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Introduction to Clinical ResearchAdaptedfromBasicEpidemiology ,WHO(2006)

DavidNarita,MD

AngkorHospitalforChildren

March29th-30th,2011

Steps in starting clinical research

• Formyourquestion• Doresearchaboutyourquestion(getalltheinformation)• Askforadvice/input• Refineyourquestion(hypothesis,aims,ideashowtoconduct,shellofresultstable)• Checkexcitementlevels• Chooseastudy

Observational Studies

DescriptiveStudies• Simpledescriptionofacommunity• Basedon:- Routinelyavailabledatae.g.deathstatistics- Dataobtainedinspecialsurveys- Doesnotshowarelationshipbetweenexposureandeffect

Simplydescribewhatisobservedatagiventime

AnalyticalStudies

• Analyzestherelationshipbetweenhealthstatusandothervariables

Ecological/CorrelationalStudies• Usedtostudygroupsorpopulations(ratherthanindividuals)• Comparingpopulationsindifferentcountries• Comparingthesamepopulationatdifferenttimes• Easytocarryout• Limitations:- Difficulttointerpret- Cannotshowthelinkbetweenindividualexposureanddevelopmentofdisease- Cannotconsiderotherfactorswhichcancontributetodevelopmentofdisease- Ecologicalfallacy(incorrectbelieforidea)- Cannotshowlinkbetweenindividualexposureanddevelopmentofdisease

Cross-sectional/PrevalenceStudies• Measuretheprevalenceofdisease• Exposureanddiseasearemeasuredatthesametime• Cannotdetermineifexposureprecededorfolloweddevelopmentofdisease• Cheapandeasy• Regularcross-sectionalsurveyscanbeusedtoassessthehealthcareneedsofapopulation

Cross-SectionalStudySurvey

Surveyshouldhaveaclearpurposeandneedsto:

- Bewell-designed- Haveanappropriatesampleofsufficientsize- Haveagoodresponserate

Types of Studies

Observational• Descriptive• Analytical- Ecological- Cross-sectional- Case-control- Cohort

Experimental• Randomizedcontrolledtrials• Fieldtrials• Communitytrials

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Case-ControlStudies• Comparespeoplewithadiseaseandpeoplewithoutadiseasetoidentifythe

exposure

• Startbyselecting(choosing)cases-thesampleshouldrepresentallthecasesfromaspecifiedpopulation

• Selectcontrolsfromthesamepopulation

• Casesandcontrolsshouldbeselectedindependentof

exposurestatus

Case-controlstudiesare:

- Cheapandeasy- Usedtoinvestigatecausesofdisease- Bestforrarediseases- Longitudinal(Dataarecollectedfrommorethanonepointintime)- Usuallyretrospective(Diseasestatusisdeterminedfirst,thenexposure)

Determiningexposurestatus

- Askthepatientorcaregiver(retrospectivedata)- Biochemicalmeasurements- Establishedrecordingsystem(e.g.patientchartoremploymentdata)

Theoddsratio(OR)

• Measurestheassociationbetweenanexposureandadisease

• Ratiooftheoddsofexposureamongcasescomparedtocontrols

•  IfOR=1,thentheexposureisnotassociatedwiththedisease

•  IfOR>1,theexposureisassociatedwithdevelopingthedisease-“ x timesmorelikelytodevelopthediseasethanthosenotexposed”

•  IfOR<1,theexposureisassociatedwithNOTdevelopingthedisease(maybeprotective)Cohortstudies

• Alsocalledfollow-upstudies

• Longitudinal• Canberetrospectiveorprospective

• Givesthebestinformationaboutdiseasecausation

• Cantakealongtime• Sometimesneedlargestudypopulation

• Expensive

PunnetSquare

Disease

Yes No Total

Exposure

Yes a b a+b

No c d c+d

Total a+c b+d a+b+c +d

Case-ControlStudy

CohortStudy

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Experimental Studies

• Testtheeffectivenessofanintervention-e.g.newdrug,medicaltreatment,behavioralintervention,etc.

RandomizedControlledTrials(RCT)

• Frequentlyusedtotesttheeffectivenessofnewdrugsormedicaltreatments

• Participantsarerandomlyassignedtoeitheran

intervention(treatment)ora

control(notreatmentorplacebo)group

- Blind:participantsdonotknowwhichgrouptheyareinbutresearchersdo

- Doubleblind:bothparticipantsandresearchersdonotknowwhichgrouptheyarein

FieldTrials

•  Involvepeoplewhoaredisease-freeandnon-hospitalizedbutthoughttobeatrisk• Sometimesinvolvesalotofparticipants• Usefulforevaluatinginterventionsthatreduceexposure(eg:Sabinoralpoliovaccine)CommunityTrials

• Treatmentgroupsarecommunities,notindividuals(eg:villagesrandomlyassignedtointerventionorcontrolgroup)

• Usedfordiseaseswhichareinfluencedbysocialconditions• Canbedifficulttocontrolconfoundingfactors• Mostcommonlyusedforhealthpromotioninterventionstochangebehavioreg:CondompromotiontoreduceHIVtransmission,educationtoencouragehealthyeating

ChoosingaStudy

 

Errors in Research

Randomerror• Thesampleisdifferentfromthepopulationbecauseofchance• 3mainsourcesoferror-  Individualbiologicalvariation:Randomvariationthatnaturallyoccurs

Randomized

ControlTrial

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- Samplingerror:Randomerrorsinchoosingparticipants(usuallybecausewedon’thavealargeenoughsample)- Measurementerror:Randomerrorsinmeasuringtheexposureoroutcome–needclearprotocols

Samplesize

• Theeasiestwaytoreducerandomerroristoincreasethesamplesize(thenumberofpeopleinthestudy)

• Epidemiologistsuseformulatodecideonsamplesizebasedon:- Thenecessarylevelofstatisticalsignificance- Howcommonthediseaseisinthecommunity- Thesizeofthegroupstobecompared- Thechanceofmissingarealevent SystematicError

• Resultsdonotshowthetruesituationbecauseofanerror(bias)indatacollection• 2maintypes:- Selectionbias- Measurementbias

SelectionBias• Occursbecausethereisadifferencebetweenthepeoplewhoagreetoparticipateinastudyandthosewhodonot,andbetweenthosewhoremaininastudyandthosewholeaveearlyExamples:Peoplewhoaresickaremorelikelytovolunteertoparticipate

Heavysmokersarelesslikelytorespondtoasurveyonthehealtheffectsof

smoking Peoplewhoareverysickmaynotneedtowithdrawfromthestudy

MeasurementBias• Happenswhentheydonotmeasurecorrectlywhattheyaresupposedtomeasureieindividualmeasurementsorclassificationsofdiseaseorexposurearewrong

•  Ifitoccursequallyinbothgroupsbeingcompared,itresultsinanunderestimateofthetruestrengthoftherelationship

RecallBias

• Peoplewhohaveadiseasearemorelikelytoremembertheexposurebecausetheyalreadyknowarelationshipexists

• Biascanexaggerate(makebigger)theeffectoftheexposuree.g.heartpatientsmorelikelytoadmithistoryoflittleexercise

• Orbiascanunderestimatetheeffectoftheexposuree.g.motherslesslikelytoadmittosmokingordrinkingduringpregnancy

ObserverBias•  InvestigatorsaskquestionsorinterprettheinformationforcasesandcontrolsdifferentlyConfounding

• Occurswhenthereisasecondexposureinthestudypopulationthatisassociatedwithboththeexposureandtheoutcome

•  Importantbecause:-  Itcanchangethedirectionofanassociatione.g.somethingthatappearstoprotectapersonfromdiseasemayactuallycausethedisease

-  Itcanmakepeoplethinksomethingcausesadiseasewhenitdoesnot•  Isnotaproblemiftheconfounderoccurswiththesamefrequencyinbothgroups• Themostcommonconfoundersaresexandage

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Controllingconfounding

Designstage

• Randomization:Randomlyassigningparticipantstoagroupshoulddistributeconfoundersequally(ifthesamplesizeislargeenough)

• Restriction:Limitthestudytoincludepeoplewhohavecertaincharacteristics(eg:non-smokers)

• Matching:Participantsinthe2groupsarematchedforconfoundingvariables(eg:ageandsex)Analysisstage

• Stratification:Groupsareanalysedincategories(strata)oftheconfoundingvariable(eg:measureanassociationwithinagegroupsorbysex)

• Statisticalmodeling:Statisticscanbeusedtomeasuretheassociationsbetweenmanyvariablesandidentifyvariablesthatareconfounders

Validity&Reliability • Validity:whethertheresultsofastudyshowthetruesituation;whetherthetest

measureswhatitissupposedtomeasure-  Internalvalidity:Howcorrecttheresultsareforthepopulationunderstudy- Externalvalidity(generalizability):Howmuchtheresultsofastudyapplytothegeneralpopulation

- Astudycanhavehighinternalvaliditybutlowexternalvalidityeg:ifthesamplepopulationdoesnotrepresentthegeneralpopulation

• Reliability:whethertheresultsarerepeatableEthics in Epidemiology

•  InformedConsent - Patientshavetherighttowithdrawfromthetrialatanytime- Researchershaveanobligationtothestudyparticipantsandotherswhosehealthmaybeaffectedbytheresults- Theymusttellcommunitieswhattheyaredoingandwhy- Theymustinformcommunitiesoftheirresultsandtheirsignificance(whattheymean)- Allproposalsforstudiesmustbesubmittedtoaninstitutionalethicscommitteebeforeworkbegins

• Confidentiality- Researchersmustrespectpersonalprivacyandconfidentialityatalltimes- Researchersneedtoobtainpermissionbeforeaccessingpatientrecordsandotherinformation

• RespectforHumanRights- Tensioncanarisebetweentheinterestsofagroupandtheinterestsoftheindividual- Needtoassurepeoplethattheirinterestswillbeprotected

• ScientificIntegrity-  “Allscientistshavethepotentialtobehaveinanunethicalmanner,perhapsinpartbecauseofthepressuretosucceed.”