[Paleopsych] SW: On Hereditary Disease Risks

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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
    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
    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
    Related Material:
    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
    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
    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
    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
    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
    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
    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
    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.
    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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