STUDYDESIGNSINMEDICALRESEARCH

OBJECTIVES:
Thestudentwillbeableto:
1.
Describethedifferentobservationalandexperimentalstudydesignsusedinmedicalresearch.
2.
Explaintheabilitytodeducecauseandeffectrelationshipsfromdifferentstudydesigns.
3.
Takedefinedhealthvariablesandscriptdifferentstudydesignsusingthosevariables.
CLASSIFICATIONOFSTUDYDESIGNS
OBSERVATIONALSTUDIESVS.EXPERIMENTALSTUDIES
Observational oneormoregroupsofpatientsareobservedandcharacteristicsaboutthepatientsarerecordedfor
analysis.
caseseries
casecontrol(retrospective)(epidemiological)
crosssectional(includingsurveys)(epidemiological)
cohort(prospective)(epidemiological)
Epidemiology fundamentalmedicalsciencethatfocusesonthedistributionanddeterminantsofdiseasefrequencyin
humanpopulations.
Experimental aninvestigatorcontrolledmaneuver,anintervention,isappliedtoanimalsorhumansundercontrolled
conditionstoassesstheefficacyoftheintervention.
CauseandEffect
observationalstudiescanassistusindevelopingcausalhypothesesandboosttheirplausibilitybut
canneverinandofthemselvesdiscerncauseandeffect.Alsoobservationalstudiescantclearlyconfirmtheeffectiveness
ofanintervention.Experimentalstudiesaretheonlytypethathavetheappropriatecontrolsanddirectionofapplication
thatcanallowustoverifycauseeffectrelationships.Themoreoften,significant,andconsistentacauseeffect
relationshipisseenthemoreconvincedwearethatthereisacauseeffectrelationship.
PyramidofCausationandLevelsofEvidence

OBSERVATIONALSTUDIES
CASESERIES
Caseapersonwhohasadiseaseofinterest.
Acaseseriesreportisasimpledescriptiveaccountofinterestingcharacteristicsobservedinagroupofpatients.Least
validapproachtodeterminingcausationandleastcontrolofnumerouscompetingvariables.
Diagram

Examples:

Takeallanorexicpatientswhohavehadinpatienttreatmentoverayearandachievedahealthyweightandlook
atalltheircharacteristicsandthenatureoftheirtreatment..
Pediatricianlooksatallchildrenshehastreatedoverthelastyearunder12yearsofagewhohaveADHDand
lookattheircharacteristics.

Thesetypesofstudiesallowthegenerationofcausalhypothesestobefurthertested.Itwouldbemajormistakefora
clinicianorresearchertoassumecausationatthispoint.Sointhetwopreviousexamplesitwouldbeinappropriatefor
thecliniciantosaythatbecausealleffectivelyrecoveringanorexicswereeatingeffectivelyinsocialsituationsorall
childrenwithADHDseemedtogetbetterwhentheyreducedsugarintake,interventionsfocusedonsocialeatingand
restrictingsugarwouldbeeffectiveinterventionsandwouldcausethepatientstogetbetter.However,caseseriesreports
cangivecliniciansideasregardingtreatmentapproachesandissuestoexplorewithpatientsthattheyotherwisewouldnot
havethoughtof.
CASECONTROL:
Anobservationalstudyinwhichsubjectsaresampledbasedonthepresence(cases)orabsence(controls)ofthediseaseof
interest.Informationiscollectedaboutearlierexposuretoriskfactorsofinterest.RetrospectiveStudysometimes
calledthisbecauseoftheirdirectionofinquiry,lookingbackatapersonshistory.Needtomatchcasestocontrols
ascloselyascan.Theyneedtobeasdemographicallysimilaraspossible.Theinvestigatorneedstogatherhistoricaldata
asaccuratelyandsystematicallyasshe/hecantoexamineexposureornonexposuretotheriskfactorofinterest.
Diagram

Example:
Findcasesofindividualswhohaverecentlyhadmyocardialinfarctionandfindindividualofsimilardemographic
characteristicswithoutMIsorotherevidenceofCHD.
InterviewandsurveythemaboutmanyfactorsthatcouldinfluencetheirriskforCHD,butmostnotablySaturatedFat
Intake.AskthemtorecalltheirintakeofSFovertheyears.Lookinanymedicalrecordchartavailabletocollect
historicaldataonhealthhabitsandfamilyhistory.
PresentationofData

RiskFactor
NoRiskFactor

Cases
a
c
a+c

Controls
b
d
b+d

a+b
c+d
a+b+c+d

Example

HighSaturatedFatIntake
LowSFIntake

CHD
a
c
a+c

NoCHD
b
d
b+d

a+b
c+d
a+b+c+d

UsestatisticalcontrolstocontrolotherpossiblevariablesthatcouldaffectriskofCHD(confoundingvariables).
ConfoundingVariableavariableorfactorotherthanthepotentialcausativeonethatisbeingstudiedthatcouldaffectthe
effectofinterest.Forexamplecigarettesmokingcouldconfoundtheexaminationofthepotentialassociationbetween
saturatedfatintakeandCHD.
SoonemustgatherhistoricaldataonothervariablesandfactorsthatmightinfluenceCHDrisksotheycanbestatistically
controlled,ruledout,orheldconstant.Inthiscasedatasuchasserumlipidlevels,weighthistory,smoking,fastingblood
sugars,gender,familyhistory,physicalactivityandothersmustbegathered.Asonecansee,perfectcontrolof
confoundingvariablesisdifficultlendingweaknesstotheapproachintermsofisolatingthecausativevariable.Onecase
controlstudyinthe70sseemedtopointtosugarconsumptionasasignificantfactorinCHD,buttheyfailedtocontrol
forfatintakeandfoundthatpeoplewhoeatalotofsugartendtoeatalotoffatalso.
Majorproblemistimingproblemintermsofcauseandeffect.
Didsaturatedfat(SF)intakechangeasaresultofhavingCHDorviceversa,didthehigherSFintakepreexisttheCHD.
Alsocantintroduceperfectcontroloverconfoundingvariables.Cannotdeducecauseandeffect.Canjustconclude
association(relationship)ornoassociation(norelationship).
DataAnalysis
OddsRatiotheoddsofaparticularexposureamongpersonswithaspecificdiseasedividedbythecorrespondingodds
ofexposureamongpersonswithoutthediseaseofinterest.

OR ad

bc

ORssignificantlygreaterthanorlessthanoneindicatesignificantlyhigherorlowerriskofdiseaseduetoexposureor
nonexposuretoafactor.Inthisexample,anORof5indicatesthatthosewithanMIare5timesmorelikelytohave
eatenahighsaturatedfatdietthanthosewithoutanMI.

CROSSSECTIONAL
Anobservationalinvestigationinwhichsubjectsaresampledatafixedpointorperiodoftime,andtheassociations
betweentheconcurrentpresenceorabsenceofriskfactorsanddiseasesaretheninvestigated.Itisasnapshotviewatone
momentintime.Surveyresearchisonekindofacrosssectionalstudy.Inpolitics,surveysaredonetolookatthe
presidentsapprovalrating.Itisimportanttonotethattheresultisvalidonlyforthatmomentintime.Thisisnot
predictiveofwhattheapprovalratingwillbeintwoweeksorwhethersheorhewillwintheelectioninayear.Hardto
deducecauseandeffectbecausehardtocontrolallconfoundingvariablesanddontknowtimingofevents.Didpresence
ofonefactorprecedethepresenceofanother?DidthepersonbecomeTypeAbecausetheyknewtheyhadhighLDL
levelsandbecauseofanxietycreatedinknowingtheyhadhighLDLmakethemmorehypervigilant,ordidTypeA
precedehavinghighLDLlevels?Wecannottellfromcrosssectionalstudies.Again,thesestudieshelpusdevelop
hypothesestotestaboutcausation.
Example:
Creactiveproteinlevelsinthebloodareindicativeofthestateofinflammationinpersonsbodyatanyonemomentin
time.ManymedicalscientistsspeculatethatlevelsofthisparameteraremorepredictiveofCHDthanLDLlevelsinthe
blood.ManyhypotheseshavebeenforwardedastohowtolowerCreactiveproteinlevelsanddecreaseinflammationin
thehumanbody.Aninvestigatorcoulddoanexploratorystudytolookatlifestylefactors,includingdiet,thatmightbe
associatedwithCreactiveproteinlevels.Thiscouldthenbecomethebasisfortryingclinicaltrialstoseeifchanging
certainlifestylefactorscouldlowertheCreactiveproteinlevels.Wecouldtake200peoplewhoarebetween18and65,
thenmeasuretheirCreactiveproteinlevelsandmeasureavarietyoflifestylefactorsusingsurveyquestionsaswellas
physicalparametermeasurements.Wecouldthenlookforassociationsandrelationshipsbetweenthesevariables.For
instance,wecouldlooktoseeifthereisanassociationbetweenlevelsofomega3fattyacidsinthediet(becausetheseare
thoughttobeassociatedwithdecreasinginflammatoryprocessesinthebody)andCreactiveproteinlevels.
DataAnalysis:
ThePearsonProductMomentCorrelationCoefficient
COHORT
Anobservationalstudyinwhichsubjectsaresampledbasedonthepresence(exposed)orabsence(unexposed)ofarisk
factorofinterest.Thesesubjectsarefollowedovertimeforthedevelopmentofadiseaseoutcomeofinterest
(prospectivestudy).FraminghamStudy,NursesHealthStudy.
Example:
Find5000peopleeatingahighfiberdietvs5000similarpeople(matchingbydemographics)eatinglowfiber.Follow
themfor
15yearsandlookforcasesofcoloncancerineachgroup.Measureotherfactorstoinitiatestatisticalcontrolssoonecan
ruleoutconfoundingvariables.
Diagram

PresentationofData(presentationissimilartothatof
casecontrolbutdesignofthestudyisdifferent).

RiskFactor
NoRiskFactor

Disease
a
c
a+c

NoDisease
b
d
b+d

a+b
c+d
a+b+c+d

ColonCa
a
c
a+c

NoColonCA
b
d
b+d

a+b
c+d
a+b+c+d

Example

LowFiber
HighFiber
DataAnalysis

RelativeRiskthelikelihoodoftheoccurrenceofaparticulardisease(coloncancer)amongpersonsexposedtoagiven
riskfactor(lowfiber)dividedbythecorrespondinglikelihoodamongunexposedpersons(highfiber).
RR

a/ab
c/c d

Relativerisksignificantlygreaterorlessthan1indicatesasignificantrelationship.ThemoreextremetheRRthestronger
therelationship.
Causation
ManyepidemiologistsbelievethatifforagivenrelationshiptherearenumerousstudiesthatdemonstrateRRs
significantlydifferentthan1inthesamedirectionandtheRRssignificantlydifferfrom1,thiscanimplycausation.A
greatexampleiscigarettesmokingandlungcancer.Cantdoclinicaltrialswithsmoking,butbecauseoftheextremely
highRR(20)andconsistencyofstudieswecan
deducecausation.Forsomesituationsitwouldbeunethicaltodoaclinicaltrialandforsomesituationsonewouldhave
toconductatrialforsolongthatitwouldbehardtomaintainappropriatecontrolsandpreventdropouts.
EXPERIMENTALSTUDIES
RANDOMIZEDCONTROLLEDTRIALS

Acomparativestudyinvolvinganinterventionormanipulationappliedundercontrolledconditionstohumanswhohave
beenrandomizedtogroups.Thisisthegoldstandardforfindingcauseeffectrelationships.Specificcomponentsto
considerwhendesigninganRCT:
Thesubjectsneedtobeselectedrigorouslytoreducepotentialconfoundingfactors.
Subjectsmustberandomizedtodifferentgroupstoreduceselectionbias.
Instructionsforapplyingtheinterventionmustbespecificanduniformlyappliedtoallsubjects.
Blindingshouldbeused(doubleblindinginvestigatorandsubjectdoesnotknowwhetherreceivingtreatment
orcontrol).
Introduceasmanycontrolsaspossibletoeliminateconfoundingvariables.Useacontrolgroupwhodoesnt
receivetheinterventionforcomparisonpurposes.Useplacebosorcontrolprocedurestoapplytothecontrol
group
Standardizingtheproceduresformeasuringtheoutcomeisveryimportant.

Diagram

Example:
ThePhysiciansHealthStudyrandomized22,000healthymalephysicianstoreceiveeitheraspirinoraplacebo.They
werefollowedforanaverageof60monthstoevaluatemortalityratefromcardiovasculardisease(MI).Theinvestigators
foundthatfewerphysiciansintheaspiringroupexperiencedaMIduringthecourseofthestudythandidphysicians
receivingplacebos.
DataAnalysis
Differentstatisticaltestsdependingonthedesign.
Causation
CausationcantbeclearlydeducedfromoneRCT.Itisdeterminedbasedonnumeroustrialsdonewithdifferent
populationsindifferentsettingsthatshowresultsinaconsistentdirection.Sowhendiscerningcausationlookforas
manyRCTsasyoucanfindforagiveninterventionormanipulation.

CrossoverDesigns
Aclinicaltrialinwhicheachgroupofsubjectsreceiveallthetreatmentandcontrolconditions,butindifferentsequences.
Example:
Take100people.Randomizethemintotwogroupsof50.Giveonegroup2gramsofomega3fattyacidsandtheothera
placebo.
LookattheirCreactiveproteinlevelsattheendof6weeks.Thenputeveryoneonaplacebofor4weeks.Thengivethe
groupwhopreviouslygottheplacebothefattyacidsandtheothergroupwhogotthefattyacidstheplacebo.
TheadvantageofaCrossoverDesignisthatyoucanconducttwoRCTsinonestudydesignpackage.Forthisdesignto
beusedtheeffectsofthetreatmentmustnotbelonglastingorpermanent.
DataAnalysis
Differentstatisticalproceduresdependingonthedesign.
MetaAnalysis
ItisastatisticalmethodofcombiningresultsfromseparateRCTsinordertoderiveoverallconclusions.
Diagram

Example:
TakeallthereasonablywellconductedRCTstestingtheeffectivenessofthenicotinepatch.Poolallthesubjectsoutcome
dataandlookattheoveralleffectivenessofthepatch.Letssay20RCTshavebeendoneeachwith50subjects.Takeall
500subjectswhoreceivedthepatchandpooltheirsmokingcessationdata.Takethe500whoreceivedthecontrol
procedureandpooltheirdataaswell.Thencomparethedatafromthosethatgotthepatchtothosethatgotthecontrol.
RatherthanusingtheconclusionsofoneRCTtomakeadecisionaboutusingthepatchwithpatients,nowyouhavethe
weightofdatafrom20RCTs.
Metaanalysesfallunderthecategoryofsystematicreviews.Asystematicreviewisapublicationthatusingrigorous
guidelinestoreviewallthestudiesconductedonagiventreatmenttomakeconclusionsaboutitsapplicability,usefulness,
andeffectiveness.

TheCochraneDatabaseisanexampleofadatabasethatcontainssystematicreviewsonmanydifferenttypesof
medicallyrelevantinterventionsandtreatments.
SUMMARYANDCONCLUSIONS

Observationalstudieshelpthemedicalinvestigatortoconstructhypothesesaboutpossiblecauseeffect
relationshipsandgaingreaterorlessconfidenceoftheirplausibility.Themostusefulobservationalstudyisthe
cohortstudy.CorrelationalStudiesareoftenusedtolookattheeffectivenessofmedicaldiagnostictests.Big
mistakeistonotdiscernthatastudyisobservationalandputtoogreatoffaithintheresultsandapplytheresults
inappropriately.
Thegoldstandardfordeducingcauseeffectrelationshipsistherandomizedcontrolledtrial.
Itisthenumber,strengthofrelationship,quality,andconsistencyofthesetrialsthatwilldeterminewhetherwe
candeducecausationandthencanfeelgoodaboutapplyingatreatmentorintervention.Therefore,welookfor
systematicreviewstohelpusmaketreatmentdecisions.

(Sourceofthesenotes:K.Kaiser,DO2005;RevbyJ.Cavenagh7/21/15)

Pyramidofcausationandlevelsofevidence
Widthofeachlevelisarepresentationoftheamountofpublishedliteratureavailableforthesetypesofresearch
Invitroresearch
Isthelargestportionofresearch,easiestresearchtoconduct,whysomuchmorearedone
Whatqualifiesasgoodresearchiseasiertoachieve
Animalresearch
Issomewhatlessthaninvitroresearch
Stilleasiertoconductresearchonanimalsthanitisonpeople
Animalshavefewercontrols,whyitseasier
Inabilitytocommunicateandgiveinformedconsent,limitedtotheobservationofthebodyof
literature
Observationtyperesearch
Ideas,editorialsandopinions
Representsusabilityofresearchasmedicalliterature
Problem;researcherisexpressingBIASandnotpurelyscientificorexperimental
Needtoreduceoreliminatebias
Opinionbelieforjudgmentthatrestsongroundsinsufficienttodeducecompletecertainty
Cantproduceenoughcertaintythatwanttoriskanythingforhumantestingortreatment
Casereports
Firstleveloftruehumanresearch
Individualreportofunusualclinicalsituationthatinvolvesahumanpatient
Observationalsomethingthatisobserved
Lookingforaspecificcharacteristicsincertaincases
Seeifthereisanythingthatexplainsadifferencebetweengroups
Moredifficulttoconstructbcneedtofindsimilargroupsofpatients,needtohaveapatienthistory
Bodyofliteratureissmaller
Caseseries
Observingwhatishappeningtothem
8

Expenseingatheringthesubjects&followingupwiththem,havingsomeoneanalyzethedataanda
leveladifficultywiththis
Casecontrolstudies
Retrospectivestudies
Starttocompareonegroupofsimilarpatientstoanotherlookingforaspecificcharacteristic
Oftenexposuretoadisease
Taking2groupsofpeople,andthenlookingbackintimeatthehistoryofthosetoseeiftherewas
anythingthatwouldexplainadifferencebetweenthose2setsofgroups
Moredifficulttoconstruct,becausehavetofindsimilargroupsofpatients
Havetofindavailablehistoryonthept.insomeform
Cohortstudies
Lookingforcorrelationbetweendsandriskfactors!
Evensmallerbodyofliterature
Moredifficultbecauseneedtofindgroupsofpatientsthatareevenmoresimilarinalargernumber
ofways
Needtoqualifyforcertainparametersthatareset
Theyalsohavetoagreetostickwiththestudytolookforanoutcomeofinterest
Havetogetpeoplewhowillagreetoparticipateinastudygoingforwardintime
Observingpt.soveraperiodoftimeandwatchingifsomethingdoesordoesnthappen
Expenseinorganizingandconductingthestudy,paysomebodytofollowthesepeopleanddo
researchlookingbackandcompilethedatacollected
Randomizeddoubleblindstudies
Smallestbodyofliterature,experimentaldesigns
Actualhypothesiscreationandexperimentation
Designedtobeabletodeterminecauseandeffect
Withoutobservationalstudieswouldnthavethehypothesesdevelopedtobeabletotestthem
Lookingforcauseandeffectforaninterventionandanoutcome
Onerandomizedcontroltrialistypicallynotenoughtoconvincinglyshowcause&effect
Systematicreviewsandmetaanalysis
Newerlooksatrandomizedcontrolstudiesandevaluatethequality
Lookingovermultiplerandomizedcontroltrials
Typeofliteraturereviewfocusedonaresearchquestionthattriestoidentify,appraise,selectand
synthesizeallhighqualityresearch/evidenceforthatquestion
Needtofilteroutnonhighqualityliterature
Systematicreviewlooksatanumberofdifferentstudiestolookforatrend
Goodscientificevidencetotheanswertheyrelookingforandananswertotheirquestion
Thelargernumberofstudiestheanswersthequestioninthesameway,themorereliablethe
answertothequestionisandthemorereliabletheevidenceis
Metaanalysistypeofsystematicreview
Largenumberofhighqualitystudiesthatareconductedverysimilarly,cancombineallof
thesestudiesusingstatisticaltechniquesandmakeitlooklike1largestudy
Theprinciplebehindthisisthatusuallythelargerthestudy(thenumberofsubjects),andthe
broaderthedemographiccharacteristicsareofthosesubjectsthemoregeneralizableitisto
thepopulationoftheUS