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ScienceWeek
MEDICAL ETHICS: ON HEREDITARY DISEASE RISKS
The following points are made by K. Offit et al (J. Am. Med. Assoc. 2004 292:1469):
1) Genetic tests for specific adult-onset disorders (eg, breast and colon cancer) are now commercially available, and results of research studies for genetic polymorphisms that predict drug effects, for example, response to statin therapy, have recently been published.(1) The failure to warn family members about their hereditary disease risks has resulted in three malpractice suits against physicians in the US.(2-4)
2) This past year, the obligation, if any, to warn family members of identification of a cancer gene mutation was the topic of discussion among professional societies and advocacy groups. Concerns have been raised regarding the conflict between the physician's ethical obligations to respect the privacy of genetic information vs the potential legal liabilities resulting from the physician's failure to notify at-risk relatives. In many cases, state and federal statutes that bear on the issue of "duty to warn" of inherited health risk are also in conflict.
3) Consider the following case: A 40-year-old woman presents for a follow-up consultation. She has a family history of breast cancer, heart disease, and Alzheimer disease. At her first visit, the physician had counseled her and provided genetic testing and now tells the patient that she was found to have an inherited BRCA2 mutation that markedly increases her risk for developing breast cancer and/or ovarian cancer. The testing laboratory has also suggested a "genomic profile" that will predict risk for Alzheimer disease as well as sensitivity to a variety of drugs. The patient's sister, who is sitting in the waiting room, has a 50% chance of inheriting this same BRCA2 mutation. Although the physician had discussed the importance of familial risk notification before testing, the patient declines the strong recommendation that she share the results of her genetic tests with her sister and asks that this information be kept completely confidential. Does this physician have an obligation to tell the patient's sister that she, too, may have inherited these genetic predispositions?
4) An expanded national discussion of the ethical and legal implications of genetic risk notification is required to guide practitioners of "molecular medicine". Fear of loss of privacy among susceptible populations could discourage families from seeking access to potentially life-saving genetic testing. In the genomic era, clinical testing will be offered to predict disease occurrence, as well as sensitivities to drugs or environmental exposures. Because the laws of Mendel will continue to apply to these new markers of genetic risk, the issues surrounding familial notification will loom even larger. The increasing availability of DNA testing will require greater emphasis on informed consent as a process of communication and education, so as to better facilitate the translation of genomic medicine to clinical practice.
5) The authors conclude: While the findings of case law and the state and federal statutes that bear on the issue of "duty to warn" of inherited health risk are still being defined, health care professionals have a responsibility to encourage but not to coerce the sharing of genetic information in families, while respecting the boundaries imposed by the law and by the ethical practice of medicine.(5)
References (abridged):
1. Chasman DI, Posada D, Subrahmanyan L, et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004;291:2821-2827
2. Pate v Threlkel, 661 So 2d 278 (Fla 1995)
3. Safer v Estate of Pack, 677 A2d 1188 (NJ App), appeal denied, 683 A2d 1163 (NJ 1996)
4. Molloy v Meier, Nos. C9-02-1821, C9-02-1837 (Minn 2004)
5. Beauchamp TL, Childress, JF. Principles of Biomedical Ethics. New York, NY: Oxford University Press; 1994
J. Am. Med. Assoc. http://www.jama.com
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Related Material:
SCIENCE POLICY: ON THE REGULATION OF HUMAN GENETIC TESTS
Notes by ScienceWeek:
As more and more human genes related to diseases are identified, the commercialization of tests designed to detect the presence of such genes in individuals gathers momentum and introduces a spectrum of problems that will most likely be of considerable importance in the coming decades.
The following points are made by Neil A. Holtzman (Science 1999 286:409):
1) The Human Genome Project has engendered "genohype", from early pronouncements that our destiny is in our genes to recent declarations that new discoveries will minimize or prevent the appearance of diseases in individuals altogether. As a result of these claims, commercial enterprises have sprung up to identify the presence of susceptibility-conferring genes in individuals. As early as 1995, over 50 biotechnology companies were developing or providing tests to diagnose genetic disorders or to predict the risk of their future occurrence. Common complex disorders, usually disorders of adult onset such as Alzheimer's disease and breast and colon cancer, make up the single largest category for which tests are under commercial development.
2) The "educational" materials prepared by companies for physicians and patients considering genetic tests frequently make exaggerated claims for predictive tests for common complex disorders. In particular are exaggerated claims for a) clinical validity (i.e., the probability of a detectable susceptibility-conferring gene occurring in those who would get the disease, and the probability that those with a susceptibility-conferring gene would actually get the disease); and b) claims for utility (i.e., how a positive test result could help people cope with future disease).
3) This situation has arisen because of the double standard which the US Food and Drug Administration (FDA) uses to regulate in vitro clinical diagnostic devices: If a genetic test is to be marketed as a kit, the manufacturer of the test kit must first demonstrate its clinical validity to the satisfaction of the FDA, and scrutiny by the FDA of the labeling of the test kit can ensure the utility of the test is not exaggerated. But if, on the other hand, a test is marketed as a clinical laboratory service, the laboratory providing the service is not even required to notify the FDA. The author states that the FDA admits it has the authority to regulate clinical laboratory tests marketed as services, but (according to the author) the FDA says it does not have the resources to carry out such regulation.
4) With respect to statements of clinical validity and utility, the FDA regulation of genetic tests marketed as services should be as stringent as the regulation of tests marketed as kits.
Science http://www.sciencemag.org
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Notes by ScienceWeek:
During the past 2 decades in the US, one relatively new feature of the scientific enterprise has been a mushrooming of the number of prominent academic researchers in molecular biology who have become high-level corporate research managers. Often these high-level research managers maintain ties to the universities that originally hosted their research, ties, for example, that may involve patent partnerships. Where patents are involved, in many cases, the research underlying the patents was financed by US federal funds, while the patents are now the basis for extensive private commercial ventures. This situation was made possible by explicit US Congressional legislation in the 1980s. An example of the various controversies follows:
In May 1998, in a long article, the journal *Science* presented a detailed profile of Allen Roses, a neurologist at Duke University (US), who in 1997 became head of genetics research at Glaxo Wellcome, Roses overseeing a US$50 million genetics research budget that is part of the Glaxo Wellcome US$2 billion annual research and development effort.
Prior to his move to Glaxo Wellcome, Roses achieved prominence as the head of a research group at Duke University that discovered a gene variant that apparently increases a carrier's risk of developing the common late-onset form of Alzheimer's disease (the most common form) -- a discovery that was initially ignored by many researchers in the field but is now considered to be of some importance.
After assuming his new position at Glaxo Wellcome, Roses apparently set about creating an international "network of clinicians" to provide data and clinical material to Glaxo in its "hunt for disease-related genes", with the evident interest of Glaxo Wellcome that of patenting key discoveries (including genes) and manufacturing drugs based on the new discoveries. The focus is on pathologies such as asthma, cardiovascular disease, mental depression, schizophrenia, inflammatory bowel disease, dermatitis, and susceptibility to infectious agents -- in other words, a wide array of human diseases with possible genetic involvements. The essential idea is apparently to build up detailed indexes of variations in human genes and use these indexes to scan the genomes of patients or volunteers.
Concerning Alzheimer's disease, the approach of Roses and his group has been criticized because their marker for Alzheimer's disease, a gene variant (called _APOE4_) of an *apolipoprotein gene called _APOE_, does not appear to cause the disease directly but appears to only increase the risk. Many researchers believe that other genes and other proteins, particularly so-called *beta-amyloid proteins, are involved in Alzheimer's disease.
The Allen Roses profile in *Science* appeared 15 May 1998.
On 28 August 1998, J.F. Merz et al, in a letter to the journal *Science*, pointed out that the article about Roses and his advocacy of wide genetic testing for Alzheimer's disease did not mention that Roses is named as an inventor on a patent claiming exclusive rights to the detection of the _APOE_ *allele, a patent now held in exclusive license from Duke University and Roses by a company called AthenaDiagnostics, and that AthenaDiagnostics has attempted to stop anyone anywhere from performing _APOE_ genotyping for the purpose of diagnosing Alzheimer's disease. In other words, AthenaDiagnostics effectively owns the gene that may be one of the causes of Alzheimer's disease, and no one can use that gene (which when present appears as part of human chromosome 19) for diagnostic purposes without paying a royalty fee. Considering the advocacy by Roses of genetic testing for Alzheimer's disease, J.F Merz et al stated: "This situation raises ethical concerns, not the least of which is that those who benefit financially from the performance of genetic testing and screening could be said to have a conflict of interest that might lead to aggressive promotion of those tests."
On 18 September 1998, Allen Roses responded to the J.F. Merz et al letter in *Science*, and also to other related commentary by J.F. Merz et al in *Nature Medicine*. In summary, Roses criticized his critics for "incorrect notions and opinions", stated that it is not true that he receives 50% of the licensing fees for the _APOE_ gene, stated that he was being attacked personally without relevant facts, and that he had not been able to respond to the criticisms in *Nature Medicine* because that journal does not entertain responses.
On 9 October 1998, A.J. Ivinson, the editor of *Nature Medicine*, published a letter in *Science* in response to the Roses letter, Ivinson stating that *Nature Medicine* does sometimes invite responses, and that during a face-to-face discussion Roses was specifically invited to respond to the *Nature Medicine* text and he failed to do so, "making his comments regarding our policy on responses all the more surprising."
Finally, we return to 19 February 1998, to a paper published in the *New England Journal of Medicine* by a large research group that included the Roses research team, in which study the authors reviewed clinical and autopsy _APOE_ data on 2188 patients at various installations referred for evaluation of dementia, and in which paper the authors (Allen Roses among them) conclude: "APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis."
All the backbiting and considerations of conflict of interest aside, the last paragraph is the essence of this brouhaha: Given that the direct and unique involvement of the _APOE_ gene in Alzheimer's disease has not been demonstrated, should _APOE_ genotyping (and consequent labeling of people as "Alzheimer's prone") be widely used? The bioethicists say no, that given the uncertainties in diagnosis, the social dangers are too great; while Allen Roses, Glaxo Wellcome, and others say yes, that genotyping can substantially improve clinical diagnostics.
Science 1998 282:239 Science 1998 281:1805 Science 1998 281:1288 Science 1998 280:1001 New England J. Med. 11998 338:505
Science http://www.sciencemag.org New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek:
apolipoprotein gene: An apolipoprotein is the protein component of a lipoprotein (lipid + protein) complex. In its non-pathological form, the apolipoprotein gene is involved in the metabolism of fats. Concerning the pathological form of the gene, apparently confirmed data indicate that white persons 60 to 80 years old with two copies of the variant allele are 9 times more likely to get Alzheimer's disease than those who do not carry the variant. But almost everything else about the gene is in controversy.
beta-amyloid proteins: Post-mortem tissue analysis of Alzheimer's disease patients and Down syndrome patients reveals anomalous protein deposits (beta-amyloid protein) in brain nerve cells. Many researchers believe these deposits are in some way related to the etiology of both of these disease entities.
allele: An allele is one of two or more forms of a given gene that control a particular characteristic, with the alternative forms occupying corresponding loci on homologous chromosomes.
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