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28 February 2000The Department of Health is requesting comments on a draft report on Prenatal genetic testing produced by the Advisory Committee on Genetic Testing. (The ACGT has now been subsumed by the new Human Genetics Commission, which is taking the report forward on the ACGT's behalf.) The report makes recommendations on the organisation of services for prenatal genetic testing, the provision of information, the importance of informed consent, support and counselling after the test, service standards and accreditation, and prenatal testing in the context of research projects. The consultation period ends on 16 June 2000. 

14 February 2000Last week (Feb 8), President Clinton signed an executive order that prohibits the use of genetic testing in connection with the hiring or promotion of any employee of a federal department or agency. The order also requires that any genetic information obtained from a federal employee for the purpose of medical treatment or research is subject to strict privacy protection. Clinton also endorsed an Act of Congress (The Genetic Nondiscrimination in Health Insurance and Employment Act, 1999) that would make similar protections available in private employment  and in the area of health insurance.  

2 February 2000The Genetics Education and Counseling Program at the University of Pittsburgh is expanding its on-line educational programs for medical professionals and the general public. Brochures and fact sheets are already available for many single-gene genetic diseases, and on-line learning modules are underway, or planned, on psychiatric genetics and mental health (for physicians), on genetic counseling and gene therapy (for medical students), and on "Community genetics: a public health guide". For information about the development of these resources, see the Program's web page.

15 February 2000An expert panel set up by the Medical Research Council and the Wellcome Trust has been considering the establishment of a huge database of medical, genetic and lifestyle information on 500,000 UK citizens aged between 45 and 65. The panel is expected to recommend that the scheme goes ahead, subject to approval by an NHS ethical committee. Its report will be considered by the MRC and the Wellcome Trust in March. The idea is that people in the database would be followed prospectively over the coming years in an effort to correlate genetic and lifestyle information with the development of diseases such as heart disease and cancer. Ideally, this information will help in understanding how genetic and environmental factors interact to cause disease. The information would be made available to selected UK-based pharmaceutical companies with the aim of boosting their efforts to develop new drug treatments targeted to a patient's individual genetic make-up. The scheme could run into problems in the areas of confidentiality and rights of access to the data. These problems are reminiscent of those encountered in Iceland as a result of the Icelandic government's decision to sell such a database to a single commercial company. However, in a crucial difference from the Icelandic situation, all participants in the proposed UK database would be people who had made a positive choice to participate.

Note added on 24/2/00: The MRC and the Wellcome Trust are currently undertaking a public consultation to investigate public attitudes towards the issues surrounding the use of human tissue samples and genetic data. They are inviting comments on interim guidelines (available in pdf format)  for the use of human tissue and genetic information, which were published in November 1999. The outcome of the public consultation will inform plans for setting up the collection. For further information about the proposed UK-based Population Biomedical Collection, see text of a briefing note from the MRC and the Wellcome Trust.

Aspects of the US perspective on some of the issues involved are discussed in a recent paper by Paul Appelbaum in JAMA [Appelbaum P. (2000) JAMA 283, 795-797]. Appelbaum notes that the US Congress was supposed to enact "comprehensive medical privacy legislation" by August 1999, but its failure to do so has meant that the Department of Health and Human Services has had to come up with regulations in this area. Appelbaum takes issue with some provisions in the draft regulations, which have recently gone through a public consultation stage, considering them too weighted in favour of third parties such as employers and health plan managers, who would be able to gain access to medical information within certain broad categories without an individual's specific consent. However, consent would be required before private medical information could be sold or used for marketing. In addition, it would be open to individual States to enact more stringent legislation to protect privacy, should they wish to do so. The (immensely long) proposed rules were published in the US Federal Register on 3 November 1999 (scroll down the contents list to Health and Human Services Department), with corrections on 5 January 2000. 

26 February 2000The Wellcome Trust has published Volume 3 of its Labnotes series, designed to provide information for A-level school students and their teachers about new developments in biomedical science. Volume 3 is entitled "New Biology and Society" and deals with social and ethical issues arising from the applications of current research in genetics and neuroscience. The current issue covers topics in genetic engineering, xenotransplantation, transgenic animals and the use of animal models to study diseases. The next issue, due to be published in May, will deal with the Human Genome Project. Labnotes, which is free, can be ordered from The Wellcome Trust's  Marketing Deparment at 183 Euston Road, London NW1 2BE, or by e-mail from labnotes@wellcome.ac.uk . Previous volumes of Labnotes can be downloaded from The Wellcome Trust's website at http://www.wellcome.ac.uk/en/1/misedurespub.html

2 February 2000O'Donnell et al report that the E2 and E4 alleles of the blood protein Apolipoprotein E (ApoE) increase the risk of recurrence of a specific type of stroke, that caused by intracerebral haemorrhage in the lobar region of the brain [O'Donnell, H.C. et al (2000) N Engl J Med 342, 240-245] (see Alzheimer's disease summary for further information on ApoE). In a prospective study of 71 elderly patients who suffered this type of stroke, they found that 28% of those who carried either an E2 or an E4 allele suffered a recurrence within 2 years, compared with 10% of those with the common E3/E3 genotype, leading to a calculated relative risk of 3.8 for the E2 or E4 alleles compared with E3/E3. An even stronger risk factor was a history of haemorrhagic stroke before the study began (relative risk 6.4); this probably reflects the effects of other underlying genetic and/or environmental factors.

Comment: The authors of the article, and Sacco in an accompanying editorial [Sacco,R.L. (2000) N Engl J Med 342, 276-279], suggest the possible use of ApoE genotyping as an aid to determining prognosis in this type of stroke, the hope being that it might enable more refined trials to test treatments for preventing recurrence, which is very often fatal. While this may be true, and research should of course continue, the prospect of ApoE genotyping in clinical practice must be approached with caution, as it gives information about predisposition to other diseases as well, most notably late-onset Alzheimer's. As the black marks against the E4 allele pile up, the issue of informed consent in ApoE testing becomes an ever more thorny one.  

7 February 2000In the UK, it has been recommended that all pregnant women who are not of northern European origin should be offered first-trimester antenatal testing for haemoglobin disorders. If a woman is found to be a carrier, her partner should be offered carrier testing, and if he is also positive the couple should be offered the option of prenatal diagnosis. The National Confidential Enquiry in Counselling for Genetic Disorders has reported the results of an audit of informed choice in antenatal screening for thalassaemia [Modell, B et al (2000) BMJ 320, 337-341]. Examining the records for 400 pregnancies between 1990 and 1994 in 138 couples who had at least one affected pregnancy in that time, the Enquiry found evidence for poor service delivery in 110 pregnancies (28%). Service failures included failure to offer testing to the woman or her partner, late offer of testing, and failures in communication and in recognising risk. Service provision appeared to be particularly poor for British Pakistanis and Bangladeshis, and in regions other than the south east.

Comment: As the authors stress, the aim of the antenatal screening service for thalassaemia is to offer informed choice. This can only be achieved if information is provided in a timely and comprehensible way to all those at risk. It appears that religious/ethnic stereotyping might be responsible for at least some of the inequitable service provision, as there is a perception that prenatal diagnosis is unacceptable to Pakistani and Bangladeshi Muslims. Modell et al point out that in fact over 70% of British Pakistanis take up an offer of prenatal diagnosis if it is made in the first trimester. In this group, therefore, it is particularly vital to ensure that testing is offered early enough. At present there are only two trained counsellors who speak the appropriate languages and they are both in the south east; clearly this deficiency needs to be remedied.

28 February 2000The Department of Health is requesting comments on a draft report on Prenatal genetic testing produced by the Advisory Committee on Genetic Testing. (The ACGT has now been subsumed by the new Human Genetics Commission, which is taking the report forward on the ACGT's behalf.) The report makes recommendations on the organisation of services for prenatal genetic testing, the provision of information, the importance of informed consent, support and counselling after the test, service standards and accreditation, and prenatal testing in the context of research projects. The consultation period ends on 16 June 2000. 

15 February 2000The Genetics and Insurance Committee has begun a consultation process to decide what criteria insurance companies should have to satisfy if they wish to use a specific genetic test for insurance risk assessment. GAIC has approached the question by producing a draft version of an application form that insurers would have to submit to GAIC, and is asking for comments from interested parties by 17 March 2000. The draft application form includes sections requiring information on, for example, the genetic basis of the condition (including penetrance and any genetic heterogeneity), test standards, any inherent weakness or technical shortcomings in the test or its interpretation, and how the interpretation of the test result will be influenced by genetic findings in other family members. It also requires the insurance company to provide evidence that the proposed test is actuarially relevant to the type of insurance covered by the application. GAIC notes that, in the short- and medium-term future, they expect applications to be made only in respect of tests for single-gene Mendelian diseases that have a large effect on health or life expectancy; at present, too little is known about genetic predisposition to multifactorial diseases to justify insurers' use of tests for predisposing polymorphisms. The draft application form is accompanied by a very useful set of notes giving further information and guidance. In particular, an excellent Annex (Annex C) gives a layman's guide to insurance underwriting in life and health insurance that should be required reading for all those with an interest in this area. Copies of the consultation can be downloaded from the GAIC website

7 February 2000For about eight years there has been controversy about whether a common polymorphism in the angiotensin converting enzyme (ACE) confers an increased risk of heart disease. Numerous small studies (fewer than 200 cases) reported risk ratios for cases versus controls ranging from about 1.4 to 1.8, but a meta-analysis of larger studies yielded a risk ratio of 0.99. Keavney et al have now reported the results of the largest case-control study to date, comparing around 5000 cases and 6000 controls [Keavney, B. et al. (2000) Lancet 355, 434-442]. Assuming a recessive genetic model for the association between the D polymorphism and myocardial infarction (that is, the risk applies only to people who have two copies of the D allele) they find a risk ratio of 1.10, with a 95% confidence interval of 1.00-1.21. Their calculation incorporated a correction for the effects of including, as controls, some healthy first-degree relatives of cases.

Comment: The results of this study emphasise the importance of large numbers of subjects in case-control studies to investigate disease associations with candidate genes. Keavney et al suggest that studies with at least 10000 cases and 10000 controls are likely to be needed in order to obtain reliable relative risk figures for common genetic variants that have only weak or moderate effects. The authors point out that weak associations might still be important from the point of view of elucidating mechanisms of disease. However, factors associated with an increased risk of less than 10% are clearly not - at least on their own - going to be useful to those who might contemplate genetic testing for predisposition to a disease. There might still turn out to be some subgroups of people for whom ACE genotype is a significant risk factor, but Keavney et al found no evidence that this was the case for any of the subgroups they investigated. 

24 February 2000Gerhardt et al have tested genetic markers of inherited thrombophilia in 119 women who experienced thrombosis during pregnancy and 233 normal women [Gerhardt, A. et al (2000) N Engl J Med 342, 374-380 (Abstract); see also Editorial by Greer (Greer, I. (2000) N Engl J Med 342, 424-425)]. They found that 43.7% of the women with pregnancy-associated thrombosis carried the Factor V Leiden mutation compared with 7.7% of normal women; the corresponding percentages for the prothrombin G20210A mutation were 16.9% and 1.3%. The relative risks calculated for these mutations were 9.3 for Factor V Leiden and 15.2 for the G20210A prothrombin mutation. Moreover, 9.3% of the women with a history of thrombosis carried both of the mutations, whereas none of the normal women did (estimated odds ratio 107). Homozygosity for the 5,10-methylenetetrahydrofolate reductase (MTHFR) mutation C677T did not confer an increased risk. Gerhardt et al have also calculated the positive predictive value of Factor V Leiden and prothrombin G20210A mutations for pregnancy-associated thrombosis: 0.2% for Factor V Leiden carriers, 0.5% for prothrombin G20210A carriers and 4.6% for women carrying both mutations.

Comment: This paper makes a useful contribution to information on the role of genetic factors in pregnancy-associated thrombosis. More research is needed, with sample sizes as large as possible, to determine as accurately as possible the extent to which mutations such as Factor V Leiden and prothrombin G20210A contribute to the risk of thrombosis both in general and in higher-risk situations such as pregnancy. Research is also needed to elucidate how combinations of such mutations can interact in a more than additive way. At present, however, genetic testing of women with a history of thrombosis does not seem warranted except for research purposes, as knowledge of genetic status does not - so far - make any difference to clinical management. 

11 February 2000Schrag et al have used decision analysis, based on published data, to estimate the gains in life expectancy that might be expected to result from prophylactic interventions in women with breast cancer who have mutations in the BRCA1 or BRCA2 genes [Schrag, E. et al. (2000) JAMA 283, 617-624 (Abstract) (see Breast cancer summary for background information]. They examined the effects of 8 different interventions, including tamoxifen treatment, prophylactic contralateral mastectomy, prophylactic oophorectomy and combinations of these. All of the interventions resulted in significant life expectancy gains, ranging from about 6 months to 2 years; tamoxifen gave the lowest gain and prophylactic contralateral mastectomy the highest. These gains should be considered in the context of a total remaining life expectancy of 34-40 years for a 30-year-old BRCA1/2-positive woman with breast cancer that has not affected the axillary nodes. Schrag et al point out that their estimates of life expectancy gain are very sensitive to the penetrance of the BRCA1 or 2 mutation, for example a woman with node-negative breast cancer would be predicted to gain 0.9 extra years of life from prophylactic mastectomy if her mutation has low penetrance (24% risk for contralateral disease) and 2.1 years if the mutation has high penetrance (65% risk).

Comment: It is still very difficult for women carrying BRCA1 or 2 mutations to decide what they should do. It is encouraging that, for these women as for the much larger number of women with sporadic disease, the chances of long-term survival are good if the disease is detected at an early stage. For some BRCA1/2-positive women, the extra life expectancy resulting from prophylactic treatments may make it worth coping with the adverse effects of these treatments; for others, it may not. The best that can be hoped for at this stage is that increasingly accurate information will become available both about penetrance (so that calculations of individual risk can be more precise) and about the long-term risks and benefits of treatments such as tamoxifen, so that women affected by BRCA1/2 mutations can make a fully informed choice.  

11 February 2000Antenatal serum screening for Down's syndrome is widely available throughout the UK, although some centres restrict screening to women over a particular age, and the screening protocol varies considerably (see Down's syndrome page for references). All screening procedures have a false-negative rate; for antenatal serum screening for Down's syndrome it ranges from about 25% to 65%. Little systematic work has been done on the effects of a Down's syndrome birth after a false-negative result. Hall et al report that in general parents adjust well to the unexpected birth of a Down's syndrome child [Hall, S et al (2000) BMJ 320, 407-412]. However, comparing parents of Down's children born after a false-negative screening result with those born to parents who declined screening and those who were not offered screening, they found a small but significant adverse effect on levels of parental stress and attitudes to the child. These factors were associated with a greater propensity to attribute blame (to health care professionals or the health care system in general) for the birth of the child.

Comment: As the number of screening programmes grows, it becomes increasingly important to understand people's reactions to screening, including their reactions to false-negative and false-positive results, and the consequences of these reactions. The results presented by Hall et all suggest that, although the difference is small, the pscyhological consequences of having a Down's syndrome child after a false-negative screening result are actually worse than if no screening had been undertaken at all. Clearly one would not want to conclude from this that screening programmes should be halted. However, there is a need for much more effective education about screening tests, particularly in conveying an understanding of their limitations. It has been suggested that screening should be re-named "risk reduction", to emphasise that a negative result does not reduce the risk to zero. 

7 February 2000The Wellcome's Medicine in Society programme is calling for applications for funding to support research on new ways of consulting the public about developments in biomedical science. Proposals should relate to developments in either human genetics or neuroscience, but the Trust is looking for new methods and approaches, rather than new topics. Further information is available from the Wellcome's web site. Closing dates for applications are 1 March 2000 and 1 September 2000.