OBJECTIVES: To assess whether healthcare professionals correctly
      incorporate the relevance of a favourable test outcome in a close relative
      when determining the level of risk for individuals at risk for
      Huntington's disease. DESIGN AND SETTING: Survey of clinical geneticists
      and genetic counsellors from 12 centres of clinical genetics (United
      Kingdom, 6; The Netherlands, 4; Italy, 1; Australia, 1) in May-June 2002.
      Participants were asked to assess risk of specific individuals in 10
      pedigrees, three of which required use of Bayes' theorem. PARTICIPANTS: 71
      clinical geneticists and 41 other healthcare professionals involved in
      genetic counselling. MAIN OUTCOME MEASURES: Proportion of respondents
      correctly assessing risk in the three target pedigrees; proportion of
      respondents who were confident of their estimate. RESULTS: 50%-64% of
      respondents (for the three targets separately) did not include the
      favourable test information and inc

Bonke, B. (Benno)

Clarke, A.J. (Angus)

Lindhout, D. (Dick)

Stijnen, Th. (Theo)

Tibben, A. (Arend)

Bonke, Benno

Tibben, A

Lindhout, D (Dick)

Clarke, AJ

Stijnen, T (Theo)

EUR Research Repository

R ESEARCHGenetic risk estimation by healthcare professionalsBenno Bonke, Aad Tibben, Dick Lindhout, Angus J Clarke and Theo StijnenErasmus MC, Rotterdam, The Netherlands.Benno Bonke, PhD, Associate Professor, Department of Medical Psychology and Psychotherapy; Theo Stijnen, PhD, Professor, Department of Epidemiology and Biostatistics. Leiden University Medical Centre, Leiden, The Netherlands.Aad Tibben, PhD, Professor, Department of Clinical Genetics and Neurology. University Medical Centre Utrecht, Utrecht, The Netherlands.Dick Lindhout, MD, Professor, Department of Medical Genetics. University of Wales College of Medicine, Cardiff, UK.Angus J Clarke, MD, Professor, Department of Medical Genetics. Reprints will not be available from the authors. Correspondence: Dr B Bonke, Erasmus MC, PO Box 1738, Rotterdam, 3000 DR, The Netherlands. b.bonke@erasmusmc.nlThe Medical Journal of Australia ISSN:0025-729X 7 February 2005 182 3 116-118©The Medical Journal of Australia 2005www.mja.com.auResearchbilities and use of Bayes’ theorem (see refer-ences 1 and 2 for simple explanations ofBayes’ theorem).We noticed that healthcare professionalsin clinical genetics, when counselling indi-viduals or couples for predictive testing forHuntington’s disease, sometimes ignore thePartigeneMainthreeResufavouthe p116 MABSTRACTObjectives:  To assess whether healthcare professionals correctly incorporate the relevance of a favourable test outcome in a close relative when determining the level of risk for individuals at risk for Huntington’s disease.Design and setting:  Survey of clinical geneticists and genetic counsellors from 12 centres of clinical genetics (United Kingdom, 6; The Netherlands, 4; Italy, 1; Australia, 1) in May–June 2002. Participants were asked to assess risk of specific individuals in 10 pedigrees, three of which required use of Bayes’ theorem.cipants:  71 clinical geneticists and 41 other healthcare professionals involved in tic counselling. outcome measures:  Proportion of respondents correctly assessing risk in the  target pedigrees; proportion of respondents who were confident of their estimate.lts:  50%–64% of respondents (for the three targets separately) did not include the rable test information and incorrectly estimated the risks as being about equal to rior risks; 77%–91% of these respondents were “sure” or “completely sure” that their estimations were correct. Twenty of the 112 respondents correctly estimated the risks for all three target pedigrees.Conclusions:  Clinical geneticists and genetic counsellors frequently use prior risks in situations where Bayes’ theorem should be applied, leading to overestimations of the MJA 2005; 182: 116–118risk for an individual.stdiscaE imating risks of inheriting a geneticease is an important skill for health-re professionals, usually clinicalgeneticists and genetic counsellors. In theabsence of genetic testing, risk estimation is afairly simple process. However, when genetictesting has shown that certain relatives arenon-carriers, estimating an individual’s risk ismore complex, requiring conditional proba-importance of favourable test outcomes infirst-degree relatives of the person beingcounselled.3 To investigate this potentialproblem, we conducted an anonymous sur-vey among healthcare professionals involvedin genetic counselling prior to, and thusunbiased by, our earlier report.3Huntington’s disease (HD) is a hereditary,neuropsychiatric disorder showing auto-somal dominance, late onset, a wide range inage at onset, and complete penetrance. Theestimated prevalence in the general popula-tion varies between less than 1 and morethan 15 per 100 000.4 Predictive testing forHD was introduced in 1987, and when thegenetic mutation was identified in 1993 test-ing became technically more simple, reliable,and available for every person at risk.5We aimed to determine the extent towhich the principles of probability theoryand, if necessary, Bayes’ theorem1,2 werefollowed when respondents estimated therisk status of a particular individual in afamily tree.METHODSWe designed 10 pedigrees of families withHuntington’s disease in which one or twoindividuals had recently been informed oftheir mutation test outcomes. All pedigreescontained at least one carrier of the HDgene. (The survey with all 10 pedigrees isavailable upon request.)Original surveys were sent to contact peo-ple in 12 centres (United Kingdom, 6; TheNetherlands, 4; Italy, 1; Australia, 1). Thesepeople were asked to copy and distributethe survey to staff in their centres. Thesurvey was conducted in May–June 2002.Respondents were asked to estimate, foreach pedigree, the probability that a particu-lar, clearly indicated individual “is a gene-carrier for Huntington’s disease”, indicatingtheir answers on a visual analogue scale withmarkers at 0, 10%, 20%, … 100%.Respondents were also asked to indicatehow sure they were of each estimate (vary-ing from 1 = “very unsure” to 5 = “com-pletely sure”).Our pedigrees included predictive testresults of individuals at 25% a priori risk orprenatal test results on fetuses at 25% a prioririsk. Although these scenarios are less frequentthan predictive testing for individuals at 50%risk,6 these are the situations where favourableresults may affect other relatives’ risks.Other parameters, such as age, are impor-tant for establishing the actual risk status ofindividuals at risk for HD.7,8 For the sake ofsimplicity and feasibility of the survey, weasked our respondents to disregard thesefactors. This simplification allowed anyneglect of conditional probabilities to be seenmore clearly than if age-dependent pene-trance had also been included. Furthermore,given the age at onset of HD, diminution ofrisk in an asymptomatic at-risk individual isnot a major factor until middle life.Six simple pedigrees and one, more com-plicated pedigree (not presented here)mainly served as distractions. These pedi-grees depicted individuals for whom riskestimation was quite straightforward with-out making use of conditional probabilitiesor Bayes’ theorem. The remaining three ped-igrees (Box 1) were our investigation targets(at positions #4, #7, and #9 in the sequenceof 10 pedigrees), in which risks were to beJA • Volume 182 Number 3 • 7 February 2005R ESEARCHestimated using conditional probabilitiesbecause of favourable genetic test resultsalready obtained in close relatives. Box 2gives an example of the correct calculation.For further information and easy calculationof conditional probabilities, see <members.aol.com/johnp71/bayes.html>.Because the survey used a visual analoguescale, we considered risk estimates for thetarget pedigrees as reasonably correct if theywere within a range around the correct risk:#4, 28%–38%; #7, 14%–19%; #9, 3%–7%.For this anonymous survey, we neithersought nor obtained ethical approval.RESULTSSeventy-one clinical geneticists (registeredor in training) and 41 other healthcareprofessionals (mainly genetic counsellors)participated voluntarily in our survey. Theyworked in 12 clinical genetics centres: six inThe Netherlands, four in the United King-dom, one in Italy, and one in Australia. Therespondents had a median of 6.5 years’experience in genetic counselling and 2years’ experience with HD.Risk estimates for the simple distractionpedigrees were 95%–99% correct. However,risks in the target pedigrees were estimatedincorrectly as being about equal to the priorrisks by more than half of the respondents(Box 3). Twenty respondents gave reasona-bly correct estimates for all three targets.The respondents’ discipline (clinicalgeneticist or other) was not significantlyrelated to the accuracy of their target esti-mates.DISCUSSIONMost of our respondents appeared to beunaware of how favourable test outcomes infirst-degree relatives may alter risks. Theydid not appreciate the need to apply Bayes’theorem in calculating conditional probabil-ities, as has been described for X-linkedrecessive disorders such as Duchenne mus-cular dystrophy.1,2 We concluded this fromthe high proportion of respondents indicat-ing confidence in their erroneous risk calcu-lations.The changes in probabilities describedhere are not only important for individualswho are considering prenatal or presympto-matic DNA testing for autosomal dominant,hereditary, late-onset diseases such as Hunt-ington’s disease; they also apply to heredi-tary forms of cancer such as breast cancer3 Summary of respondents’ accuracy in estimating risk for our target pedigrees (Box 1)Pedigree #4 Pedigree #7 Pedigree #9Respondents estimating reasonably correctly*24% (26/107) 25% (28/112) 26% (28/108)Respondents estimating incorrectly, as if prior risk61% (65/107) 64% (72/112) 50% (54/108)Respondents who used prior probability and were “sure” or “completely sure” of their estimate†91% (59/65) 85% (58/68) 77% (39/51)* Within range specified in Methods. † Some respondents failed to answer the question about being sure.2 Example calculation for pedigree #9 (Box 1)TaskCalculate probability individual IV is a carrier, denoted as P(IV carrier).Prior probability (no test results known)There is a 50% chance of the gene being passed to a child.Thus, P(IV carrier)= 0.5  P(III carrier)= 0.5  0.5  P(II carrier)= 0.5  0.5  0.5= 0.125 (12.5%)Posterior probability (when two children of individual II are known to be non-carriers, and no other children have been tested)P(IV carrier) = 0.5  0.5  P(II carrier)The results of testing II’s children change P(II carrier).P(II carrier) = 0.2Therefore, P(IV carrier) = 0.5  0.5  0.2 = 0.05 (5%)Status of II Non-carrier CarrierPrior probability (A) 0.5 0.5Probability of two non-carrier children (B)1.0 0.25 (0.5 for each child; independent events so multiply: 0.5  0.5)Joint probability (A  B) 0.5 0.125Posterior probability 0.5 / (0.5 + 0.125) = 0.8 0.125 / (0.5 + 0.125) = 0.21 Pedigrees requiring Bayes’ theorem for calculating risksSquares are males, circles are females. Solid symbols indicate people with the disease. Respondents were asked to calculate the probabilities that individuals marked with ? are carriers, disregarding age at time of testing and age-related penetrance.Prior probabilities (in absence of test results) are #4, 50%; #7, 25%; #9, 12.5%. The correct probabilities (taking into account the known non-carrier status of the marked individuals) are #4, 33%; #7, 16.7%; #9, 5%.See Box 2 for example calculation for pedigree #9.non-carriernon-carriernon-carrierPedigree #4Pedigree #7Pedigree #9non-carrier???IIIIIIIVMJA • Volume 182 Number 3 • 7 February 2005 117R ESEARCH(BRCA1/2) and colorectal cancer (FAP orHNPCC).Our findings raise several important ques-tions about the adequacy of continuing edu-cational and training programs for clinicalgeneticists and genetic counsellors, and themathematical expertise available in clinicalgenetics centres. Perhaps clinical geneticistsand genetic counsellors are easily misled bythe less complicated risk calculations, andless ambiguous implications, after unfavour-able test results compared with favourabletest results. Consider, for instance, the plightof a parent at 50% risk who has two childrenor fetuses tested consecutively, with the firstone being negative but the next one positive.Such a parent’s risk status would havechanged from a prior risk of 50% to 33.3%after the favourable first test result, butsubsequently to 100% (as an obligate car-rier) after the adverse second test result.Provision of full and adequate informa-tion is one of the essential conditions to befulfilled in genetic counselling. If, in appro-priate circumstances, such as in our targetscenarios, the risk is overestimated, then theindividual at risk may remain unnecessarilyanxious. Learning that the risk of carryingthe HD gene has diminished to a largeextent may reduce the anxiety about thisdistressing disorder.The perceived risk may also influence acouple’s decisions. For example, in pedigree#9, the risk for the father of the unbornchild has decreased from a prior risk of 25%to 10% — a change in risk of this magnitudeis quite likely to affect the decision aboutwhether to have children. Furthermore,with the risk of miscarriage after a prenataltest at 1%–2%, parents at risk may considernot having a prenatal test in later pregnan-cies, knowing that favourable test results inprevious pregnancies have considerablyreduced their own risk.It is important to remember that,although these parents have been informedcorrectly of their diminished risk based ontheir children’s favourable test results, theircarrier status is still unknown. Especially incases of autosomal-dominant, hereditarydisorders with late onset, such as Hunting-ton’s disease, revealing a parent’s obligatecarrier status can be very distressing. Thus,people may choose prenatal testing to avoidpassing the disease to their children whileavoiding testing themselves, as they may notwish to learn their own status. Of course,they must realise and accept that an unfa-vourable result in a child will reveal theirown status as a carrier.There is a further potential problem ifhealthcare professionals in clinical geneticscontinue to use prior risks inappropriately:the “bystander effect”. This refers to thesituation when, as more professionals fail totake appropriate action (ie, they do not takethe favourable test results of close relativesinto account), others will be inclined toignore such results. Bystanders (colleagues)can thus become the victims of “pluralisticignorance”.9Our survey shows that there is a continu-ing need for improvement in genetic riskassessment. Our findings underline thathealthcare professionals in clinical geneticsare often using prior risks in situationswhere Bayes’ theorem should be applied. Werecommend that greater attention be paid togenetic risk calculations in continuing edu-cation and training programs for clinicalgeneticists and genetic counsellors.ACKNOWLEDGEMENTSWe thank Cecile Janssens and Reinier Timman forhelp and support, and the anonymous reviewers,who provided valuable suggestions. We alsogratefully acknowledge all those who kindly coop-erated by enlisting colleagues in the project and/orby participating in the survey. We thank JackieSenior for critical reading of the manuscript.COMPETING INTERESTSNone identified.REFERENCES1 Bridge PJ. The calculation of genetic risks.Baltimore: Johns Hopkins University Press;1994.2 Gelehrter TD, Collins FS, Ginsburg D. Princi-ples of medical genetics. 2nd ed. Baltimore:Williams & Wilkins; 1998.3 Bonke B, Tibben A, Lindhout D, Stijnen T.Favourable mutation test outcomes for individ-uals at risk for Huntington disease change theperspectives of first-degree relatives. HumGenet 2002; 111: 297-298.4 Harper PS. The epidemiology of Huntington’sdisease. In: Bates G, Harper P, Jones L, editors.Huntington’s disease. 3rd ed. Oxford: OxfordUniversity Press; 2002: 159-197.5 Maat-Kievit A, Vegter-van der Vlis M, Zoeteweij M, et al. Paradox of a better test for Hunting-ton’s disease. J Neurol Neurosurg Psychiatry2000; 69: 579-583.6 Benjamin CM, Lashwood A. United Kingdomexperience with presymptomatic testing ofindividuals at 25% risk for Huntington’s disease.Clin Genet 2000; 58: 41-49.7 Brinkman RR, Mezei MM, Theilman J, et al. The likelihood of being affected with Huntingtondisease by a particular age, for a specific CAGsize. Am J Hum Genet 1997; 60: 1202-1210.8 Maat-Kievit A, Losekoot M, Zwinderman K, etal. Predictability of age at onset in Huntingtondisease in the Dutch population. Medicine2002; 81: 251-259.9 Brehm SS, Kassin SM. Social psychology.Geneva, Illinois: Houghton Mifflin; 1996.(Received 24 May 2004, accepted 30 Nov 2004) ❏118 MJA • Volume 182 Number 3 • 7 February 2005

English

Genetic risk estimation by healthcare professionals

OBJECTIVES: To assess whether healthcare professionals correctly
      incorporate the relevance of a favourable test outcome in a close relative
      when determining the level of risk for individuals at risk for
      Huntington's disease. DESIGN AND SETTING: Survey of clinical geneticists
      and genetic counsellors from 12 centres of clinical genetics (United
      Kingdom, 6; The Netherlands, 4; Italy, 1; Australia, 1) in May-June 2002.
      Participants were asked to assess risk of specific individuals in 10
      pedigrees, three of which required use of Bayes' theorem. PARTICIPANTS: 71
      clinical geneticists and 41 other healthcare professionals involved in
      genetic counselling. MAIN OUTCOME MEASURES: Proportion of respondents
      correctly assessing risk in the three target pedigrees; proportion of
      respondents who were confident of their estimate. RESULTS: 50%-64% of
      respondents (for the three targets separately) did not include the
      favourable test information and incorrectly estimated the risks as being
      about equal to the prior risks; 77%-91% of these respondents were "sure"
      or "completely sure" that their estimations were correct. Twenty of the
      112 respondents correctly estimated the risks for all three target
      pedigrees. CONCLUSIONS: Clinical geneticists and genetic counsellors
      frequently use prior risks in situations where Bayes' theorem should be
      applied, leading to overestimations of the risk for an individual

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Genetic risk estimation by healthcare professionals

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