11/29/08

EPIDEMIOLOGICSTUDY

A.Observational

STUDYDESIGNS:
Crosssectional
Casecontrol
Beforeafter,Validation

Prof.JudithM.Sison,MD,MPH,FPOGS

2008

Crosssectional

B.Experimental

NOTrandomized
Communitytrials

Randomized
Clinicaltrials

Casecontol

Samplingw/regardtoDisease/
Effect
ExposureofcharacteristicsATtime
ofstudy
Samplingw/regardtoDisease/
Effect
Retrospectivehistoryofexposure
ofcharacteristicsPRIORtotimeof
study

Cohort

Samplingw/regardtoExposureor
Cause
Prospective/Historical

J.M.Sison, MD, MPH, FPOGS

OBSERVATIONALSTUDIES

CROSSSECTIONALSTUDY

Crosssectional(Survey,Prevalence)
Diseasedescription
Diagnosis&staging
Diseaseprocesses&mechanisms

Casecontrol
Causesofdiseases
Identificationofriskfactors

CHARACTERISTICS:
Singledefinedpopulation
PIOwelldefined
Concurrentcontrol(fromsamepopulation)

CohortProspective(Incidence)
Causesofdiseases
Identificationofriskfactors
Naturalhistory,Prognosis

CohortRetrospectiveHistorical

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CROSSSECTIONALSTUDY
Bothdescriptive&analytical
Donefordiseasesofslowonset&long
duration
Generatehypothesis&preliminarytesting
Identifypotentialcause/sofanoutcome

CROSSSECTIONALSTUDY
Evidenceforcausalityisonlysuggestive
Nocriteriainselectionofsubjectsconfounders
NocontroloverexposureNoblinding
Nostandardizedoutcomeassessment
Nosimilar/comparableE&Egrps

Servesasaninitialstageofacohortstudy

CROSSSECTIONALSTUDY
USES:
Determine&verifyanevent(Exploratory
study)
Establishbaselinedatatoquantifyhealthstatusof
thecommunity
Evaluatehealthservicedelivery
Determinemagnitudeofadisease

CROSSSECTIONALSTUDY
Advantages
Generalizability
Lesscostly:nofollowup
Lesstimeinvolved

Disadvantages
Notappropriate
Rare
Shortdurationdiseases
Diseasesw/periodsofexacerbations&remissions

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CROSSSECTIONALSTUDY

CROSSSECTIONALSTUDY
DESIGN:
EO
EO
NNe
EO
EO

TABLE:

Exposed

Not
exposed

Fromthetargetpopulation,subjectsareselectedthen,exposureand
outcomearemeasuredatthesametime

with
outcome

w/o
outcome

CROSSSECTIONALSTUDY
STATISTICS:

Oddsofbeingexposed

aO
Odds(E)=OROdds(E)=
bO
Oddsofbeingunexposed

cO
Odds(E)=OROdds(E)=
dO

14

14 28

10

12 22
50

odds(E)
OddsRatio=
odds(E)
e.g.
Odds(E)=14/14=1
Odds(E)=10/12=.833
OR=1/.833=1.2
OddsofhavingOinEis1.2
higherthantheE

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CROSSSECTIONALSTUDY
TodetermineiftheresanassociationbetE&O,we
have2choices:
CalculateprevalenceofOinEsubjects

PREVALENCE
Measureoffrequency
Prevrate=

andcompareittoprevalenceofOinE
CalculateprevalenceofEinsubjectsw/O
andcompareittoprevalenceofEinsubjO

INCIDENCE
MeasuresthenumberofNEWcasesduringa
specificperiod
Incidencerate=

Interviewquestions

Typeofmeasure

Doyoucurrentlyhaveasthma?

Pointprevalence

Haveyouhadasthmaduringthelast(n)years?

Periodprevalence

Haveyoueverhadasthma?

Cumulativeincidence

BIASESinPREVALENCESTUDIES:
TEMPORALCONSEQUENCES
Possible causes

Incidence Study

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

Disease or Outcome
Development of cases
overtime

Prevalence Study

Past or present
exposure to possible
causes

Population of
existing cases &
noncases

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USESofPREVALENCERATE
Decidingtheneedforhealthcare
Planningofhealthservices
Investigatingpotentiallycausalrelationshipb/
wriskfactors&adiseaseorprognosticfactors
&anoutcome
Assigningaprobabilitythatapatienthasthe
condition

PREVALENCEvsINCIDENCE
LOWPREVALENCEDISEASES:
Shortlived
Rapidlycured
Fatalatanearlystage

HIGHPREVALENCEDISEASES:
Lowmortality
Lowcurerate
Highdisablingeffect

CHARACTERISTICSof
PREVALENCE&INCIDENCE

PREVALENCEvsINCIDENCE
HIGHINCIDENCEDISEASES:
Common

LOWINCIDENCEDISEASES

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

Rare

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CASECONTROLSTUDY
ExplorestherelationshipbetpriorEtoa
specificriskfactor&thelikelihoodof
developingaparticulardisease.
Retrospectivestudythatcomparesagrpof
cases&1grpofcontrolsw/respecttoa
currentorpreviousexposure

CASECONTROLSTUDY
Populationbasedsampling
Incidentcases
Lessexpensive
Maybecompletedmorerapidly

CASECONTROLSTUDY
CHARACTERISTICS:
observationalwelldefinedpopulation,specific
outcomeandfactor/s
Comparativethecasesandthecontrols
Retrospectivelookbacktofindwhatmaycause
theeffect
Analyticrelationshipofoutcometoprobable
cause/s

CASECONTROLSTUDY
Cases:hospitalrecords,surveillancesystems,
deathcertificates
Controls:sampledfrompopulationthatgave
risetothecases
Hospitalbased

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SELECTIONCRITERIAforHOSPITAL
BASEDCONTROLS
TODO:
Variousdiagnostic
groupsnospecificRF
isoverrepresented
Patientsw/acute
conditionsearlierE
couldnothadbeen
influencedbythe
condition

TOAVOID:
Patientswhohave
multipleconcurrent
conditions
Patientsw/dxknownto
berelatedtotheRisk
Factorofinterest

CASECONTROLSTUDY
Weakness
Recallbias
Selectionbias
Validityissue

Matching
confoundingormixingtheeffectsofEtotherisk
factor
statisticalprecisionofestimatesallowingsmaller
samplesize
Timeconsuming

CASECONTROLSTUDY
USES/APPLICATIONS:
Exploringforprobablecauses
Determiningharmfulagentsthatcouldhave
causedapresentcondition
Appropriatefordiseases:
Rare
Chronicorwithlonglatency

CASECONTROLSTUDY
DESIGN:
EO
O
EO
N
EO
O
EO
Fromthesamepopulation,cases&controlareselectedthen,look
backintimetofindprobablefactor/sthatcouldhaveaneffectto
theoutcome

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CASECONTROLSTUDY
TABLE:

Exposed Unexposed
Case
Control

CaseExposureProblty
=Exposedcases(a)
Allcases(a+b)
OddsofCaseExposure
=Exposedcases(a)
Allcases(a+b)
Unexposedcases(b)
Allcases(a+b)
=a/b
OddsofControlExposure
=c/d

NESTEDCASECONTROLSTUDY
Population
DevdiseaseDoNOTdevdisease

CASECONTROLSTUDY
STATISTICS:

OddsofhavingtheEinCases&Control

ac
Odds(O)=Odds(O)=
bd
odds(O)a/baxd
OddsRatio==
odds(O)c/dbxc
OR:associationbetweenE&Ounlikelytohave
occurredbychancealone

NESTEDCASECONTROLSTUDY
Advantages:
Dataobtainedbeforeanydiseasehas
developedrecallbias
Riskfactorsarerepresentedthanearly
subclinicaldisease
Moreeconomicaltoconductthancohort
study

CasesControl

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BEFOREAFTERSTUDY

BEFOREAFTERSTUDY

Transitiondesign
Retrospectivemeasureoutcomethenassess
exposure
Prospectiveapplyexposurethenmeasure
outcomefollowingexposure
Comparative2groupsonly

MeasurementofoutcomescanNOTbeconcurrent
Same/differentstudypopulation

BEFOREAFTERSTUDY

BEFOREAFTERSTUDY

CHARACTERISTICS:
Studysubjectsideallymustbethesamebeforeand
after(issues:comparable,selectionbiasanddrop
outs)but,maybedifferent
Interventionideallybeundercontrolofinvestigator
(standardized)butisnot,speciallyinHARMstudies
Outcomeisassumednotpresentatthestartofstudy
(before)anddevelopedafterduetoexposure

Differentstudypopulation:
WhenNe1isdonesimultaneouslyw/Ne2convertedtoa
COHORT

USES/APPLICATIONS:
HARMstudiesEhappensatthestart&
beyondthecontrolofinvestigator
Evaluatingeffect/sofnewpoliciesand
strategies(Mgt,BZ,marketing&sales)

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BEFOREAFTERstudy
DESIGN:

BEFOREAFTERstudy
TABLE:

Samepopulation

OO
NNeEE
OO
beforeafter
Twodifferentsubjectpopulations,identifyN1&
Ne1forbeforeandN2,Ne2forafter

BEFOREAFTERSTUDY
STATISTICS:
Riskofdevelopingoutcomeduetoexposure
ac
Risk(E)=Risk(E)=
a+bc+d
RiskRatio:R(E)
RR=
R(E)

OUTCOME

presentabsent
Exposed a b
Not
Exposedc d

VALIDATIONOFADIAGNOSTICTEST

Aspecialresearchstudytodetermine
howacertaindiagnostictestcompared
toareferencestandard
PurposeofthisstudydesignisNOTfindingthe
BESTdxtestbutgeneratingdatausefulfor
clinicaldecisionmaking

RR=riskofdevelopingOinEis>/<thanthe
riskofdevelopingOinunexposed

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ELEMENTSOFAVALIDATIONDIAGNOSTIC
TESTSTUDY
Diagnostictest
Reference(gold)standard
Reproducibility
Blindandindependentcomparison
Studysubjectssuspectstohavedisease
Dataonaccuracyofthetest

VALIDATION
REFERENCE(GOLD)STANDARD
TRUTH
Globallyacceptablecriteriathatadiseaseis
presentorabsent(100%certainty)
Couldbeanyoffollowing:
Histopathology
Anydiagnostictestresult
Consensusofexperts

LEVELSofEVIDENCEforRATING
ACCURACYofDIAGNOSTICTESTS
Level1
Indptinterpretationofdxtestresult
Indptinterpretationofgold/referncestdresult
Subjectsarepatientssuspectedtohavedisease
Reproducibilityofbothdx&stdtests
Samplesize:atleast50patientsw/disease&
50patientsw/outdisease

Level24/5criteriaaremet
Level33/5
Level42/5
Level51/5
Level6NONE

Validation
Diagnostictestunderstudy

Examination(radiography,laboratory,etc.)use
todeterminethepresenceofadisease
Onediagnosticoptionwhendoinggold
standardisnotpossible
Performanceislowerthangoldstandard
(<100%)

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VALIDATION
STUDYSUBJECTS

Atthestartofstudy:

Noonehasthedisease
Allaresuspects(withsignsandsymptoms)to
havethedisease

Ideally,allundergogoldstandardand
diagnostictests

VALIDATION
INDEPENDENCE&BLINDING

Validation
Reproducibility(method&results)
Boththegoldstandardanddiagnostictests
aredescribedindetailtoallowthosenotpart
ofthestudyduplicatetheprocedure
Generating,readingandinterpretingresults
canberepeatedanywhere

VALIDATION

COEFFICIENTOFAGREEMENT(VARIABILITY)

Thedoerandreaderofthediagnostictest
isnotinfluencedbyanddoesnotknowthe
referencestandardresultandviceversa
Referencestandardanddiagnostictestsare
doneseparatelyandpreferably
concurrently

Intraobservervariabilityinreadings/
interpretationdonebyonepersonat
differenttimes
Interobservervariabilityinreadings/
interpretationofanumberofpersons

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KAPPASTATISTIC
Expressestheextenttow/ctheobserved
agreementexceedsthatw/cwouldbe
expectedbychancealone(numerator)
relativetothemostthattheobservers
couldhopetoimprovetheiragreement
(denominator)
Kappa=observedagreement(OA)
potentialagreement(PA)
OA=observedchanceagreement
PA=100%chanceagreement

Percentagreement
=41+27/75x100
=90.7%
The2pathologists
agreedon90.7%of
thereadings

Grading
Pathologist
A
Gr II Gr
III
Grding Gr II 41
3
44
Pth B
GrIII 4
27 31
45

30

75

Grading
Pathologist A

%chanceagreement
=26.4+12.4x100
75
Grding
=51.7%
Pth B
The2pathologists
expectedtoagreeby
chanceon51.7%of
thereadings
Totals
by A

Gr2

Gr3

Totals by B

Gr 26.4 17.6 44
II

58.7%

Gr 18.6 12.4 31
III

41.3%

45

30

75

OA=observedchanceagreement
PA=100%chanceagreement
Kappa=90.7%51.7%=39%=0.81
100%51.7%48.3%

Kappa=observedagreement(OA)
Thereisasubstantialagreementbetween
potentialagreement(PA)
the2pathologists

60% 40%

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Validation
BasicTable

STRATIFIEDQUALITATIVEEQUIVALENTofKAPPA
NUMERICALVALUES
00.2Slight
0.20.4Fair
0.40.6Moderate
0.60.8Substantial
0.81Almostperfect

REFERENCE (GOLD)STANDARD

DIAGNOSTIC
TEST

Validation
BasicStatistics
Sensitivity
a
sn=
a+c
Specificity

d
sp=
b+d
a+d
Accuracy

positive

negative

positive

True (+)
a

False (+)
b

negative

False (-)
c

True (-)
d

SENSITIVITY(Sn)
Sn
ThegreatertheSn,themorelikelythetestwill
detectpersonsw/disease
UsefulclinicallytoR/Othepresenceofadisease
(SnOUT)
Iftestishighlysensitive,anegativeresultwould
excludethepossibilitythatthepatienthasthe
disease
Percentageoffalse()errorislow

a+b+c+d

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SPECIFICITY(Sp)

RELATIONSHIPBET.PREVALENCE&
PREDICTIVEVALUE

ThegreatertheSp,themorelikelythetestwill
detectpersonsw/odisease
UsefulclinicallytoR/Ithepresenceofadisease
(SpIN)
Iftestishighlyspecific,apositiveresultwould
includeorstronglysuggestthatthepatienthas
thedisease
Percentageoffalse(+)errorislow

Thehighertheprevalence,thehigherthePV
Screeningprogramismostefficientifdirected
toahighrisktargetpopulation

VALIDATION
DATAFORCLINICALAPPLICATION

RELATIONSHIPBET.SPECIFICITY&
PREDICTIVEVALUE

Sp

Predictivevalues
ad
Ppv=Npv=
a+bc+d

Anincreaseinspecificityresultsinamuch
greaterincreaseinpredictivevaluethandid
thesameincreaseinsensitivity

LikelihoodRatios
Forpositiveresultfornegativeresult
ac
a+ca+c
LR(+)==Sn/1SpLR()==1Sn/Sp
bd
b+db+d

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LIKELIHOODRATIO
ThebiggertheLR+,thestrongerthe
associationbetweenhavinga+testresult&
havingthedisease
ThesmallertheLR,thestrongerthe
associationbetweenhavingatestresult&
NOThavingthedisease
DoNOTvaryaccordingtoprevalenceof
disease

RECEIVEROPERATING
CHARACTERISTIC(ROC)CURVE

RECEIVEROPERATING
CHARACTERISTIC(ROC)CURVE
Ateverypt.alongthisdashed
line,theLR+is1&a+testresultis
equallylikelyforpersonsw/&w/
odisease
Aclinicallyusefuldxtesthasan
ROCcurvethatisfarfromthis
dashedline
Towardthelefthandportion,
thereissteepriseinSnw/only
modestreductioninSp
Towardtherighthandportion,
theslopeofROCisflatlittle
improvementinSnfora
substantialincreaseinSp

RECEIVEROPERATING
CHARACTERISTIC(ROC)CURVE

Summaryindexofoveralltestperformance
calculatedastheareaundertheROCcurve
Highestpossiblevaluefortheareaunderthe
ROCcurveis1almostperfecttest
Thegreaterthearea,thebetterthetest
performance

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THANKYOU
Formultilevelorcontinuousoutcometest
results,thechoiceofacutoffpointvalue
threshold+willSp(fewerfalse+)butalossof
Sn(>falseresultsormissedcases)
threshold+willSn(fewerfalse)butalossof
Sp(>false+results)

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