NIPT–EmergingIssues:GeneticCounselors'Experiences&PerspectiveswithIncidentalFindings

Master’sThesis

Presentedto

TheFacultyoftheGraduateSchoolofArtsandSciencesBrandeisUniversity

GraduatePrograminGeneticCounselingJudithE.Tsipis,Ph.D.,Advisor

InPartialFulfillmentoftheRequirementsfortheDegree

MasterofSciencein

GeneticCounseling

byAliciaS.Orta

May2016

Copyrightby

AliciaS.Orta

©2016

iii

ACKNOWLEDGEMENTSTheBrandeisUniversityGraduateSchoolofArtsandSciencesandtheNSGCPrenatalSpecialInterestGroupGrantAwardprovidedfundingforthisresearchproject.Tomycommitteemembers—JudithTsipis,GeorgeAnnas,andAmandaBuchanan—thankyouforyourinvaluablehelpandguidancethroughoutthisproject.I’mgratefultohavebeenabletouseAmanda’sThesisasafoundationformystudy.Thedevelopmentofthisproject,thelogicalprocess,andmuchofthesuccessofthisstudywasduetoJudith’stenacitywithencouragingdecision-making.Iwillbeforeverappreciative.ThankyouverymuchJudyJacksonandEmilyLazarforyourhelpwithmyresearchtopicdevelopmentandforreviewingmysurvey.ThankyouMargaritaCorralforyourmanyhoursofassistanceinsurveydesign,useofSPSSsoftware,anddataanalysis.Yourpatienceisremarkable.TotheBrandeisGeneticCounselingProgramfaculty—CassieBuck,GretchenSchneider,GayunChan-Smutko,MissyGoldberg,JanetRosenfield,DavidRintell,JudyJackson,KateKramer,JoeCunningham—thankyouforyoursupport,encouragement,wisdom,andtissues.Tomyclassmates—thankyouforprovidingopportunitiesforgrowthandreflection.Tomyfriends—thankyouforprovidinglaughterandinspiration.Tomyfamily—thankyouforprovidingthegiftofreflection.ToMatthew,theloveofmylife.Thankyousomuch.Yournameshouldbe[afootnote]onthisdocument,aswellasonmydegree.

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ABSTRACT

NIPT–EmergingIssues:GeneticCounselors'Experiences&PerspectiveswithIncidentalFindings

AthesispresentedtotheGraduatePrograminGeneticCounseling

GraduateSchoolofArtsandSciencesBrandeisUniversity

Waltham,Massachusetts

ByAliciaS.Orta,M.P.H.

Sincecompaniesbeganmarketingtheanalysisofcell-freeDNA inthematernalplasmaas

non-invasive prenatal testing (NIPT) to screen for fetal aneuploidy and other conditions,

healthcareprovidersandpatientsalikehaveencountereddiscordantinvasiveandnon-invasive

testingresults,withunexpectedincidentalfindingsasararecause.Thepurposeofthisstudywas

to investigate prenatal genetic counselors’ practices and perspectives regarding counseling

patients for the possibility of incidental findings identified through NIPT. We emailed a 58-

question anonymous survey to the NSGC membership to recruit clinical prenatal genetic

counselorsthatofferNIPT.Ofthe147surveyrespondents,74%obtaininformedconsentforNIPT

verbally and over half (54%) do not involve the patient in the documentation of informed

consent,astheproviderisresponsiblefordocumentingthepatient’sconsent.Morethanhalf

(57%) do not always include the possibility of incidental findings in their pre-test counseling

v

discussions.Yet,47%ofthegeneticcounselorrespondentshavehadasuspectedorconfirmed

incidental finding identified through NIPT. Almost all respondents indicated that post-test

counselingapatientwithan incidental finding is challenging, citinga lackof informationand

variationamongNIPTlaboratorieswithhowtheycommunicateincidentalfindingsandalackof

clinicalguidelinesfromprofessionalsocietiesasthemost importantfactors.Fromcounselors’

responses,unknownmaternalconditionsaccountforalargeproportionoftheincidentalfindings

identifiedbyNIPT.Giventhesefindingswerecommendthatpre-testcounselingforNIPTinclude

adiscussionofpossibleunexpectedfindingsandtoestablishclearexpectationsforthecategories

ofresultsthatmaybereturned,thecreationofprofessionalguidelinesoutlininghowincidental

findingsshouldbediscussedinbothpre-andpost-testcounselingdiscussions,andthecreation

of a centralized database for the collection of findings, outcomes, and clinical follow-up to

facilitateappropriatecareforpatients.

Keywords:non-invasiveprenatalscreening,cell-freeDNAscreening,geneticcounseling,prenataltesting,pre-testcounseling,post-testcounseling,informedconsent,incidentalfinding

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TABLEOFCONTENTS

ACKNOWLEDGEMENTS........................................................................................................................III

ABSTRACT..........................................................................................................................................IV

TABLEOFCONTENTS..........................................................................................................................VILISTOFTABLES..................................................................................................................................VII

LISTOFFIGURES...............................................................................................................................VIII

INTRODUCTION....................................................................................................................................1METHODOLOGIESOFCFDNATESTING.....................................................................................................2INCIDENTALFINDINGS.............................................................................................................................3PRE-TESTCOUNSELINGPRACTICES..........................................................................................................5RESEARCHSTUDYGOALS.........................................................................................................................5

METHODS.............................................................................................................................................6STUDYDESIGN..........................................................................................................................................6PARTICIPANTSANDRECRUITMENT..........................................................................................................6PROCEDURES...........................................................................................................................................6DATAANALYSIS........................................................................................................................................8

RESULTS...............................................................................................................................................9DEMOGRAPHICS&NIPTUTILIZATION......................................................................................................9

Table1ParticipantDemographics..................................................................................................11Table2NIPTUtilization...................................................................................................................12

OBTAININGINFORMEDCONSENTFORNIPT&COUNSELINGPRACTICES................................................12GENETICCOUNSELORS’EXPERIENCESWITHNIPTRESULTS...................................................................16

Table3GeneticCounselors’ExperienceswithVariousNIPTResults...............................................17COUNSELINGCHALLENGESWITHINCIDENTALFINDINGSBYNIPT.........................................................20GENETICCOUNSELORS’RECOMMENDATIONSFORFUTUREGUIDELINES.............................................21

DISCUSSION.......................................................................................................................................23ASSESSMENTOFCURRENTPRE-TESTCOUNSELINGPRACTICES.............................................................24COUNSELINGCHALLENGESWITHNIPT..................................................................................................26PRACTICEIMPLICATIONS.......................................................................................................................27STUDYLIMITATIONS...............................................................................................................................28RESEARCHRECOMMENDATIONS/FUTUREDIRECTIONS........................................................................29

CONCLUSION......................................................................................................................................30

REFERENCES.......................................................................................................................................31

APPENDICES.......................................................................................................................................35APPENDIXA:RECRUITMENTNOTIFICATION..........................................................................................35APPENDIXB:INSTRUMENT....................................................................................................................36

vii

LISTOFTABLESTABLE1PARTICIPANTDEMOGRAPHICS...............................................................................11

TABLE2NIPTUTILIZATION...................................................................................................12

TABLE3GENETICCOUNSELORS’EXPERIENCESWITHVARIOUSNIPTRESULTS.......................17

viii

LISTOFFIGURES

FIGURE1:COUNSELORS’PRE-TESTCOUNSELINGSESSIONSANDNIPTORDERSPERWEEK.......10

FIGURE2:TYPESOFRESOURCESUSEDDURINGPRE-TESTCOUNSELING..................................13

FIGURE3:METHODSFOROBTAININGINFORMEDCONSENTFORNIPT....................................14

FIGURE4:INDICATIONSFORPRE-TESTCOUNSELINGFORINCIDENTALFINDINGS....................15

FIGURE5:NIPTRESULTSTHATINDICATEPOST-TESTCOUNSELINGFORINCIDENTALFINDINGS16

FIGURE6:COUNSELORS’EXPERIENCEWITHPOSITIVENIPTRESULTS.......................................16

FIGURE7:TOTALREPORTEDINCIDENTALFINDINGSIDENTIFIEDTHROUGHNIPT.....................18

FIGURE8:SUSPECTED&CONFIRMEDINCIDENTALFINDINGSIDENTIFIEDBYNIPT...................19

FIGURE9:COUNSELINGABOUTANINCIDENTALFINDINGISCHALLENGING.............................20

FIGURE10:FACTORSIMPACTINGCOUNSELINGABOUTINCIDENTALFINDINGS.......................21

1

INTRODUCTION

Lo et al.’s (1997) discovery of cell-free DNA (cfDNA) fragments representing the fetus in

maternalplasmahasledtoeverexpandingpossibilitiesforprenataldiseaseidentificationnon-

invasively and has now changed the clinical paradigm of prenatal screening for aneuploidy

(ACOG,2015;Warsof,Larion,&Abuhamad,2015).MostcfDNAinmaternalcirculationderives

fromthemother’sbloodcells,withanaverageof10%to15%ofthetotalcfDNAinmaternal

bloodoriginating fromthefeto-placentalcirculation(Chiuetal.,2011;Palomakietal.,2011).

StudieshavereportedthatthefetalcomponentofcfDNAisreleasedintomaternalcirculation

primarily from apoptotic placental cells (Hahn, Huppertz, & Holzgreve, 2005) and increases

proportionately as the pregnancy progresses. Screeningwith fetal cfDNA, also know as non-

invasiveprenataltesting(NIPT),isavailablefromweek10ofgestationuntilterm,thuswomen

are able to obtain a risk assessment earlier in pregnancy than by traditional serum analyte

screening,whichhaveamorelimitedtimeduringspecificstagesinpregnancywhentheycanbe

performed.Evenwithitsapparentadvantages,researchersandprofessionalorganizationshave

identifiedseveral limitationsofNIPTandrecommendthat itshouldbeoffered inconjunction

withotherformsofscreening,likeultrasonographyand/orMSAFPscreening,bothwithuniquely

beneficialtestcharacteristics(ACOG,2016;Gil,Quezada,Revello,Akolekar,&Nicolaides,2015).

2

METHODOLOGIESOFcfDNATESTING

LaboratoriesperformingNIPT todetect thepresenceof fetal aneuploidies frommaternal

bloodsamplesvaryintheirclinicaltestingmethods(Bianchietal.,2012;Chiuetal.,2011;Jensen

etal.,2013;Nicolaides,Syngelaki,Gil,Atanasova,&Markova,2013;Nortonetal.,2012;Palomaki

etal.,2011;Zimmermannetal.,2012).Thetwomostwidelyusedmethodsaremassivelyparallel

shotgun sequencing (MPSS) and more targeted methods such as chromosome-selective

sequenceanalysis(CSS)orsinglenucleotidepolymorphism(SNP)-basedanalysis.Researchersuse

CSS or SNP-based methods to select the chromosomes of interest and measure their fetal

fractionbeforesequenceanalysis,whiletheyuseMPSStorandomlysequencetheentirecfDNA

sample, therebycapturingsequence information fromabroadersampleof thegenome.Asa

result,MPSScanidentifynotonlythemajortrisomiesbutotherchromosomalabnormalitiesas

well(Jani,RegodeSousa,&Benachi,2015).

WhenSequenomfirstlaunchedNIPTin2011,theyprimarilyprovidedinformationontrisomy

21and,withinthreeyears,beganscreeningfortrisomy13andtrisomy18,aswellasX-andY-

chromosomeaneuploidies(withfetalsexidentificationasaderivative)(Palomakietal.,2012).

By 2014, laboratories began to expand their NIPT panels to include screening for specific

microdeletionandmicroduplicationsyndromesandotherchromosomalaneuploidies.InAugust

2015,SequenomlaunchedMaterniTGENOME,anexpandedscreendesignedtoscantheentire

genomeforcopynumberalterationsgreaterthanorequalto7MB(Sequenom,2015).

WhileresearchershavereportedNIPTashavingahigherdetectionrateanda lower false

positiveratecomparedtotraditionalscreeningmethodsthatutilizematernalage,ultrasound,

andserumanalytes(Giletal.,2015;Palomakietal.,2011;Zimmermannetal.,2012),professional

3

societiesstressthatNIPTisnotadiagnostictest.Theycitethatthepositivepredictivevalue(PPV)

ofthetest,anumberuniquetoeachpatient,willvarydependingonanumberoffactorslikeage,

the particular condition in question, the gestation at which the screen was performed, and

whether or not there are any ultrasound anomalies that suggest theremay be a genetic or

chromosomalcondition.Anotherconcernisthatevenwhenatestisaccurate,themorerarethe

condition, the higher the percentage of false positive results. Similarly, as the number of

conditions assessed by a test increases, the false-positive rate will also increase. They also

acknowledge that counselingwill prove challengingwhen testing for conditionswith unclear

clinicalrelevanceorwhicharesorarethatthePPVofthetestislow.

Aswithtraditionalprenatalscreens,professionalguidelinesadvisethatapositiveNIPTresult

beconfirmedwithadiagnostic test,eitheramniocentesisorchorionicvillus sampling (ACOG,

2015;Bennetal.,2015;Deversetal.,2013;Greggetal.,2013).IfNIPTisnotabletoyieldaresult

(an indeterminate or “no-call” result), this slightly increases the risk for chromosomal

abnormalities;furthercounseling,comprehensivefetalultrasoundassessmentandtheoptionof

diagnostictestingforthefetusaresuggestedwheneverthereisa“nocall”result(ACOG,2015).

INCIDENTALFINDINGS

Occasionally,laboratoriesdetectaneuploidiesinthesamplethatmaynotberepresentative

of the fetus. Studies show that such falsepositive findingsoccur inapproximately1%of test

results(Bianchietal.,2012;Gratietal.,2015;Nicolaidesetal.,2013;Nortonetal.,2012),with

most due to confined placentalmosaicism (CPM). Additionally, NIPTmay raise suspicion for

maternal or fetal conditions other than the fetal aneuploidies for which the test is being

performed(Bianchi,2015a).Researchershavepublishedbiologicalexplanationsformanyofthe

4

discrepanciesbetweenNIPTresultsanddiagnostictestingorneonataloutcomes,including:co-

twindemise (Curnowet al., 2015; Futchet al., 2013); fetal, placental ormaternalmosaicism

(Flowers, Kelley, Sigurjonsson, Bruno, & Pertile, 2015; Grati et al., 2014; Lau et al., 2013);

unrecognized maternal conditions, including maternal copy number variants (Snyder et al.,

2015), undetected maternal malignancies (Bianchi et al., 2015b; Osborne et al., 2013) and

maternalsexchromosomeaneuploidies(Lauetal.,2013;Wangetal.,2014;Yaoetal.,2012).

Wangetal.(2014)foundthat8.6%ofpositiveNIPTresultsforsexchromosomeaneuploidywere

attributable to thematernal karyotype. Recently, Snyder, Curnow, Bhatt, and Bianchi (2016)

publishedclinicaloutcomesfor79caseswhereNIPTreportedeitheramonosomy,atrisomywith

asexchromosomeaneuploidy,ormultipleaneuploidies,toassisthealthcareproviderswithpost-

testcounselingandmanagement.Outof79cases,9%hadamaternaletiologyfortheabnormal

NIPTresults,and53%werediscordantwiththefetalkaryotypeandremainunexplained(Snyder

et al., 2016). NIPT is not clinically validated to screen for these or other maternal or fetal

conditions, and cfDNA screening results cannot be interpreted to preclude them. NIPT

laboratoriesdifferwithregardtoifandhowtheycommunicatethistypeofincidentalinformation

toproviders.TherecentliteraturesuggestsaneedforconsiderablecautionininterpretingNIPT

resultsbecauseoffalsepositiveratesthatarehigherthanpreviouslyreportedwhencompared

withinvasivetesting(Cheung,Patel,&Leung,2015).Sahoo,Strecker,andCommander(2016)

reaffirmedsuchcautionuponfindingthatthefalsepositiverateswereuniformlyhighforthe

commonmicrodeletionsproviderstestedforusingexpandedversionsofNIPT.Emergingissues

related to the detection of maternal findings such as sex chromosome abnormalities,

5

microdeletions,andmalignanciesfollowingunusualNIPTresultsraisecomplexconcernsabout

informedconsent,thedutytoinform,andthelackofvalidationofthetestsformaternalfindings.

PRE-TESTCOUNSELINGPRACTICES

CommercializationhasdrivenrapidglobaldisseminationofNIPT(Minear,Lewis,Pradhan,&

Chandrasekharan,2015)andrecentadvancesinthistechnologyhaveexpandedandimproved

genetic testing options available towomen during pregnancy. In providing awide variety of

screening test options, each offering varying levels of information and accuracy, healthcare

providers become even more essential in counseling patients as they make very complex

decisions.Onestudyproposedgeneralapproachestopre-testcounselingandobtaininginformed

consentforNIPT(Buchanan,Sachs,Toler,&Tsipis,2014),andSachs,Blanchard,Buchanan,and

Bianchi(2015)publishedrecommendationsforgeneticcounselorsregardingpre-testcounseling

toaidintheinformedconsentprocesswithpatientswhoareconsideringNIPT.Comprehensive

pre-testcounselingiscomplicatedbythecontinuousemergenceofnewinformationaboutthe

benefitsandlimitationsoftesting,aswellasthepotentialforincidentalfindingsfromNIPT.

RESEARCHSTUDYGOALS

Thepurposeofthisstudywastoinvestigategeneticcounselors’practicesandperspectives

withcounselingpatientsforincidentalfindingsidentifiedthroughNIPT.Wehopedtohighlight

challengesthattheprenatalfieldcanfocusonovercomingaswellasideasthatthefieldcanbuild

on.Thegoalsofthisstudywereto:(1)identifythecurrentpre-testcounselingpracticesforNIPT,

includingmethodsforobtaininginformedconsent;(2)learnaboutgeneticcounselors’personal

experienceswith incidental findings identified byNIPT; and (3) delineate the challenges that

counselorsfacewhendiscussingthepossibilityofincidentalfindingswithpatients.

6

METHODS

STUDYDESIGN

Thiscross-sectionalstudyanonymouslysurveyedclinicalgeneticcounselorspracticing ina

prenatalsettingwhoaremembersoftheNationalSocietyofGeneticCounselors(NSGC)through

theuseofanonlinesurveytool,Qualtrics®.TheBrandeisUniversityInstitutionalReviewBoard

CommitteeforProtectionofHumanSubjectsdeemedthe(IRBProtocol#16022)protocoltobe

exemptfromIRBoversight,effectiveSeptember4,2015.

PARTICIPANTSANDRECRUITMENT

Weselectedclinicalgeneticcounselorspracticinginaprenatalsettingwhoaremembersof

NSGCandsubscribetoitslistservasthesamplingpopulation,andlimitedtheinclusioncriteria

toprenatalgeneticcounselorswhoarecurrentlyprovidingNIPTtopatientseitherinperson,over

thephone,oronline.Wedidnotexcludebasedonage,gender,geographiclocation,orother

demographic characteristics. The e-blast recruitment notice (See Appendix A: Recruitment

Notification)soughtprenatalgeneticcounselorspracticinginaclinicalsetting.

PROCEDURES

WesentthesurveytoNSGCmembersviaane-blasttoitslistservthatwasavailablefordata

collectionfromSeptember11throughOctober14,2015,withanemailremindersenttwoweeks

7

aftertheinitialinvitationtoparticipate.Participationinthisstudywasvoluntaryandthosethat

participated were free to withdraw at any time. Likewise, since all survey questions were

voluntary,weanticipatedafluctuationinquestion-specificresponserate.

Prior to beginning the survey, we provided participants with a series of definitions. We

definedanincidentalfindingas“anunexpectedfindingofamaternalorfetalconditionother

than the typically screened for conditions specifically targeted by NIPT. These unanticipated

‘secondaryfindings’mayinclude:unrecognizedmaternalconditions,co-twindemise,andfetal

orplacentalchromosomedifferences,amongothers.”Wedefinedano-callNIPTresultas“a

failure to receive an interpretable result from cell-free DNA testing. Depending on the NIPT

laboratory, the “non-reportable” resultmaybedue to insufficient sample, low feto-placental

DNA fraction,orbecause the interpretation falls intoan indeterminate range.”Wedefineda

positiveNIPTresultas“aresultthatsuggestsapregnancyisatriskofhavingaconditionthatis

among the typically screened for conditions specifically targeted byNIPT. The resultmay be

reportedas‘aneuploidydetected’or‘highrisk’anddoesnotinclude‘no-call’NIPTresults.”

The survey consisted of several exclusion/inclusion criteria questions followed by

questions inquiring into genetic counselor (1) perspectives and practices regarding pre-test

counseling (20 items); (2) personal experienceswith incidental findings revealedbyNIPT (11

items);and(3)experiencedchallenges,ortheirperceptionsofthechallenges,associatedwith

counselingforanincidentalfinding(5items).Weincludedanopen-endedquestiontoaskabout

thedesirabilityofnationalguidelinesforclinicalfollow-upandevaluationforincidentalfindings

from NIPT. We collected professional demographic information and NIPT utilization

characteristics (12 items). We used a four-point Likert-type scale to rate (1) the level of

8

agreementofastatementassessingwhethercounselingaboutanincidentalfindingidentified

throughNIPTischallenging,and(2)thelevelofimportanceofthirteenitemsassessingpotentially

challenging factors.We presented seven items that provided “yes,” “no,” and “don’t know”

options;andthirteenitemsthatusedpre-givencategoricalresponseoptionswithoutrestriction

(e.g., Selectall thatapply). Lastly,we includeda space forcommentsoneachpageof items.

SeeAppendixB(Instrument)foracompletelistofsurveyquestions.

DATAANALYSIS

Weanalyzedsurvey responsedatawithSPSSstatistical softwareandMicrosoftExcel.We

useddescriptivestatisticstosummarizeresponsestoeachsurveyitem.Tofacilitateanalysisand

interpretation, we collapsed response categories for Likert-scale-type items to construct an

“important” category combining both “extremely important” and “important” and a

corresponding “not important” category. To assess response bias, we performed a bivariate

comparison of our respondents’ demographic data to reported estimates of demographic

characteristics from the 2014 study conducted among the NSGC membership to determine

generalizability.Weperformedfurtherbivariateanalysesusingindependentsamplet-tests,chi-

square(χ2)testsofindependence,andcross-tabulations.Wesetstatisticalsignificanceatp=.05.

We manually analyzed responses to open-ended questions using an inductive approach to

identifythemesinopinionsaboutrecommendationsforfollow-upclinicalevaluationapproaches

toincidentalfindingsidentifiedbyNIPT.

9

RESULTS

Theresultsofthesurveyareorganizedintofourparts:(1)demographicsandNIPTutilization,

(2) obtaining informed consent for NIPT and counseling practices, (3) genetic counselors’

experienceswithNIPTresults,and(4)counselingchallengeswithincidentalfindingsbyNIPT.

DEMOGRAPHICS&NIPTUTILIZATION

Of the 210 responses,we removed 63 from our analysis because they did notmeet the

inclusioncriteriaorfailedtocompletethemajorityofthesurveyitems.Consideringonlythose

whomettheinclusioncriteria,147prenatalgeneticcounselorscompletedthemajorityofthe

surveyquestions.AllNvaluesinthispaperwillbereflectiveof147participants,unlessotherwise

stated. The 147 respondents represent a response rate of 12-15% based on the number of

prenatalcounselorslistedinthe2014NSGCProfessionalStatusSurvey(PSS)(NSGC,2014).

Respondents were from all six NSGC regions with a slightly higher representation from

Regions 2 (19%), 4 (25%), and6 (20%), thanotherRegions. Themajority of respondents are

employedinaprivate,public,oruniversityhospitalsetting(80.8%,118/146),withanaverageof

fourprenatalgeneticcounselorspersetting.Theyearsoftotalgeneticcounselingexperienceand

yearsofexperienceinaprenatalgeneticcounselingsettingrangedfrom1to33(M=8.6)and

from1to31(M=7.9),respectively.(seeTable1).

10

Almost85%ofrespondentsspendgreaterthan50%oftheircounselingtimewithprenatal

patientsandmostcounselpatientsin-personand/oroverthetelephone(82%).Threequarters

(N=145)of respondentsprovidepre-test counselingand/ororderNIPT forbetween5and24

patientsperweek (seeFigure1). The twomost frequentlyusedNIPT companies areNatera,

which offers Panorama™ NIPT (51%), and Sequenom Laboratories, which offers VisibiliT™

(15.6%),MaterniT21®PLUS(61.2%),andMaterniT™GENOME(10.2%),anexpandedcfDNApanel

thatscanstheentiregenomeformicrodeletionsorduplicationsgreaterthanorequalto7MB.

Most respondents (73%) reportedusing twoormoredifferent companies toprovideNIPT to

patients.(seeTable2).

Figure1:Counselors’Pre-TestCounselingSessionsandNIPTOrdersperweek

18%(n=26)

28%(n=40)

33%(n=48)

12%(n=18)

7%(n=10)

2%(n=3)

34%(n=49)

38%(n=55)

21%(n=31)

3%(n=5)

3%(n=4)

1%(n=1)

0% 10% 20% 30% 40%

1-4

5-9

10-14

15-19

20-24

25+

Numbero

fPatients

Pre-testcounseling OrderNIPT

11

Table1ParticipantDemographics n % M SDTimeSpentCounselingPrenatalPatients 147 100

<25% 13 8.8 25–50% 10 6.8 51–74% 18 12.2 76–100% 106 72.1

TotalYearsofGeneticCounselingExperience 145 100 8.82 8.59≤5 77 53.1 6–10 21 14.5 11–15 17 11.7 16–20 12 8.3 21–25 8 5.5 26–30 9 6.2 >30 1 0.7

YearsasaPrenatalGeneticCounselor 145 100 7.85 7.89≤5 83 57.2 6–10 19 13.1 11–15 17 11.7 16–20 11 7.6 21–25 10 6.9 26–30 4 2.8 >30 1 0.7

CounselingModalities 147 100 In-person+Telephone 121 82.3 Telegenetics+In-person+Telephone 26 17.7

PrimaryWorkSetting 146 100 CommunityHospital 17 11.6 GovernmentOrganization/MedicalFacility 1 0.7 HealthMaintenanceOrganization(HMO) 3 2.1 Laboratory/Industry 3 2.1 Outreach/Satellite/FieldClinic 2 1.4 PrivateClinic/Practice 27 18.5 PrivateHospital/MedicalFacility 31 21.2

RegionofPractice 147 100 Region1(CT,MA,ME,NH,RI,VT,CanadianMaritimeProvinces) 17 11.6 Region2(DC,DE,MD,NJ,NY,PA,VA,WV,Quebec,PR,VI) 28 19 Region3(AL,FL,GA,KY,LA,MS,NC,SC,TN) 18 12.2 Region4(AR,IA,IL,IN,KS,MI,MN,MO,ND,NE,OH,OK,SD,WI,

Ontario) 37 25.2

Region5(AZ,CO,MT,NM,TX,UT,WY,Alberta,Manitoba,Saskatchewan) 18 12.2

Region6(AK,CA,HI,ID,NV,OR,WA,BritishColumbia) 29 19.7

12

Table2NIPTUtilization n % M SDNIPTCompaniesandTests 147 100

AriosaDiagnostics(Harmony™) 62 42.2 Counsyl(InformedPregnancyScreen) 36 24.5 IntegratedGenetics-LabCorp(informaSeqSM) 33 22.4 Natera(Panorama™) 75 51 PerkinElmer(verifi®fromPerkinElmerLabs) 4 2.7 Progenity(VerifibyProgenity) 25 17 Quest(QNatal™Advanced) 16 10.9 Recombine(ChromoMap) 1 0.7 SequenomLaboratories(MaterniT™GENOME) 15 10.2 SequenomLaboratories(MaterniT21®PLUS) 90 61.2 SequenomLaboratories(VisibiliT™) 23 15.6 VerinataHealth-Illumina(verifi™) 10 6.8

No.ofCompaniesutilizedtoprovideNIPTtopatients 147 100 2.41 1.36

1 40 27 2 49 333 35 244 11 75 8 56+ 4 2

OBTAININGINFORMEDCONSENTforNIPT&COUNSELINGPRACTICES

Over two-thirds of respondents (81%) reported using resources during their pre-test

counselingsession,with60%(n=88)using twoormore typesof resources to informpatients

aboutNIPT.ThetwomostcommonlyusedresourcesarethosecreatedbytheNIPTcompany

(46%)and/orpublishedgeneticcounselingvisualaids(43%).(seeFigure2)

13

Figure2:TypesofResourcesUsedDuringPre-TestCounseling

AmajorityofcounselorsreportedobtainingconsentforNIPTverbally(74%)and/orbyusing

aformdocumentingpatientconsentforNIPTthatonlythehealthcareprovidersigns(54%).The

twoleastcommonmethodsforobtaininginformedconsentincludehavingthepatientsignan

informedconsentformspecificallyforNIPT(16%)andhavingthepatientsignarequisitionform

provided by theNIPT lab company (3%). Two respondents do not routinely obtain informed

consentforNIPT(seeFigure3).

3%(n=5)

5%(n=7)

14%(n=21)

19%(n=28)

24%(n=35)

35%(n=51)

43%(n=63)

46%(n=68)

0% 20% 40% 60%

Web-basedorapp-baseddecision-makingaids

Resourcescreatedbyotherprofessionalsocieties

(e.g.,ISPD,ACOG)

Self-creatededucationalorvisualaids

Idonotuseanyprintedresources

ResourcescreatedbytheNSGCPrenatalSIG

Resourcesdevelopedbymyinstitution

Publishedgeneticcounselingvisualaids

ResourcescreatedbytheNIPTCompany

14

Figure3:MethodsforObtainingInformedConsentforNIPT

Halfoftherespondents(56.5%,n=83)indicatedthattheydonotalwaysincludethepossibility

ofincidentalfindingsintheirpre-testcounselingdiscussionofNIPT.Thetopthreereasonsfor

not including incidental findings inpre-testcounselingwere that the test isnotdesignednor

validatedforthedetectionofincidentalfindings(65%,n=54),theinclusionofincidentalfindings

complicate thediscussion (50%,n=41), and incidental findingsare too rare tomention (46%,

n=38).However,manyrespondentswouldalwaysincludethepossibilityofincidentalfindingsin

their pre-test counseling discussion with a patient under certain circumstances, such as a

personalorfamilyhistoryofchromosomeabnormalities(64%and44%,respectively),apersonal

historyofrecurrentmiscarriages(38%)andotherindividualindications(38%).Otherreasonsfor

discussingincidentalfindingsinpre-testcounselingwerewhenorderinganexpandedNIPTthat

screens formicrodeletions ormicroduplications, the presence of an ultrasound finding (e.g.,

74%(n=109)

54%(n=79)

35%(n=52)

18%(n=27)

16%(n=23)

3%(n=4)

1%(n=2)

0% 20% 40% 60% 80%

Verbally(eitherinperson,overthephone,orviavideocounseling)

ThereisaformspecificallyforNIPTsignedbytheproviderdocumentingthepatient’sconsent

NIPThasbeenincorporated intoapre-existinginformedconsent formforscreeningthatthepatientsigns

NIPThasbeenincorporated intoapre-existinginformedconsent formforinvasivediagnostictestingthatthepatientsigns

ThereisaninformedconsentformthatthepatientsignsspecificallyforNIPT

PatientsignsarequisitionformprovidedbytheNIPTlabcompany

IdonotroutinelyobtaininformedconsentforNIPT

15

vanishingtwin,heartdefect),andifthepatienthadahistoryofuterinefibroids,organtransplant,

orapreviousorcurrentcancerdiagnosis.(seeFigure4).

Figure4:IndicationsforPre-testCounselingforIncidentalFindings

* Individual indications:orderinganexpandedNIPTpanel,anultrasound finding (e.g., vanishingtwin,heartdefect),andahistoryofuterinefibroids,organtransplant,oracancerdiagnosis.

By contrast, almost all respondents indicated that post-test counseling was necessary

wheneveranincidentalfindingwassuspectedbytheNIPTlaboratory.Almost75%ofcounselors

felt that post-test counseling was indicated whenever NIPT identified a sex chromosome

aneuploidy(73%),ormultipleaneuploidies(74%)(seeFigure5).

38%(n=24)

38%(n=24)

44%(n=28)

64%(n=41)

0% 20% 40% 60% 80%

Other*

Personalhistoryofrecurrentmiscarriages

Familyhistoryofchromosomeabnormalities

Personalhistoryofchromosomeabnormalities

16

Figure5:NIPTResultsthatIndicatePost-testCounselingforIncidentalFindings

GENETICCOUNSELORS’EXPERIENCESWITHNIPTRESULTS

Whenaskedaboutthefrequencywithwhichtheyhadpersonallycounseledpatientswitha

positiveNIPTresult,allbuttworespondentshadcounseledapatientwithapositiveNIPTresult

witharangeof1tomorethan15(seeFigure6).

Figure6:Counselors’ExperiencewithPositiveNIPTResults

44%(n=64)

55%(n=81)

56%(n=82)

58%(n=84)

73%(n=107)

74%(n=108)

92%(n=134)

0% 20% 40% 60% 80% 100%

2ormoreno-callNIPTresults

Microdeletionormicroduplication

Autosomalmonosomy

No-callNIPTresult

Sexchromosomeaneuploidy

Multipleaneuploidies

IncidentalfindingsuspectedbyNIPTlaboratory

1%(n=2)

10%(n=15)

19%(n=28)

13%(n=19)

5%(n=8)

10%(n=15)

41%(n=60)

0% 10% 20% 30% 40% 50%

None

1–3

4–6

7–9

10–12

13–15

15<

17

Over75%ofrespondentshadcounseledatleastonepatientwithapositiveNIPTresultthat

diagnostictestingorneonataloutcomelaterfoundtobediscordant.Themostcommonlyseen

discordantNIPTresultswereforsexchromosomeaneuploidies,microdeletions,andtrisomy13.

Approximately76%ofrespondentshadcounseledoneormorepatientswithano-callNIPTresult

after repeat screening, while 47% of respondents had counseled a patient where the NIPT

laboratorysuspectedapossibleincidentalfinding.Nearly30%ofrespondentshadcounseledone

ormorepatientswithaconfirmedincidentalfindingidentifiedthroughNIPT(seeTable3).

Table3GeneticCounselors’ExperienceswithVariousNIPTResults

No.ofPatientsCounseledDiscordantNIPTResult

No-callNIPTResult

SuspectedIncidentalFindinga

ConfirmedIncidentalFindingb

n % n % n % n %None 31 21.4 35 23.8 78 53.1 103 70.11 14 9.7 32 21.8 31 21.1 22 152 16 11 21 14.3 13 8.8 5 3.43 26 17.9 11 7.5 7 4.8 8 5.44 6 4.1 7 4.8 3 2 1 0.75 13 9 7 4.8 3 2 1 0.7

Morethan5 15 10.3 24 16.3 3 2 2 1.4Don’tknowbutatleast1 24 16.6 10 6.8 9 6.1 5 3.4

Total 145 100 147 100 147 100 147 100aPearsonχ2(1)=6.087,p=.019;bPearsonχ2(1)=10.298,p=.002Note:Crosstabulationofwhetherpre-testcounselingincludesincidentalfindingsversuscounselorexperiencewithincidentalfindings;Chi-squaretestsignificantatp<.05.

Counselors reported encountering a total of 107 cases of incidental findings identified

throughNIPT,24ofwhichwerecasesofmaternalsexchromosomeaneuploidy,24wereco-twin

demise,19wereconfinedplacentalmosaicism,14werematernalcopynumbervariation,8were

fetalorplacentalmosaicism,5werematernalmosaicism,3werematernalcancer,and2were

maternaluterine leiomyoma.Additionally,8wereothertypesof incidental findings identified

18

through NIPT, including consanguinity, a balanced translocation, and a case of uniparental

disomy,amongothers(seeFigure7).

Figure7:TotalReportedIncidentalFindingsidentifiedthroughNIPT

*Includingconsanguinity,abalancedtranslocation,andacaseofuniparentaldisomy,amongothers.

Of the55counselorswhoreportedencountering incidental findings throughNIPT in their

practice, 44 respondents reported experience with cases of incidental findings that were

confirmedbyfollow-uptesting,and11respondentsreportedexperiencewithincidentalfindings

originally suspected by the NIPT laboratory, but that were not confirmed with follow-up

diagnostictestingoraneonataloutcome(seeFigure8).Belowisarespondent’sexperienceof

howtheNIPTlaboratorysuspectedanincidentalfinding:

“Labdirectorcalledtoletmeknowthatdataindicatedaz-scoresuggestiveofmonosomy18.Patienthadamniocentesiswithmicroarray,whichidentifiedalongstretchofhomozygosityalongchromosome18.Noultrasoundfindingsandpatient

declinedtoscheduleageneticseval[sic]postdelivery”

44% (n=24)

44% (n=24)

35% (n=19)

25% (n=14)

15% (n=8)

15% (n=8)

9% (n=5)

6% (n=3)

4% (n=2)

0% 10% 20% 30% 40% 50%

Co-twindemise/vanishingtwin

Maternalsexchromosomeaneuploidy

Confinedplacentalmosaicism

Maternalcopynumbervariation

Fetalorplacentalmosaicism

Other*

Maternalmosaicism

Maternalcancer

Maternaluterineleiomyoma

19

Figure8:Suspected&ConfirmedIncidentalFindingsidentifiedbyNIPT

*Includingconsanguinity,abalancedtranslocation,andacaseofuniparentaldisomy,amongothers.

Additionally,24 respondents includedcasedescriptionsand follow-up testing information

thatwereofferedand/ororderedtoinvestigatethefindingfromNIPT.Sixcounselorsreported

thatNIPTdetectedacaseofmaternal22qdeletionsyndromeastheincidentalfinding,almost

halfofthetotalcasesofmaternalcopynumbervariationreported.Threecounselorsreported

discordanceoffetalsexbetweentheNIPTresultandultrasoundwithdifferentoutcomes:

“Ihavehadincorrectgenderduetodemiseofaco-twin”

“Therewasonecongenitaladrenalhyperplasiawedetected(u/ssexwasmalewhileNIPTsaidfemale)”

“NIPTpositiveforTurnersyndrome-normalmalegenitaliaonultrasound,fetalkaryotypefromamniocentesis45,X/46,XYfetalmosaicism,pregnancyterminated”

TworespondentsnotedacancerdiagnosisinthemotherascauseforabnormalNIPTresults:

“oneknownbreastcancerandNIPTwasperformedafterdiagnosisthatwaspositive”

13%

11%

4%

2%

2%

7%

2%

31%

33%

31%

25%

13%

13%

2%

4%

4%

0% 10% 20% 30% 40% 50%

Co-twindemise/vanishingtwin

Maternalsexchromosomeaneuploidy

Confinedplacentalmosaicism

Maternalcopynumbervariation

Fetalorplacentalmosaicism

Other*

Maternalmosaicism

Maternalcancer

Maternaluterineleiomyoma

Suspected (n=22)

Confirmed (n=85)

20

“onelymphomadiagnosedafterNIPTwaspositivefortrisomy13andmonosomy18”

COUNSELINGCHALLENGESWITHINCIDENTALFINDINGSBYNIPT

When asked if counseling a patient with an incidental finding identified through NIPT is

challenging on a four-point scale from “strongly disagree” to “strongly agree,” 94% of

respondentswhohadencounteredasuspectedorconfirmedincidentalfinding(n=126)either

agreed or strongly agreed that it was challenging. Of the genetic counselors who had not

experiencedcounselingapatientwithanincidentalfindingidentifiedthroughNIPT(n=21),90.5%

eitheragreedorstronglyagreedthatitwouldbechallenging.(seeFigure9).

Figure9:CounselingaboutanIncidentalFindingisChallenging

Whenaskedtoratetheimportanceoffactorscontributingtothechallengeofcounselingfor

asuspectedorconfirmedincidentalfinding,thethreemostimportantfactorsselectedwere:a

lack of information on incidental findings from the NIPT laboratory, variation among NIPT

0% (n=0)

10% (n=2)

57% (n=12)

33% (n=7)

2% (n=3)

4% (n=5)

54% (n=68)

40% (n=50)

0% 10% 20% 30% 40% 50% 60%

StronglyDisagree

Disagree

Agree

StronglyAgree

Experienced(M=3.31) Inexperienced(M=3.24)

21

laboratorieswithhowtheycommunicateincidentalfindingsandfollow-up,andalackofclinical

guidelinesfromprofessionalsocieties.Thethreefactorsratedashavingthelowestimportance

were:alackofinstitutionalguidelinesonclinicalmanagementofincidentalfindings,limitedtime

duringgeneticcounselingsessions,andalackofpersonalexperienceincounselingforincidental

findings(seeFigure10).

Figure10:FactorsImpactingCounselingaboutIncidentalFindings

GENETICCOUNSELORS’RECOMMENDATIONSFORFUTUREGUIDELINES

Participantswereencouragedtosharetheirrecommendationsforahypotheticalcommittee

writing national guidelines for follow-up clinical evaluation for incidental findings identified

throughNIPT.Seventy-fourcounselorsprovidedwrittenresponses.

7%

11%

15%

19%

21%

25%

27%

21%

30%

28%

41%

42%

44%

93%

89%

85%

81%

79%

75%

73%

79%

70%

72%

59%

58%

56%

0% 20% 40% 60% 80% 100%

LackofinformationonincidentalfindingsfromNIPTlaboratory

VariationamongNIPTlaboratorieswithcommunicationofincidentalfindingsandfollow-up

Lackofclinicalguidelinesfromprofessionalsocieties

Lackofresourcestoprovidethepatientabouttheincidentalfinding

Lackofacentralizeddatabase tocatalogueincidentalfindingsbyNIPT

Counselingthepatientthroughaninterpreter/languagebarrier

Patientnotprovidedpre-testcounselingaboutpossibleincidentalfindings

TherarityofincidentalfindingsidentifiedbyNIPT

LackofsupportservicesfromNIPTlaboratory

Limitedtimeforincidentalfindinginterpretationintheprenatalsetting

Lackofinstitutionalguidelinesonclinicalmanagementofincidentalfindings

Limitedtimeduringgeneticcounselingsession

Lackofpersonalexperiencecounselingforincidentalfindings

NotImportant Important

M=3.43

M=3.29

M=3.13

M=3.10

M=3.06

M=2.99

M=2.91

M=2.89

M=2.71

M=2.64

M=3.35

M=2.89

M=2.73

22

Some respondents (n=23) expressed support for discussing the possibility of incidental

findings in pre-test counseling and during the informed consent process and many (n=12)

recommended providing patients the choice of either an opt-in or opt-out provision. Others

expressed that theyhadconsideredhavingadiscussionwithpatientsabout thepossibilityof

incidental findingsbut struggledwithwhen theappropriate time todoso isor if it isevena

necessarydiscussion.

“Thediscussionofincidentalfindingshastobeapartoftheconsentprocess.Patientshouldbeabletooptinoroutontheconsent.Allpatientsshouldbescheduledfor

geneticcounselingwhenfound.”

“Riskofidentifyingincidentalfindingsmustbedisclosedpriortotestingandincludedonconsentform”

Counselors(n=35)alsorecommendedthatanypatientreceivinganunusualresultorfinding

meetwith a genetic counselor for post-test counseling regarding the possibility of incidental

findings,inadditiontoappropriatefollow-upclinicalevaluationandtestingoptionsforboththe

fetusandmother.

“Considercreatinganalgorithmforhowtoclinicallyfollow-upincidentalfindings(e.g.whatisthenextbesttesttoconfirmthefinding)”

Anothergroupofcounselors(n=28)emphasizedtheneedforastandardsystemforreporting

resultsthatallNIPTlaboratoriesshouldberequiredtoadhereto,withmanyrecommendinga

nationalcentralizeddatabaseforcollectionoffindingsandfollow-upoutcomes.

“ALLlabsadheretosamesystemofreporting/whichfindingstheyreport;thereshouldbeadequatepretestcounselingbasedonthesestandards”

“Centralizeddatabaseforcollectionoffollow-upinformation.”

“Weneedclear-cutguidelinesforthemanagementofincidentalfindings.”

23

DISCUSSION

Throughthisresearchstudy,wesoughttoexploreprenatalgeneticcounselors’experiences

andcharacterizetheirchallengesassociatedwithincidentalfindingsidentifiedthoughNIPT.The

study’sfindingsareconsistentwiththeincreasingnumberofreportsofincidentalfindingsfirst

identifiedbyNIPT thathavehealth implications for the fetus and themother (Bianchi et al.,

2015b;Lauetal.,2013;Osborneetal.,2013;Snyderetal.,2016;Wangetal.,2014;Yaoetal.,

2012). Literaturespecific to thegeneticcounselingprofession thus farhas focusedmainlyon

counseling practices and experienceswith findings forwhich the initial NIPT technologywas

designedtoscreen(Horstingetal.,2014;Suskin,Hercher,Aaron,&Bajaj,2016).Thisisthefirst

study of prenatal genetic counselors’ perspectives, practices, and challenges with incidental

findingsidentifiedbyNIPT.

DespitetheAmericanCollegeofObstetriciansandGynecologists(ACOG)andtheSocietyfor

Maternal-FetalMedicine(SMFM)professionalpracticerecommendations(2015),morethan60%

ofrespondentsinourstudyroutinelyofferNIPTthatincludesanexpandednumberofconditions,

including microdeletions and other autosomal aneuploidies. While these expanded panels

increasethechanceofincidentalfindings,participantsindicatethattheycanbeusefulforcertain

situations,suchasapersonalorfamilyhistoryofmultiplemiscarriages,chromosomeconditions,

andwhenthereisafetalindicationofacardiacanomalyonultrasound.Thisisconsistentwith

24

therecentfindingspresentedbySequenominwhichtheyfoundthatMaterniTGENOMENIPTis

usedmostfrequentlyforindicationsthatincludeultrasoundfindingsandmultipleriskfactors,

suggestingthathealthcareprovidersareusinggenome-wideNIPTanalysisforclinicallycomplex

cases(McCulloughetal.,2016).

ASSESSMENTOFCURRENTPRE-TESTCOUNSELINGPRACTICES

Of the genetic counselors who completed the survey, almost half offer three or more

differenttypesofNIPTteststoregularlyprovidepre-testcounselingforNIPTtotheirpatients.

ThemoretypesofcfDNAteststhatcounselorsutilizetoprovideNIPTfortheirpatients(M=2.99,

SD=1.63),thelesslikelytheyaretouseNIPTcompany-specificresourcesduringtheircounseling

sessioncomparedtothosecounselorswhoofferfewerNIPToptionstotheirpatients(M=2.37,

SD=1.42),t(145)=-2.45,p=.015.Thisismostlikelyduetothedifferencesintechnologythat

eachNIPTcompanyusestoanalyzetheirsamples,aswellasthevarietyofcurrentconditions

screened foroneachNIPTpanel,making itmore challenging to relyononeNIPT company’s

patienteducationresourceduringpre-testcounselingsessions.

ThemajorityofthegeneticcounselorsobtaininformedconsentforNIPTverballyandover

half do not always include the possibility of incidental findings in their pre-test counseling

discussions.Morethanhalfdonotrequirethepatient’ssigningofaninformedconsentformfor

NIPT,insteadtheproviderisheldresponsiblefordocumentingthepatient’sconsentforNIPT.

Thesefindingsdemonstratealackoftransparencyaboutprenatalscreeninginpracticeandextra

attentionshouldbegiventotheprocessofobtainingconsentfrompatientstofindoutabout

their ownor their fetus’ health beforeNIPT is ordered. Efforts need to bemade to educate

25

patients,providethemwithaconsentformtoreadandtimetoaskquestions,andtoensurethat

theyhavefullycontemplatedallofthepotentialimplicationsofelectingordecliningNIPT.

Ourstudyfoundthatyearsofexperienceasaprenatalgeneticcounselordoesnothavean

influence on the discussion of incidental findings during pre-test counseling with patients.

However,ourfindingsdosuggestthatgeneticcounselorswhohavecounseledapatientfora

suspectedorconfirmedincidentalfindingidentifiedthroughNIPTaremorelikelytoincludethe

possibilityofincidentalfindingsintheirfuturepre-testcounselingdiscussions(p<.05).Thismay

beduetothecounselors’ increasedcomfort levelwithdiscussingthepossibilitiesforunusual

findingsbyNIPTandtheabilitytocallupontheirexperienceswithpriorpatientsasguidance.

Many counselors that do not include incidental findings in pre-test counseling cited the

complexityofdiscussingincidentalfindingsconsideringtheirinfrequency;therefore,theymay

notfeelconfidentenoughwiththeirunderstandingofthepotentialcausesofafalsepositive,

falsenegative,oranunusualresulttofeelcomfortablediscussingthevarietyofexplanations.

Regardlessofthefactorsassociatedwithcounselors’reportedpre-testcounselingpractices,

theACOGandSMFMreiteratethe“absoluterequirement”thatwomenunderstandnotonlythe

riskofaneuploidybutalsothebenefits,risks,andlimitationsofavailablescreeningtestsinpre-

test counseling, allowing for an informed patient choice “that fits the patient's clinical

circumstances,values,interests,andgoals”priortoperformingthetest(ACOG,2016).Further,

genetic counselors are crucial to the provision of complex counseling and test result

interpretation,andshould serveasa resource formorecomplicated findings thatgobeyond

otherhealthcareproviders’ scopeofunderstanding. It is not thedutyof thepatient to keep

abreastofdevelopmentsinprenatalscreeninganddiagnosis.Whiletheconcernsofincidental

26

findingswill grow as the breadth of information analyzed in NIPT expands, the findings and

reportedcasesfromourstudyillustratethattherearecurrentlymanyissuesthatneedattention.

COUNSELINGCHALLENGESWITHNIPT

ConfirmationoffalsepositiveresultsorunusualfindingsreportedbytheNIPTlaboratory,and

explanationof their significance, canbe costly. The incidental findings reported in this study

highlighttheongoingprocessthatoccurs inNIPT laboratorieswherebyfindingsare identified

that are clearly abnormal, and theremay be suspicion of a particular cause; however, every

findingneedstobeanalyticallyandclinicallyvalidated.Testingcompanies,iftheyplantoreturn

these types of findings,may need to reevaluate their reporting policies to determinewhich

suggestiveresultsareactuallylinkedtocancerorotherconditionsthatshouldbedisclosedto

maternalpatients,andwhicharenot.However,policiesonreportingresultsdiffersconsiderably

betweenlaboratories.Mostlaboratoriescannotofficiallyreportasuspicionofpotentialcancer

ofmaternalorigin,sincetherearenostudiestovalidatesuchaclaim.Ignoringthesesuspicions,

bynotreportingordiscussingthemwiththeorderingproviders,instead,raisesethicalconcerns

given that there is some evidence that these suspicions could have medically actionable

consequencesforthepatient.

Sequenomhasestablishedtheirreportingoffindingssuspiciousofmaternalcanceras“non-

informative,”alongwiththeassurancethattheyalerttheorderingprovidertotheirconcerning

finding(Ashford,2015).Othercompanieshavechosentonotreportorcommunicateanyunusual

or suspicious findings in similar circumstances. For instance,Natera has stated that their lab

personnel and the clinical teamareblinded to anymaternal findingsdue to their SNP-based

methodofanalysis.WhenofferingtheirPanoramaNIPT,theyencourageproviderstonotinclude

27

incidental findings intheirpre-testcounselingdiscussionforNIPT(Gross,2015).Yet,Natera’s

analysisincludesthefetal-riskscore,whichmakesit inherentlycapableofidentifyingapartial

deletionofchromosome22ofmaternalorigin,acommonmicrodeletionsyndromethatcanbe

variablyexpressedwithinfamilies(Hui,2016).

PRACTICEIMPLICATIONS

Despite the limitations of self-reporting and smaller frequency of suspected and/or

confirmed incidental findings in this study, the examples noted in this study encompass the

breadthofpossibilitiesforunusualNIPTfindingsinthepublishedliterature;theyincludeseveral

possible explanations for atypical NIPT results that genetic counselors should considerwhen

addressing the possible underlying explanations for a patient’s test result. The reported

frequency of prenatal counselors with experience with suspected or confirmed incidental

findingsandtheconsensusoftheassociatedchallengesreinforcetheimportanceofconfirmatory

diagnostictesting,inadditiontoareviewofthepatient’sclinicalhistoryfollowinganyabnormal

orunusualNIPTresult,alltoassistwithpost-testcounselingandmanagement.

The counselors’ responses varied greatly with regards to their recommendations for a

nationalguidelineforfollow-upclinicalevaluationforincidentalfindingsidentifiedthroughNIPT.

Theresponsesalsoindicateareasofsignificantconcernforgeneticcounselors,inparticular,the

variationamongNIPT laboratorieswith informationandcommunicationof incidental findings

andfollow-up,aswellasalackofacentralizeddatabasetocatalogueincidentalfindingsbyNIPT.

AsNIPTtechnologyandunderstandingevolves,theutilityandfocusofthisscreeningtoolwill

likelyexpandbeyondfetalstatuspredictiontoincludebroaderpregnancyhealthconcernsand

risks.Understandingandappreciatingthepotential implicationsofconcordantanddiscordant

28

NIPTresultsalikecangreatlyassistinthemanagementofpregnancies.False-positiveandfalse-

negativeratescanonlybeestablishedifcompletefollow-upinformationisobtainedfromclinical

validationstudies.Similartootherdecentralizedlaboratorytesting,nationalregulatingbodies

mayneedtoconsiderinter-laboratorycomparisonstoensureahighstandardofcfDNAtesting

optionsareavailable(Janietal.,2015).Laboratory-specificqualityassuranceprocesseswhich

include registry-basedclinical follow-updata linked toNIPT results isencouragedbynational

professionalsocieties(Benn,Cuckle,&Pergament,2013;Greggetal.,2013)andshouldbebased

onconsensusguidelinesforcfDNAaneuploidyscreening(ACOG,2016).

An additional consideration is that most established NIPT laboratories offer support by

geneticcounselorsandotherexpertstointerpretunexpectedresultsorprovidestrategiesfor

furthertestingwhenthe laboratory isunableto issuearesult.Withsmaller laboratoriesnow

offeringcfDNAtesting,andanalyzingfewersamples,thistypeoffollow-upserviceismuchmore

challengingandlesslikelytobeapartofthelaboratory’sservices.

STUDYLIMITATIONS

Alimitationofthisstudyisthelowresponserate,estimatedat14%,whichraisesquestions

aboutthegeneralizabilityofthefindingstothepopulationofclinicalprenatalgeneticcounselors.

Anotherlimitationincludesselectionbiasamongtherespondents.Thesubjectoftherecruitment

e-blastincludedtheterm“incidentalfindings,”sogeneticcounselorswithexperiencewiththese

types of NIPT results may have beenmore likely to complete the survey; conversely, those

withoutexperiencewithincidentalfindingsmaynothavebeeninterestedtoparticipateinthis

study.Althoughthe inclusioncriteriaconsistedofcurrentlypracticinggeneticcounselors, the

surveyrequiredaself-reportoftheircounselingpracticesandreliesontheirrecallbias.Finally,

29

respondents were not required to answer all questions encountered in the survey, which

contributedtominorinconsistencieswithdataanalysis.

RESEARCHRECOMMENDATIONS/FUTUREDIRECTIONS

These findingsemphasize theneed todevelop recommendations foradynamic informed

consentprocess thatwillbe flexibleover time, toaccommodateboththechangingnatureof

NIPTofferingsandpatientvalues,aswellasthepotentialforincidentalfindings.Weidentified

common challenges and concerns that genetic counselors face when offering NIPT to their

patients.Ourfindings,andthoseresultingfromfuturestudies,mayhelptoinformalternative

modelsforpre-testcounselingandobtaininginformedconsent,andpossiblyforotherguidelines

addressingthereturnofunusualNIPTresults, including incidental findings.Additionalstudies

shouldbedonetocharacterizethesortofinformationthatfacilitatespatients’understandingof

varioustypesofunusualNIPTresultsandthesortofinformationthatispotentiallyoverwhelming

and/orunhelpful tothem.NIPT isexpanding itscapabilitiesrapidlyandfutureresearchcould

examine how genetic counselorswill respond to the availability of these new tests and new

findings. Moreover, the lack of a standardized approach for returning potential incidental

findings from NIPT or guidelines for post-test counseling and management warrant further

research.

30

CONCLUSION

TheexpansionofNIPTand the conditions forwhich it screensprovidegreater choice for

patients,butcomewiththeinevitablechallengesinvolvedinappropriatepre-testcounselingand

obtaining informed consent due to the possibility of unanticipated findings. Themajority of

genetic counselor respondents obtain informed consent for NIPT verbally and about half

reportedthattheydonotincludethepossibilityofincidentalfindingsintheirpre-testcounseling

discussionofNIPT.Yet,almosthalfofthegeneticcounselorrespondentshavehadasuspected

or confirmed incidental finding identified throughNIPTandalmostallof them indicated that

post-testcounselingapatientwithanincidentalfindingidentifiedthroughNIPTischallenging.

Fromcounselors’responses,unknownmaternalconditionsaccountforalargeproportionof

the incidental findings identified by NIPT. Given these findingswe recommend that pre-test

counselingforNIPTincludeadiscussionofpossibleunexpectedfindingsandtoestablishclear

expectations for the categories of results thatmay be returned, the creation of professional

guidelines outlining how incidental findings should be discussed in both pre- and post-test

counseling discussions, and the creation of a centralized database for the collection of NIPT

findings,outcomes,andclinicalfollow-uptofacilitateappropriatecareforpatients.

31

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Devers, P.L., Cronister, A., Ormond, K.E., Facio, F., Brasington, C.K., & Flodman, P. (2013).Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the NationalSocietyofGeneticCounselors.JournalofGeneticCounseling,22(3),291–295.

Dondorp, W.J., Page-Christiaens, G.C.M.L., de Wert, G.M.W.R. (2015). Genomic futures ofprenatalscreening:ethicalreflections.ClinicalGenetics,1–8.

Flowers,N.,Kelley,J.,Sigurjonsson,S.,Bruno,D.L.,Pertile,M.D.(2015).Maternalmosaicismforalargesegmentalduplicationof18qasasecondaryfidningfollowingnon-invasiveprenataltestingandimplicationsfortestaccuracy.PrenatalDiagnosis,35,1–4.

Futch, T., Spinosa, J., Bhatt, S., de Feo, E., Rava, R.P., & Sehnert, A.J. (2013). Initial clinicallaboratory experience in noninvasive prenatal testing for fetal aneuploidy frommaternalplasmaDNAsamples.PrenatalDiagnosis,33,569–574.

Gil,M.M.,Quezada,M.S.,Revello,R.,Akolekar,R.,&Nicolaides,K.H.(2015).Analysisofcell-freeDNAinmaternalbloodinscreeningforfetalaneuploidies:updatedmeta-analysis.UltrasoundinObstetrics&Gynecology,45(3),249–266.

Grati,F.R.,Malvestiti,F.,Ferreira,J.C.P.B.,Bajaj,K.,Gaetani,E.,Agrati,C.,&Simoni,G.(2014).Fetoplacental mosaicism: potential implications for false-positive and false-negativenoninvasiveprenatalscreeningresults.GeneticsinMedicine,16(8),620–624.

Grati,F.R.,Bajaj,K.,Malvestiti,K.,Agrati,C.,Grimi,B.,Malvestiti,B.,...Ferreira,J.C.(2015).Thetype of feto-placental aneuploidy detected by cfDNA testingmay influence the choice ofconfirmatorydiagnosticprocedure.PrenatalDiagnosis,35(10),994–998.

Gregg,A.R.,Gross,S.J.,Best,R.G.,Monaghan,K.G.,Bajaj,K.,Skotko,B.G.,&Watson,M.S.(2013).ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genetics inMedicine,15(5),395–398.

Gross,S.(2015).Focusonmorespecificfetaltesting.Nature,523.Hahn,S.,Huppertz,B.,Holzgreve,W.(2005).Fetalcellsandcellfreefetalnucleicacidsinmaternal

blood:newtoolstostudyabnormalplacentation?Placenta,26,515–526.Horsting, J.M.H., Dlouhy, S.R., Hanson, K., Quaid, K., Bai, S., & Hines, K.A. (2014). Genetic

Counselors’ experiencewith cell-free fetalDNA testingas aprenatal screeningoption foraneuploidy.JournalofGeneticCounseling,23(3),377–400.

Hui, L. (2016). Cell-free DNA testing for 22q11.2 deletion syndrome: appraising the viability,effectivenessandappropriatenessofscreening.UltrasoundinObstetrics&Gynecology,47,137–141.

Jani,J.,RegodeSousa,M.J.,&Benachi,A.(2015).Cell-freeDNAtesting:howtochoosewhichlaboratorytouse?UltrasoundinObstetrics&Gynecology,46,515–517.

Jensen,T.J.,Zwiefelhofer,T.,Tim,R.C.,Džakula,Ž.,Kim,S.K.,Mazloom,A.R.,...Ehrich,M.(2013).High-throughputmassivelyparallelsequencingforfetalaneuploidydetectionfrommaternalplasma.PLoSONE,8,e57381.

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Lau,T.K.,Jiang,F.M.,Stevenson,R.J.,Lo,T.K.,Chan,L.W.,Chan,M.K.,Lo,P.S.,Wang,W.,Zhang,H.Y.,Chen,F.,&Choy,K.W.(2013).Secondaryfindingsfromnon-invasiveprenataltestingforcommonaneuploidiesbywholegenomesequencingasaclinicalservice.PrenatalDiagnosis,33(6),602–608.

Lo,Y.M.D.,Corbetta,N.,Chamberlain,P.F.,Rai,V.,Sargent,I.L.,Redman,C.W.,&Wainscoat,J.S.(1997).PresenceoffetalDNAinmaternalplasmaandserum.Lancet,350,485–487.

McCullough, R.,Wardrop, J., Boomer, T., Almasri, E., Caldwell, S., Broshes, S., & Cacheris, P.(2016).Earlyclinicaladoptionandutilizationofgenome-wideNIPT.Tampa:PosterpresentedattheACMGAnnualClinicalGeneticsMeeting.

Minear,M.A.,Lewis,C.,Pradhan,S.,&Chandrasekharan,S.(2015).GlobalperspectivesonclinicaladoptionofNIPT.PrenatalDiagnosis,35(10),959–967.

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Nicolaides,K.H.,Syngelaki,A.,Gil,M.,Atanasova,V.&Markova,D.(2013).Validationoftargetedsequencing of single-nucleotide polymorphisms for non-invasive prenatal detection ofaneuploidyofchromosomes13,18,21,XandY.PrenatalDiagnosis,33,575–579.

Norton,M.E.,Baer,R.J.,Wapner,R.J.,Kuppermann,M., Jelliffe-Pawlowski,L.L.,&Currier,R.J.(2016). Cell-free DNA vs sequential screening for the detection of fetal chromosomalabnormalities.AmericanJournalofObstetrics&Gynecology,1.e1–1.e6.

Norton,M.E.,Brar,H.,Weiss,J.,Karimi,A.,Laurent,L.C.,Caughey,A.B.,&Song,K.(2012).Non-InvasiveChromosomalEvaluation(NICE)Study:resultsofamulticenterprospectivecohortstudy for detection of fetal trisomy 21 and trisomy 18.American Journal of Obstetrics&Gynecology,207(2),137.e1–137.e8.

Osborne,C.M.,Hardisty,E.,Devers,P.,Kaiser-Rogers,K.,Hayden,M.A.,Goodnight,W.,Vora,N.L.(2013).Discordantnoninvasiveprenataltestingresultsinapatientsubsequentlydiagnosedwithmetastaticdisease.PrenatalDiagnosis,33,609–611.

Palomaki,G.E.,Deciu, C., Kloza, E.M., Lambert-Messerlian,G.M.,Haddow, J.,Neveux, L., . . .Canick, J. (2012). DNA sequencing of maternal plasma reliably identifies trisomy 18 andtrisomy 13 as well as Down syndrome: an international collaborative study. Genetics inMedicine,14(3),296.

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Sahoo, T., Strecker, M.N., Commander, S. (2016). Expanding noninvasive prenatal testing toincludemicrodeletionsandsegmentalaneuploidy:causeforconcern?GeneticsinMedicine,18(3),275–276.

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APPENDICESAPPENDIXA:RECRUITMENTNOTIFICATIONSubject:NIPT:EmergingIssues—GeneticCounselors’Experiences&PerspectiveswithIncidentalFindings

SeekingPrenatalGeneticCounselorstoParticipateinaResearchStudy

Youareinvitedtoparticipateinanonlineresearchsurveytoinvestigategeneticcounselors’practicesandperspectivesincounselingpatientsregardingthepossibilityofunanticipatedincidentalfindingsthroughnon-invasiveprenataltesting(NIPT).ThisstudyisopentoprenatalgeneticcounselorswhoprovidecounselingforNIPTtopatientseitherinperson,overthephone,oronline.Thespecificgoalsofthisresearchstudyareto:§ identifythecurrentpre-testcounselingpracticesforNIPT,includingmethodsforobtaining

informedconsent;§ learnaboutgeneticcounselors’personalexperienceswithincidentalfindingsbyNIPT;and§ delineatechallengescounselorsfacewhendiscussingthepossibilityofincidentalfindingsby

NIPTwithpatients.Thesurveywilltake10-15minutesofyourtime.Allparticipantswhocompletethesurveywillhavetheopportunitytoenteradrawingforoneofthree$50giftcardstoAmazon.com.Yoursurveyresponseswillnotbeconnectedtoyouremailaddress.ThisstudywasreviewedandapprovedbytheBrandeisUniversityInstitutionalReviewBoard.Ifyouhaveanyquestions,concerns,orcomments,pleasefeelfreetocontactmebyemailataorta@brandeis.edu,ortheBrandeisUniversityfacultysponsor,JudithTsipis,attsipis@brandeis.edu.Clickheretotakethesurvey!Thankyouinadvanceforyourtimeandparticipation.Sincerely,AliciaOrta,MPHMaster’sDegreeCandidate,Classof2016GeneticCounselingProgramBrandeisUniversity

JudithE.Tsipis,PhDDirector,GeneticCounselingProgramProfessorofBiologyBrandeisUniversity

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APPENDIXB:INSTRUMENTNIPT:EmergingIssuesWelcome!AspartofaMaster’sthesisresearchprojectatBrandeisUniversity,thefollowingstudyisinvestigatinggeneticcounselors’practicesandperspectivesincounselingpatientsregardingthepossibilityofunanticipatedincidentalfindingsthroughnon-invasiveprenataltesting(NIPT).ThisstudyisopentoprenatalgeneticcounselorswhoprovidecounselingforNIPTtopatientseitherinperson,overthephone,oronline.Thespecificgoalsofthisresearchstudyareto:§ identifythecurrentpre-testcounselingpracticesforNIPT,includingmethodsforobtaining

informedconsent;§ learnaboutgeneticcounselors’personalexperienceswithincidentalfindingsbyNIPT;and§ delineatechallengescounselorsfacewhendiscussingthepossibilityofincidentalfindingsby

NIPTwithpatients.Thisanonymoussurveyisexpectedtotake10-15minutestocomplete.Youareencouragedtorespondtoallsurveyquestions;however,youmayskipanyquestionsthatyouarenotcomfortableansweringorendyourparticipationatanypoint.Ifyouwouldliketobeeligibletowinoneofthree$50giftcardstoAmazon.com,pleaseenteryouremailaddressontheseparateunlinkedsiteasdirectedattheendofthesurvey.ThisstudywasreviewedandapprovedbytheBrandeisUniversityInstitutionalReviewBoard(IRB).Ifyouhavequestionsaboutyourrightsasaresearchsubject,pleasecontacttheBrandeisIRBatirb@brandeis.eduor781-736-8133.Byclickingthe"Next"buttonbelowyouareconsentingtoparticipateinthisstudy.Thankyou!

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DefinitionsForthepurposeofthissurvey,thefollowingdefinitionsareprovided.Theywillbeavailablethroughoutthesurveybyplacingyourcursoroverthecoloreditem.

IncidentalFinding:anunexpectedfindingofamaternalorfetalconditionotherthanthetypicallyscreenedforconditionsspecificallytargetedbyNIPT.Theseunanticipated‘secondaryfindings’mayinclude:unrecognizedmaternalconditions,co-twindemise,andfetalorplacentalchromosomedifferences,amongothers.

No-CallNIPTResult:afailuretoreceiveaninterpretableresultfromcell-freeDNAtesting.DependingontheNIPTlaboratory,the“non-reportable”resultmaybeduetoinsufficientsample,lowfeto-placentalDNAfraction,orbecausetheinterpretationfallsintoanindeterminaterange.

PositiveNIPTResult:aresultthatsuggestsapregnancyisatriskofhavingaconditionthatisamongthetypicallyscreenedforconditionsspecificallytargetedbyNIPT.Theresultmaybereportedas“aneuploidydetected”or“highrisk”anddoesnotinclude“no-call”NIPTresults.Q1. Doyoucurrentlyworkasageneticcounselorinaclinicalprenatalsetting?

m Yesm No

IfNoIsSelected,ThenSkipToEndofSurveyQ2. Whatpercentageofyourcounselingtimeisspentwithprenatalpatients?

m Lessthan25%m 26-50%m 51-75%m 76-100%

Q3. Whichmodalitiesdoyouutilizetocounselpatientsatyourclinicalpractice?(Selectall

thatapply)q In-persongeneticcounselingq Telephonegeneticcounselingq Telegenetics(counselingoccurringremotelyusingvideoconferencing)

Answerif:TelephonegeneticcounselingIsSelectedOrTelegenetics(counselingoccurringremotelyusingvideoconferencing)IsSelectedQ4. Whatpercentofyourpatientcontacttimedoyouspendeachweekutilizingtelephone

geneticcounselingortelegenetics(counselingoccurringremotelyusingvideoconferencing)?(Indicateapercentage)

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Q5. Doyouoffernon-invasiveprenataltesting(NIPT)topatients?m Yesm No

IfNoIsSelected,ThenSkipToEndofBlockQ6. Forhowmanypatientsperweekdoyoutypicallyprovidepre-testcounselingforNIPT?

(Approximately)m 1-4m 5-9m 10-14m 15-19m 20-24m Morethan24

Q7. ForhowmanypatientsperweekdoyoutypicallyorderNIPT?(Approximately)

m 1-4m 5-9m 10-14m 15-19m 20-24m Morethan24

Q8. Whichcompany/companiesandcorrespondingtest(s)doyoucurrentlyusetoprovide

NIPTtoyourpatients?(Selectallthatapply)q AriosaDiagnostics(Harmony™)q Counsyl(InformedPregnancyScreen)q IntegratedGenetics-LabCorp(informaSeqSM)q Natera(Panorama™)q PerkinElmer(verifi®fromPerkinElmerLabs)q Progenity(VerifibyProgenity)q Quest(QNatal™Advanced)q Recombine(ChromoMap)q SequenomLaboratories(MaterniT™GENOME)q SequenomLaboratories(MaterniT21®PLUS)q SequenomLaboratories(VisibiliT™)q VerinataHealth-Illumina(verifi™)q Other,pleasespecify:____________________

Q9. Howmanyprenatalgeneticcounselors(includingyourself)workinyourclinicalpractice?

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SurveyBlock:NoNIPTUtilizationQuestionsQ10. PleasebrieflyexplainwhyNIPThasnotbeenincorporatedintoyourclinicalpractice.

Q11. DoesyourclinicintendtoincorporateNIPTintoyourclinicalpractice?

m Yesm No

IfNoIsSelected,ThenSkipToEndofSurveyAnswerIf:DoesyourclinicintendtoincorporateNIPTintoyourclinicalpractice?YesIsSelectedQ12. PleasedescribewhenyouexpectNIPTtobeincorporatedintoyourclinicalpractice.

IfNoIsSelected,ThenSkipToEndofSurveySurveyBlock:ResourcesQuestionsQ13. AreyourpatientsprovidedwithinformationaboutNIPTbeforetheirgeneticcounseling

appointment?m Yesm No

AnswerIf:YesIsSelectedQ14. Whichtypesofresources,includingweb-basedorapp-basededucationaltools,are

providedforpatientsaboutNIPTbeforetheirgeneticcounselingappointment?(Selectallthatapply)q Printmaterialssentinthemailtothepatient’saddressq Emailwithlinkstoonlinewritteneducationalinformationq Emailwithalinktoanonlineeducationalvideotoviewathomeq Educationaltoolsanddecisionaidsonmyinstitution'swebsiteq Educationalvideoinpracticewaitingroomq Other,pleasespecify:____________________

Q15. WhattypesofresourcesdoyouutilizetoinformpatientsaboutNIPTduringtheirgenetic

counselingsession?(Selectallthatapply)q ResourcescreatedbytheLaboratory/Companyq ResourcescreatedbytheNSGCPrenatalSIGq Resourcescreatedbyotherprofessionalsocieties(e.g.,ISPD,ACOG)q Resourcesdevelopedbymyinstitutionq Publishedgeneticcounselingvisualaidsq Web-basedorapp-baseddecision-makingaidsq Idonotuseanyprintedresourcesq Other,pleasespecify:____________________

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Q16. HowdoyouroutinelyobtaininformedconsentforNIPT?(Selectallthatapply)

q Verbally(eitherinperson,overthephone,orviavideocounseling)q ThereisaformspecificallyforNIPTsignedbytheproviderdocumentingthepatient’s

consentq NIPThasbeenincorporatedintoapre-existinginformedconsentformforinvasive

diagnostictestingthatthepatientsignsq ThereisaninformedconsentformthatthepatientsignsspecificallyforNIPTq NIPThasbeenincorporatedintoapre-existinginformedconsentformforscreening

thatthepatientsignsq Thereisaninformedconsentformthatboththeproviderandpatientsigns

specificallyforNIPTq PatientsignsarequisitionformprovidedbytheNIPTlabcompanyq IdonotroutinelyobtaininformedconsentforNIPTq Other,pleasespecify:____________________

Q17. Whatotherhealthcareprovider(s),ifany,obtaininformedconsentforNIPTinyour

clinicalpractice?(Selectallthatapply)q GeneticCounselor(otherthanyourself)q GeneticCounselingStudentInternq Maternal-FetalMedicineSpecialistq MedicalGeneticistq Midwifeq NursePractitionerq Obstetricianq PhysicianAssistantq Noneq Other,pleasespecify:____________________

SurveyBlock:InformedConsentFormQuestionsQ18. IstheNIPTinformedconsentformthatyouuseavailableinmultiplelanguages?

m Yesm No

Q19. DoestheNIPTinformedconsentformthatyouuseincludethepossibilityofincidental

findings?m Yesm No

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SurveyBlock:Pre-testCounselingQuestionsQ20. Whichofthefollowingitemsdoyoucurrentlydiscusswithyourpatientsasanoptionto

opt-inoropt-outforthereportingofresultswithNIPT?Opt-Outoption Opt-Inoption NOOpt-In/Outoptions NotApplicable___Fetalsex ___Fetalsex ___Fetalsex ___Fetalsex___Microdeletions ___Microdeletions ___Microdeletions ___Microdeletions___Microduplications ___Microduplications ___Microduplications ___Microduplications___Otherautosomalaneuploidies(e.g.,trisomy22)

___Otherautosomalaneuploidies(e.g.,trisomy22)

___Otherautosomalaneuploidies(e.g.,trisomy22)

___Otherautosomalaneuploidies(e.g.,trisomy22)

___Sexchromosomeaneuploidies

___Sexchromosomeaneuploidies

___Sexchromosomeaneuploidies

___Sexchromosomeaneuploidies

___Other,pleasespecify:

___Other,pleasespecify:

___Other,pleasespecify:

___Other,pleasespecify:

Q21. Doyoucurrentlyincludethepossibilityofincidentalfindingsinyourpre-testcounseling

discussionofNIPTwitheverypatient?m Yesm No

SurveyBlock:Pre-testCounseling—NoIncidentalFindingsQuestionsQ22. Whichofthefollowingarereasonswhyyoudonotincludethepossibilityofincidental

findingsinyourpre-testcounselingdiscussionofNIPTwitheverypatient?(Selectallthatapply)q Incidentalfindingsaretoorareq Incidentalfindingscomplicatethediscussionq There’salackofrecommendationsorguidelinesonwhattodoifanincidentalfinding

isidentifiedq Thetestisnotdesignednorvalidatedforthedetectionofincidentalfindingsq ThisinformationisincludedontheNIPTinformedconsentformthatIuseq Thisinformationmayinfluencepatient’sdecision-makingabouttheirprenatal

screeningoptionsq Thegeneticcounselorsinmypracticehavebeenadvised–orhavedecided–asa

grouptonotdiscussincidentalfindingswitheverypatientq Other,pleasespecify:____________________

Q23. Whenwouldyoudefinitelydiscussthepossibilityofanincidentalfindingwithapatient

beforetheyelecttohaveNIPT?(Selectallthatapply)q Wheneverthereisapersonalhistoryofchromosomeabnormalitiesq Wheneverthereisafamilyhistoryofchromosomeabnormalitiesq Wheneverthereisapersonalreproductivehistoryofrecurrentmiscarriages

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q Other,pleasespecify:____________________AnswerIf:WheneverthereisapersonalhistoryofchromosomeabnormalitiesIsSelectedQ24. Whatqualifiesasapersonalhistoryofchromosomeabnormalities?

AnswerIf:WheneverthereisafamilyhistoryofchromosomeabnormalitiesIsSelectedQ25. Whatqualifiesasafamilyhistoryofchromosomeabnormalities?

AnswerIf:WheneverthereisapersonalpregnancyhistoryofrecurrentmiscarriagesIsSelectedQ26. Whatqualifiesasapersonalreproductivehistoryofrecurrentmiscarriages?

SurveyBlock:Opt-OutQuestionsQ27. Whenwouldyoudefinitelydiscussthepossibilityofanincidentalfindingwithapatient

aftertheyreceiveaNIPTresult,butbeforeanyfurther(diagnostic)testing?(Selectallthatapply)q Wheneverano-callNIPTresultisreportedq Whenever2ormoreno-callNIPTresultsarereportedq WheneveraNIPTresultreportsasexchromosomeaneuploidyq WheneveraNIPTresultreportsanautosomalmonosomyq WheneveraNIPTresultreportsmultipleaneuploidiesq WheneveraNIPTresultreportsamicrodeletion/microduplicationq WheneverapossibleincidentalfindingissuspectedbytheNIPTlaboratoryq Other,pleasespecify:____________________

Q28. Althoughthereiscurrentlynooptiontoopt-outofincidentalfindingsfromNIPT,which

ofthefollowingwouldyousupportasopt-outoptionsforyourpatients?(Selectallthatapply)q AllpotentialincidentalfindingsidentifiedthroughNIPTq Incidentalfindingsindicativeofanymaternalhealthconditionq Incidentalfindingsindicativeofamaternalaneuploidyq Incidentalfindingsindicativeofmaternalcopynumbervariationsq Incidentalfindingsindicativeofanadult-onsetconditioninthefetusq Potentialincidentalfindingsofconsanguinityq Potentialincidentalfindingsofnon-paternityq Other,pleasespecify:____________________

Q29. Hasyourclinicalpracticediscussedtheneedforanoptiontoopt-outofthereportingof

atleastsomeincidentalfindingswithNIPT?

43

m Yesm Nom Don'tknowm Prefernottoanswer

AnswerIf:YesIsSelectedQ30. Whydidyourclinicalpracticebegindiscussingtheneedforthisoption?

Q31. Doyouthinkgivingpatientsanoptiontochoosewhichincidentalfindingstoreceive

wouldimprovepatientcare?m Yesm Nom Don'tknowm Prefernottoanswer

Q32. Doyouthinkanonlineorweb-basedtoolwouldfacilitateassessmentofpatient

preferencesforpossibleincidentalfindingsthroughNIPT?m Yesm Nom Don'tknowm Prefernottoanswer

SurveyBlock:PersonalExperiencewithIncidentalFindingsfromNIPTQuestionsQ33. Sinceyoufirstbeganpracticinginaclinicalprenatalsetting,howmanypatientshaveyou

personallycounseledwithapositiveNIPTresult?(Approximately)m Nonem 1-3m 4-6m 7-9m 10-12m 13-15m Morethan15

IfNoneIsSelected,ThenSkipTo#ofNon-ReportableNIPTresultsQ34. OfthesepatientswithapositiveNIPTresult,howmanywerereferralsfromadifferent

office(e.g.,primarycarephysician,OB/GYN)withnopre-testcounselingpriortotesting?(Approximately)m Nonem 1-2m 3-4m 5-6m 7-8m 9-10

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m Morethan10Q35. OfallthepatientsthatyouhavecounseledwithapositiveNIPTresult,please

approximatethepercentagewhoelectedeachofthefollowing.(Answersmusttotalto100%)______TerminatedthepregnancybasedonNIPTresultonly(withnoadditionalultrasoundfindings)______TerminatedthepregnancybasedonNIPTresultandthepresenceofultrasoundfindings______ConfirmedresultwithamniocentesisorCVSandcontinuedthepregnancy______ConfirmedtheresultwithamniocentesisorCVSandterminatedthepregnancy______HadanamniocentesisorCVSresultthatdidnotconfirmtheNIPTresult______Decidedagainstinvasivediagnostictestingandcontinuedthepregnancy

Q36. OfallthepatientsyouhavecounseledwithapositiveNIPTresult,howmanywerelater

foundtobenegativebydiagnostictestingorneonataloutcome(i.e.,discordantwithNIPTresult)?m NoneorNonethatIknowofm 1m 2m 3m 4m 5m Morethan5m Don’tknowbutatleast1

Q37. Sinceyoufirstbeganpracticinginaclinicalprenatalsetting,howmanypatientshaveyou

personallycounseledwithano-callNIPTresultafterrepeatscreening(i.e.,2ormorebloodsamplesforNIPT)?(Approximately)m NoneorNonethatIknowofm 1m 2m 3m 4m 5m Morethan5m Don’tknowbutatleast1

AnswerIf:1Or2Or3Or4Or5OrMorethan5OrDon’tknowbutatleast1IsSelectedQ38. Ofthepatient(s)youhavecounseledwithano-callNIPTresultafterrepeatscreening,

pleasedescribetherecommendedfollow-uptestingthatwasofferedandtheirclinicaloutcome(s),includingthereason(s)formultipleNIPTfailures,ifknown.

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Q39. Sinceyoufirstbeganpracticinginaclinicalprenatalsetting,howmanypatientshaveyoupersonallycounseledwheretheNIPTlaboratorysuspectedapossibleincidentalfindingfromNIPT?(Approximately)m NoneorNonethatIknowofm 1m 2m 3m 4m 5m Morethan5m Don’tknowbutatleast1

Q40. Sinceyoufirstbeganpracticinginaclinicalprenatalsetting,howmanypatientshaveyou

personallycounseledwithaconfirmedincidentalfindingidentifiedthroughNIPT?m NoneorNonethatIknowofm 1m 2m 3m 4m 5m Morethan5m Don’tknowbutatleast1

AnswerIf#ofCONCERNSOr#ofCONFIRMEDIncidentalFindingsIs1ormoreSelectedQ41. Whichtypesofconfirmedincidentalfinding(s)identifiedthroughNIPThaveyou

personallyencountered?(Selectallthatapplyandincludeexamplesifyourecall)q Confinedplacentalmosaicismq Co-twindemise/vanishingtwinq Fetalorplacentalmosaicismq Maternalcancerq Maternalcopynumbervariationq Maternalmosaicismq Maternalsexchromosomeaneuploidy(mosaic)q Maternalsexchromosomeaneuploidy(non-mosaic)q Maternaluterineleiomyomaq Other,pleasespecify:____________________

Q42. Includeanyexamplesandadditionalcommentsbelow:

AnswerIf#ofCONCERNSOr#ofCONFIRMEDIncidentalFindingsIs1ormoreSelectedQ43. Whichresourcesdidyoufindhelpfulwhenpreparingtocounselthepatient(s)aboutthe

incidentalfinding(s)fromNIPT?(Selectallthatapply)

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q LaboratoryDirectorwhereNIPTwasperformedq GeneticCounselorfromtheNIPTLaboratoryq PediatricGeneticCounselorq CancerGeneticCounselorq Websitesofthetestinglaboratories/companiesq NSGCPrenatalSIGforumq OMIM/PubMed—peerreviewedliteraturesearchq Guidelinesfromprofessionalsocietiesq GenomeBrowsers(DECIPHER,ECARUCA,Genecards,TorontoDatabase,UCSC)q Other,pleasespecify:____________________

SurveyBlock:ChallengeswithExperiencewithIncidentalFindingsQuestionsQ44. Towhatextentdoyouagreeordisagreewiththefollowingstatement:

StronglyDisagree Disagree Agree Strongly

Agree“Counselingapatientwithanincidental

findingidentifiedthroughNIPTischallenging.”

¡ ¡ ¡ ¡

Q45. Pleaseindicatethelevelofimportanceeachofthefollowingfactorscontributetothe

challengeofcounselingapatientwithanincidentalfindingidentifiedthroughNIPT:

NotatallImportant

OfLittleImportance Important

ExtremelyImportant

TherarityofincidentalfindingsbyNIPT ¡ ¡ ¡ ¡Lackofpersonalexperienceincounselingfor

incidentalfindings¡ ¡ ¡ ¡

LackofinformationonincidentalfindingsfromtheNIPTlaboratory

¡ ¡ ¡ ¡

LackofsupportservicesfromtheNIPTlaboratory

¡ ¡ ¡ ¡

Lackofclinicalguidelinesfromprofessionalsocieties(e.g.,ACOG,NSGC)

¡ ¡ ¡ ¡

Lackofinstitutionalguidelinesonclinicalmanagementofincidentalfindings

¡ ¡ ¡ ¡

LackofacentralizeddatabasetocatalogueincidentalfindingsbyNIPT

¡ ¡ ¡ ¡

VariationamongNIPTlaboratorieswithcommunicationofincidental

findingsandfollow-up¡ ¡ ¡ ¡

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Patientwasnotprovidedpre-testcounselingaboutpossibleincidentalfindings ¡ ¡ ¡ ¡

Lackofresourcestoprovidethepatientabouttheincidentalfinding ¡ ¡ ¡ ¡

Counselingthepatientthroughaninterpreter/languagebarrier ¡ ¡ ¡ ¡

Limitedwindowoftimeforincidentalfindinginterpretationintheprenatalsetting ¡ ¡ ¡ ¡

Limitedtimeduringgeneticcounselingsession ¡ ¡ ¡ ¡

Q46. Towhatextentdoyouagreeordisagreewiththefollowingstatementsregarding

thereturnofincidentalfindingsidentifiedthroughNIPT:

StronglyDisagree Disagree Agree

StronglyAgree

Mosthealthcareprovidersdonothavethetimeand/orexpertisetoreturnincidental

findings.¡ ¡ ¡ ¡

Patientsshouldbeallowedtoselectwhichincidentalfindingstheywanttoreceivebased

ontheirvalues.¡ ¡ ¡ ¡

Thereisinsufficientevidenceaboutthebenefits,risks,andcostsofreporting

incidentalfindings.¡ ¡ ¡ ¡

IdentifyingincidentalfindingswillbeburdensomeforNIPTlaboratories.

¡ ¡ ¡ ¡

Returningincidentalfindingswillincreasehealthcarecosts.

¡ ¡ ¡ ¡

Patientsusuallydonotknowaboutthepossibilityofincidentalfindingsandare

caughtcompletelyoff-guard.¡ ¡ ¡ ¡

Q47. Howoftendoyoureviewthecurrentpublishedliteratureorcasereportsregarding

incidentalfindingsfromNIPT?(Approximately)m Rarelym 2-3TimesaYearm OnceaMonthm 2-3TimesaMonthm OnceaWeekm 2-3TimesaWeek

48

SurveyBlock:ChallengeswithNOExperiencewithIncidentalFindingsQuestionsQ48. Towhatextentdoyouagreeordisagreewiththefollowingstatement:

StronglyDisagree Disagree Agree Strongly

Agree“CounselingapatientwithanincidentalfindingidentifiedthroughNIPTwouldbe

challenging.”¡ ¡ ¡ ¡

Q49. Pleaseindicatethelevelofimportanceeachofthefollowingfactorswouldcontributeto

thechallengeofcounselingapatientwithanincidentalfindingidentifiedthroughNIPT:

NotatallImportant

OfLittleImportance Important

ExtremelyImportant

TherarityofincidentalfindingsbyNIPT ¡ ¡ ¡ ¡Lackofpersonalexperienceincounselingfor

incidentalfindings ¡ ¡ ¡ ¡

LackofinformationonincidentalfindingsfromtheNIPTlaboratory ¡ ¡ ¡ ¡

LackofsupportservicesfromtheNIPTlaboratory ¡ ¡ ¡ ¡

Lackofclinicalguidelinesfromprofessionalsocieties(e.g.,ACOG,NSGC) ¡ ¡ ¡ ¡

Lackofinstitutionalguidelinesonclinicalmanagementofincidentalfindings ¡ ¡ ¡ ¡

LackofacentralizeddatabasetocatalogueincidentalfindingsbyNIPT ¡ ¡ ¡ ¡

VariationamongNIPTlaboratorieswithcommunicationofincidental

findingsandfollow-up¡ ¡ ¡ ¡

Patientwasnotprovidedpre-testcounselingaboutpossibleincidentalfindings ¡ ¡ ¡ ¡

Lackofresourcestoprovidethepatientabouttheincidentalfinding ¡ ¡ ¡ ¡

Counselingthepatientthroughaninterpreter/languagebarrier ¡ ¡ ¡ ¡

Limitedwindowoftimeforincidentalfindinginterpretationintheprenatalsetting ¡ ¡ ¡ ¡

Limitedtimeduringgeneticcounselingsession ¡ ¡ ¡ ¡

Q50. Towhatextentdoyouagreeordisagreewiththefollowing

statementsregardingthereturnofincidentalfindingsidentifiedthroughNIPT:

49

StronglyDisagree Disagree Agree

StronglyAgree

Mosthealthcareprovidersdonothavethetimeand/orexpertisetoreturnincidental

findings.¡ ¡ ¡ ¡

Patientsshouldbeallowedtoselectwhichincidentalfindingstheywanttoreceivebased

ontheirvalues.¡ ¡ ¡ ¡

Thereisinsufficientevidenceaboutthebenefits,risks,andcostsofreporting

incidentalfindings.¡ ¡ ¡ ¡

IdentifyingincidentalfindingswillbeburdensomeforNIPTlaboratories.

¡ ¡ ¡ ¡

Returningincidentalfindingswillincreasehealthcarecosts.

¡ ¡ ¡ ¡

Patientsusuallydonotknowaboutthepossibilityofincidentalfindingsandare

caughtcompletelyoff-guard.¡ ¡ ¡ ¡

Q51. Whichresourceswouldyouutilizewhenpreparingtocounselapatientwithanincidental

findingfromNIPT?(Selectallthatapply)q LaboratoryDirectorwhereNIPTwasperformedq GeneticCounselorfromtheNIPTLaboratoryq PediatricGeneticCounselorq CancerGeneticCounselorq Websitesofthetestinglaboratories/companiesq NSGCPrenatalSIGforumq OMIM/PubMed—peerreviewedliteraturesearchq Guidelinesfromprofessionalsocietiesq GenomeBrowsers(DECIPHER,ECARUCA,Genecards,TorontoDatabase,UCSC)q Other,pleasespecify:____________________

Q52. Howoftendoyoureviewthecurrentpublishedliteratureorcasereportsregarding

incidentalfindingsfromNIPT?(Approximately)m Rarelym 2-3TimesaYearm OnceaMonthm 2-3TimesaMonthm OnceaWeekm 2-3TimesaWeek

SurveyBlock:Open-EndedQuestion

50

Q53. Ifyouwerepartofacommitteewritinganationalguidelineforthefollow-upclinicalevaluationforincidentalfindingsidentifiedthroughNIPT,whatrecommendationswouldyoumake?

SurveyBlock:DemographicsQuestionsQ54. InwhichNSGCregionareyoucurrentlypracticing?

m Region1:CT,MA,ME,NH,RI,VT,CN,MaritimeProvincesm Region2:DC,DE,MD,NJ,NY,PA,VA,WV,PR,VI,Quebecm Region3:AL,FL,GA,KY,LA,MS,NC,SC,TNm Region4:AR,IA,IL,IN,KS,MI,MN,MO,ND,NE,OH,OK,SD,WI,Ontariom Region5:AZ,CO,MT,NM,TX,UT,WY,Alberta,Manitoba,Saskatchewanm Region6:AK,CA,HI,ID,NV,OR,WA,BritishColumbia

Q55. Whatisthesettingofyourpractice?(Selectallthatapply)

q CommunityHospitalq GovernmentOrganization/MedicalFacilityq HealthMaintenanceOrganization(HMO)q Laboratory/Industryq Outreach/Satellite/FieldClinicq PrivateClinic/Practiceq PrivateHospital/MedicalFacilityq PublicHospital/MedicalFacilityq UniversityMedicalCenterq Other,pleasespecify:____________________

Q56. Whichofthefollowingbestdescribesthelocationoftheinstitutionwhereyouprimarily

practice?m Urbanm Suburbanm Ruralm Notapplicable

Q57. Howmanyyearstotalhaveyoubeenpracticingasageneticcounselorinanysetting?

(Approximately)

Q58. Ofthese,howmanyyearshaveyouspentinaclinicalprenatalsetting?(Approximately)