Psychological distress in applicants for predictive DNA testing for autosomal dominant, heritable, late onset disorders. The Rotterdam/Leiden Genetics Workgroup

32Med Genet 1997;34:382-390

Psychological distress in applicants for predictiveDNA testing for autosomal dominant, heritable,late onset disorders

A C DudokdeWit, A Tibben, H J Duivenvoorden, P G Frets, MW Zoeteweij,M Losekoot, A van Haeringen, M F Niermeijer, J Passchier, and the other members of theRotterdam/Leiden Genetics Workgroup*

*Participating in the Rotterdam/Leiden Genetics Workgroup are, besides the authors already mentioned: D Lind-hout, E J Meijers-Heijboer, Department of Clinical Genetics, Rotterdam; L N Lodder, RW Trijsburg, DepartmentofMedical Psychology and Psychotherapy, Rotterdam; JGM Klijn, "Daniel den Hoed" Cancer Centre, Rotterdam;A Brocker-Vriends, A T J M Helderman, Y Hilhorst-Hofstee, S Kant, J A Maat-Kievit, J C Oosterwijk, J J van derSmagt, M Vegter-van der Vlis, M-A C S Vries-van der Weerd, Department of Clinical Genetics, Leiden; E Bakker,C J Cornelisse, P Devilee, C Tops, Department of Human Genetics, Leiden; H F A Vasen, Dutch Foundation ofHereditary Tumours (STOET), Leiden, The Netherlands.

Departments ofMedical Psychologyand Psychotherapy,Erasmus UniversityRotterdam, PO Box1738, 3000 DRRotterdam, TheNetherlandsA C DudokdeWitA TibbenH J DuivenvoordenP G FretsMW ZoeteweijJ Passchier

Department of ClinicalGenetics, ErasmusUniversity andUniversity HospitalDijkzigt, StateUniversity Leiden, TheNetherlandsA TibbenP G FretsM F Niermeijer

Department of ClinicalGenetics, UniversityHospital Leiden, TheNetherlandsA C Dudok de WitM W ZoeteweijM LosekootA van Haeringen

Correspondence to:Dr DudokdeWit.

Received 29 August 1996Revised version accepted forpublication 3 January 1997

AbstractIn a comparative study on the effects ofpredictive DNA testing for late onsetdisorders, pre-test psychological distresswas assessed in people at risk for Hunting-ton's disease (HD, n=41), cerebral haem-orrhage (HCHWA-D, n=9), breast andovarian cancer (HBOC, n=24), and poly-posis coli (FAP, n=45). Partners, if avail-able, also participated in the study.Distress was measured with the subscalesIntrusion and Avoidance of the Impact ofEvent Scale.People at risk for the neurodegenerative

disorders reported more avoidance thanthose at risk for the cancer syndromes.People at risk for FAP and partners ofthose at risk for HBOC reported lessintrusion than the others at risk and theother partners. Subjects who were moredistressed reported more experienceswith the disease in close relatives, the dis-ease having a great impact on their lives,having considerations against predictivetesting, expecting that being identified asa gene carrier would have adverse effects,and expecting relief after being identifiedas a non-carrier. Test candidates whoexpected an increase ofpersonal problemsshowed higher avoidance, whereas thosewho could better anticipate future life as acarrier had higher intrusion levels.

Generally, subjects with high distresslevels are of more concern to the health-care professional than those with low dis-tress levels. However, high distress mayreflect worrying as a mental preparationfor the test result, whereas low distressmay indicate denial-avoidance behaviourand poor anticipation of the test outcome.In pre-test counselling sessions, thisshould be acknowledged and addressed.(7Med Genet 1997;34:382-390)

Keywords: predictive DNA testing; pre-test psychologi-cal distress; hereditary neurodegenerative disorders;hereditary cancer syndromes

The rapid developments in molecular geneticshas made predictive testing by linkage analysisand direct mutation analysis possible for agrowing number of neurodegenerative disor-ders (for example, Huntington's disease (HD),myotonic dystrophy (MD), hereditary cerebralhaemorrhages with amyloidosis-Dutch type(HCHWA-D), familial Alzheimer's disease)`-and cancer syndromes (for example, hereditarybreast and ovarian cancer (HBOC), familialadenomatous polyposis (FAP), hereditary non-polyposis colonic cancer (HNPCC)).6'-0 In-formativeness and reliability of predictive test-ing is increasing and, as techniques becomewidely available, testing will be offered by anincreasing number of institutes. Methods forfamilial genetic studies and counselling ofpeople requesting testing will be essential inevery programme. More knowledge about theimplications of predictive testing is also neededby society, in order to be able to decide uponthe appropriate uses to which predictive testingmay be put and about any controls that mightbe deemed necessary."1

Predictive testing for HD has been suggestedto be a useful paradigm for the study of otherlate onset disorders, such as cancer syndromes(for example, HBOC, FAP, HNPCC).'2 Thesimilarities between HD and these hereditarycancer syndromes are autosomal dominantinheritance, the onset of a variety of symptomswith increasing age, and major impact on thefamily. The cancer syndromes differ, however,from HD by absence of neuropsychiatricsymptoms and the availability of choices fortreatment."3 Study is needed as to what extentthe experiences with presymptomatic testingfor HD can be generalised to other dominant,heritable, late onset disorders, such as cancersyndromes.

Experience so far indicates that, as forHD,"4-6 the uptake of the predictive DNA testfor HBOC has been lower than expected.'7Although a higher uptake of the test has beenreported for the cancer syndromes in TheNetherlands, so far 26% of those at risk forFAP have taken the test (STOET, personal

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Table I Autosomal dominant neurological disorders and cancer syndromes in The Netherlands, as included in the study

HBOC (caused by the BRCAlHD5358 HCHWA-D54 FAR5 gene)5961

Age of onset 40 ± 12 years 40-65 years From 12 years onwards From 25 years onwardsDisease characteristics Involuntary movements, Acute occurrence of headache, Development of numerous (at Breast and ovarian cancer for

changes in behaviour and nausea, and focal neurological least 100) colorectal polyps women, possible colonic cancerpersonality, cognitive deficits with or without loss of and multiple extracolonic for both men and women,impairment consciousness symptoms possible prostatic carcinoma for

menDuration of the illness ± 15 years Variable* ± 4 years after manifest ± 2 years after manifest

without treatment malignancy malignancySurveillance - Colonoscopy, sigmoidoscopy, Breast examination, palpation,

rectoscopy mammography, ultrasoundscreening, etc

Treatment - - Colectomy (Prophylactic)mastectomy/oophorectomy

Degree of penetrance 100% (lifetime) 100% (by age 60) 100% (by age 40) 95% (lifetime)Predictive DNA testing

Linkage analyses since: 1987 1991 1989 1994Mutation analyses since: 1993 1991 1991 1995

Frequency ±3100 at risk ±400 at risk 536t at risk -

Incidence - - ± 750 new patients each yearUptake ±490 tested ±45 tested 193t tested ± 120 tested

HD=Huntington's disease, HCHWA-D=hereditary cerebral haemorrhages with amyloidosis-Dutch type, FAP=familiar adenomatous polyposis. HBOC=hereditarybreast and ovarian cancer.*Two-thirds of the patients die as a consequence of their first stroke: in the remaining patients neurological deficits depending on the location of the lesions modifythe clinical picture.tRegistered with the Dutch Foundation of Hereditary Tumours (STOET). It is estimated that there are still five or six families not registered and new cases do occur,owing to new mutations.

communication) in The Netherlands, while inRotterdam 33% ofthose at risk forHBOC havebeen tested (L N Lodder, E J Meijers-Heijboer, personal communication). It is esti-mated that in The Netherlands about 15% ofpeople at risk for HD"5 and about 10% of thoseat risk for HCHWA-D" have been presympto-matically tested. Those coming for the test are

considered to be a selection who believe thatthey are better equipped to handle "bad news"and have considerable mental resources.2021Those not taking the test had a significantlymore pessimistic outlook on themselves andtheir futures.22 Reasons for being tested were toend uncertainty, to have some control over thefuture (planning future life and family), and togive information to offspring and relatives. 23-27Those at risk for the cancer syndromesreported the same reasons for wanting the test,with additional mention of the preventivetreatment options.28The consequences of predictive testing for

the family have been shown in limited studiesso far. Personal stories and case descriptions,however, have indicated that hereditary diseasehas a profound impact on the family.29-31Furthermore, partners of identified carriers feltburdened by the distressing prospect,32'15 andmore so when they had children.36

Clinical and empirical evidence has shownthat potentially traumatic events may producepsychological symptoms.37 Alternating phasesof experiencing intrusive feelings and avoid-ance of certain ideas and thoughts associatedwith the specific traumatic event are often seenin maladaptive reactions to such stressors.38The stress response theory of Horowitz et alP9and our observations on people at risk andtheir families leads to the expectation thatpost-test adjustment involves (re)experiencinguntoward intrusive feelings and thoughts anddenial-avoidance of situations associated withthe specific hereditary disease. On the otherhand, intrusive feelings may reflect worrying as

psychological anticipation of a threatening

event,40 which can be useful in preparation forthe test outcome.The present study aimed to gain insight into

reported pre-test psychological distress interms of preparation for the test result. Thefirst question addressed was whether thepre-test psychological distress in participants inpredictive testing for HD, HCHWA-D, FAP,and HBOC would differ, and the same wasassessed for partners. The second question waswhether the psychological distress experiencedcould be predicted by the experience with thedisorder in the family, that is, with the affectedparent/relatives. The third question waswhether the motivation to be tested predictedpre-test psychological distress and, finally,whether the expected impact of the test resultpredicted pre-test psychological distress.

This study is a part of a longitudinal followup study on predictive testing focusing on: (1)the course of adjustment of subjects at risk andtheir partners after the DNA test results, and(2) identification of psychological determi-nants of adjustment problems after test disclo-sure. The aim is to increase the understandingof the psychological ramifications of predictivetesting for late onset disorders, in order todevelop counselling and support strategies.

Subjects and methodsSELECTION OF GENETIC DISORDERS IN THISSTUDY (TABLE 1)All neurological and cancer syndromes in thisstudy show autosomal dominant inheritance.All participants at risk for HD in this studyreceived their test result by direct mutationtesting, giving a reliability of >99%.' 41 42 Allparticipants at risk for HCHWA-D could alsobe offered direct mutation testing, giving a reli-ability of >99%.'

Predictive testing for FAP is performed in astepwise fashion. First an index patient isscreened for the presence of a mutation,43 44 sothe family members can be offered directmutation testing. In about one third of the

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families no mutation is found. In this case,when the family structure is appropriate,linkage analysis can be attempted. In this study,four participants at risk for FAP were offeredpresymptomatic testing by linkage analysiswith a reliability varying from 95-99%. In thisstudy, all participants at risk for HBOC couldbe offered direct mutation testing for the

45 46BRCA1 gene.

PARTICIPANTSPredictive DNA testing and psychologicalfollow up was offered to subjects aged 18 yearsand over at 50% risk. The inclusion criteria forthe psychological study were an ability to giveinformed consent and adequate understandingof the questionnaires. Between 1 September1993 and 31 August 1995, 149 subjects at riskfor HD (n=47), HCHWA-D (n= 12), FAP(n=60), and HBOC (n=30) who met the crite-ria were asked to participate in the psychologi-cal study. Partners were also invited to join thestudy. Nine at risk subjects withdrew from thepredictive testing procedure. Thirteen subjectsat risk (10 of them for FAP) opted for the DNAtest but decided against the psychologicalstudy. Another six, who initially consented toparticipate, did not return their pre-testquestionnaires. In total, 121 people at risk and80 partners entered the study.

PROCEDURESInformation about the availability of the DNAtest was given either by the generalpractitioner, neurologist, oncologist, clinicalgenetic service, relatives, or one of the respec-tive patient organisations. Families who didparticipate in the research phase for linkage ormutation testing or both of the cancersyndromes were informed about the possibilityof predictive testing by the Department ofClinical Genetics in Leiden and Rotterdam, orby the Dutch Foundation for HereditaryTumours (STOET). Information from thepublic media made a number of participantsaware of the autosomal dominant inheritanceof the disorders in their family.The study protocol was adapted from the

HD protocol.47 The genetic counselling andthe psychological study were conducted at theDepartments of Clinical Genetics of theUniversity Hospital Leiden and of the Univer-sity Hospital Dijkzigt Rotterdam from Septem-ber 1993. Two pre-test and two post-testsessions were held with a psychologist(ACDdW). At the first appointment at theDepartment of Clinical Genetics the psycho-logical study was introduced. Subsequently,psychological self-report inventories were givento both the participants at risk and theirpartners.The psychological questionnaires given at

the pre-test interview to the participants at riskand their partners included the Impact ofEvent Scale (IES) and the Attitude Question-naire (AQ) (see below).

QUESTIONNAIRESThe IES classifies the effects of stress into twomajor categories: intrusion and avoidance.

Intrusion refers to intrusively experiencedideas, images, feelings, or bad dreams. Avoid-ance refers to consciously recognised avoid-ance of certain ideas, feelings, or situations.39 48It is a reliable, self-report scale that can beanchored to any specific life event. It permitsassessment of people over time, comparison ofthe degree of distress between subgroups, andcomparison of the impact of various lifeevents.49 We anchored it to HD, HCHWA-D,FAP, and HBOC.The IES consists of seven items that form the

intrusion subscale (score range 0-35, with ahigher score indicating more intrusion) andeight items that underlie the avoidance sub-scale (score range 0-40, with a higher scoreindicating more avoidance).An Attitude Questionnaire (AQ) was used,

consisting of 15 questions covering three areas:(A) experience of the disorder, (B) motivationfor the test, and (C) expected impact of the testresult. Seven questions were open ended andnine were multiple choice. Answer categorieswere compiled to accommodate the commonthemes emerging from the responses on theopen ended questions.

(A) Experience with the disorder wasassessed by the following data: the age of learn-ing about the hereditary nature of the disorderin the family, the event that prompted thisinformation to be given, the number of affectedfamily relatives, the most significant recollec-tions about the affected parent and other rela-tives, the age they learned about their own risk,and the effect of the disease on their life untilnow.

(B) The motivation to be tested was assessedby asking participants and their partners abouttheir considerations for and against testing.

(C) The expected impact of the test resultwas assessed by the following data. Statementquestions were asked (to answer with "agree","don't know", or "disagree") regarding thefuture when proven to be a gene carrier: life willbecome less worthwhile, problems will in-crease, will try to keep away from my family,will be better able to plan the future, willbecome depressive, the problems and worriesfor partner will increase, it will have a negativeeffect on marriage/relationship, problems forchildren will increase, and will be better able toplan the future for wife and children; whetherthey expected that their future might differfrom their actual life; whether they woulddoubt the test result when proven to be a genecarrier.

Similar questions on the expected impact ofbeing a non-gene carrier were posed. Partici-pants were asked to respond with "agree","don't know", or "disagree" to the followingstatements: life will become more worthwhile,problems will decrease, will try to keep awayfrom my family, will be better able to plan thefuture, mood will improve, the problems andworries for partner will decrease, will have a

positive effect on marriage/relationship, prob-lems for children will decrease, and will be bet-ter able to plan the future for wife and children.Further, they were asked whether they ex-pected their future to differ from their actual

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385Psychological distress in applicants for predictive DNA testing

Table 2 Pretest characteristics ofparticipants at risk

HCHWA-DHD (n=42) (n=10) FAP (n=45) HBOC (n=24) Statistic df p

Male/female at risk 15/27 4/6 22/23 5/19Age (y),mean (SD) 37.1 (10.9) 35.1 (16.4) 29.8 (11.5) 41.3 (11.6) F=5.68 3,116 0.01Age (y) learned about the disorder in the

family, mean (SD) 25.8 (14.9) 25.6 (4.2) 17.9 (11.6) 27.9 (15.2) F=1.12 3,115 0.35Age (y) learned about being at risk, mean

(SD) 28.8 (15.2) 26.3 (4.9) 20.1 (19.6) 33.5 (12.6) F=3.79 3,115 0.02Married/common law No (%) 31 (74) 8 (80) 19 (43) 22 (92) x2=l9.89 3 0.001Child(ren) No (%) 21 (50) 8 (80) 16 (36) 21 (87.5) x'=24.2 6 0.15

df, F, x2, see text for details. n=number of persons.

Table 3 Intrusion and avoidance in the four groups of at risk participants and their partners

At risk

HD (n=41) CHWA-D (n=9) FAP (n=45) HBOC (n=24)

Variable Mean SD Mean SD Mean SD Mean SD F df p

Intrusion 9.3 1.3 7.3 1.1 4.0 1.6 6.3 1.3 101.45 3,115 <40.001Avoidance 8.1 1.1 7.6 0.6 4.4 1.4 4.4 1.3 82.22 3,115 .40.001

Partner

HD (n=32) HCHWA-D (n=7) FAP (n=18) HBOC (n=8)

Mean SD Mean SD Mean SD Mean SD F df p

Intrusion 4.8 0.7 3.8 0.4 3.3 0.7 1.4 0.6 105.86 3,70 40.001Avoidance 4.6 0.9 4.6 0.5 3.3 0.9 1.3 0.7 66.93 3,71 <40.001

life, and whether they would doubt the testresult when proven not to be a gene carrier. Anadjusted version of the questionnaire was givento the partners, which covered the partners'experiences with the disorder in the family ofhis/her spouse/partner at risk.The questionnaire was modified from the

Dutch HD study to accommodate both theneurodegenerative disorders and the cancersyndromes.47 (A translation of the question-naire used in this study in available uponrequest.) Each answer was scored separatelyand no total scores were calculated.

Additionally, biographical data, includinggender, age, marital status, employment status,number of children, level of education, andreligious practice were assessed.

Table 4 Experience with the disorder as a predictor ofpsychological distress: intrusion andavoidance *

At risk

Intrusion Avoidance

Experience Bt P B p

Report of specific disease characteristics inaffected parent 0.19 0.04

Report of specific disease characteristics inaffected family members 0.19 0.05 - -

Emotional report of the impact of thedisorder on one's life up to now (eg shame,fear, anger) 0.21 0.02 0.26 0.005

Partner

Intrusion Avoidance

Experience B p B p

Emotional report of the impact of thedisorder on one's life up to now (eg shame,fear, anger) 0.40 .40.001 0.27 0.03

*Experience was assessed with section A of the Attitude Questionnaire.tB= standardised regression coefficient.

STATISTICAL ANALYSES

All data analyses were obtained using SPSS forWindows, version 6.1. To examine whether thefour groups of subjects at risk for, respectively,HD, HCHWA-D, FAP, and HBOC differed,one way analysis for continuous data wasapplied. Scores were adjusted for gender andage, so that findings could be subscribed to thetype of disorder (table 3). Chi-square test wasused for nominal data, like the biographicaldata in table 2. When the testing wasstatistically significant, post hoc comparisonsfor continuous data according to Scheffe's Smethod were done between the four geneticdisorders in order to establish which group ofparticipants differed from which. For nominaldata Bonferoni's procedures were applied. Inorder to estimate the association between atti-tudinal characteristics (for example, experiencewith the disease, motivation to be tested, andthe expected impact of the test result) and thetwo subscales of the IES, intrusion andavoidance respectively, the standardisedregression coefficient (B) was estimated (tables4, 5, and 6). The level of statistical significancewas set at 0.05, two sided.

ResultsDESCRIPTIVEGeneral characteristics of the study populationare given in table 2. We found that participantsat risk for FAP were younger than those at riskfor HD and HBOC, using Scheff&'s S methodto differentiate between the four groups. Therewas no significant difference between thegroups of participants concerning the age theylearned about the hereditary nature of the dis-order in the family. The participants at risk forFAP were younger when they learned abouttheir own risk than those at risk for HBOC.This is, however, over the age of 12 years when

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Table 5 The motivation to be tested*

Cited by,tConsiderations to take the testThe burden of being at risk 62%To know for the children 35%For preventive treatment or check up 16%To plan the future 13%Regarding the wish to have children 11.5%Consideratlons against testintgExpected adverse reactions of knowing

oneself to be a gene carrier 34%New uncertainties after knowing oneself

to be a gene carrier 5%oNo gain by knowing 5%(YoCould think of no reason against testing 31 %

*Motivation was assessed with section B of the Attitude Ques-tionnaire.tPercentages of the total population.

screening is first advised for participants at riskfor FAP. Participants at risk for FAP areyounger, more often single, and withoutchildren.

DIFFERENCE IN PSYCHOLOGICAL DISTRESS IN THEFOUR GROUPS AT RISK AND PARTNERSTable 3 presents mean scores on the twosubscales of the IES, intrusion and avoidance,for participants at risk for HD, HCHWA-D,FAP, and HBOC and their partners. The groupdifferences were tested for significant differ-ences.

Participants at riskA statistically significant difference (p<0.001)was found between the four groups of partici-pants for both subscales of the IES. Concern-ing intrusion, we found, using Scheff&'s Smethod, that participants at risk for HDreported more intrusion than the other threegroups at risk (HCHWA-D, HBOC, and FAP).Subjects at risk for FAP reported less intrusionthan the others three groups at risk (HD,HCHWA-D, and HBOC). Concerning avoid-ance, we found that participants at risk for theneurodegenerative disorders (HD andHCHWA-D) reported more avoidance thanthose at risk for the cancer syndromes (FAPand HBOC).

PartnersA statistically significant difference (p<0.001)was also found for the four groups of partnersfor both subscales of the IES. We found, usingScheff&'s S method, that partners of partici-pants at risk for HD reported more intrusionthan the other partners (HCHWA-D, HBOC,and FAP). Partners of participants at risk for

Table 6 The motivation to be tested as predictor ofpsychological distress: intrusion and avoidance *

Intrusion Avoidanice

Bt p B p

Considerations not to takethe test

Psychological burden ofknowing oneself to be atrisk 0.30 <0.001 0.29 0.002

No idea -0.18 0.05 -0.28 0.05

*Motivation was assessed with section B of the Attitude Ques-tionnaire.tB=standardised regression coefficient.

HBOC reported less intrusion than the otherpartners (HD, HCHWA-D, and FAP), andalso less avoidance than the other partners(HD, HCHWA-D, and FAP). The partners ofparticipants at risk for the neurodegenerativedisorders (HD and HCHWA-D) reportedmore avoidance than those at risk for the can-cer syndromes (FAP and HBOC).

In order to establish whether the previousexperiences with the disease were associatedwith psychological distress, we conducted aregression analysis with intrusion and avoid-ance as the dependent variable for the partici-pants at risk and the partners, respectively, andthe experiences with the disorder (section A ofthe AQ), age, and the specific disorder aspotential predictor variables. The sameregression analyses were conducted with,respectively, the motives for and against testing(section B of the AQ) and the expectationsabout the impact of the test result (section C ofthe AQ) as potential predictor variables. Onlythe statistically significant results are presentedin tables 4, 6, and 7.

EXPERIENCE WITH THE DISORDER AS PREDICTOROF PSYCHOLOGICAL DISTRESS (TABLE 4)Participants at riskIt was found that intrusion was associated withkey experiences with the disease and byemotional descriptions of the impact of thedisease on the participant's life so far. Partici-pants who reported disease specific key experi-ences such as: "seeing Mum and Dad cleaningthe bed in the middle of the night" (FAP),"hearing people laughing at and scorning theaffected parent for drunken-like behaviour","seeing Father tied to his chair" (HD),"Mother in her hospital bed unable to use herarm", or "Mother having a fat belly and alwaysin pain" (HBOC), and "parent rubbing hishead all the time because of headaches"(HCHWA-D), had high levels of intrusion.Test candidates who described the impact ofthe disorder on their personal life in emotionalterms (for example, shame, fear, or anger) alsohad higher intrusion and avoidance levels. Nei-ther age nor the type of disorder was associatedwith psychological distress.

PartnersPartners who described the impact of thedisease on their own life in emotional terms(for example, shame, fear, or anger) had higherscores on both intrusion and avoidance.

MOTIVATION TO BE TESTED AS PREDICTOR OF

PSYCHOLOGICAL DISTRESS

Commonly cited considerations for and againsttesting are presented in table 5.

Participants at risk (table 6)None of the motives for undergoing testing wasassociated with psychological distress. How-ever, participants who regarded the negativeimplications of knowing oneself to be a genecarrier as a possible reason against testing hadhigh intrusion and avoidance levels. Those whocould not think of any considerations against

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Table 7 The expected impact of test result as a predictor ofpsychological distress: intrusionand avoidance*

At risk

Intrusion Avoidance

Future expectations Bt p B p

When proven to be a gene carrierLife becomes less worthwhile 0.19 0.04 0.40 40.001Problems increase - - 0.18 0.05Try to avoid family 0.17 0.04 0.22 0.02Become depressive 0.30 <0.001 0.26 0.005Has not that much effect* -0.30 40.001 -0.20 0.04Anticipate the futuret 0.21 0.03 - -

When proven to be a non-carrierLife becomes more worthwhile 0.28 0.002 0.31 <0.001Problems decrease 0.34 40.001 0.28 0.003Be able to plan the future better 0.24 0.02 0.24 0.02Mood improvement 0.43 40.001 0.37 <0.001Experience reliefj 0.35 40.001 0.22 0.02Doubt the test result 0.18 0.05 - -

Partner

Intrusion Avoidance

Bt p B P

When partner proves to be a gene carrierProblems increase 0.28 0.03Try to avoid family 0.25 0.03 - -

Doubt the test result 0.22 0.05 0.24 0.04When partner proves to be a non-carrierTry to avoid family 0.25 0.03 - -

Nothing changes* -0.23 0.05 -0.31 0.009Think everything over 0.35 0.003 - -

*The expected impact was assessed with section C of the Attitude Questionnaire.tStandardised regression coefficient.4:Answer to open ended question.

uptake had low distress scores on bothintrusion and avoidance. Neither age nor thetype of disorder was associated with psycho-logical distress.

PartnersNo statistically significant results were found.

EXPECTED IMPACT OF THE TEST RESULT ASPREDICTOR OF PSYCHOLOGICAL DISTRESS(TABLE 7)Participants at riskThose who reported that knowing oneself to bea gene carrier would not affect their personallife had the lowest scores on intrusion andavoidance. Test candidates who thought thatknowing oneself to be a gene carrier allowedthem to anticipate the future better reportedthe most intrusion. Those who thought thatconfirmation of gene carriership would in-crease their problems reported more avoid-ance.

Participants who acknowledged that know-ing oneself not to be a gene carrier would affecttheir lives in a positive way, resulting in bettermood and relief, and allowing them to plan thefuture better, reported more intrusion. How-ever, high intrusion was also associated withthe expectation that an exclusion of gene carri-ership could be doubted. Neither age nor thetype of disorder was associated with psycho-logical distress.

PartnersIn the partner groups, high levels of psycho-logical distress were associated with the strongbelief that confirmation of gene carriershipcould be doubted. Partners with high intrusion

were those who expected that problems mightincrease and that such a result would lead toavoiding the relatives of the identified gene car-rier.

Partners with high intrusion also expectedthat exclusion of gene carriership might lead toavoiding the non-carrier's relatives. Those whowould re-evaluate their personal situationreported the highest intrusion. Partners whobelieved that an exclusion of gene carriershipwould have no influence on their life had thelowest intrusion and avoidance scores.

DiscussionINTERPRETATION OF THE REPORTEDPSYCHOLOGICAL DISTRESSTo introduce the discussion of the findings, wedescribe the possible implications of high andlow distress scores. The reported psychologicaldistress is measured as intrusively experiencedideas, images, feelings, or bad dreams (intru-sion) and the consciously recognised avoidanceof certain ideas, feelings, or situations (avoid-ance). The resulting score implies more thanthat people with high scores are doing "badly"and people with low scores are doing "well". Itwas in fact the intolerable psychologicalburden of being at risk that was the prime rea-son for uptake of the predictive test for HD, asmentioned previously,14 23 25 26 and these par-ticipants were considered to have considerablemental resources.20 21 Moreover, the well beingof HD carriers had improved one year aftertesting.50 High intrusion levels may reflect greatsuffering from being at risk, but also worryingas a preparation for the test result.40 A follow upstudy on effects of predictive testing for HD5"reported that high avoidance levels predictedpost-test feelings of hopelessness, whereas highpre-test intrusion levels did not. Thus, highpre-test intrusion scores could also be valuedpositively and be seen as indicative of anadjustment process.

It should be noted that low scores on "men-tal health scales" can reflect opposite condi-tions. Low scores usually indicate good psycho-logical health; on the other hand distress maybe present, but denied in order to "maintain anillusion of mental health".52 A participant atrisk (or a partner) may try to convincethemselves that there is no reason to worry andreport very low distress scores, while in factthey are emotionally affected by the predictivetest.

MAJOR FINDINGSDifference in psychological distress in the fourgroups at risk and partnersInterestingly, subjects at risk for HD reportedthe highest levels of distress (high intrusion andavoidance scores), while those at risk for FAPreported the lowest levels of distress (lowintrusion and avoidance scores). No treatmentoptions are available for the first group,whereas there are (drastic) options for peopleat risk for FAP. Also the long and veryincapacitating course ofHD will influence thepre-test distress. The perception of immediaterisk may also differ among the various partici-pants. Those at risk for HD, HCHWA-D, and

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HBOC are within the average age for diseaseoccurrence in gene carriers; FAP participantsare mostly older than the average age atonset.53 56 This could explain why participantsat risk for FAP report significantly lessintrusion than the other three groups at risk.HD imposes a considerable burden on the

partner,32 especially when there are offspring.35Partners of people at risk for HD reported sig-nificantly higher levels of distress than the otherpartners. Unexpectedly, we found that partnersof participants at risk for HBOC reported sig-nificantly lower psychological distress than allthe other partners. Six out of eight partners inthe HBOC sample are male. This led us tospeculate whether these men were just undis-turbed by the predictive test, or whether otherpsychological mechanisms were at work (forexample, defensive denial). Breast cancer isreported to have a significant impact on thewoman's partner.57 Further studies in a largersample may show how partners of women atrisk for HBOC cope with the impending threatof breast and ovarian cancer and the treatmentoptions for their wife.Although in the present study a profound

difference was found in reported psychologicaldistress when comparing the four groups ofdisorders, there was no indication that the typeof disease or age predicted pre-test psychologi-cal distress in the additional analyses. Weexamined whether experience with the disor-der, motivation to be tested, and the expectedimpact of the test result could predict distress.To a certain extent they did, as discussedbelow. Other characteristics of the population(for example, educational level, cultural iden-tity, religious faith, thoughts and beliefs abouttheir luck and destiny, other perceived dangersin life) were not analysed, although thesefactors are obviously relevant in coping withpersonal risks and test results.

Experience with the disorder as predictor ofpsychological distressA clear recollection of symptoms observed bythe participant in the affected parent/relativespredicted high levels of intrusion. Also, whenparticipants at risk and partners described theimpact of the disease on their life in emotionalterms (such as, anger, fear, and shame) anassociation was found with high levels of bothintrusion and avoidance. They tried to distractthemselves from ideas, images, and feelingsthey intrusively experience. This pattern mayreflect problems in adjusting to the effects ofthe disease on their life and needs to be paidattention to.

Motivation to be tested as predictor ofpsychological distressAs previously described for neurodegenerativedisorders,'4 23 25-27 we found that the mainreasons for testing were intolerable psychologi-cal burden of being at risk, giving informationto offspring and relatives, and planning futurelife and family. Only 16% of all participants(while 57% were at risk for the hereditary can-cer syndromes) stated that preventive treat-ment or check up was their reason for testing.

Interestingly, those who were worried aboutthe possible adverse effects of knowing oneselfto be a gene carrier and who considered it as apossible reason not to take the test reported thehighest psychological distress (high intrusionand avoidance scores), yet they all took the test.This "worrying" can be considered as prepara-tion for the test result. The possible adverseeffects of being a gene carrier are consideredand acknowledged."0 It is important, however,to enable the participant to discuss his/herworries in order to demystify fears sometimesrooted in childhood experiences with thedisease. Those who had no reasons against thetest reported little or no psychological distress.Experience with HD test candidates haveshown that some participants, who had gonethrough lengthy considerations, are not willingto undergo all the ramifications of pre-testcounselling.35 They were determined to havethe test and were anxious at that stage aboutre-experiencing previous ambivalence. Thereluctance to consider reasons against testingmay reflect a denial-avoidance behaviour tominimise the full impact.52 The mechanisms ofdefensive denial which enable test candidatesto ward off anxieties should be respected ashis/her way of dealing with threat; this shouldbe handled carefully but with acknowledge-ment of the underlying fear.

Expected inmpact of the test result as predictor ofpsychological distressIn general, the anticipation of adverse effects ofbecoming identified as a gene carrier was asso-ciated with high levels of intrusion andavoidance (all participants wanted to betested). An expected increase of personal diffi-culties after confirmation of gene carriershipwas associated with high avoidance but notwith intrusion. High pre-test avoidance wasearlier found to be associated with a pessimis-tic post-test attitude.35 The possible adverseeffects of being a gene carrier are kept awayinstead of being worked through, and this "lackof worrying" can be considered to lead to beingless prepared.4"

Preparation for the future was associatedwith high intrusion but not with avoidance,which supports our hypothesis that suchbehaviour reflects worrying.40 Those whoexpected their life to become better/easierwhen proven to be a non-carrier reported highdistress (high intrusion and avoidance scores).High expectations about exclusion of gene car-riership reflects the difficulties experienced indealing with the threat of the disease. Such anexpected outcome leads to vulnerability giventhat the test outcome is unsure. It also reflectsan underestimation of the possible adverseeffects of exclusion of gene carriership, as wasdescribed in several studies on HD.23 3 Part-ners who would doubt a diagnosis of gene car-riership in the at risk subject reported high dis-tress (high intrusion and avoidance scores).This is in accordance with the finding thatpartners of identified carriers felt burdened bythe distressing prospect.32 36

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Psychological distress in applicants for predictive DNA testing

AREAS FOR FURTHER STUDYThis is the first comparative study of predictivetesting for hereditary neurodegenerative andcancer syndromes in two centres. The relativelysmall numbers in some groups is a limitation.The higher number of participants at risk forFAP and HBOC opting against the psychologi-cal protocol reflect a possible specific attitudein this group. They were determined to take thetest without further psychological assessment,since they experienced their choice as a purelymedical decision. The HBOC group consistedof some individual subjects and the first threeDutch families that could be tested. This mightintroduce some bias by potential extensiveattention from the researchers.'3 5O Futureanalysis of test candidates with and withoutpsychological evaluation and support, usingself-reporting as well as observer reports, isindicated.52

Furthermore, in future follow up research onpredictive testing for late onset genetic disor-ders, the IES as a measure of psychologicaldistress may be standardised for specific groupswith high personal risk of developing a specificdisease.

ConclusionsCandidates at risk for the four disordersdiffered from each other in the reporteddistress, as did the partners. The type of disor-der, however, was not found to predict thereported distress. Aspects of the experienceswith the disease, the motivation to be tested,and the expected impact of the test result wereassociated with the reported distress. However,other more sociodemographic characteristics(for example, educational level, cultural iden-tity, religious faith) were not taken intoaccount; these may be associated with thereported distress and should therefore be takeninto account in genetic counselling.For clinical practice it is important to be

aware that those responding to the subject(remembering affected relatives, preparing forthe future) or those who may seem preoccu-pied or even overly involved might in fact beengaged in preparing themselves for the testresult. Participants at risk may be very upsetwhen recounting the impact of the disease andtheir reasons for being tested, which may worrythe healthcare professional. However, profes-sionals must be able to value positively these"states of mind" as they may be indicative ofpsychological strength and adequate prepara-tion for the test result. Those who refrain fromdiscussing the implications of the test (seeingno reason not to take the test, reporting little orno distress) may be unable to face all possibleoutcomes and need to convince themselvesthat everything is under control. However, suchapparent strength may lead to underdiagnosisof distress, while some may need specific atten-tion. In short, people with high distress scores

may be actively dealing with the problem, whilepeople with low distress scores might (as yet)be unable to face the problems.

It is important to identify and respect thechosen strategy of coping with threat. Addi-tional research is needed to gain more

understanding of the relationship between the(un)reported psychological distress and thepreparation for, and later adaptation to, the testresult. Only then will it be possible to decideupon the appropriate uses to which predictivetesting may be put and about any controls thatmight be deemed necessary.1'

This research was supported by NWO grant 960 10 803 to thefirst author. The authors are very grateful to the people at riskand their partners who have participated in this study.

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doi: 10.1136/jmg.34.5.382 1997 34: 382-390J Med Genet

 A C DudokdeWit, A Tibben, H J Duivenvoorden, et al. The Rotterdam/Leiden Genetics Workgroup.dominant, heritable, late onset disorders.predictive DNA testing for autosomal Psychological distress in applicants for

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