Genetic Testing Is Different
by Ellen Wright Clayton, Vanderbilt University
Notice of Copyright
Stephen G. Post and Peter J. Whitehouse, eds. Genetic Testing for Alzheimer Disease: Ethical and Clinical Issues. Baltimore, MD: Johns Hopkins University Press, 1998. 512 pp. $45.00 cloth.
Task Force on Genetic Testing, NIH-DOE Working Group on Ethical, Legal, and Social Implications of Human Genome Research. Promoting Safe and Effective Genetic Testing in the United States: Principles and Recommendations. Baltimore, MD: Johns Hopkins University Press, 1998. 204 pp. $60.00 cloth, $28.00 paper; also available on-line at www.nhgri.nih.gov/ELSI/TFGT_final/.
Our health care system is characterized by solemn affirmations of the importance of evidence-based medicine and the constant proliferation of clinical practice guidelines, which may or may not rest on solid bedrock of rigorously collected data as opposed to expert opinion. When one looks closely, however, one observes that the outcomes thought to be relevant are pretty narrow. Typical questions are does the intervention reduce blood pressure or reduce premature mortality or at best, does the drug improve quality of life?
When compared with the focus on physiological outcomes that characterizes most policy making in medicine, the analyses that are typically undertaken to define the appropriate use of genetic tests are remarkable for their breadth. These latter efforts have been far more attentive to the limitations of genetic testing and to the ways in which numerous aspects of our health care system and more general social structures affect the meaning and impact of genetic test results. The collection of essays about genetic testing for Alzheimer disease (AD), Genetic Testing for Alzheimer Disease: Ethical and Clinical Issues, edited by Stephen G. Post and Peter J. Whitehouse, is a superb explication of these problems. The authors of this text do discuss the heritability of the early onset forms of AD that are inherited in an autosomal dominant fashion, but the majority of the essays in the book focus on the role of the protein ApoE on the occurrence of AD.
When most people think of genetics, they think of single-gene disorders like cystic fibrosis, sickle cell disease, and Huntington disease. Single-gene disorders cause much human suffering and raise important social questions that have been topics of discussion for years and even decades. Yet far more of human disease, including almost all of the diseases afflicting people in resource-rich countries, is multifactorial in origin, resulting from the action of one or usually many more genes and environmental factors. Here the questions are murkier. How does one find contributing genes? What can and should one do with the knowledge that certain genes predispose a person to develop disease? What should one do if a mutation affects more than one organ, organ system, or disease process?
The ApoE story demonstrates these dilemmas very well. Alzheimer disease is a major public health problem, affecting an estimated 4 million Americans and imposing substantial health care and personal costs. In this cognitively oriented culture, the idea of becoming demented is the ultimate nightmare for many people. Some therapies are beginning to be developed, but all clinical researchers acknowledge that we are nowhere near to having truly effective interventions. It is known that many factors predispose people to develop AD, including a history of prior head trauma, lower educational attainment, and having two copies of or being homozygous for the e4 allele of the ApoE gene, although the impact of each of these factors, taken independently, is quite modest. One can be homozygous for ApoE4 and not get AD, and one can get AD without having even one copy of ApoE4. To make matters even more complicated, ApoE also demonstrates a characteristic called pleiotropy that will almost surely apply to many genes, namely that it affects more diseases than just AD. ApoE is also strongly correlated with cardiovascular risk, a condition that has even more profound public health consequences but for which effective therapies are available. We should not be surprised by the phenomenon of pleiotropy. It makes sense that important genes would affect more than one disease process in an organism as complex as the human, but it makes it harder to decide how to proceed.
The great strength of this book is its disciplined exploration from a variety of perspectives of the difficulties of deciding what to do with the knowledge about the contribution of ApoE to the development of AD. Let me give a few examples to provide a flavor of the richness of these essays. Kimberly Quaid, one of the leading experts in genetic testing for Huntington disease (HD) and its impact on individuals and families, explores the extent to which the lessons learned from HD can be extrapolated to the setting of AD. Eric Juengst argues persuasively that even though knowledge of ApoE status may have significant clinical utility in the prevention of cardiovascular disease, testing should not be done without full disclosure of the relevance of these findings to the risk of developing AD and the potential social consequences for those who are found to be at increased risk for the latter disease. Leonard Fleck thoughtfully explores the closely linked questions of whether ApoE testing should be made available and covered by third-party payment in a health care system that inevitably has limited resources. Stephen Post discusses the pressing need to bring public expectations of what genetics can deliver more closely in line with what can actually be delivered. Atwood Gaines concludes the book with an examination through the lens of medical and cultural anthropology of the social meanings of Alzheimer disease, genetics, and medical research. Not every perspective is included in this collection. Feminist voices, for example, are not heard, which is regrettable since women bear the brunt of having and caring for those afflicted with AD. Nonetheless, readers of this book will come away with a clear understanding of the importance of considering genetic testing from a wide array of perspectives, a breadth of inquiry that does not typify the rest of medicine.
But thinking about all the issues is not enough. What is really needed is a way to use all these insights to inform clinical practice. Some of the authors in Post and Whitehouse's book do make suggestions about practice, but ultimately their recommendations are only as effective as their persuasive power to those who actually read the book. Notably, however, the genetics community has been unusually proactive in attempting to develop recommendations for practice that take into account all the implications of genetic information. Shortly after the cystic fibrosis gene was discovered, leading geneticists and genetics organizations quickly called for a moratorium on the routine offering of carrier testing, calling instead for studies to be conducted about how best to proceed (American Society of Human Genetics 1990; National Institutes of Health 1990). More than ten years later, studies have been done and consensus guidelines have been promulgated and are in the process of being implemented. More recently, geneticists and oncologists called for caution in testing for mutations that predispose individuals to develop cancer (for these mutations, the predisposition is far stronger than that of ApoE and AD). (National Advisory Council for Human Genome Research 1994; American Society of Clinical Oncology 1996).
This process of dealing with disease genes one by one, laudable as it is, nonetheless raises cause for concern. It depends on the interest of particular individuals and groups about particular disease processes, which may not always be present as knowledge about genetics increases. The ten-thousandth-disease gene may not be as exciting as the first few even though the implications of its use may be just as complex. The action of independent groups also creates the possibility that conflicting approaches will be adopted. The Task Force on Genetic Testing (Task Force), which had both lay and professional membership, was convened by the NIH-DOE Working Group on Ethical, Legal, and Social Implications of Human Genome Research to develop a more durable and consistent framework for policy making.
In their comprehensive report, Promoting Safe and Effective Genetic Testing in the United States: Principles and Recommendations, the Task Force addressed a number of issues relating to genetic testing, of which the more prominent are the role of voluntariness, full disclosure, and informed consent for genetic testing.1 The group affirmed the importance of preserving the privacy and confidentiality of genetic information. They were very concerned about ensuring optimal practices in both the research and clinical contexts and discussed both the role of institutional review boards and the critical need to educate clinicians about the appropriate use of these tests. The Task Force discussed at length the need for quality control and long-term oversight as well as the vexing problem of how to ensure the availability of high-quality testing for rare disorders, particularly in light of some of the requirements imposed by the Clinical Laboratory Improvement Act.
More to the point of this review, the Task Force described several issues that in their view must be addressed in assessing the appropriateness of genetic testing. These include: (1) determining whether the presence of mutations is causally related to the presence of disease; (2) assessing the analytical validity of a test (does it accurately detect the presence or absence of a mutation); (3) assessing the clinical validity of a test (does the test result accurately predict/detect the occurrence of disease, an analysis affected by such factors as the penetrance and heterogeneity of the disorder); and (4) finally assessing the clinical utility of a test. The authors made clear that addressing the last of these issues requires consideration not only of the availability of effective interventions but also of the larger social implications of the test results. The breadth of inquiry in Post and Whitehouse's book would appear to be what the Task Force had in mind. The important contribution of setting forth this framework is to demonstrate that while these issues are interrelated and overlap in various ways, each involves special problems that deserve to be addressed separately. The Task Force did not tell us how
to weigh these issues but rather called for the Secretary of Health
and Human Services to establish an advisory committee to decide these questions.
The Secretary accepted this invitation, chartering the Secretary's Advisory Committee on Genetic Testing (SACGT) in June 1998. This committee will soon complete a report on the adequacy of oversight of genetic testing. Although their report is not final, it appears that the SACGT will call for a multipronged process involving the Food and Drug Administration, the Department of Health and Human Services, especially the Centers for Disease Control and Prevention, and the public.2 One of the disappointing aspects of the proposed recommendations
is that while the committee appropriately recognizes that some tests require more scrutiny than others—for example, where the contribution of mutations to disease is poorly understood, where effective interventions are lacking, or where the social implications of test results are particularly challenging—it eschews the responsibility of deciding which tests require what level of examination or even providing a detailed set of criteria for making these distinctions.
While it is not yet clear who ultimately will decide which genetic tests are ready for clinical use and which are not or precisely how it will be done, much progress has been made in defining what factors need to be taken into account and in developing a process that ensures that a wide variety of perspectives are taken into account. The progress toward developing an appropriate process is aided by the many other attempts to promote the appropriate use of genetic tests that are proceeding in parallel. One example is the project undertaken by the American Academy of Pediatrics and the Maternal and Child Health Branch to consider the future of newborn screening in the United States (AAP Newborn Screening Task Force 2000). Another is the ongoing effort, nationally and internationally, to define best practices for detecting and treating hereditary hemochromatosis (Burke et al. 1998). These efforts, too, were characterized by consideration of a broad array of risks and benefits. The optimal method for defining the use of genetic tests has not yet been achieved, but the direction is clear, due in no small part to the Task Force's efforts.
In thinking about these and many other concerted attempts to ensure that genetic testing is delivered optimally, I understand why genetic testing has come under such intense scrutiny. Some of the reasons are historical. Most of us cringe when we think about the history of eugenics in this country and the practices of forced sterilization described in Buck v. Bell (274 U.S. 200 ) and Skinner v. Oklahoma (316 U.S. 535 ). It did not help that genetics next came into the public view in the context of reproductive genetic testing. Both carrier testing and prenatal diagnosis raise touchy issues for many people. Some of the reasons for heightened concern about genetics are biological. We cannot change our DNA, at least not yet; if you have a mutation, you have it, whether or not you can do something to ameliorate its actions and effects.
As a general pediatrician, however, I am struck by how many of the concerns expressed about genetic testing could appropriately be voiced about other aspects of medicine as well. New tests and techniques frequently are introduced into practice before their risks and benefits are fully understood, only to be withdrawn or modified after widespread use demonstrates problems. To pick an example from my own experience, when I was a resident, we routinely did exchange transfusions on otherwise healthy, full-term neonates whose bilirubin levels exceeded twenty. Now we treat almost all of those babies, if at all, far less invasively, with phototherapy and fluids. Many medical diagnoses have implications that extend far beyond the clinic. Physicians find themselves under enormous pressure from parents and teachers to put children on Ritalin for attention deficit hyperactivity disorder. Yet a few years ago, it was reported that the military refused to enlist anyone who had been given that diagnosis, thereby foreclosing a course that many young people have taken to enter into the labor market (Lansford 1998). And in our system of health care and employment, almost any diagnosis of disease or predisposing conditions can be harmful to your health and your pocketbook. Many of the most important determinants of health in our society—poverty, diet, education, cigarette smoking—are familial even though they are not in any meaningful way genetic. Given the striking parallels, why is most outcomes research and policy development so narrowly focused? The far-reaching process, as described in Post and Whitehouse, the Task Force, and the SACGT documents, that is evolving to govern the use of genetic testing should become a blueprint for evaluating the full array of medical practice.
References and Notes
American Academy of Pediatrics (AAP) Newborn Screening Task Force. 2000. Serving the Family from Birth to the Medical Home. Newborn Screening: A Blueprint for the Future—Call for a National Agenda on State Newborn Screening Programs. Pediatrics 106 (2 Pt. 2):389-422.
American Society of Clinical Oncology. 1996. Statement of the American Society of Clinical Oncology: Genetic Testing for Cancer Susceptibility, Adopted on 20 February. Journal of Clinical Oncology 14:1730-1736.
American Society of Human Genetics. 1990. The American Society of Human Genetics Statement on Cystic Fibrosis Screening. American Journal of Human Genetics 46:393.
Burke, W., E. Thomson, M. J. Khoury, S. M. McDonnell, N. Press, P. C. Adams,
J. C. Barton, E. Beutler, G. Brittenham, A. Buchanan, E. W. Clayton, M. E. Cogswell, E. M. Meslin, A. G. Motulsky, L. W. Powell, E. Sigal, B. S. Wilfond, and F. S. Collins. 1998. Hereditary Hemochromatosis: Gene Discovery and Its Implications for Population-Based Screening. Journal of the American Medical Association 280:172-178.
Lansford, A. 1998. ADHD and the Military. Developmental and Behavioral News (fall). Available on-line at www.dbpeds.org/section/fall98/adhd_military.html (9 June 2000).
National Advisory Council for Human Genome Research. 1994. Statement on Use of DNA Testing for Presymptomatic Identification of Cancer Risk. Journal of the American Medical Association 271:785.
National Institutes of Health. 1990. Statement from the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis Gene. New England Journal of Medicine 323:70-71.
1. This report also contains some wonderful appendixes addressing current practices in genetic testing, an analysis of the informational materials that are used for genetic testing, a history of newborn screening for phenylketonuria, and a history of reproductive genetic testing for sickle cell disease, Tay-Sachs disease, Down's syndrome, and neural tube defects.
2. The final report, entitled Enchancing the Oversight of Genetic Tests: Recommendations of the SACGT, can be found at www.4.od.nih.gov/oba/FINAL%20SACGTreport713700correctedpage27.htm.
Genetic Testing Is Different. Review Essay. Journal of Health Politics, Policy and Law, 26:2, April 2001. Copyright 2001, Duke University Press. All rights reserved; posted with permission. For information on the journal or to order a hard copy, go to http://www.dukeupress.edu/jhppl/