research goals in epidemiology - jones & bartlett...

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Research Goals in Epidemiology

Learning Objectives

By the end of this chapter the reader will be able to:OO Use the research goal as the organizing principle of a study design.OO Distinguish between general research goals.OO Explain the requirements for causality.OO Realize the practical limitations of a research goal.

chapter OutLine

I. IntroductionII. Types and Examples of Research Goals

III. Practical Limitations of a Research GoalIV. ConclusionV. Vocabulary

VI. Study Questions and Exercises

What is the meaning of life?

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intrOductiOn

Well,thatquestionisprobablybettersuitedforaphilosopherthananepidemi-ologist.Todetermineappropriate researchgoals inepidemiology, significance,scientificrigor,andfeasibilityarekeyconsiderations.Questioningthemeaningoflifeiscertainlysignificantintermsofimportancetohumankind,butdesign-ingastudytoanswerthisquestionisdecidedlynotfeasibleintermsofscope,time,andcost;andarigorousscientificdesign,giventhescopeofthisquestion,wouldbeimpossible.

Startingwithaquestionthatisnotfeasibleorevenpossibletoanswerillus-trateshowtheresearchgoalistheorganizingprincipleforeveryelementofthestudy.Inthischapter,wewillreviewthefeasibleepidemiologicresearchgoalsaswellastheirpracticallimitations.

types and exampLes Of research gOaLs

Wewillstartwiththeleastambitiousandmostlimitedtypeofgoalandmovetothemostambitiousandleastlimitedresearchgoal.Withinthecontextoftheoverallsubstantivegoalsofepidemiologyasafield,alimitedandlessambitiousgoalisnotacompromiseofpracticalsignificance.Descriptionisusuallythefirststepinthequestforcausality.

Descriptive Research GoalAdescriptiveresearchgoalisintendedto“describe”ahealthphenomenonintermsofitsdistributionacrossperson,place,andtime.Thegoalisnottotestahypothesisabout the causesor evencorrelatesof thephenomenon.Rather, thevalueof adescriptivestudyistogaininformationnecessarytoformulateahypothesis.Thisgoalisappropriateforemergingorrarediseasesorhealthproblemsaboutwhichlittleisknown.Itisalsousefulformonitoringandtrackingdiseasesovertime.

Incidence and Prevalence

Thehealthphenomenonunderstudycanbeanythingthatcompromiseshumanphysicalandmentalhealth, fromcancer to infectiousdiseases,andfromdrugabusetotrafficinjuries.Thehealthproblemistypicallymeasuredasincidenceandprevalence.Briefly,incidenceisthenumberofnewcasesofdiseaseordeathduringaspecificperiodoftimeoutofthetotalpopulationatriskforthediseaseordeath.Thepopulationatriskcanbeeitherthenumberofsubjectswithout

8 Chapter 2 researCh Goals in epidemioloGy

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thediseaseattheonsetofthestudy(cumulativeincidence)orthetotalnumberwithoutthediseasemultipliedbytheirtimeatriskduringthestudyperiod(inci-dencedensityor incidencerate).Prevalence is thenumberofexistingcasesofdiseaseordeathsoutofthetotalpopulationof interest.Calculatingincidenceorprevalenceisabasic,butveryimportantcomponentofadescriptivestudy.*

Person, Place, and Time

Beyondincidenceandprevalence,adescriptivestudycouldfocusonthe“who,when,andwhere”(person,time,andplace)ofthehealthphenomenonofinter-est.Characteristicsof thepersonwith thehealthproblemincludesociodemo-graphiccharacteristics, suchasageandgender,aswellasothercharacteristics,suchas generalhealth status,or risk factors (like cigarette smoking) thatmayberelevanttothedisorder.Characteristicsoftimeincludethehour,day,week,andsoonofanoutbreak,aswellascollectivemeasuresof time likehistoricalperiods,cycles,andtrends.Characteristicsoftheplacewherethehealthproblemoccursincludegeographic,geologic,climactic,andsimilarcriteria.Inthecaseofoutbreaks,specificbuildingsorsimilarlocalizedareaswouldbethefocus.Thegoalofdescriptiveresearchistogather“clues”abouttheconcentrationofhealthphenomenaamongspecificpopulations,duringparticulartimes,andlocalizedinkeyareas.Ideally,thesecluessuggestpotentialcausesand,subsequently,hypoth-esestobetestedandinterventionstobeevaluated.

Example: Obesity Research

Technically,childhoodobesity in theUnitedStates isanepidemic (thepreva-lenceandincidenceishigherthanwhatwouldbeexpectedhistorically)withitsbeginningincreaseinthelate1970s(Ogden,Carroll,Curtin,etal.,2010).Theincreaseinprevalencesince1971isshowninFigure 2–1.Theseresultsareanexampleofadescriptivestudywithafocusonthetimingofthediseaseorcon-dition.Theunexpectedincreaseinprevalenceamongchildrenandadolescents,andevenamongadultsintheUnitedStateswasalarmingenoughtostimulateadditionaldescriptiveandanalyticresearchonobesity.

FocusonthepersoncharacteristicsofchildhoodobesityshowsthatHispanicboysandnon-Hispanicblackgirlsareatincreasedriskforobesity(Ogdenetal.,2010).Morefocusedperson-centeredresearchonadolescentobesityshowsthat

*Formoredetailedinformationaboutincidenceandprevalence,seeEssential Epidemiology: Principles and ApplicationsbyWilliamOleckno(2002)andEpidemiology for Public Health PracticebyRobertFriisandThomasSellers(2009).

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adolescentswithautismandDownsyndromehaveanexceptionallyhighprevalenceofobesity(Murray&Ryan-Krause,2010;Rimmer,Yamaki,Lowry,etal.,2010).Thesedescriptiveresultsstimulateafocusonpotentialcultural,genetic,andbio-logicalcausesofobesityinthesesubgroupsofadolescents,aswellasidentifythesegroupsasappropriatetargetpopulationsforpreventionandintervention.

We move to Canada for an example of a descriptive study of obesity thatfocusesonclusteringandcomparisonsofprevalencebyplace—urbanandrural.TheCanadianHeartHealthSurveysResearchGroup(Reeder,Chen,Macdonald,etal.,1997)comparedobesityprevalenceinnineCanadianprovincesfrom1986to1992.Theyfoundnourban–ruraldifferencesinobesityformenandwomeninallprovincesexceptthoseinwesternCanada.InwesternCanada,ruralmenandwomenaremorelikelytobeobesecomparedtotheirurbancounterparts.These results stimulate research to pinpoint the reasons why there are rural–urbandifferencesinwesternCanadaandindicateaneedfortailoredinterventionprogramsinthisregionofCanada.

Association Research GoalAnextimportantresearchgoalinepidemiologyistodeterminefactorsthatareassociatedwithorrelatedtomorbidityandmortality.Thistypeofstudytypicallymoves beyond person, place, and time comparisons to comparisons based onpotentialriskfactorsfordiseaseanddeath.

Figure 2–1 IncreaseinChildhoodObesity

Source:DatafromOgden,C.L.,Carroll,M.D.,Curtin,L.R.,Lamb,M.M.,&Flegal,K.M.(2010).PrevalenceofhighbodymassindexinUSchildrenandadolescents,2007–2008.Journal of the American Medical Association, 303(3),242–249;AMAPublishingGroup©2010.

United States, 1971–2008

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Risk Factors

Riskfactorsareexposuresthatareassociatedwithadisease(Friis&Sellers,2009).Exposurescanbeavastarrayofexperiencessuchascontactwithaninfectiousagent,behaviorsincludinghigh-fatdietandexcessivealcoholuse,contactwithenviron-mentalpoisons,andconditionsoflifesuchascrowdedhousing,lowincome,andstress.Riskfactorsareespeciallyrelevantforepidemiologicresearchbecausetheetiologyofmostdiseasesisacomplexcombinationofcausesandpotentialcauses.Formanypracticalandempiricalreasons,therelationshipsbetweenriskfactorsanddiseaseonsetcannotalwaysbeshowntobecausal.Forexample,asreviewedlaterinthischapter,coronaryheartdiseasehasbeenassociatedwithanumberofrisk factors, including elevated serumcholesterol,highbloodpressure,obesity,andcigarettesmoking(Kagan,Kannel,Dawber,etal.,1963).

According toFriisandSellers (2009),anexposure that isassociatedwithadiseaseorotherhealthproblemcanbeconsidereda risk factor if itmeets thefollowingcriteria:

1. Thereisadose-responserelationship—thehigherthelevelorintensityoftheexposure,thehighertheprobabilityorseverityofthedisease.

2. Temporalityof theexposureanddiseaseareappropriate—theexposureprecedestheonsetofthediseaseintime.

3. Theobservedrelationshipbetweenexposureandthediseaseisnotduetosomesourceoferrorinthedesignorconductofthestudy.

Thesecriteriaareasubsetofthecriterianeededtoestablishcausality,asdiscussedlaterinthischapter.

Butlikemostthingsinlife,theidentificationofriskfactorsismorecompli-cated than simply demonstrating a relationship between exposure and diseaseonset.Robustresultsarethosethatconsiderpotentialsourcesoferrorinrelation-ships, aswell asother factors thatmay influence the significance, strength,ordirectionofrelationshipsbetweenanexposureanddisease.

Measures of Association or Effect

Inepidemiologicstudies,measuresofassociationtestrelationshipsbetweenexpo-suresandoutcomes.Thesemeasuresareusedinstudiesfocusingonassociationsandthosetestingcausalrelationships(effects).Theirinterpretationdependsonwhethercertain criteria for causality are met (discussed shortly).The measures are bestunderstoodinthecontextofcontingencyortwo-by-twotableswiththeexposurereportedintherowsandtheoutcomeinthecolumns.Table 2–1showsanexamplecontingencytable,aswellasformulasforthemostcommonlyusedmeasures.


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Thepurposeofallofthesecalculationsistomeasurehowstronglytheoutcomeisassociatedwithorattributabletotheexposure.Theycanbecalculatedbycomparingincidencesorcomparingprevalencesoftheoutcome.Riskratiosandriskdifferences(calledrateratiosandratedifferencesforcomparisonsofincidencedensities)areusedincross-sectionandcohortstudydesigns,andoddsratiosareusedincase-controlstudies.Attributablerisk(AR)andpopulationattributablerisk(PAR)aredescriptivemeasuresshowingtheproportionoftheincidenceorprevalenceoftheoutcomethatisattributedto(ortheresultof,orexplainedby,orassociatedwith)theexposure.*

Confounding

Confounding is present when a third factor or variable distorts the relationshipbetweenanexposure anddisease (Rothman,1986).Thedistortioncan take theformoferroneouslyinflatingordeflatingthestrengthoftheassociationbetweentheexposureanddisease.Consequently,confoundingisoftenaformofsystematicerror

*Formoredetailedinformationaboutmeasureofassociation,seeEssential Epidemiology: Principles and ApplicationsbyWilliamOleckno(2002)andEpidemiology for Public Health PracticebyRobertFriisandThomasSellers(2009).

Table 2–1 �Two-by-Two�Table�Showing�the�Relationship�Between�an��Exposure�and�an�Outcome

Outcome

Has outcome Does not have outcome Total

Expo

sure Exposed a b a + b

Not exposed c d c + d

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

Risk Ratio = [ /( )][ /( )]a a +

+b

c c d = [prevalence or incidence of outcome for the exposed group] divided

by [prevalence or incidence of the outcome for the unexposed group]

Risk Difference = [ /( )] [ /( )]a a b c c d+ − + = [prevalence or incidence of outcome for the exposed group] minus [prevalence or incidence of the outcome for the unexposed group]

Odds Ratio = ( / )( / )a cb d

= (exposed divided by unexposed for those with the outcome, or cases)

divided by (exposed divided by unexposed for those without the outcome, or controls)

Attributable Risk = [ /( )] [ /( )]

[ /( )]a a b c c d

a a b+ − +

+ = Proportion of the prevalence or incidence of the

outcome for the exposed group that can be attributed to the exposure

Population Attributable Risk = [( ) /( )] [ /( )]

[( ) /( )a c a b c d c c d

a c a b c d+ + + + − +

+ + + + ]] = Proportion of the total

prevalence or incidence that can be attributed to the exposure


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orbias.Reportinganassociationbetweenexposureanddiseasewithouttestingforobviousorevenpotentialconfoundingintheassociationisabiasedstudyandresult.

Testingforconfoundinginvolvescomparingthemagnitudeandevendirec-tionofthesimpleassociationbetweenexposureandoutcome(crudeassociation)withtheadjustedassociationwhenthepotentialconfounderisincludedintheanalysis.Confoundingispresentwhenthefollowingcriteriaaremet:

1. Theconfoundingvariablehasaneffect,eitherasariskfactororcause,onthedisease.

2. Theconfoundingvariablehasaneffectontheexposure,independentofthedisease.

3. Theconfoundingvariabledoesnotinterveneintimeandthecausalchainbetweentheexposureanddisease.Inotherwords,theexposuredoesnotinfluencetheconfoundingvariable.

Figure 2–2aillustratesthesecriteriaofassociations.Althoughnotepidemiologic,thefollowingexampleprovidesaclearillustra-

tionofconfounding.Acityplanninginternnoticedthatthereisadose-responserelationshipbetweenthenumberoffiretruckspresentatafireandtheamountofpropertydamageatthesiteofthefire.Specifically,thegreaterthenumberoffiretrucks,thegreatertheamountofpropertydamage,asillustratedinFigure 2–2b.

The intern proposes to his preceptor that efforts should be made to limitthenumberoffiretruckscalledtoafireinordertolimittheamountofprop-ertydamage.Thepreceptor suggests that the intern study this relationshipbyobservingseveralfiresandmeasuringanyfeasiblerelevantfactorsassociatedwithpropertydamage.Figure 2–2cillustratestheresultsofthestudy.

Figure 2–2a illustration of the Criteria for Confounding

Confounder

Exposure Disease

Figure 2–2b relationship Between the Number of Fire Trucks and the Severity of Property Damage

Number of Fire Trucks Property Damage


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Theinternwasabletoshowthattheassociationbetweenthenumberoffiretrucksandpropertydamagewasveryweakandnotstatisticallysignificantwhentheseverityofthefireisconsideredbyexaminingtheassociationsbetweentrucksanddamageformildfires,formoderatefires,andforseverefires.Inaddition,hefoundthattheseverityofthefireinfluencesboththenumberoftruckscalledtothefireandtheamountofpropertydamageduetothefire.Subsequently,theinternwithdrewhisoriginalproposal.

Confoundingcanbecontrolledorpreventedinallstagesoftheresearchstudy.Inthedesignorplanningstage,potentialconfounderscanbeincludedinthemea-suresplannedfordatacollection.Inthesamplingstage,subjectscanberandomlyselectedorrandomlyassignedtogroupsinordertominimizesystematicdiffer-encesbetweengroupsandbetweenthoseselectedandnotselectedforthestudy.Otherpreventativesamplingmeasuresincludematchingcharacteristicsbetweenstudy groups and restriction (limiting or excluding) based on the confounder.Finally, in theanalysis stage, analyses canbeconductedwithin stratificationorgrouping based on the confounder, or multivariate models including the con-foundercanbetested.

Effect Modification (Interaction)

Whileanunrecognizedconfoundingrelationshipcanbeabiasinastudy,effectmodification, also called interaction, is a meaningful result. Effect modifica-tion is present if the strength or direction of the relationship between expo-sureanddiseasediffers for subgroupsofa third factor, suchasgenderoragegroup (Hennekens, Buring, & Mayrent, 1987).The demonstration of effectmodification adds additional information about the association betweenexposureanddiseaseonset.

Figure 2–2c Severity of the Fire Confounds the relationship Between the Number of Fire Trucks and Amount of Property Damage

Severity of Fire

Number ofFire Trucks

Property Damage


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For example, an investigator determines, in a hypothetical study, that ameasureof associationbetween lead exposure andbraindamagehas a valueof5.0(aquitestrongrelationship).Becauseshealsohypothesizesthattheriskofleadexposureforolderchildrenwithbraindamagewouldbegreaterthanthatforinfantswithbraindamage,sheexaminestherelationshipbetweenleadexposureandbraindamageseparatelyforinfants(youngerthan1yearofage),preschoolchildren (ages1 to4years), andyoung schoolchildren (ages5 to9years).She finds that themeasureofassociation is2.0 for infants,4.5 forpreschoolchildren,and6.0foryoungschoolchildren.Sheconcludesthattheriskof leadexposureincreasesbyageamongchildrenwithbraindamage.Inotherwords,agemodifiestheeffectofleadexposureonbraindamage.Again,thisisahypotheticalresult.

Thepresenceofeffectmodificationcanbetestedintwogeneralways.Aswasdoneinthehypotheticalstudy,thedatacanbestratifiedorgroupedaccordingtocategoriesofthepotentialmodifierandtheassociationbetweenexposureanddiseasedeterminedwithinthegroups,thencomparedacrossthegroups.Second,aninteractionterm,essentiallymultiplyingtheexposurebythemodifier,canbetestedinmultivariatemodels.

Example: The Framingham Heart Study

This, then, is what has been called the coronary profile, a picture of theindividualmostpronetodevelopcoronaryheartdisease.Withsomeofthesefeaturesstillsubjecttoconfirmation,hemaybedescribedasamesomorphic,obese,middle-agedmale,withhigh serumcholesterol, highbloodpressure,lowvitalcapacity,andanabnormalelectrocardiogram.Heeatstoomuchoftoorichfoods,smokescigarettestoexcess,andisphysicallyinactivebothinoccupationandinrecreation.Heisambitious,aggressive,andsubjecttofre-quentdeadlinesandotheremotionalstresses.Thecloseranindividualcomestofittingthispattern,thegreatershouldbetheeffortsofhisphysiciantoalter,where practicable, these characteristics of the patient and his environment(Kaganetal.,1963,p.893).

Muchofwhatweknowcurrentlyabouttheriskfactorsforcardiovasculardis-ease (CVD) has been demonstrated in a long and ongoing history of studiescollectivelyknownastheFraminghamHeartStudy.Thestudybeganin1948inresponsetotheshiftinthe20thcenturyfrominfectiousdiseasestochronicdisordersastheleadingcausesofdeathintheUnitedStates.Atthistime,CVDemergedastheleadingcauseofdeath.


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Morethan5,000adultsaged30to62yearsandfreeofCVDwererecruitedforthestudyinFramingham,Massachusetts.Framinghamwaschosenasthestudysitebecauseitsresidentsnumberedhighenoughtoprovidethedesiredquotaofsubjects,were relatively heterogeneous in ethnicity and socioeconomic status,and were stable in terms of limited out-migration (Feinleib, 1983). Subjectsreturned to the study every 2 years for medical examinations and testing. In1971,theiradultchildrenwereenrolledinthestudy.In2002,theiradultgrand-childrenwererecruitedtoparticipate.Inaddition,anothergroupwasenrolledin1994toreflectthegrowingethnicandsocioeconomicdiversityofFramingham(FraminghamHeartStudy,2012).Asthestudyhasprogressed,theresearchgoalshavealsoexpandedtoincludeexaminationsofhealthphenomenabeyondCVD.

InadditiontotheriskfactorsforCVDsummarizedinthequotationonthepreviouspage(Kaganetal.,1963),Framinghamstudieshavefoundassociationsin the form of risk factors between menopause and CVD (Gordon, Kannel,Hjortland,etal.,1978),useoforalcontraceptivesandbothhypertensionandthromboembolism(Kannel,1979),chronicatrialfibrillationandstroke(Wolf,Dawber,Thomas, et al.,1978), cigarette smokingand reduced levelsofhigh-densitylipoproteins(HDL)(Garrison,Kannel,Feinleib,etal.,1978),diabetesandCVD(Kannel&McGee,1979),combineduseoforalcontraceptivesandsmoking and thrombosis among women 35 years and older (Castelli, 1999),andchroniccoughandmyocardialinfarction(Haider,Larson,O’Donnell,etal.,1999).IdentifiedprotectivefactorsagainstCVDincludehigherlevelsofHDL(Gordon,Castelli,Hjortland,etal.,1977)andmoderatealcoholuse(Kannel&Ellison,1996).

Confounding and effect modification have also been demonstrated in theFramingham studies. A perplexing negative relationship between low bodyweightandelevatedmortalityinmenwasfoundtobeconfoundedbycigarettesmoking(Garrison,Feinleib,Castelli,etal.,1983).Cigarettesmokingleadstobothlowbodyweightandelevatedmortalityamongmen.However,morerecentstudiesoftherelationshipbetweenlowbodyweightandmortalityhavedemon-stratedarelationshipindependentofcigarettesmoking(Woods,Iuliano-Burns,&Walker,2011).Manycasesofeffectmodificationhavealsobeenshown,usu-allymodificationbygenderandage.Therelationshipbetweenhigherserumcho-lesterolandCVDamongmenismodifiedbyageinthattheincreaseinriskissevenfoldamongmenyoungerthan50yearsofage,butonlytwo-and-one-half-foldformenage50yearsandolder(Kaganetal.,1963).ThereisanassociationbetweengoutandCVDformen,butnotforwomen(Abbott,Brand,Kannel,et al., 1988).Amongmen,Raynaud’sphenomenon (a circulatorydisorder) isassociatedwithageandwithsmoking,butamongwomen,itisassociatedwith


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maritalstatusandalcoholuse(Fraenkeletal.,1999).Theseresultsmaybeduetodifferencesintheprevalenceofbehavioralfactorsbetweengendersratherthantruecausalmechanisms.Amongmenandwomenyoungerthan65years,TypeAbehaviorandemotionallabilityareassociatedwithCVDforwomen,butworriesaboutagingareassociatedwithCVDformen(Haynes,Feinleib,Levine,etal.,1978).As theFramingham traditioncontinues, these andmanymoreprovenassociationshaveledtohypotheses,bothtestedanduntested,aboutthecausesofCVDandotherhealthphenomena.

Causal Research GoalTheultimategoalofepidemiologicresearchistodeterminethecausesofmor-bidityandmortality.Confidencethatafactoristrulyacausedependsonarigor-ousstudydesign,repetitionofstudiesshowingthesameresult,andadherencetostrictcriteriadevelopedthroughcenturiesofresearchbyscientific thinkers,includingRobertKochandJakobHenle(Evans,1976),SirAustinBradfordHill(1965),andMervynSusser(1977).

Validity and Reliability

Althoughavalidandreliablestudyistheidealforallresearchgoals(descriptive,association,causal,evaluation),accuracyandprecisionarevitaltomakeinfer-encesaboutcausality.Confoundingbiasinarelationshipbetweenexposureanddiseasewouldcompromisethestatusofanexposureasatruecause.Asamplethat does not adequately represent the target population to which results aregeneralized(lackofexternalvalidity)compromisestheinferencethattheexpo-sureisacauseinthepresumedcontext.Apotentialcausethatisnotaccuratelymeasuredcannotrepresentatruecausenomatterthestrengthoftherelationshipbetweenexposureanddisease.Biasanderrorinstudydesignandconductcom-promisetheabilitytoconcludethatanexposureisanactualcauseofmorbidityormortality.

The Scientific Method

Adiscussionofthescientificmethodisparticularlyinformativeinthecontextofappreciatingwhatisrequiredtoinferacausalrelationship.ThemethodhasitsrootsinancientEgyptandGreecewithsubstantialrefinementsandexpansionsmadebyMuslimscientistal-Haythaminthe11thcentury,FrancisBaconandRenéDescartesinthe17thcentury,andJohnStuartMillinthe19thcentury.

Figure 2–3illustratesamodernconceptualizationofthenecessarystepsinthescientificmethod.


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Note that the first step in the scientific method, to observe and describehealthphenomena, is thegoalofdescriptiveepidemiologydescribedearlier inthischapter.Therequirementsforacausalresearchgoalincludetheremainingstepsofformulating,testing,andretestinghypotheses.SupposeweobservethatsicklecellanemiaismorecommonamongAfricanAmericanscomparedtootherracial or ethnic groups. Naturally, we begin to hypothesize about the reasonsfor thisobservation.Ourhypothesismight focusongenetic factorsunique toAfricanAmericans.Perhapswewouldfocusonenvironmentalfactorsorculturalfactorsor somecombinationof these.Next,wewould testourhypothesisbydesigningastudytoobtainasamplethatisrepresentativeofAfricanAmericansandtomeasurewithoptimalvalidityandprecisioncandidategenes,prevalenceof potentially relevant factors (such as exposure to malaria) in the historicalenvironment,andwhateverelsewehypothesizetoberelevant.Notonlydowestrivetodesignavalidandprecisestudy,butalsoonethatisreplicablebyotherinvestigatorsandinothercontexts.Everyaspectofourstudymustbeempiricalor observable and measurable.The greater the number of subsequent studiesthatreplicateourresults,especiallyindifferentcontextssuchasmultiplestudydesigns,alternativebutstillprecisemeasurements,andvarioussamplesofAfricanAmericans,thestrongerourcaseforacausalrelationship.

Criteria for Causality

In1882,RobertKochdemonstratedthe“germtheory”ofdiseasebyspecifyingdiseaseorganismsasthecausesofspecificdiseases.Withlaterrefinementofthe

Figure 2–3 StepsintheScientificMethod

Observe and Describe Health Phenomena

Formulate a Hypothesis to Explain the Phenomena

Test the Hypothesis in a Research Study

Replicate the Hypothesis Test in Additional Studies


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theorybyJakobHenlein1887,theHenle-Kochpostulatesweredevelopedinanefforttoprovethepathogenesisofdisease(Evans,1976).Theyspecifiedthattheinfectiousagentmustbe:

1. Presentineverycaseofthedisease;2. Isolatedandgrowninpureculture;3. Thecauseofthediseasewhenintroducedintoahealthyhost;4. Recoverableandgrownagaininpureculture;and5. Thecauseofnootherdisease.

Thesecriteriaarerelevantforexplaininginfectiousdiseases,butinfectiousdis-eases are only part of the focus of epidemiology.They do little to guide thediscoveryofthecausesofchronicdiseases,whicharethepredominantcausesofdeathincontemporarydevelopedcountries.

Anexpandedsetofcriteriafordeterminingcausalitywasoutlinedinmedi-cal statisticianSirAustinBradfordHill’sPresident’sAddress to theSectionofOccupationalMedicineoftheRoyalSocietyofMedicinein1965(Hill,1965).This seminaladdress identifiedninecriteria thatareapplicable tocausality inepidemiologicresearch:

1. Strengthoftheassociationbetweenexposureanddisease.Astrongasso-ciationislesslikelytobeduetobiasorrandomerror.

2. Consistency in observing the association in multiple investigations.Ideally,theadditionalstudiesshouldbeconductedbymultipleinvesti-gatorsexaminingthepotentialassociationinvariouscontextsofplaces,circumstances,andtimes.

3. The association is specific to particular persons, places, times, and/orhealthphenomena.

4. The exposure precedes in time the development of the disease. If thisparticularcriterionisnotmet,thereisnopointinfurtherinvestigatingthepossibilityofcausality.

5. Dose-responseorbiologicalgradientinlinearrelationships.Thegreatertheexposure,thegreatertheriskofdisease.

6. Plausibility.Itisbiologicallypossible,atleastwithinthecurrentknowl-edgeofbiology,thattheexposurecancausethedisease.

7. Coherence.Theassociationmakessensegivenwhatisknownaboutthebiologyandnaturalhistoryoftheparticulardisease.

8. Experiment.Causalityismoreplausiblewhentheinvestigatorisabletomanipulatetheexposureandobservetheresults.


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9. Analogy.Causalityismoreplausibleifanassociationbetweenasimilarexposureand/orasimilardiseasehasalreadybeenestablished.

Someof these criteria are illustrated in the following landmarkepidemiologiccasestudy.

Example: Cigarette Smoking and Lung Cancer

TogetherwithRichardDoll,SirAustinBradfordHilldemonstratedthatcigarettesmokingcauseslungcancerbyfindingevidencethatmeetsmanyofHill’scriteriaforcausality(Doll&Hill,1950,1952,1954,1956,1964).Thisseriesofstudiesgrewoutofclinicalobservationsinthe1920sthatcigarettesmokingmightcauselungcancer. Itwasnotuntil the1964SurgeonGeneral’sReportonSmoking(U.S.PublicHealthService,1964)thatenoughevidencewascollectedtobeginconvincingthegeneralpublicthatcigarettesmokingisstronglyassociatedwithmorbidityandmortality.Whatfollowsisabriefsummaryofresearchevidenceinthecontextofcriteriaforcausality.

1. Strength of the association between exposure and disease. Figure 2–4presents measures of association between smoking and lung cancer.Thesemeasuresindicatethatsmokerswerenearly10timesmorelikelythan nonsmokers to have lung cancer and 18 times more likely todie from lung cancer.More than90%of lung cancerdeaths amongsmokerswereattributabletosmoking.Theseassociationsareundeni-ablystrong.

2. Consistency in observing the association in multiple investigations. In the1950s,DollandHilldemonstratedastrongrelationshipbetweensmok-ingandlungcancerintwolarge-scaleandlong-termstudies(case-controland prospective cohort) of British physicians. A search of the medicalliterature in 2011 produced 13,559 articles about cigarette smokingandlungcancer.Resultsofafewofthemostrecentstudiesshowedthatexposuretosecondhandsmokeincreasescontinine(analkaloidfoundintobacco)levelsamongnonsmokers(Baltaretal.,2011);cigarettesmokingexplainsmorethan50%ofthedifferenceinlifeexpectancyat50yearsbetween U.S. immigrants (nonsmokers) and U.S. citizens (smokers)(Blue&Fenelon,2011);andsmokershavesignificantlyelevatedwhitebloodcellcountscomparedtononsmokers(Frost-Pinedaetal.,2011).

3. Specificity.Arecentcase-controlstudyoflungcancershowedthatoccu-pational exposure to sulfuric acid (a known carcinogen) in mist form


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isassociatedwithdamagetothelarynx,butnotwithlungcancer.Theonly demonstrated risk factor for lung cancer was cigarette smoking(Soskolneetal.,2011).Theseresultsoffersomesupportthatlungcancerisspecifictocigaretteexposure,butnottoasimilarinhaledcarcinogen.

4. The exposure precedes the development of the disease.DollandHill’sstudiesmeasuredcurrentorrecentlungcancerandcurrentorformercigaretteuse.Theprospective cohort studyhelped to establish that ahistoryofsmoking precedes the onset of cancer. However, the temporal order iscloudedbycurrentsmoking,andthelonglatencyperiodbetweenexpo-sure and the onset of lung cancer can allow other potential causes tointervene.

5. Dose-response.DollandHillwereabletoprovideverystrongevidenceforadose-responserelationshipbetweencigarettesmokingandlungcancer.Figure 2–5presentsthisevidence.Thesedatashowthattheriskforlungcancermortalityincreaseslinearlywiththenumberofcigarettessmokedperday.Clearly,riskincreaseswithexposure.

Figure 2–4 Strength of the Association Between Cigarette Smoking and Lung Cancer

Source:DatafromDoll,R.,&Hill,A.B.Astudyoftheaetiologyofcarcinomaofthelung.British Medical Journal, 2(4797),1271–1286,BMJPublishingGroup,©1952;Data fromDoll,R.,&Hill,A.B.Mortalityinrelationtosmoking:Tenyears’observationonmaleBritishdoctors.British Medical Journal, 1(5395),1399–1410,BMJPublishingGroup,©1964.

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Evaluation Research GoalThemostimportantgoalofepidemiologyasafieldistodiscoverwaystopreventmorbidityandmortality.Oncea cause is identified,preventionefforts canbedevelopedtoeliminateorminimizethecause,therebypreventingorminimiz-ingthehealthphenomena.However,evenwithaknownandconfirmedcause,the prevention program will not be effective if it does not affect the cause.Thepurposeofanevaluationstudyistodeterminewhetherornottheprogramisefficacious(effectivechangeforthosereceivingthetreatmentandnotforthosenotreceivingthetreatment)inpreventingthehealthoutcome.

Ideally, the evaluation will use the traditional experimental research designwithapretestmeasuringthehealthphenomenabeforetheintervention,acon-currentmeasureofthefidelityinimplementingtheintervention,thenaposttesttomeasureanychangeinthehealthphenomenasubsequenttotheintervention.Astrongdesignwouldincludeacontrolgroupthatdoesnotreceivetheinterven-tionandrandomassignmentofsubjectsintotheexperimentalandcontrolgroupstominimizebiasbetweengroups.Astrongdesignwouldalsoincludearelativelylongfollow-upperiodtodeterminewhetherornotaneffectisenduring.Asseen

Figure 2–5 RelationshipBetweenNumberofCigarettesSmokedandtheRiskofLungCancerDeaths

Source:DatafromDoll,R.,&PetoR.Mortalityinrelationtosmoking:20yearsofobserva-tiononmaleBritishdoctors.British Medical Journal, 2(6051),1525–1536.BMJPublishingGroup,©1976.

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Nonsmoker 15–24 Cigarettes1–4 Cigarettes 25 + Cigarettes


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inthefollowingcasestudy,studiesshowingthataninterventionisnoteffectivearevaluableinindicatingthatinterventionsotherthantheoneevaluatedshouldbeimplemented.

Example: Evaluation of Drug Abuse Resistance Education (DARE)

D.A.R.E.wasfoundedin1983inLosAngelesandhasprovensosuccessfulthatitisnowbeingimplementedin75percentofournation’sschooldistrictsandinmorethan43countriesaroundtheworld(DARE,2012).

Thisschool-baseddrugabusepreventionprogramwasfoundedin1983,andevaluationstudiesbegan in themid-1980s.This reviewwill focusonevalua-tions that used the essential features of the experimental design—control orcomparison group, pretest–posttest measures, or posttest only with randomassignment.Thesefeatureshelptominimizestudybias(byrandomlyassigningstudentstotheexperimentalorcontrolgroup)andisolateeffectsthataredueto the intervention (by comparing outcomes for those who did and did notparticipateintheprogramandmeasuringchangesintheoutcomefrombeforetoaftertheprogram).

EvaluationsoftheeffectofDAREparticipationonstudents’drugusecon-ducted in Illinois (Ennett, Rosenbaum, Flewelling, et al., 1994), Kentucky(Faine&Bohlander,1989),NorthCarolina(Ringwalt,Ennett,&Holt,1991),andSouthCarolina(Harmon,1993)showedthatDAREhadnegligibleeffectsonparticipants’druguse.MorerecentstudiesindicatedthatarevisedDAREhadnoimpactondruguseamongelementaryschoolstudentsinurbanschools(Vincus,Ringwalt,Harris,etal.,2010),butastudyofTennesseeschoolsdidshowthattheprogramhadaneffectonpreventingtheinitiationofcigaretteuse(Ahmed,Ahmed,Bennett,etal.,2002).

WithsucharelativelylongtraditionofDAREevaluationstudies,itispossibleto“studythestudies”or“analyzetheanalysis”throughtheuseofmeta-analysis.Meta-analysisisaprocessusedtosummarizeandevenanalyzetheresultsofsev-eralevaluationstudies(Sutton,Jones,Abrams,etal.,1999).Measuresofinter-ventioneffectsontheoutcomeofinterestfromindividualstudiesarecombinedandweightedtocalculateonemeaneffectsizeacrossallstudies.Inameta-analysisofeightevaluationstudies,Ennett,Tobler,Ringwalt,andcolleagues(1994)cal-culatedameaneffectsizeofonly0.06.Anotherstudy(West&O’Neal,2004)analyzed10studiesandreportedanevensmallereffectsizeof0.01.PanandBai(2009)analyzed20studiesandfoundaverysmall(withinthecontextofrelevantstudyfactorssuchassamplesizes)overalleffectofDAREonadolescentdruguse.


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DAREmaybeaneffectiveprograminsomeways,buttheseevaluationsshowthatitislikelynoteffectiveinpreventingdruguseamongyoungpeople.

practicaL LimitatiOns Of a research gOaL

Onemistakeevenseasonedresearcherssometimesmakeistodrawimplicationsfromtheirstudyresultsthatgobeyondtheiroriginalresearchgoal.Adescriptivestudy can suggest, but not actually test the associationbetween exposure anddisease.Anassociationstudydoesnotdemonstratecausality.Anevaluationstudywithouttheessentialelementsofanexperimentaldesigndoesnotdemonstratetheefficacyofanintervention.Asaresearcherandaconsumerofresearch,par-ticularattentionshouldbepaidtotheconnectionoftheresearchgoaloutlinedintheintroductionoftheresearcharticle,thesis,capstone,andsoon,andtheimplicationsofresultsdrawninthediscussionsection.Generalizationsofresultsbeyondthescopeoftheresearchgoalhavenovalue.

cOncLusiOn

Westilldonotknowmuchabouttheindisputablemeaningoflife,butweshouldhaveabetterunderstandingofthedifferentlevelsofresearchquestionsandtheconclusionsthatcanbedrawnfromthem.Descriptivegoalsdescribehealthphe-nomenaand incidenceandprevalenceofmorbidityandmortality in termsofthe distribution of the disease among particular groups of people, in specificareas,andinfocusedperiodsoftime.Associationgoalsmovetothenextstepofdiscoveringadditionalfactorsthatarerelatedtothedisease.Careshouldbetakentoshowthattheexposureistrulyassociatedwiththeoutcomeandtherelation-shipisnotconfoundedbyotherfactorsorexposures.Thedeterminationoftrueriskfactorssuggestshypothesestobetestedincausalstudiestosupportorrefutetheirroleasthecauseofdisease.Ideally,causalstudiesidentifyfactorsthatshouldbemanipulatedtopreventorinterveneinthecourseofthedisease.Thisistheidealbecausemanyinterventionprogramsaredesignedandimplementedwith-outknowledgeofwhetherornotthefocusoftheprogramisevenrelatedtotheoutcomeof interest.Theyarenot“evidence-based.”Finally,evaluationstudiesindicatewhetherornottheinterventionchangesthecause,therebypreventingthedisease.

Studiesthataddressthesegoalsshouldbedesignedspecificallyforthegoal.Theyshouldbefree,totheextentpossibleandpractical,ofbiasandrandomerror.


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Finally,theimplicationsdrawnfromstudyresultsmustbelimitedtothescopeoftheresearchgoal.Astudydesignedandimplementedaccordingthesecriteriamaysomedaytellusthemeaningoflife.

vOcabuLaryAnalyticgoal Exposure ReliabilityAttributablerisk Evaluation RiskdifferenceCausalresearchgoal Evidence-based RiskfactorConfounding Incidence RiskratioCriteriaforcausality Oddsratio ScientificmethodDescriptivegoal Outcome TemporalityDose-response Person,place,time ValidityEffectmodification PopulationattributableriskEfficacy Prevalence

study QuestiOns and exercises

1. AbusinessmanreturnshometoSanDiegofromatriptoChina.Onthewayhome,hehadalayoverinHawaiiwherehevisitedrelatives.WhileinHawaii,hestartedtofeelill.Hissymptomsincludedrespiratoryprob-lems, fever, fatigue, and vertigo.When he returned home, he suffereda seizure anddied. In1week’s time,4ofhis familymembers inbothHawaiiandSanDiegoweredead,asweremorethan10peopleinChina.AsanepidemiologistattheCentersforDiseaseControlandPrevention(CDC),youareassignedtogettothebottomofthisoutbreak—quickly.a.Whatresearchfocusshouldyouusetobeginyourinvestigation?b.Whatfactorsshouldyouexamineandenumerate?

2. Continuing the scenario from problem 1, you discover that this newillnessisspreadeasilybyairborneandhard-surfacecontacts.Fromtwoofthevictims,laboratorypersonnelonyourteamsuccessfullyisolateandreplicateavirussimilartotheH1N1(birdflu)virus.a.Whatresearchfocusshouldyouuseinyournextstudy?b.Whatfactorsshouldyouexamineandenumerate?

3. Continuingthescenariofromproblems1and2:a.Howwouldyoudemonstrate,scientifically,thatthisnewviruscauses

thisnewillness?b.Howwouldyouaddressthekeycriteriaforcausality?

s t u d y Q u e s t i o n s a n d e x e r C i s e s 25

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4. Continuingthisexamplefromproblems1–3,yourteamhasdevelopedapromisingvaccinetopreventthisnewillness.a.Whatresearchfocusshouldyouusetodemonstratetheefficacyofthe

vaccine?b.Whatfactorsshouldyouexamineandenumerate?

5. Ifyouarepreparingtoconductyourownresearchstudy,whatresearchfocusismostimportantforyourresearchidea?Whyisthisfocusappro-priate foryour study?Whatpracticalproblemsdoyouanticipatewiththisfocusatthispointinyourstudy?

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