Annals of Medicine
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Ethical Aspects of Genetic Screening Bernadette Modell To cite this article: Bernadette Modell (1992) Ethical Aspects of Genetic Screening, Annals of Medicine, 24:6, 549-555, DOI: 10.3109/07853899209167009 To link to this article: http://dx.doi.org/10.3109/07853899209167009
Published online: 04 Aug 2009.
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Special Section: Molecular Genetics and Genetic Epidemiology of Cardiovascular Disease and Diabetes
Ethical Aspects of Genetic Screening
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Bernadette Modell
Public and professional concern associated with the idea of genetic screening has generated numerous publications on the ethics of genetic screening (e.g. 1-4). Concerns revolve around inadequate consultation before screening is carried out, the unearthing of worrying risks, the use of genetic information in ways that could be disadvantageous to the person involved, stigma, and a phenomenon known as the ‘technological imperative’, which means that simply because a technology is available there is a tendency to use it. Most reports agree that, in practice, the main ethical problems are likely to involve screening for risk of common diseases of adult life, because of the possible impact on a person’s healthy self-image, implications for health and life Insurance, and the possibility of commercial exploitation of people who know themselves to be vulnerable. In this paper I do not propose to address these issues directly. I have been invited to discuss this subject as a clinician involved with genetic screening, counselling and prenatal diagnosis for the haemoglobin disorders, the most common serious human recessively inherited diseases. Since we are scientists, any recommendationswe make should be based on experience: my aim is to show that experience is often surprising, and that it is often possible to meet public concerns by taking quite simple practical steps. Key words: screening; genetics; ethics; haemoglobin disorders. (Annals of Medicine 24: 549-555,1992)
Genetic screening is already extensively practised, mainly in the area of maternal and child health. Current experience has recently been summarized for the World Health Organization (5). Table 1 lists current accepted population screening programmes. As yet, we have practically no experience of screening for genetic risk for common disease, so I propose to examine a few important ethical issues that have arisen with current screening programmes, for the light that they cast on general principles, and on the future application of genetic screening for personal risk.
Ethical Principles of Genetic Counsel1ing The core ethical principles of genetic counselling are, the autonomy of the individual or couple, their right to full From the WHO Collaborating Centre for Community Control of Hereditary Disease, Department of Obstetrics and Gynaecology, University College London, UK. Address and reprint requests: B. Modell, Ph.D.. FRCP, FRCPath. Department of Obstetrics and Gynaecology, University College London, 86-96 Chenies Mews, London WCl E 6HX, U.K.
information, and the highest standard of confidentiality (6). These principles were derived from an empirical study of the practice of clinical geneticists. If we could be sure that they would always be followed, there might be little cause for public anxiety. However, in practice most genetic counselling is provided by obstetricians, midwives, nurses and paediatricians. Screening is not always equitably delivered, counselling is not always done according to the above principles, and there is some anxiety that financial pressures will be allowed to have an effect (7). Health workers are in great need of better education in genetics and the principles of genetic counselling.
Criteria for Genetic Screening Experience has shown that genetic screening can be useful and successful when the following three requirements are satisfied (1). 1. A clear diagnosis. 2. The possibility of providing clear information on risk. 3. An effective solution.
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Table 1. Established population screening services. Prenatal Screening for Primary Prevention Rhesus blood group, for prevention of rhesus haemolytic disease of the newborn by post-partum administration of anti-D globulin, Prenatal Screening for Fetal Abnormalities For congenital malformations: ultrasound, fetal anomaly scan, maternal serum alphafetoprotein estimation. For chromosomal abnormalities:maternal age, maternal serum factors. For inherited diseases: family history, and carrier screening for haemoglobin disorders and Tay Sachs disease. Neonatal Screening for Early Treatment Examinationof the newborn for congenital malformations,e.g. congenital dislocation of the hip. Biochemical tests for phenylketonuria,congenital hypothyroidism,and sickle cell disease.
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Based on ref. 5
In addition there are other requirements, e.g. the condition should be common and important, screening should be affordable, and the solution should be acceptable to the population concerned. The forms of genetic screening now widely practised, listed in Table 1, in general fulfil these requirements. They fall into two main groups, with different ethical and psychological implications.
Screening for Reproductive Risk At present, most genetic screening is carried out during pregnancy, the main (but not the only) objective being to identify couples at risk of having a child with a major genetic abnormality in time to allow them the option of selective abortion. The antenatal period is very convenient for screening, and fetal malformations and chromosomal abnormalities can be detected only during pregnancy. Screening for risk of inherited disease is also mostly done in antenatal clinics, though there are reasons, discussed below, why it should be done earlier when possible. In the U.K., in many districts with a significant proportion of relevant ethnic minorities, pregnant women are routinely screened for haemoglobin disorders and Tay Sachs disease. Carrier screening for cystic fibrosis will probably be added in the near future, and carriers of Fragile X mental retardation may also become detectable.
Screening for Personal Genetic Risk The benefits of neonatal screening for phenylketonuria, congenital hypothyroidism, and sickle cell disease in relevant populations are well established. However, there is little experience of screening adults for personal genetic risks, and what experience there is is atypical. Genetic testing can be conducted on the level of the family, or of the whole community. Family studies are central in classical clinical genetic practice, and carrier testing can increasingly be offered to relatives of people with an inherited disease. Family testing is relatively small scale, and family members are often familiar with the disease and may already be concerned for themselves, so testing can relieve pre-existing anxiety. In addition, because an affected family includes many carriers, there are relatively few false positive and false negative results. Screening the whole population prospectively (i.e. before an affected individual is born in the family) is a completely different matter, and can be asso-
ciated with important potential problems. Since the population being tested is usually ignorant of the conditions involved there is a risk of creating considerable unnecessary anxiety, there may be many false positives and negatives, and large costs are involved for health services. Great care must therefore be taken to establish the value of screening before it is introduced at the population level. When a new genetic test becomes available, it is recommended to test it with affected families before moving onto population screening (5). I now propose to illustrate some ethical aspects of genetic screening from a few examples.
Who Should Decide About the Use of Genetic Information? The significance of this key question can be illustrated from the Montreal Tay Sachs carrier screening programme. Tay Sachs disease is a remorsely progressive, recessively inherited neurodegenerative disorder that usually leads to death before 4 years of age. It is relatively common among Ashkenazi Jews, anU was the first condition for which prevention by carrier screening, prenatal diagnosis and selective abortion was introduced, in the United States in the early 1970s (8).Due to a founder effect 3-4% of French Canadians carry the Tay Sachs trait, and carrier screening was introduced in Montreal High Schools towards the end of 1970s (9). It was associated with a careful education programme emphasizing that carriers are healthy, that they can be clearly identified, that risk exists only when two carriers marry, and then there is a 1 in 4 chance of having a child with Tay Sachs disease. The programme was followed up by a questionnaire, sent 8 years later to sets of definite carriers and non-carriers (10). The primary aim was to find out whether the young people had retained the information they had been given, and they had. The questionnaire also included the following questions. (a) ‘If both of the prospective couple found that they were Tay Sachs carriers do you think they would alter their marriage plans?’ (b) ‘Would you alter your own plans?’ The results are shown in Table 2. The questions were expected to show a difference between carriers and non-carriers, but instead the majority of both carriers and non-carriers felt that other people would alter their marriage plans under these circumstances,while very few
Ethical Aspects of Genetic Screening Table 2. Expectations of Participants in the Montreal High School Tay Sachs Screening Programme. Answer to the question ‘If both of a couple planning to marry found they were carriers of Tay Sachs disease, do you think they would alter their marriage plans’?’
Respondents
Others would alter their plans I would alter my own plans
Carriers (%)
Non-carriers(%)
73
92
3
11
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Data from ref. 10.
would alter their own. The study reminds us that we all think our own emotional (and moral) life is more profound than other peoples’, and that the simple recommendation ‘love thy neighbour as thyself’ is as difficult to follow today as it was 2,000 years ago. The implication of this well-known fact, so beautifully illustrated for genetics, is that only people or couples who are personally involved can perceive the true moral issues associated with genetic screening. They are the people who should make the decisions, and they should be our guide. The first role of professionals is to provide information and support: it is also our responsibility to collect and report statistical information on the choices that people at risk actually make, as ‘the choices that people make in practice provides a simple mechanism for joint assessment of genetic testing by the community and the medical profession and should be the key determinant in the future development of community genetic services’ (5). This leads on to the importance of collaborating with Patients’ and Parents’ Support Groups. Many of the concerns aroused by the concept of genetic screening are to do with confidentiality, and whether results could be used by outside agencies to coerce or exploit genetically vulnerable people (4). For instance, there are (quite reasonable) fears that health workers might be made to put insidious or direct pressure on women to terminate affected pregnancies in order to save money (7). In addition, prenatal diagnosis is often thought to conflict with the interests of patients (e.g. its aim may be perceived as ‘to eliminate the handicapped from society’), though in reality it is as much a service for patients as for the rest of the population. To protect the ethical principles of medical genetics and ensure that social and political pressures do not affect service delivery, we need the safeguard of working closely with patients and with Support Associations that represent their interests, and being seen to do so. When we do collect information on peoples’ uptake of services, it can give very clear results and is very useful in decision-making. I will illustrate this with reference to the haemoglobin disorders, but my main objective is not to describe a programme. It is to outline methods that are applicable for genetic disease in general. The haemoglobin disorders occur worldwide, because recent migrations have carried them from sub-tropical and tropical countries where they are endemic to most developed countries. For instance, in the U.K. today,
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about 9% of births are to people in ethnic groups at risk for haemoglobin disorders, and 3-25% of various ethnic minorities carry sickle cell or beta thalassaemia trait. Until recently, couples of carriers of most recessively inherited disorders could be identified only after the birth of their first affected child. In this situation, prenatal diagnosis allows them to have further, healthy children, but has relatively little effect on the population frequency of the disorder, because relatively few families would have a second affected child, even in the absence of prenatal diagnosis. By contrast, it has been possible to detect carriers of haemoglobin disorders for many years by cheap and simple blood tests. Carrier couples can therefore be identified and advised prospectively, i.e. before they have any affected children. In this situation, if screening and counselling is provided effectively, there is the possibility of a major effect on the incidence of the disorder. When prenatal diagnosis for haemoglobin disorders was developed in the US. and the U.K. (between 1974 and 1977) it was based on fetal blood sampling, which could be done only after 18 weeks’ gestation, and affected pregnancies could be terminated only at around 20 weeks. The only way to find out to what extent couples at risk would make use of this approach was to identify them and offer prenatal diagnosis, so carrier screening was started in antenatal clinics in North London, where there is a sizeable population of Greek and Turkish Cypriot origin. About 17% of Cypriots carry beta thalassaemia trait, and the birth rate of infants with thalassaemia major used to be about 7/1000 in this population. The experience of screening the Cypriot population for thalassaemia has taught us a great deal. Pregnant women ‘not of northern European origin’ were tested at their first visit to the antenatal clinic for carrier status. When a women was positive the husband was also tested, and couples at risk so identified were referred for genetic counselling and the offer of prenatal diagnosis. Table 3 shows the choices made by the first 78 at-risk couples (without a thalassaemic child) detected during pregnancy: 98% of the Cypriot couples determined the outcome of the pregnancy as a result of genetic counselling; only one continued the pregnancy undiagnosed (11). Uptake among Indians and Pakistanis was lower: we subsequently found that this was largely because prenatal diagnosis was so late. Now that it can be done at 9 weeks of gestation onwards by chorionic villus sampling (12), about 80% of British Pakistani (Muslim) couples at risk request prenatal diagnosis for t halassaemia. From the very beginning most Cypriots chose prenatal diagnosis, so this whole population was prepared to use genetic screening and prenatal diagnosis to preserve their family life. Table 4 gives an analysis of the reproductive behaviour of Cypriot couples who attended for prenatal diagnosis in the first 3 years; many already had one affected child. Their reproductive history fell into three phases. In phase 1, when they were ignorant of risk, they had 2.6 married years per pregnancy. However, many of their children had thalassaemia major, so their ‘biological viability’, which can be expressed in married years per healthy child, was about half what they had
Modell Table 3. Choices of the first 75 couples at risk for having children with thalassaemia major, detected by screening in North London antenatal clinics. Ethnic origin
counselled
Number (%)choosing prenatal diagnosis
50 22
47 (94) 13 (59)
Couples
Cypriot Indian or
Number (%) terminating the pregnancy
Number (%) continuing an undiagnosed pregnancy
Pakistani Italian
1
3
61 (81)
75
Total
Data from ref. 11
Table 4. Reproductive behaviour of 59 families choosing prenatal diagnosis for thalassaernia. ~
~~
Number of couples
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~~
Pregnancies started and completed in ignorance of risk Pregnancies started knowing risk, but PND not available Pregnancies started knowing risk, and that PND available
Married
Married
years
yr/preg
~
Prenatal diagnosis %
Termination of preg %
Healthy children, %
Married yr/ healthy child
~
40
145
26
0
26
95
48
0
70
33
47
137
24
98
35
97
14
43
63 48 39
Data from ref. 10.
been aiming at (6.3 married years per healthy child). Once the thalassaemic child was diagnosed and they were informed of the recurrence risk, they tried not to reproduce. Married years per pregnancy doubled, and 70% of pregnancies accidentally conceived were aborted for fear of having a second thalassaemic child. This was despite the fact that most of the pregnancies would have ended with the birth of a healthy child, and most of the couples desperately wanted further, healthy children. Unfortunately, some of the pregnancies that continued also led to the birth of thalassaemic children, and in this phase, the couples had almost 50 married years per healthy child. This amounts to ‘biological suicide’ as a result of knowledge of major genetic risk. As soon as prenatal diagnosis was introduced, pregnancies were undertaken at the initial rate, the vast majority underwent prenatal diagnosis, the proportion of pregnancies terminated was less than when the service was not available, and the married years per healthy child (3.9) reached something near the initial ‘target’ value (11). This analysis clearly shows a population group using prenatal diagnosis and selective abortion to preserve their family life. This experience has led to general acceptance of the obligation to provide screening and genetic counselling for couples at risk for thalassaemia. With this attitude among Mediterranean populations at risk, it is not surprising that thalassaemia ’control’ programmes, combining the best possible patient care with information, screening, genetic counselling and the offer of prenatal diagnosis spread rapidly throughout the Mediterranean area (13). The objective of these programmes is not to ’eliminate’ thafassaemia. The objective of screening and genetic counselling is to provide informed choice. It so happens that for thalassaemia, over 90% of informed couples at risk choose prenatal diagnosis and selective abortion, so if the service is satisfac-
torily delivered one should expect a more than 90% fall in affected births. (For other conditions such as sickle cell disease, where only about half the couples at risk choose prenatal diagnosis (14, 15), a programme that reached all the population would lead to a 50% fall in affected births.) In 1982 the World Health Organization requested the directors of several thalassaemia control programmes to measure their impact by monitoring the birth rate of affected children. Some results are shown in Figure 1. It is important to emphasize that the fall in the affected birth rate reflects the effectiveness of public and professional education, and carrier screening, even more than the technology for prenatal diagnosis. The Cyprus programme has had the quickest and most marked effect: there have been practically no new affected births among either Greek or Turkish Cypriots since 1986. It takes longer to get such a service delivered to large populations as in Italy or Greece, because it must be integrated into general national health services. The fall in affected birth rate has been least in the U.K., where the service has to be delivered to several different ethnic minorities in a large population that is not itself at risk. The quality of service delivery can be more fully assessed by following up the children born since the start of the programme, with an enquiry designed to find if their birth was the result of informed parental choice, or of failure to identify or appropriately inform couples at risk. Figure 2 shows the result of such an enquiry for WHO (16). About 80% of residual thalassaemic births were the result of failure to inform couples at risk. A confidential enquiry has confirmed this finding for the U.K. It also revealed marked inequity in service delivery to different ethnic groups, as most residual births are to couples of Indian or Pakistani origin whose risk was not detected and who were not counselled (17). Similar
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Ethical Aspects of Genetic Screening
100
90
30 70
60
50 40
30
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20 10
-
-
-
I
"1'7,
-
li i
---
-
I - '
1972
I
1974
1
1
1976
1
I 1978
I
I
1980
I
I
1982
I
1984
1986
Year Figure 1. Fall in the birth rate of infants with thalassaemia major associated with selected thalassaernia control programmes (data from ref. 7).
Laboratory error (mainly in
heterozygote
Choice not to terminate on affected pregnancy
Figure 2. Causes for the births of 193 thalassaernic children in three regions with thalassaernia control programmes.
problems exist in the delivery of other genetic screening services, and a WHO study concluded 'the inadequate and inequitable delivery of genetic screening services is a central ethical problem of genetic services in the European region' (5). The investigation described above shows that the lack of information for the public, and the poor education of
existing health professionals in basic genetics and the ethics of genetic counselling is a major problem for all genetic screening services. It will certainly cause difficulties in screening for genetic risk factors in the future. The Cyprus thalassaemia control programme has further lessons to teach (18). Because thalassaemia is a priority health problem there, it was proposed that the Cyprus parliament should legislate for mandatory premarital carrier testing; but the proposal was rejected as unconstitutional. Consequently, screening was done only during pregnancy, as in the U.K. today. The thalassaemia screening and prenatal diagnosis service is housed, together with treatment for thalassaemic patients, in the Thalassaemia Unit of the Archbishop Makarios Memorial hospital which, when finally completed, was opened by the Greek Orthodox Archbishop of Cyprus. His unfavourable view of abortion was well known, and his speech extremely to the point. He expressed concern about the morality of carrier screening only during pregnancy. He pointed out that in this case women had practicaljy no option other than to abort affected fetuses, but had they known of their risk earlier they would have had a wider range of choices (including choosing a different partner, avoiding pregnancy, adoption, etc). He therefore introduced an ecclesiastical ruling that all couples marrying in church must show a 'pre-marital certificate' of testing for thalassaemia trait. The certificate does not give results: it shows only that the couple have been tested at the government laboratory and appropriately counselled. As civil marriage is rare in Cyprus, this ruling effectively imposed mandatory pre-marital testing, and gave an opportunity for further interesting observations. Firstly, it complements the Tay Sachs study reported above. Only 2% of Cypriot couples who planned to marry and then found they were both carriers changed their plans; 98%
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proceeded with the marriage, and later made use of prenatal diagnosis. Genetic information provided at this late stage changes peoples’ reproductive behaviour rather than their choice of partner. There is, however, evidence that if people become aware of risk at an earlier stage, there may be some effect on choice of partner. Secondly, mandatory screening means universal screening, and this has contributed significantly to the completeness of thalassaemia control in Cyprus. When couples must be motivated to seek testing by public education, the most educated sections of society are most likely to benefit from the service. Whether the mandatory nature of testing in Cyprus is approved of or not, the Bishop’s point that it is unethical to test late when earlier testing is possible, is universally valid. The introduction of first trimester prenatal diagnosis has added strong practical reasons to this moral argument. Early prenatal diagnosis is particularly important for couples at high, recurrent genetic risk, and it is unacceptable for prenatal diagnosis for these couples to take place in the second trimester if it could have been done in the first. However, to benefit from early prenatal diagnosis, couples need to be aware of risk before they start a pregnancy, or in its earliest stages. Thus it has become necessary to promote genetic screening in primary care (19). and to develop a health education campaign to stimulate healthy people to ask for screening. In Hungary, where a large-scale programme of preconception counselling in primary care reaches more than 30% of young couples, it has been realized that this is also a convenient time to offer screening to both young men and women, for adult risk factors such as hypertension, and coronary heart disease (by taking a family history) (A. Czeizel, personal communication).
Population Screening for Genetic Risk of Late-Onset Disorders The objective would be to promote changes in lifestyle, or initiate treatments, that would ‘normalize’ the prognosis of those at increased risk. But we know very little about peoples’ reactions to being informed that they are at relatively high or relatively low risk of a common disorder such as coronary heart disease or cancer. There is as yet little evidence about the compliance of large numbers of people with dietary and exercise advice, nor of the requirements to promote and maintain compliance, nor of the overall effect on peoples’ health. And there is the possibility that people identified as at-risk could be exploited commercially, e.g. by organizations promoting proprietary remedies. Presymptomatic testing for Huntington’s disease is sometimes seen as a model for adult genetic screening, but is very far from fitting the criteria for acceptable screening, as there is no treatment for those found to be carriers. Carrier testing for this disorder is associated with considerable problems. For instance Crawfurd and co-workers found that though about 80% of family members at risk were in favour of carrier detection, the actual uptake rate of testing is low (20). In addition, one
could assume-that people who find that they are carriers of Huntington’s disease will experience a severe psychological reaction, while those who are not carriers will be greatly relieved: however in practice, most identified carriers soon revert to their pre-existing coping pattern, while identified non-carriers often experience quite complicated reactions, particularly in their reactions to other family. members (survivor’s guilt) (21). Adult polycystic disease of the kidney, another lateonset dominant disorder, is a rather better model, as a considerable amount can be done to minimize complications for carriers of the disease, and delay the onset of illness. However, the condition is not truly treatable, and people at risk can also be deterred from seeking definitive diagnosis because of implications for employment and insurance (22). Familial hypercholesterolaemia would provide a better model of genetic screening for personal risk, since with intensive support the serum cholesterol, and presumably the prognosis, can be normalized. The social and psychological implications of screening for this condition should be studied carefully. We dso know little of peoples’ reaction when they learn that they are at relatively low risk. It is quite possible that some may neutralize their advantage by risk-taking behaviour such as smoking. It is therefore conceivable that effective screening for a truly controllable risk could end by transforming a heterogeneous population with people at high and low risk, into a population where the risk has been largely equalized. It will be irrational to adjust insurance policies on the basis of genetic risk, until we know more about peoples’ reaction to information on personal genetic risk. If there is an intention to weight policies, it may be most effective to weight them using an intermediate, not explicitly genetic, factor such as serum cholesterol level. It is also possible to balance the interests of the individual and the concerns of the insurance companies. At present they argue that they will be forced to weight the policies of individuals identified as genetically susceptible, to protect us against over-insurance by genetically vulnerable people. In the Netherlands, legislation has already been introduced forbidding insurance companies to ask for genetic information unless the sum insured is above a certain, large limit.
Conclusion The examples given above show that specific steps are needed to solve the main ethical problem of genetic screening, namely poor service delivery. Among the requirements are: 1. good clinical genetic epidemiology (for service planning); 2. genetic education for medical and nursing students, health professionals now in practice, and the public; 3. evaluation and reporting of existing genetic screening services, including information on the choices that people make and on the quality of service delivery; 4. assessment of costs and benefits of genetic screening services; ’
Ethical Aspects of Genetic Screening 5. coltaboration with Patients Associations and Support Groups. To do all this effectively requires a great deal of work, but not to do it means that services will continue to be inadequately delivered. The people who do such tasks may come to be called community geneticists (23).
1.
2.
3.
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References 1. National Research Council. Genetic screening: programs, principles and research. Washington DC: National Academy of Sciences, 1975. 2. US Congress Office of Technology Assessment. Genetic monitoring and screening in the workplace. Washington DC: US. Government Printing Office, 1990. 3. Wertz DC, Fletcher JC. (eds). Ethics and human genetics. A cross-culturalperspective. Springer-Verlag,Berlin, 1989. 4. Holtzman NA. Proceed with caution. Predicting genetic risks in the recombinant DNA era. Baltimore:Johns Hopkins University Press, 1989. 5. Modell B, Kuliev AM, Wagner M. Community genetics services in Europe. WHO Regional Publications, European Series No 38. Copenhagen: WHO Regional Office for Europe, 1992. 6. Fletcher JC, Berg K, Tranoy KE. Ethical aspects of medical genetics. A proposal for guidelines in genetic counselling, prenatal diagnosis and screening. Clin Genet 1985; 27: 199-205. 7. Report of the Royal College of Physicians. Prenatal diagnosis and genetic screening; community and service implications. Royal College of Physicians of London, 1989. 8. Kaback MM, Zeigler RS, Reynolds LW, Sonneborn M. Approaches to the control and prevention of Tay Sachs disease. f r o g Med Genet 1974; 10: 103-34. 9. Clow CL, Scrlver CR. Knowledge about and genetic attitudes towards genetic screening among high-school students: the Tay Sachs experience. Pediatrics 1977; 59: 86-91. 10. Zeesman S, Clow CL, Cartier L, Scrlver CR. A private view of heterozygosity: eight-year follow-up study on
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carriers of the Tay Sachs gene detected by high-school screening in Montreal. Am J Med Gen 1984; 18: 769-78. Modell B, Ward RHT, Fairweather DVI. Effect of introducing antenatal diagnosis on the reproductive behaviour of families at risk for thalassaemia major. Br Med J 1980; 2: 737. Old JM, Ward RHT, Petrou M, Karagozlu F, Modell 6, Weatherall DJ. First-trimester fetal diagnosis for the haemoglobinopathies:three cases. Lancet 1982; ii: 1413-6. WHO 1987. The haemoglobinopathies in Europe WHO Regional Office for Europe, unpublished document IPC/ MCH 110. (May be obtained free of charge from: Maternal and Child Health Division. Copenhagen: WHO Regional Office for Europe. Anionwu EN, Patel N, Kanji G, Renges H, Brosovic M. Counselling for prenatal diagnosis of sickle-cell disease and B-thalassaemia major. A four year experience. J Med Genet 1987; 25: 769. Petrou M, Brugiatelli M, Ward RHT, Modell 5. Factors affecting the uptake of prenatal diagnosis for sickle cell disease. J Med Genet 1992 (in press). WHO 1985. Update of the progress of haemoglobinopathies control. Unpublished Report HMG/WG/85.8. The Hereditary Diseases Programme. Geneva: WHO. Moisley C, Modell 6, McKeigue P, Petrou M, Varnavides L, Old J. Use of a patient register for evaluating delivery of screening and genetic counselling for thalassaemia in the UK. 1992 (in press). Angastiniotis MA, Kyrlakidou S, Hadjimlnas M. How thalassaemia was controlled in Cyprus. World Health Forum 1986; 7: 291-7. Modell M, Modell B. Genetic screening for ethnic minorities. Br Med J 1990; 300: 1702-4. Crawfurd D, Dodge A, Kerzin-Storrar L, Harris R. Uptake of presymptomatic predictive testing for Huntington's disease. Lancet 1989; ii: 603-5. Morris MJ, Tyler A, Lazarou L, Meredith L, Harper PS. Problems in genetic prediction for Huntington's disease. Lancet 1989; ii: 601-3. Zerres K, Stephan M. Attitudes to early diagnosis of polycystic kidney disease. Lancet 1986; ii: 1395. Modell B. Screening as public policy. In: Brock D, Rodeck C, Ferguson-Smith MA, eds. Prenatal diagnosis and screening. Churchill Livingstone (in press), 1992.
ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
Ethical Aspects of Genetic Screening Bernadette Modell To cite this article: Bernadette Modell (1992) Ethical Aspects of Genetic Screening, Annals of Medicine, 24:6, 549-555, DOI: 10.3109/07853899209167009 To link to this article: http://dx.doi.org/10.3109/07853899209167009
Published online: 04 Aug 2009.
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Special Section: Molecular Genetics and Genetic Epidemiology of Cardiovascular Disease and Diabetes
Ethical Aspects of Genetic Screening
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Bernadette Modell
Public and professional concern associated with the idea of genetic screening has generated numerous publications on the ethics of genetic screening (e.g. 1-4). Concerns revolve around inadequate consultation before screening is carried out, the unearthing of worrying risks, the use of genetic information in ways that could be disadvantageous to the person involved, stigma, and a phenomenon known as the ‘technological imperative’, which means that simply because a technology is available there is a tendency to use it. Most reports agree that, in practice, the main ethical problems are likely to involve screening for risk of common diseases of adult life, because of the possible impact on a person’s healthy self-image, implications for health and life Insurance, and the possibility of commercial exploitation of people who know themselves to be vulnerable. In this paper I do not propose to address these issues directly. I have been invited to discuss this subject as a clinician involved with genetic screening, counselling and prenatal diagnosis for the haemoglobin disorders, the most common serious human recessively inherited diseases. Since we are scientists, any recommendationswe make should be based on experience: my aim is to show that experience is often surprising, and that it is often possible to meet public concerns by taking quite simple practical steps. Key words: screening; genetics; ethics; haemoglobin disorders. (Annals of Medicine 24: 549-555,1992)
Genetic screening is already extensively practised, mainly in the area of maternal and child health. Current experience has recently been summarized for the World Health Organization (5). Table 1 lists current accepted population screening programmes. As yet, we have practically no experience of screening for genetic risk for common disease, so I propose to examine a few important ethical issues that have arisen with current screening programmes, for the light that they cast on general principles, and on the future application of genetic screening for personal risk.
Ethical Principles of Genetic Counsel1ing The core ethical principles of genetic counselling are, the autonomy of the individual or couple, their right to full From the WHO Collaborating Centre for Community Control of Hereditary Disease, Department of Obstetrics and Gynaecology, University College London, UK. Address and reprint requests: B. Modell, Ph.D.. FRCP, FRCPath. Department of Obstetrics and Gynaecology, University College London, 86-96 Chenies Mews, London WCl E 6HX, U.K.
information, and the highest standard of confidentiality (6). These principles were derived from an empirical study of the practice of clinical geneticists. If we could be sure that they would always be followed, there might be little cause for public anxiety. However, in practice most genetic counselling is provided by obstetricians, midwives, nurses and paediatricians. Screening is not always equitably delivered, counselling is not always done according to the above principles, and there is some anxiety that financial pressures will be allowed to have an effect (7). Health workers are in great need of better education in genetics and the principles of genetic counselling.
Criteria for Genetic Screening Experience has shown that genetic screening can be useful and successful when the following three requirements are satisfied (1). 1. A clear diagnosis. 2. The possibility of providing clear information on risk. 3. An effective solution.
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Table 1. Established population screening services. Prenatal Screening for Primary Prevention Rhesus blood group, for prevention of rhesus haemolytic disease of the newborn by post-partum administration of anti-D globulin, Prenatal Screening for Fetal Abnormalities For congenital malformations: ultrasound, fetal anomaly scan, maternal serum alphafetoprotein estimation. For chromosomal abnormalities:maternal age, maternal serum factors. For inherited diseases: family history, and carrier screening for haemoglobin disorders and Tay Sachs disease. Neonatal Screening for Early Treatment Examinationof the newborn for congenital malformations,e.g. congenital dislocation of the hip. Biochemical tests for phenylketonuria,congenital hypothyroidism,and sickle cell disease.
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Based on ref. 5
In addition there are other requirements, e.g. the condition should be common and important, screening should be affordable, and the solution should be acceptable to the population concerned. The forms of genetic screening now widely practised, listed in Table 1, in general fulfil these requirements. They fall into two main groups, with different ethical and psychological implications.
Screening for Reproductive Risk At present, most genetic screening is carried out during pregnancy, the main (but not the only) objective being to identify couples at risk of having a child with a major genetic abnormality in time to allow them the option of selective abortion. The antenatal period is very convenient for screening, and fetal malformations and chromosomal abnormalities can be detected only during pregnancy. Screening for risk of inherited disease is also mostly done in antenatal clinics, though there are reasons, discussed below, why it should be done earlier when possible. In the U.K., in many districts with a significant proportion of relevant ethnic minorities, pregnant women are routinely screened for haemoglobin disorders and Tay Sachs disease. Carrier screening for cystic fibrosis will probably be added in the near future, and carriers of Fragile X mental retardation may also become detectable.
Screening for Personal Genetic Risk The benefits of neonatal screening for phenylketonuria, congenital hypothyroidism, and sickle cell disease in relevant populations are well established. However, there is little experience of screening adults for personal genetic risks, and what experience there is is atypical. Genetic testing can be conducted on the level of the family, or of the whole community. Family studies are central in classical clinical genetic practice, and carrier testing can increasingly be offered to relatives of people with an inherited disease. Family testing is relatively small scale, and family members are often familiar with the disease and may already be concerned for themselves, so testing can relieve pre-existing anxiety. In addition, because an affected family includes many carriers, there are relatively few false positive and false negative results. Screening the whole population prospectively (i.e. before an affected individual is born in the family) is a completely different matter, and can be asso-
ciated with important potential problems. Since the population being tested is usually ignorant of the conditions involved there is a risk of creating considerable unnecessary anxiety, there may be many false positives and negatives, and large costs are involved for health services. Great care must therefore be taken to establish the value of screening before it is introduced at the population level. When a new genetic test becomes available, it is recommended to test it with affected families before moving onto population screening (5). I now propose to illustrate some ethical aspects of genetic screening from a few examples.
Who Should Decide About the Use of Genetic Information? The significance of this key question can be illustrated from the Montreal Tay Sachs carrier screening programme. Tay Sachs disease is a remorsely progressive, recessively inherited neurodegenerative disorder that usually leads to death before 4 years of age. It is relatively common among Ashkenazi Jews, anU was the first condition for which prevention by carrier screening, prenatal diagnosis and selective abortion was introduced, in the United States in the early 1970s (8).Due to a founder effect 3-4% of French Canadians carry the Tay Sachs trait, and carrier screening was introduced in Montreal High Schools towards the end of 1970s (9). It was associated with a careful education programme emphasizing that carriers are healthy, that they can be clearly identified, that risk exists only when two carriers marry, and then there is a 1 in 4 chance of having a child with Tay Sachs disease. The programme was followed up by a questionnaire, sent 8 years later to sets of definite carriers and non-carriers (10). The primary aim was to find out whether the young people had retained the information they had been given, and they had. The questionnaire also included the following questions. (a) ‘If both of the prospective couple found that they were Tay Sachs carriers do you think they would alter their marriage plans?’ (b) ‘Would you alter your own plans?’ The results are shown in Table 2. The questions were expected to show a difference between carriers and non-carriers, but instead the majority of both carriers and non-carriers felt that other people would alter their marriage plans under these circumstances,while very few
Ethical Aspects of Genetic Screening Table 2. Expectations of Participants in the Montreal High School Tay Sachs Screening Programme. Answer to the question ‘If both of a couple planning to marry found they were carriers of Tay Sachs disease, do you think they would alter their marriage plans’?’
Respondents
Others would alter their plans I would alter my own plans
Carriers (%)
Non-carriers(%)
73
92
3
11
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Data from ref. 10.
would alter their own. The study reminds us that we all think our own emotional (and moral) life is more profound than other peoples’, and that the simple recommendation ‘love thy neighbour as thyself’ is as difficult to follow today as it was 2,000 years ago. The implication of this well-known fact, so beautifully illustrated for genetics, is that only people or couples who are personally involved can perceive the true moral issues associated with genetic screening. They are the people who should make the decisions, and they should be our guide. The first role of professionals is to provide information and support: it is also our responsibility to collect and report statistical information on the choices that people at risk actually make, as ‘the choices that people make in practice provides a simple mechanism for joint assessment of genetic testing by the community and the medical profession and should be the key determinant in the future development of community genetic services’ (5). This leads on to the importance of collaborating with Patients’ and Parents’ Support Groups. Many of the concerns aroused by the concept of genetic screening are to do with confidentiality, and whether results could be used by outside agencies to coerce or exploit genetically vulnerable people (4). For instance, there are (quite reasonable) fears that health workers might be made to put insidious or direct pressure on women to terminate affected pregnancies in order to save money (7). In addition, prenatal diagnosis is often thought to conflict with the interests of patients (e.g. its aim may be perceived as ‘to eliminate the handicapped from society’), though in reality it is as much a service for patients as for the rest of the population. To protect the ethical principles of medical genetics and ensure that social and political pressures do not affect service delivery, we need the safeguard of working closely with patients and with Support Associations that represent their interests, and being seen to do so. When we do collect information on peoples’ uptake of services, it can give very clear results and is very useful in decision-making. I will illustrate this with reference to the haemoglobin disorders, but my main objective is not to describe a programme. It is to outline methods that are applicable for genetic disease in general. The haemoglobin disorders occur worldwide, because recent migrations have carried them from sub-tropical and tropical countries where they are endemic to most developed countries. For instance, in the U.K. today,
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about 9% of births are to people in ethnic groups at risk for haemoglobin disorders, and 3-25% of various ethnic minorities carry sickle cell or beta thalassaemia trait. Until recently, couples of carriers of most recessively inherited disorders could be identified only after the birth of their first affected child. In this situation, prenatal diagnosis allows them to have further, healthy children, but has relatively little effect on the population frequency of the disorder, because relatively few families would have a second affected child, even in the absence of prenatal diagnosis. By contrast, it has been possible to detect carriers of haemoglobin disorders for many years by cheap and simple blood tests. Carrier couples can therefore be identified and advised prospectively, i.e. before they have any affected children. In this situation, if screening and counselling is provided effectively, there is the possibility of a major effect on the incidence of the disorder. When prenatal diagnosis for haemoglobin disorders was developed in the US. and the U.K. (between 1974 and 1977) it was based on fetal blood sampling, which could be done only after 18 weeks’ gestation, and affected pregnancies could be terminated only at around 20 weeks. The only way to find out to what extent couples at risk would make use of this approach was to identify them and offer prenatal diagnosis, so carrier screening was started in antenatal clinics in North London, where there is a sizeable population of Greek and Turkish Cypriot origin. About 17% of Cypriots carry beta thalassaemia trait, and the birth rate of infants with thalassaemia major used to be about 7/1000 in this population. The experience of screening the Cypriot population for thalassaemia has taught us a great deal. Pregnant women ‘not of northern European origin’ were tested at their first visit to the antenatal clinic for carrier status. When a women was positive the husband was also tested, and couples at risk so identified were referred for genetic counselling and the offer of prenatal diagnosis. Table 3 shows the choices made by the first 78 at-risk couples (without a thalassaemic child) detected during pregnancy: 98% of the Cypriot couples determined the outcome of the pregnancy as a result of genetic counselling; only one continued the pregnancy undiagnosed (11). Uptake among Indians and Pakistanis was lower: we subsequently found that this was largely because prenatal diagnosis was so late. Now that it can be done at 9 weeks of gestation onwards by chorionic villus sampling (12), about 80% of British Pakistani (Muslim) couples at risk request prenatal diagnosis for t halassaemia. From the very beginning most Cypriots chose prenatal diagnosis, so this whole population was prepared to use genetic screening and prenatal diagnosis to preserve their family life. Table 4 gives an analysis of the reproductive behaviour of Cypriot couples who attended for prenatal diagnosis in the first 3 years; many already had one affected child. Their reproductive history fell into three phases. In phase 1, when they were ignorant of risk, they had 2.6 married years per pregnancy. However, many of their children had thalassaemia major, so their ‘biological viability’, which can be expressed in married years per healthy child, was about half what they had
Modell Table 3. Choices of the first 75 couples at risk for having children with thalassaemia major, detected by screening in North London antenatal clinics. Ethnic origin
counselled
Number (%)choosing prenatal diagnosis
50 22
47 (94) 13 (59)
Couples
Cypriot Indian or
Number (%) terminating the pregnancy
Number (%) continuing an undiagnosed pregnancy
Pakistani Italian
1
3
61 (81)
75
Total
Data from ref. 11
Table 4. Reproductive behaviour of 59 families choosing prenatal diagnosis for thalassaernia. ~
~~
Number of couples
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~~
Pregnancies started and completed in ignorance of risk Pregnancies started knowing risk, but PND not available Pregnancies started knowing risk, and that PND available
Married
Married
years
yr/preg
~
Prenatal diagnosis %
Termination of preg %
Healthy children, %
Married yr/ healthy child
~
40
145
26
0
26
95
48
0
70
33
47
137
24
98
35
97
14
43
63 48 39
Data from ref. 10.
been aiming at (6.3 married years per healthy child). Once the thalassaemic child was diagnosed and they were informed of the recurrence risk, they tried not to reproduce. Married years per pregnancy doubled, and 70% of pregnancies accidentally conceived were aborted for fear of having a second thalassaemic child. This was despite the fact that most of the pregnancies would have ended with the birth of a healthy child, and most of the couples desperately wanted further, healthy children. Unfortunately, some of the pregnancies that continued also led to the birth of thalassaemic children, and in this phase, the couples had almost 50 married years per healthy child. This amounts to ‘biological suicide’ as a result of knowledge of major genetic risk. As soon as prenatal diagnosis was introduced, pregnancies were undertaken at the initial rate, the vast majority underwent prenatal diagnosis, the proportion of pregnancies terminated was less than when the service was not available, and the married years per healthy child (3.9) reached something near the initial ‘target’ value (11). This analysis clearly shows a population group using prenatal diagnosis and selective abortion to preserve their family life. This experience has led to general acceptance of the obligation to provide screening and genetic counselling for couples at risk for thalassaemia. With this attitude among Mediterranean populations at risk, it is not surprising that thalassaemia ’control’ programmes, combining the best possible patient care with information, screening, genetic counselling and the offer of prenatal diagnosis spread rapidly throughout the Mediterranean area (13). The objective of these programmes is not to ’eliminate’ thafassaemia. The objective of screening and genetic counselling is to provide informed choice. It so happens that for thalassaemia, over 90% of informed couples at risk choose prenatal diagnosis and selective abortion, so if the service is satisfac-
torily delivered one should expect a more than 90% fall in affected births. (For other conditions such as sickle cell disease, where only about half the couples at risk choose prenatal diagnosis (14, 15), a programme that reached all the population would lead to a 50% fall in affected births.) In 1982 the World Health Organization requested the directors of several thalassaemia control programmes to measure their impact by monitoring the birth rate of affected children. Some results are shown in Figure 1. It is important to emphasize that the fall in the affected birth rate reflects the effectiveness of public and professional education, and carrier screening, even more than the technology for prenatal diagnosis. The Cyprus programme has had the quickest and most marked effect: there have been practically no new affected births among either Greek or Turkish Cypriots since 1986. It takes longer to get such a service delivered to large populations as in Italy or Greece, because it must be integrated into general national health services. The fall in affected birth rate has been least in the U.K., where the service has to be delivered to several different ethnic minorities in a large population that is not itself at risk. The quality of service delivery can be more fully assessed by following up the children born since the start of the programme, with an enquiry designed to find if their birth was the result of informed parental choice, or of failure to identify or appropriately inform couples at risk. Figure 2 shows the result of such an enquiry for WHO (16). About 80% of residual thalassaemic births were the result of failure to inform couples at risk. A confidential enquiry has confirmed this finding for the U.K. It also revealed marked inequity in service delivery to different ethnic groups, as most residual births are to couples of Indian or Pakistani origin whose risk was not detected and who were not counselled (17). Similar
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Ethical Aspects of Genetic Screening
100
90
30 70
60
50 40
30
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20 10
-
-
-
I
"1'7,
-
li i
---
-
I - '
1972
I
1974
1
1
1976
1
I 1978
I
I
1980
I
I
1982
I
1984
1986
Year Figure 1. Fall in the birth rate of infants with thalassaemia major associated with selected thalassaernia control programmes (data from ref. 7).
Laboratory error (mainly in
heterozygote
Choice not to terminate on affected pregnancy
Figure 2. Causes for the births of 193 thalassaernic children in three regions with thalassaernia control programmes.
problems exist in the delivery of other genetic screening services, and a WHO study concluded 'the inadequate and inequitable delivery of genetic screening services is a central ethical problem of genetic services in the European region' (5). The investigation described above shows that the lack of information for the public, and the poor education of
existing health professionals in basic genetics and the ethics of genetic counselling is a major problem for all genetic screening services. It will certainly cause difficulties in screening for genetic risk factors in the future. The Cyprus thalassaemia control programme has further lessons to teach (18). Because thalassaemia is a priority health problem there, it was proposed that the Cyprus parliament should legislate for mandatory premarital carrier testing; but the proposal was rejected as unconstitutional. Consequently, screening was done only during pregnancy, as in the U.K. today. The thalassaemia screening and prenatal diagnosis service is housed, together with treatment for thalassaemic patients, in the Thalassaemia Unit of the Archbishop Makarios Memorial hospital which, when finally completed, was opened by the Greek Orthodox Archbishop of Cyprus. His unfavourable view of abortion was well known, and his speech extremely to the point. He expressed concern about the morality of carrier screening only during pregnancy. He pointed out that in this case women had practicaljy no option other than to abort affected fetuses, but had they known of their risk earlier they would have had a wider range of choices (including choosing a different partner, avoiding pregnancy, adoption, etc). He therefore introduced an ecclesiastical ruling that all couples marrying in church must show a 'pre-marital certificate' of testing for thalassaemia trait. The certificate does not give results: it shows only that the couple have been tested at the government laboratory and appropriately counselled. As civil marriage is rare in Cyprus, this ruling effectively imposed mandatory pre-marital testing, and gave an opportunity for further interesting observations. Firstly, it complements the Tay Sachs study reported above. Only 2% of Cypriot couples who planned to marry and then found they were both carriers changed their plans; 98%
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proceeded with the marriage, and later made use of prenatal diagnosis. Genetic information provided at this late stage changes peoples’ reproductive behaviour rather than their choice of partner. There is, however, evidence that if people become aware of risk at an earlier stage, there may be some effect on choice of partner. Secondly, mandatory screening means universal screening, and this has contributed significantly to the completeness of thalassaemia control in Cyprus. When couples must be motivated to seek testing by public education, the most educated sections of society are most likely to benefit from the service. Whether the mandatory nature of testing in Cyprus is approved of or not, the Bishop’s point that it is unethical to test late when earlier testing is possible, is universally valid. The introduction of first trimester prenatal diagnosis has added strong practical reasons to this moral argument. Early prenatal diagnosis is particularly important for couples at high, recurrent genetic risk, and it is unacceptable for prenatal diagnosis for these couples to take place in the second trimester if it could have been done in the first. However, to benefit from early prenatal diagnosis, couples need to be aware of risk before they start a pregnancy, or in its earliest stages. Thus it has become necessary to promote genetic screening in primary care (19). and to develop a health education campaign to stimulate healthy people to ask for screening. In Hungary, where a large-scale programme of preconception counselling in primary care reaches more than 30% of young couples, it has been realized that this is also a convenient time to offer screening to both young men and women, for adult risk factors such as hypertension, and coronary heart disease (by taking a family history) (A. Czeizel, personal communication).
Population Screening for Genetic Risk of Late-Onset Disorders The objective would be to promote changes in lifestyle, or initiate treatments, that would ‘normalize’ the prognosis of those at increased risk. But we know very little about peoples’ reactions to being informed that they are at relatively high or relatively low risk of a common disorder such as coronary heart disease or cancer. There is as yet little evidence about the compliance of large numbers of people with dietary and exercise advice, nor of the requirements to promote and maintain compliance, nor of the overall effect on peoples’ health. And there is the possibility that people identified as at-risk could be exploited commercially, e.g. by organizations promoting proprietary remedies. Presymptomatic testing for Huntington’s disease is sometimes seen as a model for adult genetic screening, but is very far from fitting the criteria for acceptable screening, as there is no treatment for those found to be carriers. Carrier testing for this disorder is associated with considerable problems. For instance Crawfurd and co-workers found that though about 80% of family members at risk were in favour of carrier detection, the actual uptake rate of testing is low (20). In addition, one
could assume-that people who find that they are carriers of Huntington’s disease will experience a severe psychological reaction, while those who are not carriers will be greatly relieved: however in practice, most identified carriers soon revert to their pre-existing coping pattern, while identified non-carriers often experience quite complicated reactions, particularly in their reactions to other family. members (survivor’s guilt) (21). Adult polycystic disease of the kidney, another lateonset dominant disorder, is a rather better model, as a considerable amount can be done to minimize complications for carriers of the disease, and delay the onset of illness. However, the condition is not truly treatable, and people at risk can also be deterred from seeking definitive diagnosis because of implications for employment and insurance (22). Familial hypercholesterolaemia would provide a better model of genetic screening for personal risk, since with intensive support the serum cholesterol, and presumably the prognosis, can be normalized. The social and psychological implications of screening for this condition should be studied carefully. We dso know little of peoples’ reaction when they learn that they are at relatively low risk. It is quite possible that some may neutralize their advantage by risk-taking behaviour such as smoking. It is therefore conceivable that effective screening for a truly controllable risk could end by transforming a heterogeneous population with people at high and low risk, into a population where the risk has been largely equalized. It will be irrational to adjust insurance policies on the basis of genetic risk, until we know more about peoples’ reaction to information on personal genetic risk. If there is an intention to weight policies, it may be most effective to weight them using an intermediate, not explicitly genetic, factor such as serum cholesterol level. It is also possible to balance the interests of the individual and the concerns of the insurance companies. At present they argue that they will be forced to weight the policies of individuals identified as genetically susceptible, to protect us against over-insurance by genetically vulnerable people. In the Netherlands, legislation has already been introduced forbidding insurance companies to ask for genetic information unless the sum insured is above a certain, large limit.
Conclusion The examples given above show that specific steps are needed to solve the main ethical problem of genetic screening, namely poor service delivery. Among the requirements are: 1. good clinical genetic epidemiology (for service planning); 2. genetic education for medical and nursing students, health professionals now in practice, and the public; 3. evaluation and reporting of existing genetic screening services, including information on the choices that people make and on the quality of service delivery; 4. assessment of costs and benefits of genetic screening services; ’
Ethical Aspects of Genetic Screening 5. coltaboration with Patients Associations and Support Groups. To do all this effectively requires a great deal of work, but not to do it means that services will continue to be inadequately delivered. The people who do such tasks may come to be called community geneticists (23).
1.
2.
3.
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carriers of the Tay Sachs gene detected by high-school screening in Montreal. Am J Med Gen 1984; 18: 769-78. Modell B, Ward RHT, Fairweather DVI. Effect of introducing antenatal diagnosis on the reproductive behaviour of families at risk for thalassaemia major. Br Med J 1980; 2: 737. Old JM, Ward RHT, Petrou M, Karagozlu F, Modell 6, Weatherall DJ. First-trimester fetal diagnosis for the haemoglobinopathies:three cases. Lancet 1982; ii: 1413-6. WHO 1987. The haemoglobinopathies in Europe WHO Regional Office for Europe, unpublished document IPC/ MCH 110. (May be obtained free of charge from: Maternal and Child Health Division. Copenhagen: WHO Regional Office for Europe. Anionwu EN, Patel N, Kanji G, Renges H, Brosovic M. Counselling for prenatal diagnosis of sickle-cell disease and B-thalassaemia major. A four year experience. J Med Genet 1987; 25: 769. Petrou M, Brugiatelli M, Ward RHT, Modell 5. Factors affecting the uptake of prenatal diagnosis for sickle cell disease. J Med Genet 1992 (in press). WHO 1985. Update of the progress of haemoglobinopathies control. Unpublished Report HMG/WG/85.8. The Hereditary Diseases Programme. Geneva: WHO. Moisley C, Modell 6, McKeigue P, Petrou M, Varnavides L, Old J. Use of a patient register for evaluating delivery of screening and genetic counselling for thalassaemia in the UK. 1992 (in press). Angastiniotis MA, Kyrlakidou S, Hadjimlnas M. How thalassaemia was controlled in Cyprus. World Health Forum 1986; 7: 291-7. Modell M, Modell B. Genetic screening for ethnic minorities. Br Med J 1990; 300: 1702-4. Crawfurd D, Dodge A, Kerzin-Storrar L, Harris R. Uptake of presymptomatic predictive testing for Huntington's disease. Lancet 1989; ii: 603-5. Morris MJ, Tyler A, Lazarou L, Meredith L, Harper PS. Problems in genetic prediction for Huntington's disease. Lancet 1989; ii: 601-3. Zerres K, Stephan M. Attitudes to early diagnosis of polycystic kidney disease. Lancet 1986; ii: 1395. Modell B. Screening as public policy. In: Brock D, Rodeck C, Ferguson-Smith MA, eds. Prenatal diagnosis and screening. Churchill Livingstone (in press), 1992.
