加強(qiáng)遺傳關(guān)聯(lián)研究報(bào)告 (STREGA) STROBE 聲明的擴(kuò)展

ACADEMIAANDCLINIC

AnnalsofInternalMedicine

STrengtheningtheREportingofGeneticAssociationStudies(STREGA):

AnExtensionoftheSTROBEStatement

JulianLittle,PhD;JulianP.T.Higgins,PhD;JohnP.A.Ioannidis,MD,PhD;DavidMoher,PhD;FranceGagnon,PhD;ErikvonElm,MD;MuinJ.Khoury,MD,PhD;BarbaraCohen,PhD;GeorgeDavey-Smith,MD;JeremyGrimshaw,MBChB,PhD;PaulScheet,PhD;

MartaGwinn,MD;RobinE.Williamson,PhD;GuangYongZou,PhD;KimHutchings,MSc;CandiceY.Johnson,MSc;ValerieTait,PhD;

MiriamWiens,MSc;JeanGolding,DSc;CorneliavanDuijn,PhD;JohnMcLaughlin,PhD;AndrewPaterson,MD;GeorgeWells,PhD;

IsabelFortier,PhD;MatthewFreedman,MD;MajaZecevic,PhD;RichardKing,MD,PhD;ClaireInfante-Rivard,MD,PhD;AlexStewart,PhD;

andNickBirkett,MD

Makingsenseofrapidlyevolvingevidenceongeneticassociationsiscrucialtomakinggenuineadvancesinhumangenomicsandtheeventualintegrationofthisinformationintothepracticeofmedi-cineandpublichealth.Assessmentofthestrengthsandweaknessesofthisevidence,andhencetheabilitytosynthesizeit,hasbeenlimitedbyinadequatereportingofresults.TheSTrengtheningtheREportingofGeneticAssociationstudies(STREGA)initiativebuildsontheSTrengtheningtheReportingofObservationalStudiesinEpidemiology(STROBE)Statementandprovidesadditionsto12ofthe22itemsontheSTROBEchecklist.Theadditionsconcernpop-ulationstratification,genotypingerrors,modelinghaplotypevaria-

tion,Hardy-Weinbergequilibrium,replication,selectionofpartici-pants,rationaleforchoiceofgenesandvariants,treatmenteffectsinstudyingquantitativetraits,statisticalmethods,relatedness,re-portingofdescriptiveandoutcomedata,andissuesofdatavolumethatareimportanttoconsideringeneticassociationstudies.TheSTREGArecommendationsdonotprescribeordictatehowage-neticassociationstudyshouldbedesignedbutseektoenhancethetransparencyofitsreporting,regardlessofchoicesmadeduringdesign,conduct,oranalysis.

AnnInternMed.2009;150:206-215.Forauthoraffiliations,seeendoftext.

Therapidlyevolvingevidenceongeneticassociationsiscrucialtointegratinghumangenomicsintotheprac-ticeofmedicineandpublichealth(1,2).Geneticfactorsarelikelytoaffecttheoccurrenceofnumerouscommondiseases,andthereforeidentifyingandcharacterizingtheassociatedrisk(orprotection)willbeimportantinimprov-ingtheunderstandingofetiologyandpotentiallyforde-velopinginterventionsbasedongeneticinformation.Thenumberofpublicationsontheassociationsbetweengenesanddiseaseshasincreasedtremendously;withmorethan34000publishedarticles,theannualnumberhasmorethandoubledbetween2001and2008(3,4).Articlesongeneticassociationshavebeenpublishedinabout1500

journalsandinseverallanguages.

Despitethemanysimilaritiesbetweengeneticassocia-tionstudiesand“classical”observationalepidemiologicstudies(thatis,cross-sectional,case–control,andcohort)oflifestyleandenvironmentalfactors,geneticassociationstudiespresentseveralspecificchallenges,includinganun-precedentedvolumeofnewdata(5,6)andthelikelihoodofverysmallindividualeffects.Genesmayoperateincom-plexpathwayswithgene–environmentandgene–genein-teractions(7).Moreover,thecurrentevidencebaseongene–diseaseassociationsisfraughtwithmethodologicalproblems(8–10).Inadequatereportingofresults,even

Seealso:

Web-Only

AppendixTable

Conversionofgraphicsintoslides

fromwell-conductedstudies,hampersassessmentofastudy’sstrengthsandweaknessesandhencetheintegrationofevidence(11).

Althoughseveralcommentariesontheconduct,ap-praisal,and/orreportingofgeneticassociationstudieshavesofarbeenpublished(12–39),theirrecommendationsdif-fer.Forexample,somepaperssuggestthatreplicationoffindingsshouldbepartofthepublication(12,13,16,17,23,26,34–36),whereasothersconsiderthissuggestionunnecessaryorevenunreasonable(21,40–44).Inmanypublications,theguidancehasfocusedongeneticassocia-tionstudiesofspecificdiseases(14,15,17,19,22,23,25,26,31–38)orthedesignandconductofgeneticassocia-tionstudies(13–15,17,19,20,22,23,25,30–32,35,36)ratherthanonthequalityofthereporting.

Despiteincreasingrecognitionoftheseproblems,thequalityofreportinggeneticassociationstudiesneedstobeimproved(45–49).Forexample,anassessmentofaran-domsampleof315geneticassociationstudiespublishedfrom2001to2003foundthatmoststudiesprovidedsomequalitativedescriptionsofthestudyparticipants(forexam-ple,originandenrollmentcriteria),butreportingofquan-titativedescriptors,suchasageandsex,wasvariable(49).Inaddition,completenessofreportingofmethodsthatallowreaderstoassesspotentialbiases(forexample,num-berofexclusionsornumberofsamplesthatcouldnotbegenotyped)varied(49).Onlysomestudiesdescribedmeth-odstovalidategenotypingormentionedwhetherresearchstaffwereblindedtooutcome.Thesameproblemsper-sistedinasmallersampleofstudiespublishedin2006(49).Lackoftransparencyandincompletereportinghaveraisedconcernsinarangeofhealthresearchfields(11,50–53),andpoorreportinghasbeenassociatedwithbi-

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asedestimatesofeffectsinclinicalinterventionstudies(54).

Themaingoalofthisarticleistoproposeandjustifyasetofguidingprinciplesforreportingresultsofgeneticassociationstudies.Theepidemiologycommunityhasre-centlydevelopedtheStrengtheningtheReportingofOb-servationalstudiesinEpidemiology(STROBE)Statementforcross-sectional,case–control,andcohortstudies(55,56).Giventherelevanceofgeneralepidemiologicprinci-plesforgeneticassociationstudies,weproposerecommen-dationsinanextensionoftheSTROBEStatementcalledtheSTrengtheningtheREportingofGeneticAssociationstudies(STREGA)Statement.TherecommendationsoftheSTROBEStatementhaveastrongfoundationbecausetheyarebasedonempiricalevidenceonthereportingofobservationalstudies,andtheyinvolvedextensiveconsul-tationsintheepidemiologicresearchcommunity(56).Wehavesoughttoidentifygapsandareasofcontroversyintheevidenceregardingpotentialbiasesingeneticassociationstudies.Withtherecommendations,wehaveindicatedavailableempiricalortheoreticalworkthathasdemon-stratedorsuggestedthatamethodologicalfeatureofastudycaninfluencethedirectionormagnitudeoftheas-sociationobserved.Weacknowledgethatformanyitems,nosuchevidenceexists.Theintendedaudienceforthereportingguidelineisbroadandincludesepidemiologists,geneticists,statisticians,clinicianscientists,andlaboratory-basedinvestigatorswhoundertakegeneticassociationstud-ies.Inaddition,itincludes“users”ofsuchstudieswhowishtounderstandthebasicpremise,design,andlimita-tionsofgeneticassociationstudiesinordertointerprettheresults.Thefieldofgeneticassociationsisevolvingveryrapidlywiththeadventofgenome-wideassociationinves-tigations,high-throughputplatformsassessinggeneticvari-abilitybeyondcommonsingle-nucleotidepolymorphisms(SNPs)(forexample,copynumbervariants,rarevariants),andeventuallyroutinefullsequencingofsamplesfromlargepopulations.Ourrecommendationsarenotintendedtosupportoropposethechoiceofanyparticularstudydesignormethod.Instead,theyareintendedtomaximizethetransparency,quality,andcompletenessofreportingwhatwasdoneandfoundinaparticularstudy.

METHODS

AmultidisciplinarygroupdevelopedtheSTREGAStatementbyusingliteraturereview,workshoppresenta-tionsanddiscussion,anditerativeelectroniccorrespon-denceaftertheworkshop.Thirty-threeof74inviteespar-ticipatedintheSTREGAworkshopinOttawa,Ontario,Canada,inJune2006.Participantsincludedepidemiolo-gists,geneticists,statisticians,journaleditors,andgraduatestudents.

Beforetheworkshop,anelectronicsearchwasper-formedtoidentifyexistingreportingguidanceforgeneticassociationstudies.Workshopparticipantswerealsoasked

toidentifyanyadditionalguidance.Theypreparedbriefpresentationsonexistingreportingguidelines,empiricalevidenceonreportingofgeneticassociationstudies,thedevelopmentoftheSTROBEStatement,andseveralkeyareasfordiscussionthatwereidentifiedonthebasisofconsultationsbeforetheworkshop.Theseareasincludedtheselectionandparticipationofstudyparticipants,ratio-naleforchoiceofgenesandvariantsinvestigated,genotyp-ingerrors,methodsforinferringhaplotypes,populationstratification,assessmentofHardy-Weinbergequilibrium(HWE),multipletesting,reportingofquantitative(contin-uous)outcomes,selectivelyreportingstudyresults,jointeffects,andinferenceofcausationinsinglestudies.Addi-tionalresourcestoinformworkshopparticipantsweretheHuGENethandbook(57,58),examplesofdataextractionformsfromsystematicreviewsormeta-analyses,articlesonguidelinedevelopment(59,60),andthechecklistsdevel-opedforSTROBE.Toharmonizeourrecommendationsforgeneticassociationstudieswiththoseforobservationalepidemiologicstudies,wecommunicatedwiththeSTROBEgroupduringthedevelopmentprocessandsoughttheircommentsontheSTREGAdraftdocuments.WealsoprovidedcommentsonthedevelopingSTROBEStatementanditsassociatedexplanationandelaborationdocument(56).

RESULTS

IntheTable,wepresenttheSTREGArecommenda-tions,anextensiontotheSTROBEchecklist(55)forge-neticassociationstudies.TheresultingSTREGAchecklistprovidesadditionsto12ofthe22itemsontheSTROBEchecklist.Duringtheworkshopandsubsequentconsulta-tions,weidentified5mainareasofspecialinterestthatarespecificto,orespeciallyrelevantin,geneticassociationstudies:genotypingerrors,populationstratification,mod-elinghaplotypevariation,HWE,andreplication.Weelab-orateoneachoftheseareas,startingeachsectionwiththecorrespondingSTREGArecommendation,followedbyabriefoutlineoftheissueandanexplanationfortherecom-mendations.ComplementaryinformationontheseareasandtherationaleforadditionalSTREGArecommenda-tionsrelatingtoselectionofparticipants,choiceofgenesandvariantsinvestigated,treatmenteffectsinstudyingquantitativetraits,statisticalmethods,relatedness,report-ingofdescriptiveandoutcomedata,andissuesofdatavolume,arepresentedintheAppendixTable(availableat).

GenotypingErrors

Recommendationforreportingofmethods(Table,item8[b]:Describelaboratorymethods,includingsourceandstor-ageofDNA,genotypingmethodsandplatforms(includingtheallele-callingalgorithmusedanditsversion),errorrates,andcallrates.Statethelaboratory/centerwheregenotypingwasdone.Describecomparabilityoflaboratorymethodsifthereismorethanonegroup.Specifywhethergenotypeswereassigned

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Table.STREGAReportingRecommendations,ExtendedFromtheSTROBEStatement

Item

Item

STROBEGuideline

ExtensionforGeneticAssociationStudies(STREGA)

Number

Titleandabstract

1

(a)Indicatethestudy’sdesignwithacommonlyusedtermin

thetitleortheabstract.

(b)Provideintheabstractaninformativeandbalanced

summaryofwhatwasdoneandwhatwasfound.

Introduction

Background

2

Explainthescientificbackgroundandrationaleforthe

rationale

investigationbeingreported.

Objectives

3

Statespecificobjectives,includinganyprespecified

Stateifthestudyisthefirstreportofageneticassociation,

hypotheses.

areplicationeffort,orboth.

Methods

Studydesign

4

Presentkeyelementsofstudydesignearlyinthepaper.

Setting

5

Describethesetting,locations,andrelevantdates,including

periodsofrecruitment,exposure,follow-up,anddata

collection.

Participants

6

(a)Cohortstudy:Givetheeligibilitycriteria,andthesources

andmethodsofselectionofparticipants.Describe

methodsoffollow-up.

Case–controlstudy:Givetheeligibilitycriteria,andthesourcesandmethodsofcaseascertainmentandcontrolselection.Givetherationaleforthechoiceofcasesandcontrols.

Cross-sectionalstudy:Givetheeligibilitycriteria,andthesourcesandmethodsofselectionofparticipants.

(b)Cohortstudy:Formatchedstudies,givematchingcriteriaandnumberofexposedandunexposed.

Case–controlstudy:Formatchedstudies,givematchingcriteriaandthenumberofcontrolspercase.

Giveinformationonthecriteriaandmethodsforselectionofsubsetsofparticipantsfromalargerstudy,whenrelevant.

Variables

7

(a)Clearlydefinealloutcomes,exposures,predictors,

(b)Clearlydefinegeneticexposures(geneticvariants)

potentialconfounders,andeffectmodifiers.Give

usingawidelyusednomenclaturesystem.Identify

diagnosticcriteria,ifapplicable.

variableslikelytobeassociatedwithpopulation

stratification(confoundingbyethnicorigin).

Datasources

8*

(a)Foreachvariableofinterest,givesourcesofdataand

measurement

detailsofmethodsofassessment(measurement).Describe

comparabilityofassessmentmethodsifthereismorethan

onegroup.

Bias 9 (a)Describeanyeffortstoaddresspotentialsourcesofbias.

Describelaboratorymethods,includingsourceandstorageofDNA,genotypingmethodsandplatforms(includingtheallele-callingalgorithmused,anditsversion),errorrates,andcallrates.Statethelaboratory/centerwheregenotypingwasdone.Describecomparabilityoflaboratorymethodsifthereismorethanonegroup.Specifywhethergenotypeswereassignedusingallofthedatafromthestudysimultaneouslyorinsmallerbatches.

Forquantitativeoutcomevariables,specifyifanyinvestigationofpotentialbiasresultingfrompharmacotherapywasundertaken.Ifrelevant,describethenatureandmagnitudeofthepotentialbias,andexplainwhatapproachwasusedtodealwiththis.

Studysize

10

Explainhowthestudysizewasarrivedat.

Quantitative

11

Explainhowquantitativevariableswerehandledinthe

variables

analyses.Ifapplicable,describewhichgroupingswere

chosen,andwhy.

Statisticalmethods

12

(a)Describeallstatisticalmethods,includingthoseusedto

controlforconfounding.

(b)Describeanymethodsusedtoexaminesubgroupsandinteractions.

(c)Explainhowmissingdatawereaddressed.

(d)Cohortstudy:Ifapplicable,explainhowlosstofollow-upwasaddressed.

Case–controlstudy:Ifapplicable,explainhowmatchingofcasesandcontrolswasaddressed.

Cross-sectionalstudy:Ifapplicable,describeanalyticalmethodstakingaccountofsamplingstrategy.

(e)Describeanysensitivityanalyses.

Ifapplicable,describehoweffectsoftreatmentweredealtwith.

Statesoftwareversionusedandoptions(orsettings)

chosen.

StatewhetherHardy-Weinbergequilibriumwasconsideredand,ifso,how.

Describeanymethodsusedforinferringgenotypesorhaplotypes.

Describeanymethodsusedtoassessoraddresspopulationstratification.

Continuedonfollowingpage

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Table—Continued

Item Item STROBEGuideline ExtensionforGeneticAssociationStudies(STREGA)

Number

(i)Describeanymethodsusedtoaddressmultiple

comparisonsortocontrolriskoffalse-positivefindings.

(j)Describeanymethodsusedtoaddressandcorrectfor

relatednessamongsubjects.

Results

Participants 13*(a)Reportthenumbersofindividualsateachstageofthestudy(e.g.,numberspotentiallyeligible,examinedforeligibility,confirmedeligible,includedinthestudy,completingfollow-up,andanalyzed).

Givereasonsfornonparticipationateachstage.

Consideruseofaflowdiagram.

Descriptivedata 14*(a)Givecharacteristicsofstudyparticipants(e.g.,demographic,clinical,social)andinformationonexposuresandpotentialconfounders.

Indicatethenumberofparticipantswithmissingdataforeachvariableofinterest.

Cohortstudy:Summarizefollow-uptime(e.g.,averageandtotalamount).

Reportnumbersofindividualsinwhomgenotypingwasattemptedandnumbersofindividualsinwhomgenotypingwassuccessful.

Considergivinginformationbygenotype.

Outcomedata

15*

Cohortstudy:Reportnumbersofoutcomeeventsorsummary

Reportoutcomes(phenotypes)foreachgenotypecategory

measuresovertime.

overtime.

Case–controlstudy:Reportnumbersineachexposure

Reportnumbersineachgenotypecategory.

category,orsummarymeasuresofexposure.

Cross-sectionalstudy:Reportnumbersofoutcomeeventsor

Reportoutcomes(phenotypes)foreachgenotype

summarymeasures.

category.

Mainresults

16

(a)Giveunadjustedestimatesand,ifapplicable,

confounder-adjustedestimatesandtheirprecision(e.g.,

95%confidenceintervals).Makeclearwhichconfounders

wereadjustedforandwhytheywereincluded.

(b)Reportcategoryboundarieswhencontinuousvariables

werecategorized.

(c)Ifrelevant,considertranslatingestimatesofrelativerisk

intoabsoluteriskforameaningfultimeperiod.

(d)Reportresultsofanyadjustmentsformultiple

comparisons.

Otheranalyses

17

(a)Reportotheranalysesdone(e.g.,analysesofsubgroups

andinteractions,andsensitivityanalyses).

(b)Ifnumerousgeneticexposures(geneticvariants)were

examined,summarizeresultsfromallanalyses

undertaken.

(c)Ifdetailedresultsareavailableelsewhere,statehow

theycanbeaccessed.

Discussion

Keyresults

18

Summarizekeyresultswithreferencetostudyobjectives.

Limitations

19

Discusslimitationsofthestudy,takingintoaccountsourcesof

potentialbiasorimprecision.Discussbothdirectionand

magnitudeofanypotentialbias.

Interpretation

20

Giveacautiousoverallinterpretationofresultsconsidering

objectives,limitations,multiplicityofanalyses,resultsfrom

similarstudies,andotherrelevantevidence.

Generalizability

21

Discussthegeneralizability(externalvalidity)ofthestudy

results.

Otherinformation

Funding

22

Givethesourceoffundingandtheroleofthefundersforthe

presentstudyand,ifapplicable,fortheoriginalstudyon

whichthepresentarticleisbased.

STREGA STrengtheningtheREportingofGeneticAssociationstudies;STROBE STtrengtheningtheReportingofObservationalStudiesinEpidemiology.

*Giveinformationseparatelyforcasesandcontrolsincase–controlstudiesand,ifapplicable,forexposedandunexposedgroupsincohortandcross-sectionalstudies.

usingallofthedatafromthestudysimultaneouslyorinsmallerbatches.

Recommendationforreportingofresults(Table,item13[a]):Reportnumbersofindividualsinwhomgenotypingwasattemptedandnumbersofindividualsinwhomgenotypingwassuccessful.

GenotypingerrorscanoccurasaresultofeffectsoftheDNAsequenceflankingthemarkerofinterest;poorqual-ityorquantityoftheDNAextractedfrombiologicalsam-ples;biochemicalartifacts;poorequipmentprecisionorequipmentfailure;orhumanerrorinsamplehandling,conductofthearray,orhandlingthedataobtainedfrom

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thearray(61).Acommentarypublishedin2005onthepossiblecausesandconsequencesofgenotypingerrorsob-servedthatanincreasingnumberofresearcherswereawareoftheproblem,butthattheeffectsofsucherrorshadlargelybeenneglected(61).Themagnitudeofgenotypingerrorshasbeenreportedtovarybetween0.5%and30%(61–64).Inhigh-throughputcenters,anerrorrateof0.5%pergenotypehasbeenobservedforblindduplicatesthatwererunonthesamegel(64).Thislowererrorratereflectsanexplicitchoiceofmarkersforwhichgenotypingrateshavebeenfoundtobehighlyrepeatableandwhoseindi-vidualpolymerasechainreactions(PCRs)havebeenopti-mized.Nondifferentialgenotypingerrors,thatis,thosethatdonotdiffersystematicallyaccordingtooutcomesta-tus,willusuallybiasassociationstowardthenull(65,66),justasforothernondifferentialerrors.Themostmarkedbiasoccurswhengenotypingsensitivityispoorandgeno-typeprevalenceishigh(85%)or,asthecorollary,whengenotypingspecificityispoorandgenotypeprevalenceislow(15%)(65).Whenmeasurementoftheenvironmen-talexposurehassubstantialerror,genotypingerrorsoftheorderof3%canleadtosubstantialunderestimationofthemagnitudeofaninteractioneffect(67).Whentherearesystematicdifferencesingenotypingaccordingtooutcomestatus(differentialerror),biasinanydirectionmayoccur.Unblindedassessmentmayleadtodifferentialmisclassifi-cation.Forgenome-wideassociationstudiesofSNPs,dif-ferentialmisclassificationbetweencomparisongroups(forexample,casesandcontrols)canoccurbecauseofdiffer-encesinDNAstorageorincollectionorprocessingproto-cols,evenwhenthegenotypingitselfmeetsthehighestpossiblestandards(68).Inthissituation,usingsamplesblindedtocomparisongrouptodeterminetheparametersforallelecallingcouldstillleadtodifferentialmisclassifi-cation.Tominimizesuchdifferentialmisclassification,itwouldbenecessarytocalibratethesoftwareseparatelyforeachgroup.Thisisoneofthereasonsforourrecommen-dationtospecifywhethergenotypeswereassignedusingallofthedatafromthestudysimultaneouslyorinsmallerbatches.

PopulationStratification

Recommendationforreportingofmethods(Table,item12[h]):Describeanymethodsusedtoassessoraddresspopu-lationstratification.

Populationstratificationisthepresencewithinapop-ulationofsubgroupsamongwhichallele(orgenotype,orhaplotype)frequenciesanddiseaserisksdiffer.Whenthegroupscomparedinthestudydifferintheirproportionsofthepopulationsubgroups,anassociationbetweenthegeno-typeandthediseasebeinginvestigatedmayreflectthegeno-typebeinganindicatoridentifyingapopulationsubgroupratherthanacausalvariant.Inthissituation,thepopula-tionsubgroupisaconfounderbecauseitisassociatedwithbothgenotypefrequencyanddiseaserisk.Thepotentialimplicationsofpopulationstratificationforthevalidityof

geneticassociationstudieshavebeendebated(69–83).Modelingthepossibleeffectofpopulationstratification(whennoefforthasbeenmadetoaddressit)suggeststhattheeffectislikelytobesmallinmostsituations(75,76,78–80).Meta-analysesof43gene–diseaseassociationscomprising697individualstudiesshowedconsistentasso-ciationsacrossgroupsofdifferentethnicorigin(80)andthusprovideevidenceagainstalargeeffectofpopulationstratification,hiddenorotherwise.However,asstudiesofassociationandinteractiontypicallyaddressmoderateorsmalleffectsandhencerequirelargesamplesizes,asmallbiasarisingfrompopulationstratificationmaybeimpor-tant(81).Studydesign(case-familycontrolstudies)andstatisticalmethods(84)havebeenproposedtoaddresspopulationstratification,butsofarfewstudieshaveusedthesesuggestions(49).Mostoftheearlygenome-wideas-sociationstudiesusedfamily-baseddesignsorsuchmeth-odsasgenomiccontrolandprincipalcomponentsanalysis(85,86)tocontrolforstratification.Theseapproachesareparticularlyappropriateforaddressingbiaswhentheiden-tifiedgeneticeffectsareverysmall(oddsratio,1.20),ashasbeenthesituationinmanyrecentgenome-wideasso-ciationstudies(85,87–105).Inviewofthedebateaboutthepotentialimplicationsofpopulationstratificationforthevalidityofgeneticassociationstudies,werecommendtransparentreportingofthemethodsused,orstatingthatnonewasused,toaddressthispotentialproblem.Thisreportingwillenableempiricalevidencetoaccrueabouttheeffectsofpopulationstratificationandmethodstoas-sessit.

ModelingHaplotypeVariation

Recommendationforreportingofmethods(Table,item12[g]):Describeanymethodsusedforinferringgenotypesorhaplotypes.

Ahaplotypeisacombinationofspecificallelesatneighboringgenesthattendstobeinheritedtogether.Therehasbeenconsiderableinterestinmodelinghaplo-typevariationwithincandidategenes.Typically,thenum-berofhaplotypesobservedwithinageneismuchsmallerthanthetheoreticalnumberofallpossiblehaplotypes(106,107).Motivationforutilizinghaplotypescomes,inlargepart,fromthefactthatmultipleSNPsmay“tag”anuntypedvariantmoreeffectivelythanasingle-typedvari-ant.ThesubsetofSNPsusedinsuchanapproachiscalled“haplotype-tagging”SNPs.Implicitly,anaimofhaplotypetaggingistoreducethenumberofSNPsthathavetobegenotyped,whilemaintainingstatisticalpowertodetectanassociationwiththephenotype.Mapsofhumangeneticvariationarebecomingmorecomplete,andlarge-scalegeno-typicanalysisisbecomingincreasinglyfeasible.Inconse-quence,itispossiblethatmodelinghaplotypevariationwillbecomemorefocusedonrarecausalvariantsbecausethesemaynotbeincludedinthegenotypingplatforms.

Inmostcurrent,large-scalegeneticassociationstudies,dataarecollectedasunphasedmultilocusgenotypes(that

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is,whichallelesarealignedtogetheronparticularsegmentsofachromosomeisunknown).Itiscommoninsuchstud-iestousestatisticalmethodstoestimatehaplotypes(108–111),andtheiraccuracyandefficiencyhavebeendiscussed(112–116).Somemethodsattempttomakeuseofacon-ceptcalledhaplotype“blocks”(117,118),buttheresultsofthesemethodsaresensitivetothespecificdefinitionsofthe“blocks”(119,120).Rep