Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor

15 Pages·2015·0.39 MB·English

RESEARCHARTICLE
Race, Ethnicity and Ancestry in Unrelated
Transplant Matching for the National
Marrow Donor Program: A Comparison of
Multiple Forms of Self-Identification with
Genetics
JillA.Hollenbach1*,AliyaSaperstein2,MarkAlbrecht3,CynthiaVierra-Green4,
PeterParham5,6,PaulJ.Norman5,6,MartinMaiers3
1 DepartmentofNeurology,UniversityofCalifornia,SanFranciscoSchoolofMedicine,SanFrancisco,
California,UnitedStatesofAmerica,2 DepartmentofSociology,StanfordUniversity,Stanford,California,
UnitedStatesofAmerica,3 BioinformaticsResearch,NationalMarrowDonorProgram,Minneapolis,
Minnesota,UnitedStatesofAmerica,4 CenterforInternationalBloodandMarrowTransplantResearch,
Minneapolis,Minnesota,UnitedStatesofAmerica,5 DepartmentofStructuralBiology,StanfordUniversity
SchoolofMedicine,Stanford,California,UnitedStatesofAmerica,6 DepartmentofMicrobiology&
Immunology,StanfordUniversitySchoolofMedicine,Stanford,California,UnitedStatesofAmerica
OPENACCESS
* [email protected]
Citation:HollenbachJA,SapersteinA,AlbrechtM,
Vierra-GreenC,ParhamP,NormanPJ,etal.(2015)
Race,EthnicityandAncestryinUnrelatedTransplant
Abstract
MatchingfortheNationalMarrowDonorProgram:A
ComparisonofMultipleFormsofSelf-Identification
withGenetics.PLoSONE10(8):e0135960. Weconductedanationwidestudycomparingself-identificationtogeneticancestryclassifi-
doi:10.1371/journal.pone.0135960 cationsinalargecohort(n=1752)fromtheNationalMarrowDonorProgram.Wesoughtto
Editor:TesfayeBMersha,CincinnatiChildren's determinehowvariousmeasuresofself-identificationintersectwithgeneticancestry,with
HospitalMedicalcenter,UNITEDSTATES theaimofimprovingmatchingalgorithmsforunrelatedbonemarrowtransplant.Multiple
Received:March1,2015 dimensionsofself-identification,includingrace/ethnicityandgeographicancestrywere
comparedtoclassificationsbasedonancestryinformativemarkers(AIMs),andthehuman
Accepted:July28,2015
leukocyteantigen(HLA)genes,whicharerequiredfortransplantmatching.Nearly20%of
Published:August19,2015
responseswereinconsistentbetweenreportingrace/ethnicityversusgeographicancestry.
Copyright:©2015Hollenbachetal.Thisisanopen
DespitestrongconcordancebetweenAIMsandHLA,nomeasureofself-identification
accessarticledistributedunderthetermsofthe
showscompletecorrespondencewithgeneticancestry.Incertaincasesgeographicances-
CreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninany tryreportingmatchesgeneticancestrynotreflectedinrace/ethnicityidentification,butin
medium,providedtheoriginalauthorandsourceare othercasesgeographicancestriesshowlittlecorrespondencetogeneticmeasures,with
credited.
importantdifferencesbygender.However,whenrespondentsassignancestrytograndpar-
DataAvailabilityStatement:Ourinformedconsent ents,weobservesub-groupsofindividualswithwell-definedgeneticancestries,including
stipulatedthatsurveydatawillonlybereportedin
importantdifferencesinHLAfrequencies,withimplicationsfortransplantmatching.While
aggregateform.SNPallelefrequenciesandHLA
weadvocatefortailoredquestioningtoimproveaccuracyofancestryascertainment,collec-
haplotypefrequenciesforthefulldatasetwillbemade
availableuponrequest([email protected]). tionofdonorgrandparents’informationwillimprovethechancesoffindingmatchesfor
manypatients,particularlyformixed-ancestryindividuals.
Funding:ThisworkwasfundedbytheOfficeof
NavalResearchN00014-12-1-0142(MA,CVG,MM).
Thefundershadnoroleinstudydesign,data
collectionandanalysis,decisiontopublish,or
preparationofthemanuscript.
PLOSONE|DOI:10.1371/journal.pone.0135960 August19,2015 1/15
Race,EthnicityandAncestryinUnrelatedTransplantMatching
CompetingInterests:Theauthorshavedeclared Introduction
thatnocompetinginterestsexist.
TheNationalMarrowDonorProgram(NMDP)registry[1]istherepositoryfordataforthe
highlypolymorphichumanleukocyteantigen(HLA)genesfromovertwelvemillionpotential
donorsforhematopoieticstemcelltransplant(HSCT).However,duetochangesovertimein
technologyandthecostsassociatedwithhighresolutionHLAgenotyping,theregistrydatafor
potentialdonorsisoftenoflowerresolutionthanrequiredformatchingwithpatients.Over
tenthousandHLAallelesarecurrentlyrecognized,withmorethan2000allelesforsomegenes
[2],andworldwidedistributionpatternscorrespondtospecificpopulationswithshareddemo-
graphichistory[3].Accordingly,theNMDPfacilitatesinitialselectionofpotentiallyHLA-
matcheddonorsbyclassifyingthemusingtheirself-identifiedrace/ethnicityfromastandard-
izedquestionnaire,incorporatingthisinformationinabioinformaticsprocessthatprojects
donors’mostlikelyhigh-resolutionHLAhaplotypesandpatientmatchprobabilities[4].
However,racialandethnicself-identificationamongAmericansisacomplexprocessthat
drawsoninformationaboutknownancestry,appearance,howpeoplewereraised,wherethey
grewup,whethertheyexperienceddiscrimination,andbywhom;andanindividual’s
responsescanalsochangeovertime[5–9].SomeAmericansdonotreportallfacetsoftheir
ancestrywhentheyareaskedtoself-identify,eveniftheyknowthem(e.g.,althoughPresident
BarackObamaoftenacknowledgeshiswhiterelatives[10],heidentifiedonlyasblackonthe
2010Census[11]).Othersmayadjusttheirresponsesbasedonwhattheyassumeisthepurpose
ofthedatacollection[12].Reportingofgeographicoriginsorancestrycanbeequallysubjective,
asmoreAmericansreportcommonorigins(e.g.Irish)thanishistoricallyfeasible[13].Thus,
theextenttowhichself-identifiedrace/ethnicityorgeographicancestrywillcorrespondto
geneticancestryisalsolikelytovaryand,apriori,itisimportanttonotprivilegeanyonemea-
sureofrace/ethnicityorancestryoveranyotherwithoutformal,rigoroustesting.Although
manystudieshaveexaminedtherelationshipbetweenself-identifiedrace/ethnicityandgenetic
ancestry[14–20],previousworkhasinvolvedonlyasingledimensionofself-identification
withoutconsiderationofalternativemeasures.
Here,wepresentthefirstsimultaneousassessmentofmultipleapproachestomeasuring
self-reportedancestrywithdirectcomparisonofsurveyresponseswithgeneticmarkers,and
examineimplicationsforunrelateddonorHLAmatchinginHSCT.Weconductedanation-
widestudycomparingseveralformsofself-identificationtogeneticclassifications,inalarge
cohortfromtheNMDP.Wecapturedmultiplefacetsofself-identification,includingrace/eth-
nicityandgeographicancestry.FormanyAmericansthesedimensionswillyieldconsistent
responses,butforotherseachmeasureproducesadifferentresponse[21].Ouraimwastochar-
acterizetheextenttowhichthesedifferentself-identificationmethodscorrespondnotonlyto
eachotherbutalsotogeneticmeasures,withtheobjectiveofimprovingcurrentpracticesfor
selectingunrelateddonorsforbonemarrowtransplantsintheUnitedStates.
MaterialsandMethods
Ourcohortincludes1752individualswhorespondedpositivelytoaletterofrequestforpartici-
pationinthestudybymailingbackbothacheekswabandacompletedpaper-and-pencilsur-
veyquestionnaire.Recipientsoftheinvitationletterwereselectedrandomlywithrespectto
originalself-identificationfromtheNMDPdonorpool.Inordertoassessconcordanceofself-
identificationwithhigh-resolutionHLAgenotype,onlydonorsforwhomsequence-leveldata
wereavailableforfiveHLAloci(HLA-A,-B,-C,DRB1,DQB1)wererecruited.Becauseweare
interestedinimprovingclassificationfordonorswithrareHLAtypes,weoversampled(2:1)
individualswhoseHLAgenotypeisunderrepresentedintheregistry(fewerthan11copies
among12million).TheNationalMarrowDonorPrograminstitutionalreviewboardapproved
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Race,EthnicityandAncestryinUnrelatedTransplantMatching
Table1. Surveyrespondentdemographics.
Total Female Male Meanage
Allrespondents 1752 1324 428 31
Originalregistryclassification
AfricanAmerican 27 22 5 30
White 1414 1090 324 31
AsianorPacificIslander 65 33 32 30
Hispanic 100 70 30 31
NativeAmerican 4 4 0 30
Multi-race 142 105 37 30
RespondentUSborn
No 100 61 39 33
Yes 1647 1259 388 30
ParentsUSBorn
Neither 159 95 64 31
One 145 114 31 31
Both 1444 1113 331 31
GrandparentsUSborn
None 177 111 66 32
One 28 23 5 29
Two 172 134 38 32
Three 133 102 31 29
Four 1225 944 281 31
doi:10.1371/journal.pone.0135960.t001
thestudy(Study#0292);allsubjectsgavewritteninformedconsent.Responseratesbyoriginal
registryrace/ethnicityclassificationandgenderaregiveninSupplementalmaterials(S1Table).
Thebaselinedemographicsofsurveyrespondents,includingtheoriginalrace/ethnicityclassifi-
cation(basedontheexistingregistryquestionnaire;S1Fig),nativityofrespondent,parents
andgrandparents,ageandgenderaregiveninTable1.Althoughpresentedontheoriginal
donorformasaseparateethnicityselection,individualsselecting“Hispanic”aretreatedas
equivalenttothemajorracialcategoriesbytheregistry,andareconsideredassuchhere.
Inonepartofthequestionnaire(S2Fig),weaskedrespondentshowtheyself-identifywith
respecttoraceandethnicity:“Markoneormoreboxestoshowtheracialorethnicgroup(s)you
usetodescribeyourself.”Thelistofpossibleresponsesincludedthefivemajorracialcategories
(AmericanIndianorAlaskaNative;Asian;BlackorAfricanAmerican;NativeHawaiianor
otherPacificIslander;White)recommendedbytheOfficeofManagementandBudget(OMB)
inits1997directive[22].Wealsoincluded“HispanicorLatino”andgavetheoptiontomark
“other.”Asimilarinstrumentiscurrentlybeingtestedforthe2020Census[12].Inthesame
section,weaskedrespondentstotellustheirperceivedracialclassificationbyothers(“Howdo
otherpeopleinthiscountrytypicallyclassifyyou?”).Thisquestionwasbasedonaninstrument
developedbytheCenterforDiseaseControl’sMeasuresofRacismWorkingGroupforthe
annualBehavioralRiskFactorSurveillanceSystemsurvey(http://www.cdc.gov/brfss/).
Wealsoaskedwhetherrespondents,theirparentsortheirgrandparentswereborninthe
UnitedStates,followedbyaquestionabouttheirgeographicancestry:“Fromwhatcountriesor
partsoftheworlddidyourancestorscome?”Theseinstrumentsweremodeledonitemsusedby
theGeneralSocialSurveysince1972[23].Respondentswereaskedtochooseasmanycatego-
riesasnecessarytodescribetheirancestryfromalistofcountries(e.g.,Cuba,Vietnam),
regionsoftheworld(e.g.,MiddleEast,Caribbean),andothercommonancestriesamong
PLOSONE|DOI:10.1371/journal.pone.0135960 August19,2015 3/15
Race,EthnicityandAncestryinUnrelatedTransplantMatching
Americans(“AfricanAmerican”or“NorthAmericanIndian”).Thelistof24countriescom-
binedthemostcommonancestriesreportedinthemostrecentAmericanCommunitySurvey,
andthecountriesfromwhichthemostimmigrantscametotheUnitedStatesinthelast
decade.Weofferedregionsoftheworldtocapturecountriesnotspecificallyincluded,aswell
astoprovideoptionsforpeoplewhomightonlyknowgeneralinformationaboutfamilyori-
gins.Finally,weaskedrespondentstoprovidethespecificcountry,regionorancestryfromthe
samelistthatappliedtoeachoftheirfourgrandparents(“Ifpossible,intheboxesbelow,enter
thebestorigincodeforeachofyourgrandparents”)usingnumericalcodesadjacenttoeachof
thegeographicancestryoptions.Inordertocomparethisself-identifiedgeographicancestryto
self-identifiedrace/ethnicityandmeasuresofgeneticancestry,weaggregatedspecificcountry
orregionresponsesintobroadercategories(S2Table),inkeepingwithfederalguidelineson
racial/ethnicclassificationintheUnitedStates[22]Forexample,wehavecombinedallAsian
geographicancestries(South,Southeast,East)underoneterm,“Asian,”asisdonebytheU.S.
Census[24].
Awell-characterizedpanel[25]of93ancestryinformativemarkers(AIMs)[26,27](S3
Table)wasgenotypedforallrespondentsusingtheSequenomiPLEXassay.Failedsinglenucle-
otidepolymorphism(SNP)callsunderwentasecondgenotypingusingtheTaqmanassay
(ABI).Fivepercentofthesamplesservedasqualitycontrolsandweretypedblindinduplicate.
AllsamplesandSNPsmetstandardqualitycontrolchecks,includingfittoexpectationsunder
Hardy-WeinbergEquilibriumandlessthan10%missingnessorfailurerates.WiththeHuman
GenomeDiversityPanel(HGDP)publicdataset[28]asareference,SNPgenotypeswereused
inancestryestimationswithStructuresoftware[29].ParametersfortheStructurerunwereas
follows:k=4,popflag=1,burnin=10,000andreps=10,000.The‘popflag’optionenableduse
oftheHGDPpopulationsasthetrainingset,whilemultiplerunsindicatedthatk=4clusters
allowedthebestresolutionofbroadcontinentalgroups(African,European[clusteredwith
MiddleEastern],AsianandAmerindian),facilitatedbyuseoftheHGDPpopulations.Aplot
oftheStructurerunshowingfourdistinctclustersisgiveninS3FigWedefinedsubpopulations
byrace/ethnicityorgeographicancestryresponses(e.g.,allindividualsthatselected“Hispanic
orLatino”aloneorincombinationwithotherrace/ethnicitychoices;orallindividualsreport-
inganyEuropeangeographicancestry).Themeanproportionofeachgeneticancestry(based
ontheAIMs)wascomputedforthesesubpopulations,andtheWilcoxonMann-Whitneytest
usedtotestdifferencesindistributionsofancestryproportionsbetweengroups.Allstatistical
analysesandplottingwereperformedintheRlanguageandenvironmentforstatisticalcom-
puting[30].
Intransplant,theprimarygenesofinterestareHLA.Toexaminecorrespondencebetween
self-identification,AIMsandHLA,aBayesianclassifier[31]customscriptedinRwasusedto
assignthemostprobablecontinentaloriginforsubjects’HLAhaplotypes.Priorprobabilities
formarginaldistributionofclassificationswerecomputedfromproportionsoftheoriginalreg-
istryclassificationsforthecohort.Foreachsubpopulationdefinedbyquestionnaireresponses,
frequenciesofAfrican,European.AsianandAmerindianHLAhaplotypeswerecalculated.
Correlationsbetweenself-identificationmeasuresandgeneticancestryproportions(calculated
fromAIMs)andHLAhaplotypeorigins,aswellascorrelationbetweengeneticancestrypro-
portionsandHLAorigins,werecomputedusingthe‘corr.test’functionintheRpackage
‘psych.’Foreachcorrelationcoefficient,95%confidenceintervalsandp-valueswerecomputed.
Allp-valueswerecorrectedformultipletests[32].
Throughoutthemanuscript,wereferto“race/ethnicity”and“geographicancestry”to
describemeasuresofself-identification.Theterm“geneticancestry”referstocontinental
ancestryproportionsascertainedthroughAIMsandStructureanalysis;and“HLAorigin”
referstothecontinentaloriginforHLAhaplotypesdeterminedviatheBayesianclassification.
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Afulldescriptionofthesetermsandtheirpossiblevaluesisgiveninsupplementalmaterials
(S4Table).
Results
Self-identificationoftenvariesbyreportingformat
Whereasallsubjectsself-identifiedbyrace/ethnicity,3%didnotprovideresponsesregarding
geographicancestry,and19%gavewhatcouldbeconsideredinconsistentresponsesforthese
twoquestions(S5Table).ApproximatelyhalfoftheinconsistentresponsesreportedAmerican
Indianancestrywithoutidentifyingtheirrace/ethnicityasAmericanIndian.Mostoften,lack
ofconcordancebetweengeographicancestryandrace/ethnicityreportingoccurswhenindivid-
ualsacknowledgeparticulargeographicancestriesbutdonotexplicitlyidentifywithacorre-
spondingracial/ethnicgroup.Lesscommonisrace/ethnicityself-identificationwithout
reportingacorrespondinggeographicancestry.Consequently,manymoreindividualsreported
multiplegeographicancestries(19%)thanmultiplerace/ethnicities(7%).Thevastmajorityof
individualswhoreportedasinglerace/ethnicityalsoreportedthatotherpeopletypicallyper-
ceivethemthesameway.However,consistentwithevidencefromothernationallyrepresenta-
tivesurveys[9],themajorityofindividualswhoreportedmultiplerace/ethnicitiesreported
thatotherpeopletypicallyperceivethemasWhite.
Correspondenceofself-identificationmeasureswithgeneticancestry
andHLAorigin
Nomeasureofself-identificationshowscompletecorrespondencewithanyspecificpatternof
geneticancestry,underscoringtheunclearboundariesandimprecisenatureofthesecategori-
zations,whichareoftenpresumedtorepresentseparateandidentifiablegroups.Wefindevi-
denceofEuropeangeneticancestryamongnearlyallsub-populations,asexpectedinaU.S.
cohort(Table2).However,theproportionofEuropeangeneticancestryrangesbroadly,with
lowestaveragevaluesobservedamongindividualswhoidentifytheirrace/ethnicityAsian.Afri-
cangeneticancestryproportionsrangefrom20–95%forindividualswhoidentifytheirrace/
ethnicityas“BlackorAfricanAmerican,”withtheremainingcomponentlargelyEuropean.
Forindividualswhoself-identifytheirrace/ethnicityas“HispanicorLatino”weobservemean
EuropeanandAmerindiangeneticancestriesof71%and21%,respectively,butthedefining
featureoftheseclassificationsisthattheproportionofeachgeneticancestryvariesbroadly
betweenindividualsevenwhentheyself-identifythesameway.
Acrossallclassificationsandquestionformats,wefindveryhighcorrelationbetweenthe
meanproportionofAfrican,European,AsianandAmerindiangeneticancestryineachsub-
population,andthefrequencyoftherespectiveHLAhaplotypesoriginsinthoseindividuals
(r=0.97,0.79,0.97,0.95,respectively;Table2).Thisdemonstratesconcordanceofpopulation
levelgeneticancestryassessedviaAIMsandHLAorigin.Thestrongestcorrelationbetween
anytwomeasuresisbetweenself-reportedAsianrace/ethnicityandself-reportedAsiangeo-
graphicancestry(r=0.94;CI=0.93–0.94;p<10−15),andeachofthesemeasuresissimilarly
correlatedwithAsianHLAoriginandgeneticancestry(Table3).Sub-SaharanAfricangeo-
graphicancestryandracial/ethnicself-identificationas“BlackorAfricanAmerican”arealso
highlycorrelated(r=0.83;CI=0.81–0.84;p<10−15),butthelattertrackssomewhatmore
closelywithAfricanHLAoriginandgeneticancestry(Table3).Wefindlower,yetsignificant
correspondencebetweenEuropeangeographicancestryandself-identificationasWhite
(r=0.68;CI=0.66–0.71;p<10−15),withrace/ethnicitybeingslightlymorepredictiveofEuro-
peanHLAoriginandgeneticancestry(Table3).IndividualsreportingLatinAmerican
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Table2. MeangeneticancestryproportionsdeterminedviaancestryinformativemarkersandHLAhaplotypeoriginfrequenciesforsubpopula-
tionsdefinedbyreportedrace/ethnicityorgeographicancestry.
N Meangeneticancestryproportion HLAhaplotypeorigin
African European Asian Amerindian African European Asian Amerindian Multi-
American origin*
Race/EthnicitySelf-ID:Single 1624
choicerespondents
BlackorAfricanAmerican 27 0.70 0.27 0.03 0.01 63% 11% 4% - 22%
White 1443 0.00 0.99 0.00 0.00 - 82% - - 17%
Asian 64 0.01 0.22 0.76 0.01 - - 97% - 3%
HispanicorLatino 71 0.05 0.63 0.05 0.28 - 13% 1% 52% 34%
AmericanIndianorAlaska 2 0.00 0.99 0.01 0.00 - 50% - - 50%
Native
NativeHawaiianorother 2 0.01 0.00 0.97 0.02 - - 100% - -
PacificIslander
Geographicancestry:Single 1373
originrespondents
AfricaorAfricanAmerican 15 0.71 0.25 0.03 0.02 67% 13% 7% - 13%
Europe 1236 0.00 0.99 0.00 0.00 - 82% - - 17%
Asia/Pacific 63 0.01 0.21 0.77 0.01 - - 97% - 3%
NorthAmericanIndian 6 0.00 0.91 0.01 0.08 - 20% - - 80%
LatinAmerica 36 0.04 0.51 0.07 0.38 - - - 72% 28%
Caribbean 17 0.19 0.71 0.03 0.07 6% - 6% 12% 77%
Race/EthnicitySelf-ID: 124 0.04 0.84 0.06 0.05 5% 48% 6% 6% 35%
Multiplechoicerespondents
BlackorAfricanAmerican 13 0.36 0.60 0.03 0.02 54% 8% - - 39%
White 120 0.03 0.85 0.06 0.05 3% 48% 7% 6% 36%
Asian 18 0.00 0.66 0.31 0.02 - 22% 33% 6% 39%
HispanicorLatino 46 0.03 0.84 0.03 0.11 4% 37% - 13% 46%
AmericanIndianorAlaska 53 0.04 0.91 0.02 0.03 6% 66% 2% 4% 23%
Native
NativeHawaiianorother 5 0.01 0.71 0.23 0.05 - 20% 60% - 20%
PacificIslander
Geographicancestry:Multiple 379 0.04 0.89 0.03 0.04 4% 63% 3% 6% 25%
originrespondents
AfricaorAfricanAmerican 27 0.40 0.57 0.02 0.02 41% 22% - - 37%
Europe 318 0.02 0.91 0.03 0.04 2% 64% 4% 5% 25%
Asia/Pacific 25 0.01 0.70 0.28 0.02 - 28% 36% 4% 32%
NorthAmericanIndian 49 0.04 0.91 0.02 0.03 2% 72% 1% 3% 23%
LatinAmerica 68 0.05 0.78 0.02 0.15 6% 40% - 22% 32%
Caribbean 21 0.19 0.75 0.04 0.02 14% 48% 5% - 33%
Classificationbyothers
BlackorAfricanAmerican 31 0.71 0.25 0.03 0.01 68% 10% - - 23%
White 1545 0.00 0.98 0.01 0.01 - 80% - - 18%
Asian 70 0.01 0.24 0.74 0.01 - 7% 90% 1% 1%
HispanicorLatino 73 0.05 0.63 0.05 0.28 1% 10% 1% 52% 36%
AmericanIndianorAlaska 6 0.01 0.74 0.11 0.14 - 67% - - 33%
Native
NativeHawaiianorother 3 0.01 0.67 0.31 0.01 - 33% 33% - 33%
PacificIslander
(Continued)
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Table2. (Continued)
N Meangeneticancestryproportion HLAhaplotypeorigin
African European Asian Amerindian African European Asian Amerindian Multi-
American origin*
Other 23 0.10 0.71 0.13 0.05 9% 26% 26% 4% 35%
*AllindividualshavetwoHLAhaplotypes.Multi-originhaplotypeclassificationindicatesthatoneoftheindividual’shaplotypesiscloselyassociatedwith
onecontinentaloriginwhiletheotherhaplotypeisassociatedwithadifferentcontinentalorigin.
doi:10.1371/journal.pone.0135960.t002
geographicancestry(e.g.,Mexico,Guatemala,CentralorSouthAmerica)tendtoself-identify
theirrace/ethnicityas“HispanicorLatino”(r=0.76;CI=0.73–0.77;p<10−15)andhaveAmer-
indianHLAoriginandgeneticancestry(Table3),whilethosereportingCaribbeangeographic
ancestry(e.g.,PuertoRico)donotidentifytheirrace/ethnicityasHispanicasfrequently
(r=0.37;CI=0.33.0.41;p<10−15),havemuchlowerproportionsofAmerindiangeneticances-
try,andarelesslikelytohaveAmerindianHLAorigin(Table3).NorthAmericanIndiangeo-
graphicancestryiscorrelatedwithreportingmultiplerace/ethnicitiesorancestries(r=0.80;
CI=0.78–0.82;p<10−15),butnotanyspecificgeneticancestry.
WhiledistinguishingbetweenreportedLatinAmericanandCaribbeangeographicancestry
affordsadvantageoverHispanicracial/ethnicidentificationinrepresentinggeneticancestry,
othergeographicancestriesaremoreweaklyrelatedtocomparablegeneticclassifications.For
example,3%ofrespondentsreportedEuropeangeographicancestryinadditiontootherori-
gins,butdidnotidentifyasWhitewithrespecttorace/ethnicity(n=52).Ofthose,nearlytwo-
Table3. Correlationbetweenself-identificationmeasuresandHLAoriginsandgeneticancestry.
Self-identification HLAorigins Geneticancestry(AIMs)
measure
African European Asian Amerindian African European Asian Amerindian
Race/ethnicity
BlackorAfrican 0.71(0.68–0.74) 0.90(0.89–0.91)
American
White 0.74(0.72–0.77) 0.77(0.74–0.79)
Asian 0.84(0.82–0.85) 0.84(0.82–0.86)
HispanicorLatino 0.58(0.54–0.62) 0.66(0.63–0.69)
NativeHawaiianor 0.14(0.09–0.19) 0.15(0.10–0.21)
otherPacific
Islander
Geographicancestry
AfricanorAfrican 0.69(0.66–0.72) 0.82(0.80–0.83)
American
European 0.72(0.69–0.75) 0.75(0.73–0.77)
Asian 0.83(0.81–0.85) 0.83(0.81–0.85)
LatinAmerican 0.54(0.50–0.58) 0.69(0.66–0.72)
Caribbean 0.13(0.07–0.18) 0.20(0.14–0.25)
Grandparentsancestry
AfricanorAfrican 0.72(0.69–0.74) 0.86(0.85–0.88)
American
European 0.77(0.75–0.79) 0.81(0.79–0.83)
Asian 0.88(0.87–0.89) 0.89(0.88–0.90)
LatinAmerican 0.62(0.59–0.66) 0.80(0.78–0.82)
Caribbean 0.10(0.05–0.16) 0.17(0.120.23) 0.18(0.12–0.23)
Thecorrelationcoefficient(r)isgivenwith95%confidenceintervals(parentheses).Onlystatisticallysignificant(p<0.05aftercorrection)valuesareshown.
doi:10.1371/journal.pone.0135960.t003
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thirdsself-identifiedtheirrace/ethnicityasHispanic(n=28)orAfricanAmerican(n=4);
however,meanEuropeangeneticancestryforself-identifiedHispanicsandAfricanAmericans
whoreportedEuropeangeographicancestry(0.73and0.34,respectively)isnotstatisticallysig-
nificantlyhigherthanthatforindividualswiththesameself-identifiedrace/ethnicitywhodo
notreportEuropeangeographicancestry(0.63and0.27).
GenderdifferencesinreportingconsistencyhaveimplicationsforHLA
matching
Insomecaseswhengeographicancestryyieldslessconsistentclassificationsrelativetogenetic
ancestrythanthosebasedonrace/ethnicity,wefindthedifferencesalsovarybygender.More
than10percentofourcohortreportedNorthAmericanIndiangeographicancestrybutdid
notself-identifyasAmericanIndianwithrespecttorace/ethnicity(n=189).ThemeanAmer-
indiangeneticancestryproportion(0.018)fortheseindividualsissimilartothosenotreporting
NorthAmericanIndianancestry(0.019).Strikingly,significantlymorewomen(n=164;12%)
thanmen(n=25;6%)reportNorthAmericanIndianancestryinadditiontoanothergeo-
graphicancestrywithoutalsoidentifyingtheirrace/ethnicityasAmericanIndian(p<0.001).
Further,andofmostimportanceintransplantmatching,selectionofmorethanonerace/eth-
nicityorgeographicancestrybymenismuchmorepredictiveofmulti-originHLAthanmulti-
originreportingamongwomen,eventhoughmenarelesslikelytoidentifywithmultiplerace/
ethnicitiesorgeographicancestries.Forexample,28%ofmenwhoself-identifywithtwoor
morerace/ethnicitygroupshavemulti-originHLAhaplotypes;incontrast,just9%ofwomen
selectingmorethanonerace/ethnicitygrouphavemulti-originHLAhaplotypes(p<0.05).
Grandparents’geographicancestrymostcloselycorrelatedwithHLA
haplotypeorigins
Incontrasttoreportinggenericfamilyorigins,whenrespondentsselectoriginsforspecific
grandparentstheresultingclassificationusingthenumberofgrandparentswithagivengeo-
graphicancestryidentifiessub-groupsofrespondentswithmoreuniformgeneticbackgrounds.
Sub-classificationbythenumberofgrandparentswithSub-SaharanAfricanorAfricanAmeri-
canancestry,forexample,showsaclearpatternofincreasingAfricangeneticancestrypropor-
tionswithincreasingnumberofreportedAfrican-ancestrygrandparents(Fig1A).The
substructureismirroredinHLAoriginfrequencies,identifyinggroupsofindividualswithdif-
ferentcombinationsofHLAhaplotypes.Thisresulthasimportantimplicationsforthetrans-
plantmatchalgorithm’sassignmentoflikelyhighresolutionHLAhaplotypes.Forexample,
welloverhalfoftheindividualswhoreportedfourAfrican-ancestrygrandparentshavetwo
AfricanHLAhaplotypes;incontrast,threeofthefourindividualswhoreportedtwoAfrican-
ancestrygrandparentshaveonlyoneAfricanHLAhaplotype(Fig1B).Theresultsaresimilar
forindividualswhoreportedgrandparentsfromLatinAmericanorigins,withrespecttoAmer-
indiangeneticancestryproportionsandHLA(Fig1Cand1D).ThesefindingsholdforEuro-
peanandAsiangeneticancestryproportionsandHLAoriginfrequenciesaswell(notshown),
demonstratingthevalueincollectinggrandparents’ancestryforallindividualsasasubstantial
improvementtocurrentracial/ethnicself-identificationpracticesforprospectivedonors.
Discussion
Inmedicalpracticeandbiomedicalresearch,subjects’self-identifiedrace/ethnicityisfre-
quentlycollected[33–35],oftenservingasaproxyforgeneticancestry.Atthesametime,there
isongoingdiscourseamongphysicians,researchersandthepublicabouthowbesttocollect
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Race,EthnicityandAncestryinUnrelatedTransplantMatching
Fig1.AfricanandAmerindiangeneticancestryproportions(a,c)andHLAoriginfrequencies(b,d)are
correlatedwiththenumberofgrandparentswithreportedAfricanandLatinAmericanancestry,
respectively.GeneticancestryproportionswereestimatedfromAIMsdatausingStructureandtheHGDP
referenceset.Forthisanalysis,k=4,reflectingbroadcontinentalancestry.Foreachsubpopulationdefined
bythenumberofrespondents’grandparentswithSub-SaharanAfrican/AfricanAmericanorLatinAmerican
ancestry,thepercentageofindividualswithzero,oneortwoAfricanorAmerindianHLAhaplotypes,
respectively,wascalculated.Individualsreportingone,two,threeorfourAfrican-ancestrygrandparents:
n=4;4;2;21,respectively.Individualsreportingone,two,threeorfourLatinAmerican-ancestry
grandparents:n=16;21;7;38,respectively.
doi:10.1371/journal.pone.0135960.g001
thiscriticalinformation[36,37],therelationshipbetweenracialclassificationandgeneticances-
try[38–46],itspossibleconfoundingroleinbiomedicalresearch[16,47]anditsapplicationin
healthcaresettings.UsingAIMs,manystudieshaveshowngoodcorrelationbetweengenetics
andself-identificationforsomeracialandethniccategoriesintheUnitedStates[16,18],buta
limitedcorrespondenceforindividualswhoidentifyasHispanicormulti-racial[14,19,48].
Geneticclusteringofworldwidehumanpopulations[27]suggeststhatidentificationaccording
togeographicancestrymaybemorebiologicallyrelevantthanthestandardrace/ethnicitycate-
goriesusedinfederaldatacollectionandreporting.Yet,manyremainwaryofassumptions
aboutinherentdifferenceandinternalhomogeneitythathaveoftencharacterizedtheuseof
raceandancestryidentificationinbiomedicalfields[49,50].Toooften,however,thesediscus-
sionstakeplaceatanabstractlevel–aboutwhatshouldandshouldnotbedoneingeneral,or
underidealcircumstances.Equallyimportantiscarefulexaminationofthepracticalityandrel-
evanceofdifferentmeasuresofancestryidentificationforspecificmedicalapplicationswhere
thesedataarecurrentlyrelieduponforpatientcare:suchasmatchingdonorsandrecipients
fortransplant.
Withtheaimofimprovingmatchingalgorithmsforbonemarrowtransplant,thisstudy
soughttodeterminehowvariousmeasuresofself-identificationintersectwithgeneticancestry.
Ourfindingthatnearlyoneinfiverespondentsprovidedanswersinconsistentbetween
reportedrace/ethnicityandgeographicancestryhighlightsthesubjectivenatureofself-identifi-
cation.Incomparingmeasuresofself-identification,wedonotmeantoimplythatwethink
responsesshouldalwaysbeconsistentacrossmeasuresorthatonetypeofresponseismore
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Race,EthnicityandAncestryinUnrelatedTransplantMatching
“correct”thananother.Rather,wewanttounderscorehowdifferentmeasuresofself-identifi-
cationrevealdifferentinformation.Moreover,itisapparentthatthereisnoclear‘winner’in
thecomplexprocessofself-identificationintheU.S.withrespecttogeneticancestry;bestprac-
ticesforcollectingthisinformationforsomepopulationsmaybeineffectiveforothers.Unrav-
elingthemyriadhistorical,politicalandsocialfactorscontributingtothesedifferencesamong
measuresofself-identification,andbetweenself-reportedandgeneticancestrymeasures,is
beyondthescopeofthiswork.Instead,ourresultspointtotheneedformoreresearchtoiden-
tifythespecificnatureofthisvariationandrefinehowwecollectandinterpretmeasuresof
race/ethnicityandgeographicancestryinmedicalcontexts.
Asexpected,incertaincases,geographicancestryreportingmorecloselycorrespondsto
geneticancestrycomparedtoself-identificationusingstandardrace/ethnicitycategories.While
oftenclassedtogetheras“Hispanic”byregistriesandinmuchbiomedicalresearch,individuals
reportingLatinAmericanoriginsdisplaymarkedlydifferentproportionsofAfricanandAmer-
indiangeneticancestrythanthosewhoreportCaribbeanorigins[51,52];ourresultsareconcor-
dantwiththesefindingsand,mostimportantfortheregistry,mirroredinthefrequencyof
HLAsubclasses.Incontrast,reportedEuropeangeographicancestryprovideslimitedaddi-
tionalinsightintogeneticancestryproportionsformost.ThereportingofNorthAmerican
Indiangeographicancestryisalsogenerallynotconsistentwithgeneticclassifications.These
individualsmaybereportingverydistantancestrythathassurvivedinfamilylore,orthismay
reflectpeopleselectingsymbolicresponsesnotbasedonspecificknowledgeoffamilyorigins
[6,13].ThatmostrespondentsreportingAfricanAmericanracialidentificationdidnotreport
sub-SaharanAfricangeographicancestryalsosuggeststhatgeographicancestryisnotaform
ofself-identificationthatresonateswitheveryone.
Startingin2000,theU.S.Censusquestionnaireallowedrespondentstoselectmorethanone
self-identifiedrace.In2010,over9millionAmericansidentifiedwithtwoormoreraces,a32%
increasefromthepreviousdecade,andasubstantialfractionofourcohortreportsmultiple
race/ethnicitiesorgeographicancestries.Likewise,individualswhoself-identifyasHispanic
nowcomprisethelargestracial/ethnicgroupwithintheUnitedStatesafternon-Hispanic
Whites[53,54].Inourstudy,grandparents’ancestryisthemostinformativepieceofdatawith
respecttomorepreciselycharacterizinggeneticancestryforindividualsfrompopulationslong
recognizedashighlyheterogeneous[48,52],andcollectionofthisinformationshouldimprove
theefficiencyandreliabilityoffindingHLA-identicaldonorsformanypatients.Althoughnot
currentlycollectedbytheregistry,inthehealthcaresetting,orformostbiomedicalresearch,
inoursample>70%respondentsprovidedageographicancestryforallfourgrandparents.
Becausereportingforeachgrandparentwaslimitedtoonlyoneoriginorancestry,these
responsesmaybeparticularlysalient,derivingfromdirectknowledgeofacloserelative.We
suggestthatregistriesconsidercollectingthesevaluabledataroutinely.Incontrast,whenasked
to“checkallthatapply”todescribeone’sfamilyoriginsingeneral,thethresholdforclaiming
particulargeographicancestriesmaybemuchlower,andtheresponsesarenotconstrainedto
fourwithequalweight.However,giventhatnotallrespondentsareabletoprovidedatafor
theirgrandparents,thismeasureshouldbeusedincombinationwithothers.Providingthe
meansforindividualstoquantifyorotherwisedescribetherelativesalienceoftheirancestries
mayalsobeofvalueinfuturestudies.
Amajorlimitationhereisover-representationofindividualswhoself-identifyasWhite
comparedtothecurrentU.S.populationandanover-representationofindividualswithEuro-
pean-originHLAtypescomparedtotheoverallmakeupoftheregistry;additionalworkinthis
areawillprofitfromstudyoflargersamplesofsubpopulationswithnon-Europeanoriginsand
ancestries.Wefocusedonlow-frequencyHLAhaplotypesinthisstudyunderaworkingprem-
isethatindividualswithcomplexancestries,whichmightnotbefullycapturedbythecurrent
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