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STUDYDESIGNS:CrosssectionalCasecontrol

Beforeafter,ValidationProf.JudithM.Sison,MD,MPH,FPOGS

2008 J.M.Sison, MD, MPH, FPOGS

EPIDEMIOLOGICSTUDY

A.Observational Crosssectional

Samplingw/regardtoDisease/Effect

ExposureofcharacteristicsATtimeofstudy

Casecontol Samplingw/regardtoDisease/

Effect Retrospectivehistoryofexposure

ofcharacteristicsPRIORtotimeofstudy

Cohort Samplingw/regardtoExposureor

Cause Prospective/Historical

B.Experimental NOTrandomized

Communitytrials Randomized

Clinicaltrials

OBSERVATIONALSTUDIES Crosssectional(Survey,Prevalence)

DiseasedescriptionDiagnosis&stagingDiseaseprocesses&mechanisms

CasecontrolCausesofdiseases Identificationofriskfactors

CohortProspective(Incidence)Causesofdiseases IdentificationofriskfactorsNaturalhistory,Prognosis

CohortRetrospectiveHistorical

CROSSSECTIONALSTUDY

CHARACTERISTICS:

Singledefinedpopulation PIOwelldefined Concurrentcontrol(fromsamepopulation)

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CROSSSECTIONALSTUDY

Bothdescriptive&analytical Donefordiseasesofslowonset&longduration

Generatehypothesis&preliminarytestingIdentifypotentialcause/sofanoutcome

CROSSSECTIONALSTUDY

EvidenceforcausalityisonlysuggestiveNocriteriainselectionofsubjectsconfoundersNocontroloverexposureNoblindingNostandardizedoutcomeassessmentNosimilar/comparableE&Egrps

Servesasaninitialstageofacohortstudy

CROSSSECTIONALSTUDY

USES: Determine&verifyanevent(Exploratorystudy)Establishbaselinedatatoquantifyhealthstatusofthecommunity

EvaluatehealthservicedeliveryDeterminemagnitudeofadisease

CROSSSECTIONALSTUDY

AdvantagesGeneralizabilityLesscostly:nofollowupLesstimeinvolved

DisadvantagesNotappropriate

Rare Shortdurationdiseases Diseasesw/periodsofexacerbations&remissions

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CROSSSECTIONALSTUDY

DESIGN:EO

EO

NNe

EO

EOFromthetargetpopulation,subjectsareselectedthen,exposureand

outcomearemeasuredatthesametime

CROSSSECTIONALSTUDY

TABLE:with outcome

w/o outcome

Exposed a b

Not exposed

c d

CROSSSECTIONALSTUDY

STATISTICS:OddsofbeingexposedaOOdds(E)=OROdds(E)=bO

OddsofbeingunexposedcOOdds(E)=OROdds(E)=dO

O O E 14 14 28 E 10 12 22

50

odds(E)OddsRatio=odds(E)e.g.Odds(E)=14/14=1Odds(E)=10/12=.833OR=1/.833=1.2

OddsofhavingOinEis1.2higherthantheE

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CROSSSECTIONALSTUDY

TodetermineiftheresanassociationbetE&O,wehave2choices:

CalculateprevalenceofOinEsubjects

andcompareittoprevalenceofOinE

CalculateprevalenceofEinsubjectsw/O

andcompareittoprevalenceofEinsubjO

PREVALENCE

Measureoffrequency Prevrate=

Interviewquestions Typeofmeasure

Doyoucurrentlyhaveasthma? Pointprevalence

Haveyouhadasthmaduringthelast(n)years? Periodprevalence

Haveyoueverhadasthma? Cumulativeincidence

INCIDENCE

MeasuresthenumberofNEWcasesduringaspecificperiod

Incidencerate=

BIASESinPREVALENCESTUDIES:TEMPORALCONSEQUENCES

Possible causes

Population free of disease but exposed/not exposed to possible causes

Development of cases overtime

Population of existing cases & noncases

Incidence Study Disease or Outcome

Prevalence Study

Past or present exposure to possible causes

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USESofPREVALENCERATE

Decidingtheneedforhealthcare Planningofhealthservices Investigatingpotentiallycausalrelationshipb/wriskfactors&adiseaseorprognosticfactors&anoutcome

Assigningaprobabilitythatapatienthasthecondition

PREVALENCEvsINCIDENCE

LOWPREVALENCEDISEASES:ShortlivedRapidlycuredFatalatanearlystage

HIGHPREVALENCEDISEASES:LowmortalityLowcurerateHighdisablingeffect

PREVALENCEvsINCIDENCE

HIGHINCIDENCEDISEASES:Common

LOWINCIDENCEDISEASESRare

CHARACTERISTICSofPREVALENCE&INCIDENCE

Characteristics Prevalence Incidence

Numerator All cases counted on a single survey or exam of a grp

New cases during a pd of time among a grp initially free of disease

Denominator All people examined, including cases & noncases

All susceptible people present at the beginning of the pd

Time Single pt Duration of the pd

How measured Prevalence (cross-sectional) study

Cohort

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CASECONTROLSTUDY

ExplorestherelationshipbetpriorEtoaspecificriskfactor&thelikelihoodofdevelopingaparticulardisease.

Retrospectivestudythatcomparesagrpofcases&1grpofcontrolsw/respecttoacurrentorpreviousexposure

CASECONTROLSTUDY

CHARACTERISTICS: observationalwelldefinedpopulation,specific

outcomeandfactor/s Comparativethecasesandthecontrols Retrospectivelookbacktofindwhatmaycause

theeffect Analyticrelationshipofoutcometoprobable

cause/s

CASECONTROLSTUDY

Populationbasedsampling Incidentcases

LessexpensiveMaybecompletedmorerapidly

CASECONTROLSTUDY

Cases:hospitalrecords,surveillancesystems,deathcertificates

Controls:sampledfrompopulationthatgaverisetothecasesHospitalbased

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SELECTIONCRITERIAforHOSPITALBASEDCONTROLS

TODO:

VariousdiagnosticgroupsnospecificRFisoverrepresented

Patientsw/acuteconditionsearlierEcouldnothadbeeninfluencedbythecondition

TOAVOID:

Patientswhohavemultipleconcurrentconditions

Patientsw/dxknowntoberelatedtotheRiskFactorofinterest

CASECONTROLSTUDY

USES/APPLICATIONS:

Exploringforprobablecauses Determiningharmfulagentsthatcouldhavecausedapresentcondition

Appropriatefordiseases:RareChronicorwithlonglatency

CASECONTROLSTUDY

WeaknessRecallbiasSelectionbiasValidityissue

MatchingconfoundingormixingtheeffectsofEtotheriskfactor

statisticalprecisionofestimatesallowingsmallersamplesize

Timeconsuming

CASECONTROLSTUDY

DESIGN:EOOEONEOOEOFromthesamepopulation,cases&controlareselectedthen,look

backintimetofindprobablefactor/sthatcouldhaveaneffecttotheoutcome

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CASECONTROLSTUDY

Exposed Unexposed

Case a b

Control c d

CaseExposureProblty=Exposedcases(a)Allcases(a+b)OddsofCaseExposure=Exposedcases(a)Allcases(a+b)

Unexposedcases(b)Allcases(a+b)=a/bOddsofControlExposure

=c/d

TABLE:

CASECONTROLSTUDY

STATISTICS:OddsofhavingtheEinCases&ControlacOdds(O)=Odds(O)=bd

odds(O)a/baxdOddsRatio==odds(O)c/dbxcOR:associationbetweenE&Ounlikelytohaveoccurredbychancealone

NESTEDCASECONTROLSTUDY

Population

DevdiseaseDoNOTdevdisease

CasesControl

NESTEDCASECONTROLSTUDY

Advantages: Dataobtainedbeforeanydiseasehasdevelopedrecallbias

Riskfactorsarerepresentedthanearlysubclinicaldisease

Moreeconomicaltoconductthancohortstudy

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BEFOREAFTERSTUDY

Transitiondesign Retrospectivemeasureoutcomethenassessexposure

Prospectiveapplyexposurethenmeasureoutcomefollowingexposure

Comparative2groupsonly

BEFOREAFTERSTUDY

MeasurementofoutcomescanNOTbeconcurrent Same/differentstudypopulation

Differentstudypopulation:WhenNe1isdonesimultaneouslyw/Ne2convertedtoaCOHORT

BEFOREAFTERSTUDY

CHARACTERISTICS: Studysubjectsideallymustbethesamebeforeand

after(issues:comparable,selectionbiasanddropouts)but,maybedifferent

Interventionideallybeundercontrolofinvestigator(standardized)butisnot,speciallyinHARMstudies

Outcomeisassumednotpresentatthestartofstudy(before)anddevelopedafterduetoexposure

BEFOREAFTERSTUDY

USES/APPLICATIONS: HARMstudiesEhappensatthestart&beyondthecontrolofinvestigator

Evaluatingeffect/sofnewpoliciesandstrategies(Mgt,BZ,marketing&sales)

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BEFOREAFTERstudy

DESIGN: SamepopulationOO

NNeEE

OO

beforeafter Twodifferentsubjectpopulations,identifyN1&

Ne1forbeforeandN2,Ne2forafter

BEFOREAFTERstudy

TABLE:

OUTCOME

presentabsent

Exposed a b

Not

Exposedc d

BEFOREAFTERSTUDY

STATISTICS: RiskofdevelopingoutcomeduetoexposureacRisk(E)=Risk(E)=a+bc+d

RiskRatio:R(E)RR=R(E)RR=riskofdevelopingOinEis>/

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ELEMENTSOFAVALIDATIONDIAGNOSTICTESTSTUDY

Diagnostictest Reference(gold)standard Reproducibility Blindandindependentcomparison Studysubjectssuspectstohavedisease Dataonaccuracyofthetest

LEVELSofEVIDENCEforRATINGACCURACYofDIAGNOSTICTESTS

Level1 Indptinterpretationofdxtestresult Indptinterpretationofgold/referncestdresultSubjectsarepatientssuspectedtohavediseaseReproducibilityofbothdx&stdtestsSamplesize:atleast50patientsw/disease&50patientsw/outdisease

Level24/5criteriaaremetLevel33/5Level42/5Level51/5Level6NONE

VALIDATIONREFERENCE(GOLD)STANDARD

TRUTH Globallyacceptablecriteriathatadiseaseis

presentorabsent(100%certainty) Couldbeanyoffollowing: Histopathology Anydiagnostictestresult Consensusofexperts

ValidationDiagnostictestunderstudy

Examination(radiography,laboratory,etc.)usetodeterminethepresenceofadisease

Onediagnosticoptionwhendoinggoldstandardisnotpossible

Performanceislowerthangoldstandard(

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VALIDATIONSTUDYSUBJECTS

Atthestartofstudy:NoonehasthediseaseAllaresuspects(withsignsandsymptoms)tohavethedisease

Ideally,allundergogoldstandardanddiagnostictests

ValidationReproducibility(method&results)

Boththegoldstandardanddiagnostictestsaredescribedindetailtoallowthosenotpartofthestudyduplicatetheprocedure

Generating,readingandinterpretingresultscanberepeatedanywhere

VALIDATIONINDEPENDENCE&BLINDING

Thedoerandreaderofthediagnostictestisnotinfluencedbyanddoesnotknowthereferencestandardresultandviceversa

Referencestandardanddiagnostictestsaredoneseparatelyandpreferablyconcurrently

VALIDATIONCOEFFICIENTOFAGREEMENT(VARIABILITY)

Intraobservervariabilityinreadings/interpretationdonebyonepersonatdifferenttimes

Interobservervariabilityinreadings/interpretationofanumberofpersons

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KAPPASTATISTIC Expressestheextenttow/ctheobservedagreementexceedsthatw/cwouldbeexpectedbychancealone(numerator)relativetothemostthattheobserverscouldhopetoimprovetheiragreement(denominator)

Kappa=observedagreement(OA)potentialagreement(PA)OA=observedchanceagreementPA=100%chanceagreement

Percentagreement=41+27/75x100=90.7%The2pathologists

agreedon90.7%ofthereadings

Grading Pathologist A Gr II Gr

III Grding Pth B

Gr II 41 3 44

GrIII 4 27 31

45 30 75

%chanceagreement=26.4+12.4x10075=51.7%

The2pathologistsexpectedtoagreebychanceon51.7%ofthereadings

Grading Pathologist A

Gr2 Gr3 Totals by B

Grding Pth B

Gr II

26.4 17.6 44 58.7%

GrIII

18.6 12.4 31 41.3%

Totals by A

45 30 75

60% 40%

Kappa=observedagreement(OA)potentialagreement(PA)

OA=observedchanceagreement

PA=100%chanceagreementKappa=90.7%51.7%=39%=0.81100%51.7%48.3%

Thereisasubstantialagreementbetweenthe2pathologists

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STRATIFIEDQUALITATIVEEQUIVALENTofKAPPANUMERICALVALUES

00.2Slight 0.20.4Fair 0.40.6Moderate 0.60.8Substantial 0.81Almostperfect

ValidationBasicTable

positive negative

positive True (+) a

False (+) b

negative False (-) c

True (-) d

REFERENCE (GOLD)STANDARD

DIAGNOSTIC TEST

ValidationBasicStatistics

Sensitivityasn=a+c

Specificitydsp=b+d

Accuracy a + d a + b + c + d

SENSITIVITY(Sn)

SnThegreatertheSn,themorelikelythetestwilldetectpersonsw/disease

UsefulclinicallytoR/Othepresenceofadisease(SnOUT)

Iftestishighlysensitive,anegativeresultwouldexcludethepossibilitythatthepatienthasthedisease

Percentageoffalse()errorislow

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SPECIFICITY(Sp)

SpThegreatertheSp,themorelikelythetestwilldetectpersonsw/odisease

UsefulclinicallytoR/Ithepresenceofadisease(SpIN)

Iftestishighlyspecific,apositiveresultwouldincludeorstronglysuggestthatthepatienthasthedisease

Percentageoffalse(+)errorislow

RELATIONSHIPBET.PREVALENCE&PREDICTIVEVALUE

Thehighertheprevalence,thehigherthePV Screeningprogramismostefficientifdirectedtoahighrisktargetpopulation

VALIDATIONDATAFORCLINICALAPPLICATION

Predictivevaluesad

Ppv=Npv=

a+bc+d

LikelihoodRatiosForpositiveresultfornegativeresultac

a+ca+c

LR(+)==Sn/1SpLR()==1Sn/Sp

bd

b+db+d

RELATIONSHIPBET.SPECIFICITY&PREDICTIVEVALUE

Anincreaseinspecificityresultsinamuchgreaterincreaseinpredictivevaluethandidthesameincreaseinsensitivity

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LIKELIHOODRATIO

ThebiggertheLR+,thestrongertheassociationbetweenhavinga+testresult&havingthedisease

ThesmallertheLR,thestrongertheassociationbetweenhavingatestresult&NOThavingthedisease

DoNOTvaryaccordingtoprevalenceofdisease

RECEIVEROPERATINGCHARACTERISTIC(ROC)CURVE

Ateverypt.alongthisdashedline,theLR+is1&a+testresultisequallylikelyforpersonsw/&w/odisease

AclinicallyusefuldxtesthasanROCcurvethatisfarfromthisdashedline

Towardthelefthandportion,thereissteepriseinSnw/onlymodestreductioninSp

Towardtherighthandportion,theslopeofROCisflatlittleimprovementinSnforasubstantialincreaseinSp

RECEIVEROPERATINGCHARACTERISTIC(ROC)CURVE

SummaryindexofoveralltestperformancecalculatedastheareaundertheROCcurve

HighestpossiblevaluefortheareaundertheROCcurveis1almostperfecttest

Thegreaterthearea,thebetterthetestperformance

RECEIVEROPERATINGCHARACTERISTIC(ROC)CURVE

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Formultilevelorcontinuousoutcometestresults,thechoiceofacutoffpointvaluethreshold+willSp(fewerfalse+)butalossofSn(>falseresultsormissedcases)

threshold+willSn(fewerfalse)butalossofSp(>false+results)

THANKYOU