametricornonparametricstatisticsforany differencesinbaselinecharacteristics:

Demographics Anthropometrics Otherpertinentclinicalvariables

Absenceofstatistically statisticallysignificant significantdifferenceisoften takentoindicatestudygroupcomparabilityandalackof confoundingbythesecovariates.

Moreconservativepvalueof0.20maybebetter Residualcofoundingmaybepresentdespitep>0.05

subjectscanbematched Doesnotassuredlycontrolforotherconfoundersand infactcanintroducehiddenconfounding RestrictioninanRCTisalooseformofmatching.

Theresultsofastatisticaltestforsignificantdifference thealmightypvalue dependonthesamplesize(N):

AsN ,anyobserveddifferenceachievesap<0.05 WithalargerN,thereisagreaterlikelihoodofbaselinedifference

AssessingforConfoundinginRCTII

Stratification
Oneofthemosteffectivetechniquesforadjustingforthe

Ho:1 =2 with=populationproportion(parameter)or 1 =2 with =populationmean(parameter) Horejectedifp<0.05 ButinassessingforconfoundinginanRCTourrequired assumptionortheHo:Anyimbalancebetweenthestudy groupsinabaselineclinicalfeatureorriskfactorissimply d tochance due h and dnotrandomization d i i Butsuccessful randomizedallocationrequiresthatany observedimbalancemustbeduetochance TheHothuscannotberejected(!)evenwithap<0.05 Anstatisticallysignificantimbalanceinabaselinerisk factorinandofitselfdoesnot reflecttheamountof confounding insteadweneedtodeterminehowmuch ofaneffect doestheriskfactorhaveontheoutcome?
Rothman, Epidemiology: An Introduction (2002), page 209

effectsofconfoundinginananalysis
Associationisevaluatedwithindistinctgroups,orstrata,

comprisedofindividualswhoarerelativelyhomogenous intermsoftheconfoundingvariable. Acrudeoverallestimateofassociationisadjusted forthe confoundingvariables. Generatedbytakingaweightedaverageofthestratum specificestimatesofassociation. Requiresstratumspecificestimatesofassociationtobe uniformacrossthelevelsofthepotentialconfounder. Otherwisestratumspecificestimatesshouldbereported.

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AssessingforConfoundinginRCTIII

CochranMantelHaenszelMethod
Oneofthemostwidelyusedmethodsforcombiningor poolingstratumspecificestimatesofassociation Generatesanadjustedestimateofassociation(oddsratio) Canalsogenerateanadjustedestimateofriskratio
Disease or Outcome (+) Exposure (+) Exposure () aj cj Disease or Outcome () bj dj nj =totalnumberofobservations inthejth table=(aj +bj+cj +dj)

Betterapproachfordichotomous (binary)outcomes: designwithstudysubjectrandomizationandrestriction

1. Controlfortheconfounderusingconventionalstudy 2. Determinethepotentially confoundedcrude results 3. Stratifytheresultsonthepotentialconfounding

variables i bl ( (e.g.,ageand dgender) d )and dthen h determine d i pooledMantelHaenszel adjusted results 4. Comparethecruderesultswiththeadjustedresults 5. Ifthetwoestimatesarecomparable concludethat confoundingisnotpresent 6. Iftwoestimatesaremeaningfullydifferent (>10%) concludethatconfoundingispresent

jlevelsofthestratificationvariable(e.g.,twostrataformaleandfemale) Createaseriesofstratumspecific2X2contingencytables jtotalnumberof2x2contingencytables

ExampleofMantelHaenszelMethodI
EntireCohort
CAD(+) Vitamin ESupplement(+) Vitamin ESupplement() 50 65 CAD() 501 384

ExampleofMantelHaenszelMethodII
Smoking and Pregnancy Outcome among African-American and White Women: The Risk for a Small for Gestational Age (SGA) Newborn

Crude odds ratio = 0.59 (95% CI, 0.40 0.87) CONFOUNDING MH adjusted odds ratio = 1.03 (95% CI, 0.64 1.65) Stratum odds ratio = 1 1.12 12 (95% CI, 0.54 2.34) INTERACTION is not present between vitamin E supplement and smoking because the stratum-specific odds ratios are not significantly different. Stratum odds ratio = 0.97 (95% CI, 0.53 1.78)

EntireCohort
SGA(+) Smokedduring pregnancy (+) Smokedduring pregnancy () 105 105 SGA() 517 1317

Crude odds ratio = 2.55 (95% CI, 1.91 3.40) NO CONFOUNDING MH adjusted odds ratio = 2.56 (95% CI, 1.89 3.45) Stratum odds ratio = 1.28 (95% CI, 0.76 2.15) INTERACTION may be present between race and smoking b/c the stratum-specific odds ratios are significantly different Stratum odds ratio = 3.74 (95% CI, 2.52 5.56)

Smokers
CAD(+) Vitamin ESupplement(+) Vitamin ESupplement() 11 49 CAD() 40 200

AfricanAmericans
SGA(+) Smokedduring pregnancy (+) Smokedduring pregnancy () 21 64 SGA() 180 702

NonSmokers
CAD(+) Vitamin ESupplement(+) Vitamin ESupplement() 39 16 CAD() 461 184

Whites
SGA(+) Smokedduring pregnancy (+) Smokedduring pregnancy () 84 41 SGA() 337 615

Fitzmaurice, Adjusting for Confounding, Nutrition 2004; 20:594-596

Modified from Savitz et al., Epidemiology 2001;12:636-642

Regression
Whentherearemanypotentialconfoundingvariables,(k),

MethodsofRegressionI
Simplelinearregression:singlecontinuousoutcome

theresultingstrata(2k)havetoofewindividualsto generateapreciseestimateofassociation. Alternatively,estimatetheexposureeffectofinterestusing aregressionmodelforthedependenceofthedisease (outcome) ( )onthep primary yexposure p andany ypotential p confoundingvariables.
AssesstheeffectoftheuseofvitaminEsupplementsonCAD,

variable(y)andasinglepredictorvariable(x)
y=b1x1 +b0 + b1 =slopeandb0 =interceptand =error(y)

Multiplelinearregression:singlecontinuousoutcome(y)

butinsteadmultiplepredictorvariables(x1, 1 2 2,3 3k k)
y=b0+b1x1 +b2x2 +b3x3 ++bkxk+

whilecontrollingfororadjustingfornotonlysmokinghistory butalsootherpotentialconfounders(e.g.,age,BMI,physical activity,LDL,HgbA1C)

Requiresassumptionsbemetandalargersamplesizeand

Thepredictorvariables(x1,x2,x3 )canbecontinuous

doesnotensureconfounderdistributionsarecomparable
Fitzmaurice, Confounding: Regression adjustment, Nutrition 2006;22:581-583

(age),ordinal(ASAstatus),and/ordichotomous(sex)ina linearregressionmodel. But youneedatleast10observations(studysubjects)for eachxvariableplacedinthemodelplusother assumptionsmustbemet

Vetter: Epidemiology and Clinical Research

ThreeStudiesAddressingtheEffectofMaternalFish IntakeandSmokingontheChildNeurodevelopment
Afteradjustingfor28potentialconfounders,maternalseafoodintakeduring

Linearregressionmaynotalwayswork
Simpleandmultiplelinearregressionisappliedwhen

pregnancyof<340gmperweekwasassociatedwithincreasedriskoftheir childrenbeinginthelowestquartileforverbalintelligencequotient(IQ): Noseafoodconsumption,oddsratio[OR]148,95%CI116190(N=11,875).

HibblenJRetal:Maternalseafoodconsumptioninpregnancyandneurodevelopmentaloutcomesin

theoutcomevariable(y)iscontinuous.
Butwhathappensif: 1. Theoutcomevariable(y)isnotlinearlyrelatedtothe

childhood(ALSPACstudy):Anobservationalcohortstudy.Lancet2007;369:57885.

Usingmultivariatelinearregression,in4yearoldchildrenbreastfedfor<6

months,maternalfishintakesof>23times/weekwereassociatedwith significantlyhigherscoresonseveralMcCarthyScalesofChildrensAbilities (MSCA)subscalescomparedwithintakes< 1time/week(N=392).

MendezMAetal:Maternalfishandotherseafoodintakesduringpregnancyandchildneurodevelopment

predictorvariables(x)? p ( )
2. Theoutcomevariable(y)isriskthatrangesfrom0to1? 3. Theoutcomevariable(y)isnotcontinuousbutinstead

atage4years.PublicHealthNutrition2008;12(10):17021710.

Usingmultivariatelinearregression,maternalsmokingduringpregnancy(in

dichotomous/binary(0=no,1=yes)likeriskofdeath?
Thenyouapplyalogisticregressionmodel

cigs/day)wasassociatedwithadecreaseinchildsMSCAglobalcognitive score[=0.60,(95%CI:1.10;0.09)]inoffspringatage4years(N=420).
JulvezJetal:Maternalsmokinghabitsandcognitivedevelopmentofchildrenatage4yearsinapopulation

basedbirthcohort.InternationalJournalofEpidemiology2007;36(4):82532.

LogisticFunction
y=1/[1+exp(b0 b1x1)]

MethodsofRegressionII
Simplelogisticregression:singlebinary(1=yes/0=no)

outcomevariable(y)andasinglepredictorvariable(x)
p=probabilityofoutcomeofinterest;odds=p (1p) logit(p) =loge (odds)=loge [p/(1p)]=loge (p)loge (1p) logit(p) =loge [p/(1p)]=b0+b1x1

oddsratio=log ge( (odds1/ /odds2)=log ge ( (odds1)log ge ( (odds2) oddsratio(withX1 =1comparedtoX1 =0)=eb0+b1x1

Multiplelogisticregression:binaryoutcome(1=yes/0=no)

butinsteadmultiplepredictorvariables(x1,2,3k)
logit(p) =loge [p/(1p)]=b0+b1x1 +b2x2 +b3x3 ++bkxk

x1
r=risk =1/[1+exp(b0 b1x1)]

oddsratio=eb0+b1x1+b2x2+b3x3++bkxk

Ordinalregression:rankorderedoutcome(1,2,3,4,5) Coxproportionalhazards:timetoaneventofinterest

ExampleofRegressionAdjustment
MaternalandPaternalRiskFactorsforCryptorchidismand Hypospadias:ACaseControlStudyinNewbornBoys
Factor CRYPT CrudeOR (univariate)
2.4(1.1,5.1) 0.7(0.4, 1.1)

ExampleofRegressionAdjustment
MaternalDietandtheRiskofHypospadiasandCryptorchidismintheOffspring
Controllingformaternalage,parity,education,&GYNdisease;paternalGUdisease&useofpesticides

CRYPT AdjustedOR (multivariate)

3.8(1.1,13.4) 0.4(0.2,0.9)

HYPOSPAD CrudeOR (univariate)

4.0(1.9,8.5) 4 1(1 4.1 (1.7, 7 9.8) 9 8) 5.5(1.8, 17.1)

HYPOSPAD AdjustedOR (multivariate)

3.6(1.6,8.1) 7 3(1.7, 7.3 (1 7 31.4) 31 4) 4.2(1.2,14.7) 3.8(1.8,8.2) 2.0(0.9,10.3)

Factor
Liver &otheroffal(>1/week) Fish(>1/week) Mostly marketfruit Friedfoods Smoked foods Plasticfood boxes/containers Mineralsupplement

CRYPT Crude
3.2(0.9,10.7)

CRYPT Adjust
5.2(1.3,14.2)

HYPOSPAD Crude
1.6(0.8,3.2) 3.5(1.0,11.9)

HYPOSPAD Adjust
2.3(1.0,5.3) 5.1(1.3,19.8)

Poormaternalhealth Vegetablerich diet(M) Lowbirthweight SGA Premature birth Currentsmoker Pesticide exposure Solvent exposure

2.0(1.0, 3.8) 2.0(1.1,3.9)

1.5(0.7,3.2) 2.5(1.2,5.3) 0.4(0.2,0.9) 0.5(0.3, 1.0) 0.5 (0.2,1.2) 0.5(0.2,1.1)

2.5(1.2,5.1) 4.5(1.4,13.9)

3.1 (1.5,6.6) 3.4(1.7,7.0) 3.8(1.1,13.4) 2.4(1.2, 4.8)

Inthepasttwodecades,concernhasbeenraisedoverapossibleincreaseindisordersofthemale reproductivetract, includingcryptorchidism,hypospadias, testicularcancer,andimpairedsemen quality.Ithasbeensuggestedthatthesedisordersareinterrelated andshareacommonetiology duringfetallife,describedasthetesticulardysgenesis syndrome(TDS).

Pierek et al., Environmental Health Perspectives 2004;112(15):1570-1576)

Thisstudysuggeststhat somematernaldietaryfactorsmayplayaroleinthedevelopmentof congenitaldefectsofthemalereproductivetract.Inparticular,ourdataindicatethat furtherresearch maybewarrantedontheendocrinedisruptingeffectsresultingfromthebioaccumulationof contaminants(fish,liver),pesticides(marketedfruit,wine)and/orpotentiallytoxicfood components (smokedproducts,wine,liver).

Giordano et al., Paediatric and Perinatal Epidemiology 2008;22:249-260

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CohortCovariateImbalances
Confounding by indication
P P P P P P P P P P P P P P P P P P P P P Population of patients prescribed an NSAID II I I II II I I I II I I
Younger Betterrenal function LowerBP Healthier Fewerdrugs

PropensityScores
Propensityscore=theprobability(0to1)thatasubject

wouldhavebeentreatedgiventheindividualscovariates
Intendedtoreduceselectionbiasand increaseprecisionin

Prescribers decisions

nonrandomized largescaleobservationalstudies
Collapseallofthebackgroundcharacteristics(X1,X2,.,Xp)

Prescribed ibuprofen (75%)

Older Worserenal function HigherBP Sicker Moredrugs

orconfoundingcovariatesintoasinglecompositevalue
Propensityscore(PS)isgeneratedusinglogisticregression
PS=P(Z=1|(X1,X2,.,Xp)}Z=1ifexposed,Z=0ifnotexposed PS=exp(b0 +b1x1 +b2x2 +b3x3 ++bkxk)

CC C CC

Covariate imbalances resulting from non-randomized treatment assignment to ibuprofen and celecoxib

1+exp(b0 +b1x1 +b2x2 +b3x3 ++bkxk)

Predictivestrength:CstatisticfromROCcurve=0.5to1.0
Rubin, Annals of Internal Medicine 1997;127:757-763 DAgostino, Statistics in Medicine 1998;17:2265-2281 Fitzmaurice, Confounding: Propensity score adjustment Nutrition 2006;22:1214-1216

Prescribed celecoxib (25%)

Modified from Perkins et al., Pharmacoepidemiology and Drug Safety 2000;9:94 Cavuto, Bravi, Grassi & Apolone, Drug Development Research 2006;67:208-216

PropensityScores
Balancingscores(applestooranges applestoapples) Canonly adjustforobserved confoundingcovariates Applicableforlargescalepatientregistrybasedclinical

NonOverlapofPropensityScores
Thenonoverlapofthe exposurepropensity scoredistributionamong treatedanduntreated studysubjectsmakesthe useofpropensityscores questionable. Inthisexamplesubjects withverylowpropensity scorearenevertreated whilesubjectswithvery highpropensityscoreare alltreated.

cohortstudiesoflongitudinaloutcomes
Createsaquasirandomizedstudy equalpropensity

score equallikelihoodtobetreatedortobeacontrol
Requireslargesamplesizestoassurebalance Requiresadequateoverlapofpropensitydistributions Randomizationtendstobalancetheunmeasuredcovariates
Propensityscoremodelingisthusnot intendedforRCTs,but

propensityscorescanpossibly beusedforANCOVA
Blackstone, Journal of Thoracic and Cardiovascular Surgery 2002;123:8-15 Glynn, Schneeweiss & Strmer, Basic & Clinical Pharmacology &Toxicology 2006;98(3):253-259 Rubin, American Journal of Ophthalmology 2010;149(1):7-9

Glynn, Schneeweiss & Strmer, Basic & Clinical Pharmacology &Toxicology 2006;98(3):253-259

ExampleofUsePropensityScores
PerioperativeUseofDobutamineinCardiacSurgeryandAdverseCardiacOutcome:PropensityadjustedAnalyses. Fellahi,JeanLuc;Parienti,JeanJacques;Hanouz,JeanLuc;Plaud,Benoit;Riou,Bruno;Ouattara,Alexandre;Anesthesiology. 108(6):979987, June2008.

ExampleofUsePropensityScores
PerioperativeUseofDobutamineinCardiacSurgeryandAdverseCardiacOutcome:PropensityadjustedAnalyses. Fellahi,JeanLuc;Parienti,JeanJacques;Hanouz,JeanLuc;Plaud,Benoit;Riou,Bruno;Ouattara,Alexandre;Anesthesiology. 108(6):979987, June2008.

Wehypothesized thatanadverse postoperativeoutcomewould occurmorefrequently whenuse ofcatecholamines issimplybased ontheclinical judgment ofthe cardiac di anesthesiologists. th i l i t Thecurrent prospectiverisk adjustedobservationalstudywas thereforedesigned toestimate theinfluenceofperioperative catecholaminesadministrationon bothmajorcardiacmorbidityand mortalityafterelectiveadult cardiacsurgery withCPB.
Baseline CharacteristicsandPostoperative OutcomeofPatients UndergoingConventional CardiacSurgerywithoutandwithPerioperative Administration ofCatecholamines ComparisonofVariablesPredictingtheUseofCatecholaminesandIncludedinthe PropensityScorebefore andafterMatching

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ExampleofUsePropensityScores
PerioperativeUseofDobutamineinCardiacSurgeryandAdverseCardiacOutcome:PropensityadjustedAnalyses. Fellahi,JeanLuc;Parienti,JeanJacques;Hanouz,JeanLuc;Plaud,Benoit;Riou,Bruno;Ouattara,Alexandre;Anesthesiology. 108(6):979987, June2008.

InstrumentalVariablesAnalysis(IVA)
Covariateanalysiscannot adjustforpotentialconfounding

variablesthatareunknown ornoteasilyquantifiable.
IVAexploitsquasiexperimentalvariationintreatment

assignmentthatisincidentaltothestudiedhealthoutcome.
ThreeassumptionsforIVA:

Catecholamines:Crude andAdjustedEffectsforMajorCardiacMorbidityandGlobal InhospitalMortalityEndpoints

1. 2. After controlling for other risk factors, the perioperative use of catecholamines was associated with increased major cardiac morbidity, regardless of the propensity score method used. After adjusting for the propensity score, the administration of perioperative catecholamines was not significantly associated with the risk of intrahospital mortality.

1. TheIVmustpredicttreatmentbutthatpredictiondoesnot havetobeperfect.AnIVthatdoesapoorjobofpredictionis saidtobeweak. 2. AvalidIVwillnotbedirectlyrelatedtooutcome,except throughtheeffectofthetreatment. 3. AvalidIVwillalsonotberelatedtooutcomethrougheither measuredorunmeasuredpaths.

Johnston, Gustafson, Levy & Grootendorst, Statistics in Medicine 2008; 27:15391556 Rassen et al., Journal of Clinical Epidemiology 2009;62:1226-1232

CausalRelationsinIVA
Generalinstrumentalvariable analysis(IVA)model
Instrument Variable(Z) Unmeasured confounders(C)

InstrumentalVariablesModel
Twostageleastsquaresregression

ExampleofIVAwithphysician specificprescribingpreference

1. Y=0 +1X+1}Y=outcome,X=exposure 2. X=0 +1Z+2}X=exposure,Z=instrumentvariable Substitutingequation2intoequation1: Y=0 +1 (0 +1Z+2)+1 Yi =0 +1Zi +i Estimatedirecttreatmenteffect(1)oftreatment(Ti)on outcome(Yi):1 =1/1
Examplesofinstrumentalvariables
Physicianprescribingpreference forNSAID Smokingcessationprograminpregnantmothers Distancetohospitalwithcardiaccatherizationlaboratory

Treatment(X)

Outcome(Y)

Bennett, Methods in Neuroepidemiology 2010;35(3):237-240 Brookhart, Wang, Solomon & Scheeweiss, Epidemiology 2006;17(3):268-275

Bennett, Methods in Neuroepidemiology 2010;35(3):237-240 Schneeweiss et al., Arthritis & Rhematism 2006;54(11):3390-3398 Brookhart, Rassen & Schneeweiss, Pharmacoepidemiology and Drug Safety 2010;19:537-554

AnalysisofCovariance(ANCOVA)
Comparesseveralmeans(likeanANOVA)butadjustsfor

JohnsHopkinsBloombergSchoolofPublic Health'sOPENCOURSEWARE (OCW)Project

providesaccesstocontentoftheSchool'smostpopularcourses.As

theeffectofoneormoreothervariables(covariates) Thesecovariatescan bethepresumedconfounders. Mayusethepropensityscoreasasinglecovariate(?) Twokey ybut oftenviolatedassumptions p foranANCOVA:

Independenceofthecovariateandexperimental effect(x) Homogeneityofregressionslopes:therelationshipbetween

challengestotheworld'shealthescalatedaily,theSchoolfeelsamoral imperativetoprovideequalandopenaccesstoinformationandknowledge abouttheobstaclestothepublic'shealthandtheirpotentialsolutions.

FundedbytheWilliamandFloraHewlettFoundation IntroductiontoBiostatistics:

htt // http://ocw.jhsph.edu/courses/introbiostats/ jh h d / /i t bi t t /
MethodsinBiostatisticsI:

thecovariateanddependentoutcome(y)istrueforallofthe subgroupsofstudysubjects
UseofANCOVAisquitecontroversial itisnotaquickfix.
Miller & Chapman, Journal of Abnormal Psychology 2001;110:40-48 Leech, Barrett, & Morgan (2005): SPSS for Intermediate Statistics: Use and Interpretation (2nd edition) Field (2009): Discovering Statistics Using SPSS (3rd edition)

http://ocw.jhsph.edu/courses/MethodsInBiostatisticsI/
MethodsinBiostatisticsII:

http://ocw.jhsph.edu/courses/methodsinbiostatisticsii/
FundamentalsofEpidemiologyI:

http://ocw.jhsph.edu/courses/FundEpi/
FundamentalsofEpidemiologyII:

http://ocw.jhsph.edu/courses/fundepiii/

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ActivEpi:www.activepi.com
ActivEpi isacollectionof

OpenEpi2.3.1:www.openepi.com

innovativetoolsforlearning epidemiology. Multimediaapproachto learningbasicandsome intermediateepidemiology Extensiveseriesofonline, downloadablePowerPoint presentations(free) EpiforClinicianssection providesapopulationbased perspectiveonclinical medicine.
A Collaborative, Open-Source Project in Epidemiologic Computing

EpiInfo3.5.3:www.cdc.gov/epiinfo
Physicians, nurses, epidemiologists, and other public health workers lacking a background in information technology often have a need for simple tools that allow the rapid creation of data collection instruments and data analysis, visualization, and reporting using epidemiologic methods. Epi Info, a suite of lightweight software tools, delivers core ad-hoc epidemiologic functionality without the complexity or expense of large, enterprise applications.

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