Executive Summary

Approximately 3 percent of all children are born with a severe disorder that is presumed to be genetic in origin, and several thousand definite or suspected single-gene diseases have been described. Most of these diseases manifest themselves early in life, although some inherited diseases—and many others that have a genetic component—have their onset much later in life (e.g., diabetes mellitus or mental illness). Then there are many disorders in which both genetic and environmental factors play major roles (e.g., coronary heart disease, hypertension). These ''complex" disorders are more common than single-gene diseases and thus, in the aggregate, constitute a greater public health burden. Many disease genes can be detected in individuals before symptoms occur, but for many common diseases with some genetic basis, such as heart disease and cancer, the detection of genetic alterations might only indicate susceptibility, not the certainty of disease.

PROMISE AND PROBLEMS IN GENETIC TESTING

The ability to diagnose genetic disease has developed rapidly over the past 20 years, and the Human Genome Project, with its ambitious goal of mapping and sequencing the entire genome, will bring a further explosion in our knowledge of the structure and function of human genes. The ultimate goals of these scientific advances are the treatment, cure, and eventual prevention of genetic disorders, but effective interventions lag behind the ability to detect disease or increased susceptibility to disease. Thus, many genetic services today consist of diagnosis and counseling; effective treatment is rare. Nevertheless, as more genes are identi-



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Assessing Genetic Risks: Implications for Health and Social Policy Executive Summary Approximately 3 percent of all children are born with a severe disorder that is presumed to be genetic in origin, and several thousand definite or suspected single-gene diseases have been described. Most of these diseases manifest themselves early in life, although some inherited diseases—and many others that have a genetic component—have their onset much later in life (e.g., diabetes mellitus or mental illness). Then there are many disorders in which both genetic and environmental factors play major roles (e.g., coronary heart disease, hypertension). These ''complex" disorders are more common than single-gene diseases and thus, in the aggregate, constitute a greater public health burden. Many disease genes can be detected in individuals before symptoms occur, but for many common diseases with some genetic basis, such as heart disease and cancer, the detection of genetic alterations might only indicate susceptibility, not the certainty of disease. PROMISE AND PROBLEMS IN GENETIC TESTING The ability to diagnose genetic disease has developed rapidly over the past 20 years, and the Human Genome Project, with its ambitious goal of mapping and sequencing the entire genome, will bring a further explosion in our knowledge of the structure and function of human genes. The ultimate goals of these scientific advances are the treatment, cure, and eventual prevention of genetic disorders, but effective interventions lag behind the ability to detect disease or increased susceptibility to disease. Thus, many genetic services today consist of diagnosis and counseling; effective treatment is rare. Nevertheless, as more genes are identi-

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Assessing Genetic Risks: Implications for Health and Social Policy fied, there is growing pressure to broaden existing screening programs, and otherwise increase both the number of available genetic tests and the volume of genetic information they generate. The rapidly changing science and practice of genetic testing raise a number of scientific, ethical, legal, and social issues. The national investment in the Human Genome Project will greatly increase the capacity to detect genes leading to disease susceptibility. It will also greatly increase the availability of genetic testing over the next 5 to 10 years, identifying the genetic basis for diseases—even some newly discovered to be genetic—and increasing the number of tests for detecting them. The emergence of the biotechnology industry increases the likelihood that these findings will be rapidly translated into widely available test kits and diagnostic products. Entrepreneurial pressure may also lead to the development of commercial and academic "genetic testing services" that would not be regulated under current Food and Drug Administration (FDA) procedures. Problems of laboratory quality control would be heightened by the introduction of "multiplex" tests that detect the presence of numerous genetic markers—for disease, carrier status, and susceptibility alike—at the same time. And the potential for generating all of this genetic information about individuals raises serious questions of informed consent, confidentiality, and discrimination. Over the next five to ten years, there will be an increasing number of personal and public policy decisions related to genetic testing; well-trained health professionals and an interested and informed public will both be key to that decision making. As genetic screening becomes more widespread, these issues threaten to outrun current ethical and regulatory standards, as well as the training of health professionals. There will be a need for greater numbers of genetics specialists, but genetic testing is no longer just for specialists. Increasingly, primary care providers will be called upon to administer tests, counsel patients, and protect their privacy. Government officials and the broader public will also be called upon to participate in setting public policy for genetic testing and in making difficult decisions, public and private, based on the results of genetic tests. Consequently, there must be a significant increase in genetics education, both in the medical curriculum and for all Americans. Finally, there will be a need for centralized oversight to ensure that new genetic tests are accurate and effective, that they are performed and interpreted with close to "zero-error" tolerance, and that the results of genetic testing are not used to discriminate against individuals in employment or health insurance. COMMITTEE ON ASSESSING GENETIC RISKS This study of the scientific, ethical, legal, and social issues implicit in the field of genetic diagnosis, testing, and screening was supported jointly by the National Center for Human Genome Research at the National Institutes of Health and the Department of Energy's Health Effects and Life Sciences Research Of-

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Assessing Genetic Risks: Implications for Health and Social Policy fice. Supplemental funding was also provided by the Markey Charitable Trust and the Institute of Medicine. The Committee on Assessing Genetic Risks hopes that this report will be widely read, not only by various health professionals interested in genetics and preventive medicine, but by a wide-ranging audience who makes and influences public policy in the United States, including members of genetic support groups and the public. The establishment of the Ethical, Legal, and Social Implications (ELSI) Program in the Human Genome Project (HGP) and the set-aside of the first 3 to 5 percent of the HGP research budget for the study of ethical, legal, and social issues is unique in the history of science. This support gives us the opportunity to "worry in advance" about the implications and impacts of the mapping and sequencing of the human genome, including several thousand human disease genes, before wide-scale genetic diagnosis, testing, and screening come into practice, rather than after the problems have presented themselves in full relief. The committee took its starting point from the wise advice of the 1975 National Academy of Sciences study Genetic Screening: Programs, Principles, and Research: Screening programs for genetic diseases and characteristics ... have multiplied rapidly in the past decade, and many have been begun without prior testing and evaluation and not always for reasons of health alone. Changes in disease patterns and a new emphasis on preventive medicine, as well as recent and rapid advances in genetics, indicate that screening for genetic characteristics will become more common in the future. These conditions, together with the mistakes already made, suggested the need for a review of current screening practices that would identify the problems and difficulties and give some procedural guidance, in order to minimize the shortcomings and maximize the effectiveness of future genetic screening programs. These words, written almost 20 years ago, remain just as valid today for genetic testing and diagnosis. The committee reaffirms the sentiments expressed in the 1975 report and hopes to update and broaden their application for the 1990s and beyond. As a result, the committee has posed its recommendations in terms of general principles that we hope will be useful today—and for some years into the future—for the evaluation of expanded genetic diagnosis, testing, and screening. Although these recommendations reflect what is known today, and what experts foresee for the next few years, the committee had no crystal ball and, therefore, tried to develop criteria and to suggest processes for assessing when new tests are ready for pilot introduction and for widespread application in the population. The committee's fundamental ethical principles include voluntariness, informed consent, and confidentiality, which in turn derive from respect for autonomy, equity, and privacy. Other committee principles described in the report include the necessity of (1) high-quality tests (of high specificity and sensitivity)

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Assessing Genetic Risks: Implications for Health and Social Policy performed with the highest level of proficiency and interpreted correctly; and (2) conveying information to clients—both before and after testing—in an easily understood manner through genetic education and counseling that is relevant to the needs and concerns of the client. These principles are the absolute foundation of genetic testing. It is the view of the committee that, until benefits and risks have been defined, genetic testing and screening programs remain a form of human investigation. Therefore, routine use of tests should be preceded by pilot studies that demonstrate their safety and effectiveness. Standard safeguards should be applied in conducting these pilot studies, and independent review of the pilot studies should be conducted to determine whether the test should be offered clinically. Publicly supported population-based screening programs are justified only for disorders of significant severity, impact, frequency, and distribution, and when there is consensus that the available interventions warrant the expenditure of funds. Informed consent should be an essential element of all screening. These principles and procedures described above should apply to genetic testing regardless of the setting, whether in primary medical practice, public programs, or any other settings. GENETIC TESTING AND ASSESSMENT Genetic tests include the many different laboratory assays used to diagnose or predict a genetic condition or the susceptibility to genetic disease. Genetic testing denotes the use of specific assays to determine the genetic status of individuals already suspected to be at high risk for a particular inherited condition because of family history or clinical symptoms; genetic screening involves the use of various genetic tests to evaluate populations or groups of individuals independent of a family history of a disorder. However, these terms are commonly used interchangeably, and the committee has generally used the term genetic testing unless a specific aspect of genetic screening alone is being discussed. Genetic counseling refers to the communication process by which individuals and their family members are given information about the nature, recurrence risk, burden, risks and benefits of tests, and meaning of test results, including reproductive options of a genetic condition, as well as counseling and support concerning the implications of such genetic information. Newborn Screening At the present time, there are 10 genetic conditions for which some states screen newborns, although the scope of such screening varies by state (see Table 1). It is also possible to extract DNA from the newborn blood "spots" that are used for these tests. There is increasing pressure to test old blood samples for a wide variety of disorders, as well as to do DNA testing on newborns for a wide

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Assessing Genetic Risks: Implications for Health and Social Policy TABLE 1 Genetic Disorders for Which Newborns Were Screened in the United States in 1990 Disorder No. of States That Provided Screeninga Phenylketonuria 52 Congenital hypothyroidismb 52 Hemoglobinopathy 42c Galactosemia 38 Maple syrup urine disorder 22 Homocysteinuria 21 Biotinidase deficiency 14 Adrenal hyperplasia 8 Tyrosinemia 5 Cystic fibrosis 3d a Includes District of Columbia, Puerto Rico, and U.S. Virgin Islands. b Only a proportion of cases have a genetic etiology. c Utah's hemoglobinopathy pilot study (6-1-90 through 3-31-91) has been discontinued. d Wisconsin's cystic fibrosis screening program is for research purposes only. SOURCE: Council of Regional Networks for Genetic Services, 1992. variety of disorders in the future. As basic principles to govern newborn screening, the committee recommends that such screening take place only when (1) there is a clear indication of benefit to the newborn, (2) a system is in place to confirm the diagnosis, and (3) treatment and follow-up are available for affected newborns. In addition, the committee does not believe that newborns should be screened using multiplex testing for many disorders at one time unless all of the disorders meet the principles described by the committee in this report (see Chapters 2 and 8). To determine clear benefit to the newborn, well-designed and peer-reviewed pilot studies are required to demonstrate the safety and effectiveness of the proposed screening program. In pilot studies for new population-based newborn screening programs, parents should be informed of the investigational nature of the test and have the opportunity to consent to the participation of their infant. Since some existing programs may not have been subject to careful evaluation, the committee recommends that ongoing programs be reviewed periodically, preferably by an independent body that is authorized to add, eliminate, or modify existing programs (see Chapters 1, 3, and 9). The need for ongoing review and revision also suggests that detailed statutory requirements for specific tests may be unduly inflexible; state statutes should provide guidance for standards—not prescriptions. The committee recommends that states with newborn screening programs for treatable disorders also have programs

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Assessing Genetic Risks: Implications for Health and Social Policy available to ensure that necessary treatment and follow-up services are provided to affected children identified through newborn screening without regard to ability to pay. Informed consent should also be an integral part of newborn screening, including disclosure of the benefits and risks of the tests and treatments. Finally, mandatory screening has not been shown to be essential to achieve maximum public health benefits; however, it is appropriate to mandate the offering of established tests (e.g., phenylketonuria, hypothyroidism) where early diagnosis leads to improved treatable outcomes. (See Chapter 8.) Newborns should not be screened for the purpose of determining the carrier status of the newborn or its parents for autosomal recessive disorders. Instead, couples in high-risk populations who are considering reproduction should be offered carrier screening for themselves (see below). When carrier status may be incidentally determined in newborn screening (e.g., in sickle cell screening), parents should be informed in advance about the benefits and limitations of genetic information, and that this information is not relevant to the health of their child. If they ask for the results of the incidentally determined carrier status for their own reproductive planning, it should be communicated to them in the context of genetic counseling, and they should be informed that misattributed paternity could be revealed. Newborn screening programs should include provision for counseling of parents who are informed that the child is affected with a genetic disorder. The committee recognizes the complexities of identifying information about misattributed paternity. On balance, the committee recommends that information on misattributed paternity be communicated to the mother, but not be volunteered to the woman's partner. There may be special circumstances that warrant such disclosure, but these situations present difficult counseling challenges (see Chapters 4 and 8). Stored newborn blood spots should be made available for additional research only if identifiers have been removed. As with other research involving human subjects, research proposals for the subsequent use of newborn blood spots should be reviewed by an appropriate institutional review board. If identifiable information is to be disclosed, informed consent of the infant's parent or guardian should be obtained prior to use of the specimen (see Chapters 2 and 8 for further discussion). Although DNA typing will provide new tools for newborn screening, in general, the committee recommends that these tools be employed only (1) when genetic heterogeneity of conditions to be detected is small; (2) when the sensitivity of detecting disease-causing mutations is high; (3) when costs are reasonable; and (4) when the benefits to newborns of early detection are clear. Carrier Identification Carrier testing is usually provided for purposes of reproductive planning. The committee recommends that couples in high-risk populations who are

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Assessing Genetic Risks: Implications for Health and Social Policy considering reproduction be offered carrier screening before pregnancy if possible. Standard safeguards such as institutional review and demonstrated safety and effectiveness should be applied in initiating any carrier detection program. First, the test should be accurate, sensitive, and specific. In the future, such screening will be done increasingly as part of routine medical care; the same principles should apply regardless of the setting. Carrier testing and screening should also be voluntary, with high standards of informed consent and attention to telling individuals or couples, in easily understood terms, the medical and social choices available to them should they be found at risk for disease in their offspring, including termination of the pregnancy. Research is needed to develop innovative methods for providing carrier testing in young adults before pregnancy and to evaluate these methods through pilot studies. The committee had reservations about carrier screening programs in the high school setting in the United States and about carrier screening of persons younger than age 18. With improving technology, carrier status for many different rare autosomal and X-linked recessive disorders will be detectable by multiplex technology (see Chapters 1 and 8). Obtaining appropriate informed consent before testing for each of these disorders will be a challenge (see Chapter 4). Multiplexed tests should, therefore, be grouped into categories of tests (and disorders) that raise similar issues and implications for informed consent and for genetic education and counseling (see Chapters 1, 4, and 8). If carrier status is detected, individuals should be informed of their carrier status to allow testing and counseling to be offered to their partners. Usually, the partner will be found not to be a carrier; however, if both partners are carriers, they should be referred for genetic counseling to help them understand available reproductive options, including the possibility of abortion of an affected fetus identified through prenatal diagnosis. Prenatal Diagnosis Anyone considering prenatal diagnosis must be fully informed about the risks and benefits of both the testing procedure and the possible outcomes, as well as alternative options that might be available. Disclosure should include full information concerning the spectrum of severity of the genetic disorders for which prenatal diagnosis is being offered (e.g., cystic fibrosis or fragile X). Furthermore, invasive prenatal diagnosis is only justified if the diagnostic procedures are accurate, sensitive, and specific for the disorder(s) for which prenatal diagnosis is being offered. Standards of care for prenatal screening and diagnosis should also include education and counseling before and after the test, either directly or by referral, and ongoing counseling should also be available following termination of pregnancies. The committee believes that offering prenatal diagnosis is an appropriate standard of care in circumstances associated with increased risk of carrying a fetus with a diagnosable genetic disorder, including the increased risks associated

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Assessing Genetic Risks: Implications for Health and Social Policy with advanced maternal age. However, the committee was concerned about the use of prenatal diagnosis for identification of trivial characteristics or conditions. It was the consensus of this committee that prenatal diagnosis should only be offered for the diagnosis of genetic disorders and birth defects. A family history of a diagnosable genetic disorder warrants the offering of prenatal diagnosis, regardless of maternal age, as does determination of carrier status in both parents of an autosomal recessive disorder for which prenatal diagnosis is available. Prenatal diagnostic services for detection of genetic disease for which there is a family history should be reimbursed by insurers (see Chapters 2 and 7). Ability to pay should not restrict appropriate access to prenatal diagnosis or termination of pregnancy of an affected fetus. The committee felt strongly that the use of fetal diagnosis for determination of fetal sex and the subsequent use of abortion for the purpose of preferential selection of the sex of the fetus represents a misuse of genetic services that is inappropriate and should be discouraged by health professionals. More broadly, reproductive genetic services should not be used to pursue eugenic goals, but should be aimed at increasing individual control over reproductive options. As a consequence, additional research is needed on the impact of prenatal diagnosis, particularly its immediate and long-term impact on women, and on the design and evaluation of genetic counseling techniques for prenatal diagnosis for the future. Testing for Late-Onset Disorders Science is moving closer to defining the genetics of such adult disorders as Alzheimer disease, a variety of cancers, heart disease, and arthritis, to name a few (see Chapter 2). A combination of genetic and environmental factors plays a predominant role in most people afflicted with these disorders, but we do not yet understand why some people with a certain gene(s) develop a disease and others do not. Although further work may eventually elucidate the gene(s) involved, there may be long delays until the time when effective interventions are available for many disorders. Furthermore, not all affected individuals will have an identifiable genetic basis to their disorder. Thus, the complexities involved in determining and establishing susceptibility, sorting out potential environmental influences, and devising a strategy for counseling and treatment will pose tremendous challenges in the future. Many of these diseases do not manifest clinically until adulthood and may become apparent only in middle age or later. Predictive or presymptomatic testing and screening can provide clues about genetic susceptibility or predisposition to genetic disorders. For monogenic disorders of late onset, such as Huntington disease, tests will usually be highly predictive. Many common diseases usually have multifactorial—or complex—causation, including both multiple genetic factors and environmental effects; for these disorders, prediction will be less certain.

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Assessing Genetic Risks: Implications for Health and Social Policy Many common diseases of adulthood, including coronary artery disease, some cancers, diabetes, high blood pressure, rheumatoid arthritis, and some psychiatric diseases, fall into this category. However, in rare forms of these common diseases, single genes may play the decisive role; screening for disease-causing alleles of these genes will be of much greater predictive value. The committee therefore recommends caution in the use and interpretation of presymptomatic or predictive tests. The nature of these predictions will usually be probabilistic (i.e., with a certain degree of likelihood of occurrence) and not deterministic (i.e., not definite, settled, or without doubt). The dangers of stigmatization and discrimination are areas of concern, as is the potential for harm due to inappropriate preventive or therapeutic measures. Since environmental factors are often essential for the manifestation of complex diseases, the detection of those at high risk will identify certain individuals who will most benefit from certain interventions (e.g., dietary measures in coronary heart disease). Identification of some persons at high risk for certain cancers suggests that more frequent monitoring may identify the earliest manifestations of cancer when treatability is greatest (e.g., colon cancer); research is needed on the psychosocial implications of such testing in both adults and children. Further research and the unfolding of the Human Genome Project are likely to reveal the underlying genes mediating predisposition to numerous common diseases, and genetic susceptibility testing will be increasingly possible. Certain environmental factors may interact with only one set of genes and not with another. There may also be interaction between the various genes involved, so that the effects of multiple gene action cannot be predicted by separate analyses of each of the single genes. In such cases, definitive prediction will rarely, if ever, be possible. When dealing with genetic testing for some non-Mendelian diseases, it will be impossible to group individuals into two distinct categories—those at no (or very low) risk and those at high risk. Extensive counseling and education will be essential in any testing for genetic susceptibility. The benefits of the various presymptomatic interventions must be weighed against the potential anxiety, stigmatization, and other possible harms to individuals who are informed that they are at increased risk of developing future disease. Population screening for predisposition to late-onset monogenic diseases should only be considered for treatable or preventable conditions of relatively high frequency. Under such guidelines, population screening should only be offered after appropriate, reliable, sensitive, and specific tests become available. Such tests do not yet exist. The committee recommends that the predictive value of genetic tests be thoroughly validated in prospective studies of sufficient size and statistical power before their widespread application. Since there will be a considerable time lag before the appearance of confirmatory symptoms, these studies will require support for long periods of time (see Chapter 3). In the case of predictive tests for mental disorders, results must be handled with stringent attention to confidentiality to protect an already vulnera-

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Assessing Genetic Risks: Implications for Health and Social Policy ble population. If no effective treatment is available, testing may not be appropriate since more harm than good could result from improper use of test results. On the other hand, future research might result in psychological or drug treatments that could prevent the onset of these diseases. Carefully designed pilot studies should be conducted to determine the effectiveness of such interventions and to measure the desirability and psychosocial impact of such testing. Interpretation and communication of predictive test results in psychiatry will be particularly difficult. To prepare for the issues associated with genetic testing for psychiatric diseases in the future, psychiatrists and other mental health professionals will need more training in genetics and genetic counseling; such training should include the ethical, legal, and social issues in genetic testing. Because of their wide applicability, it is likely there will be strong commercial interests in the introduction of genetic tests for common, high-profile complex disorders. Strict guidelines for efficacy therefore will be necessary to prevent premature introduction of this technology. Testing of Children or Minors Children should generally be tested only for genetic disorders for which there exists an effective curative or preventive treatment that must be instituted early in life to achieve maximum benefit. Childhood testing is not appropriate for carrier status, untreatable childhood diseases, and late-onset diseases that cannot be prevented or forestalled by early treatment. In general, the committee believes that testing of minors should be discouraged unless delaying such testing would reduce benefits of available treatment or monitoring. It is essential that the individual seeking testing understand the potential abuse of such information in society, including in employment or insurance practice, and that the provider should ensure that confidentiality is respected (see Chapter 8 for discussion of disclosure to relatives). Because only certain types of genetic testing are appropriate for children, multiplex testing that includes tests specifically directed to obtaining information about carrier status, untreatable childhood diseases, or late-onset diseases should not be included in the multiplex tests offered to children. Research should be undertaken to determine the appropriate age for testing and screening for genetic disorders, both to maximize the benefits of therapeutic intervention and to avoid the possibility of generating genetic information about a child when there is no likely benefit and there is possibility of harm to the child. LABORATORY ISSUES IN GENETIC TESTING The committee's review of laboratory issues in genetic testing included a workshop with the nation's experts in laboratory quality assurance in genetic testing and meetings with federal officials responsible for implementing federal reg-

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Assessing Genetic Risks: Implications for Health and Social Policy ulations under the Clinical Laboratory Improvement Amendments of 1988 (CLIA88) and the medical devices legislation under which the Food and Drug Administration regulates genetic testing products such as test kits, probes, and reagents. The committee found that although adequate legislative authority exists to oversee the quality of genetic testing, this authority is not in fact being implemented for genetic testing. For example, existing CLIA88 regulations could ensure the quality of genetic laboratory testing, but these regulations are not being applied to genetic testing at all. Similarly, FDA has authority to regulate genetic testing kits and associated genetic test reagents and DNA probes, but such tests are rarely being submitted to FDA for approval. The safety and effectiveness of genetic tests should be established before they are used routinely and, even when that comes to pass, great care should be taken in performing the tests and interpreting the results. The committee is concerned that the regulatory burden not impede further development of tests or the offering of genetic testing services by laboratories; nevertheless, the committee believes that the nature of genetic tests and their interpretation, and the magnitude of the personal and clinical decisions that may be made based on those results—including the abortion of affected fetuses—warrant a standard with close to ''zero" chance of error for such tests. Consequently, laboratories and personnel performing these tests should participate in proficiency testing programs, including review of the interpretation provided by the laboratory to referring physicians. Laboratories with any error should be placed on probation, and proficiency testing repeated, preferably using blinded methods. Unless the laboratory can attain this standard, its certification to perform this test should be removed. Existing quality assurance in genetic testing is voluntary and has improved laboratory quality in its participants, but the committee finds that current laboratory quality control programs are inadequate to address the special issues posed by genetic testing primarily because these programs lack essential enforcement authority. As genetic testing expands, these voluntary programs should and will be replaced by the requirements of CLIA88. In the interim, the committee believes that the impact of voluntary programs could be strengthened by publishing the names of laboratories that have satisfied proficiency and other requirements. This is now done by the National Tay-Sachs Disease and Allied Disorders Association, Inc., which publishes results of the quality assessment conducted by the International Tay-Sachs Disease Quality Control Reference Standards and Data Collection Center. Before publication, any laboratory not satisfying these requirements should be given ample opportunity to rectify its deficiencies. Genetics laboratories should provide reports in an easily understandable form for referring physicians who are not genetics specialists. The evaluation of the quality of these reports should be an important component of the proficiency testing process. These reports, including interpretation of the results, should also be reviewed by the Health Care Financing Administration (HCFA) as part of

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Assessing Genetic Risks: Implications for Health and Social Policy crease the knowledge and skills that will equip consumers to make the most appropriate decisions for themselves (see Chapter 5). The National Science Foundation, the Department of Energy, the National Institutes of Health, and other organizations should expand their investment in public education related to the human genome. These efforts should (1) expand programs that support model educational initiatives for precollege science and undergraduate molecular biology; (2) collaborate with the Ethical, Legal, and Social Implications component of the Human Genome Project to encourage such programs to focus on the health, social, legal, and ethical issues raised by genetic testing and screening; and (3) require evaluation of educational interventions. Broad public participation will be required to develop educational approaches that respect the widely varying personal and cultural perspectives on issues of genetics, and are tolerant and respectful of individuals with genetic disorders of all kinds. Particular effort will be needed to include the perspectives of women, minorities, and persons with disabilities, who may feel especially affected by developing genetic technologies. There is much to be learned from those who are particularly affected by genetic testing technologies, and from those affected by genetic disorders, including persons with disabilities and their families and support groups. The committee believes that genetics professionals and qualified educators must work with public representatives to identify the essential components of genetic literacy. A "Consumer's Guide to Genetic Testing" should be developed (also see Chapters 1, 5, and 9) to provide information on genetic services, various genetic tests, and the implications of the tests so as to aid in providing balanced, reliable, readily understandable, and available sources of needed information. Innovative computer and interactive computer systems should also be developed to provide patients/clients with the latest information on genetic disorders and on genetic diagnosis, testing, and screening. If designed and used appropriately, such computer resources could assist genetics specialists and primary care practitioners by presenting patients with basic, self-paced genetics education and even presenting possible options for consideration of patients. The ELSI Program should therefore coordinate with the National Library of Medicine in developing innovative methods of providing information to the public similar to the on-line AIDS bibliography. More research is needed to determine which tasks in genetics education and counseling can be appropriately accomplished by using such techniques and to evaluate these techniques in various settings and populations. PROFESSIONAL EDUCATION The committee sees no prospect, in the foreseeable future, of having enough highly specialized genetics personnel to handle all genetic testing, including essential genetics education and genetic counseling. Therefore, policy discussion

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Assessing Genetic Risks: Implications for Health and Social Policy should focus not only on training more genetic counselors and other genetic specialists, but on better educating the obstetrics, pediatrics, and family practice communities about the nature of genetic testing, diagnosis, and counseling. Some progress has been made in increasing physicians' knowledge of genetic testing and their ability to take good family histories, particularly in specialties that involve more genetic tests (e.g., pediatrics and obstetrics; see Chapter 6). More recent graduates also know more than older physicians. Nevertheless, the committee is very concerned that relatively little progress has been made—certainly not enough to prepare physicians-in-training for the increasing requirements for genetic testing, education, and counseling projected for the future. The committee strongly recommends that medical education begin to incorporate a genetic point of view throughout its curriculum, but especially in the critical clinical years, and that medical board examinations should include more questions on genetics. More research is needed on knowledge of genetics and skills needed for genetics education and genetic counseling among all of these professional groups so that proper reforms can be implemented. The biggest potential contribution of genetics to medical education may be its ability to document a major biological basis for human variation. Conventional teaching in medical school often disregards differences in etiology, presentation, response to therapy, personal preferences, and prognosis of people who may be "lumped" together under a single disease label. A true revolution will come much more from introducing a new way of learning about disease and health, of emphasizing the importance of individual differences, some but not all of which are genetically determined. Historically, the discovery of germs as causative agents in disease led to a reductionist germ theory that explained everything in terms of germs; the committee is concerned that the explosion of genetics knowledge may replace the reductionist germ theory with a reductionist gene theory—to the detriment of medical progress. Genetics professionals and all others offering or referring for genetic testing should be trained in the ethical, legal, and social issues surrounding genetic diagnosis, testing, and screening. Laboratory personnel should be a special focus of such training about the complexities of genetic testing to adequately interpret tests, including a knowledge of test limitations and social issues surrounding genetic testing. Of particular importance is training to deal with the sensitivities of genetics education and counseling, including the need for nondirectiveness, in counseling about reproductive options and about disorders for which no treatment exists. Expanded undergraduate and graduate training of nurses in genetics, genetics education, and genetic counseling is also needed, along with the training of social workers in the special requirements of genetics education and counseling. With proper training, the integration of other health professionals such as nurses, nurse practitioners, social workers, psychologists, and primary care physicians, into the existing genetics services network will supplement the time and skills of traditional genetic counseling (see Chapter 4).

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Assessing Genetic Risks: Implications for Health and Social Policy The accelerating developments of new knowledge in genetic testing will also require expanded formal continuing education programs in clinical genetics, including those geared to the genetic counselor, primary care practitioner, and social worker (see Chapter 5). The Ethical, Legal, and Social Implications Program should coordinate with professional genetics organizations and the National Library of Medicine to develop genetics education and dissemination programs for interested health professionals. Genetics specialists should develop and provide continuing education and training for other professionals, as well as take a leadership role in genetics education for the public. Other health care professionals should also participate in programs intended to increase public awareness and education about genetics. More minorities should be recruited for training programs in all aspects of clinical genetics. This will be especially important in providing culturally sensitive and appropriate genetic testing, education, and counseling services in the future (see above), when so-called minority groups will comprise a majority of the population of the United States (see Chapters 4 and 6). FINANCING OF GENETIC TESTING SERVICES The cost and financing of genetic testing and counseling have had a profound effect on access to these services in the United States. No matter what aspect of genetics is discussed, it is almost impossible to keep the discussion from turning to issues related to financing, in particular the role of health insurance in genetic testing and counseling (see Chapter 7). The United States is the only developed country in the world without a social insurance or statutory system to cover basic expenses for medical services for most of its population. This creates problems of access and equity, especially for those low-income or high-risk individuals who are self-employed, work part-time, or are employed by small businesses and who may not be able to afford or obtain health insurance. Over 37 million people are without health insurance coverage in the United States. Even for those who have health insurance, coverage for most preventive, screening, and counseling services may be excluded. These limitations of health care coverage in the United States particularly affect genetic services, which have an important counseling component. Insurance reimbursement or other financing of genetic testing is not generally available now in the United States. The committee also heard testimony that individuals whose insurance does cover some or all genetic services may be reluctant or unwilling to file claims for such services. They may fear that the genetic information they sought might be used to evaluate and deny their future applications for health or life insurance coverage, or lead to higher premiums or limited coverage. And, because so much coverage in the United States is employment based, people may also worry that their employer will have access to the information and use it (overtly or covertly) to discriminate against them (see Chapters 7 and 8).

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Assessing Genetic Risks: Implications for Health and Social Policy In order to develop appropriate financing for genetic testing and counseling services, private and public health plans, and geneticists and consumers, should work together to develop guidelines for the reimbursement of genetic services. Such guidelines should address the issue of how each new genetic test should be assessed for its sensitivity and specificity in light of the availability of effective treatment, the consequences of the test, the evaluation of pilot study results, and when new tests are appropriate for use in routine clinical practice (see Chapters 1 and 7). In addition, the insurance concept of what is considered medically necessary (and therefore reimbursable) should be expanded to include the offering of appropriate genetic testing and related education and counseling, making these genetic services reimbursable under health insurance plans. Medical appropriateness can often be established by a family history of the disorder. In pregnancy, medical necessity should be considered established for cytogenetic testing in pregnancies in women of advanced maternal age or considered at high risk based on other methods of assessing risk. The committee also recommends that newborn screening and MSAFP screening in pregnant women of any age be considered within the insurance definition of medically appropriate and be reimbursable under health insurance plans (see Chapter 7). SOCIAL, LEGAL, AND ETHICAL ISSUES IN GENETIC TESTING The committee recommends that vigorous protection be given to autonomy, privacy, confidentiality, and equity. These principles should be breached only in rare instances and only when the following conditions are met: (1) the action must be aimed at an important goal—such as the protection of others from serious harm—that outweighs the value of autonomy, privacy, confidentiality, or equity in the particular instance; (2) it must have a high probability of realizing that goal; (3) there must be no acceptable alternatives that can also realize the goal without breaching those principles; and (4) the degree of infringement of the principle must be the minimum necessary to realize the goal. Voluntariness Voluntariness should be the cornerstone of any genetic testing program. The committee found no justification for a state-sponsored mandatory public health program involving genetic testing of adults or for unconsented-to genetic testing of patients in the clinical setting . There is evidence that voluntary screening programs achieve a higher level of efficacy in screening, and there is no evidence that mandating newborn screening is necessary or sufficient to ensure that the vast majority of newborns are screened. Mandatory offering of newborn screening is appropriate for disorders with treatments of demonstrated efficacy

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Assessing Genetic Risks: Implications for Health and Social Policy where very early intervention is essential to improve health outcomes (e.g., phenylketonuria and congenital hypothyroidism). One benefit of voluntariness and informing parents about newborn screening is that of quality assurance: parents can check to see if the sample was actually drawn. In addition, since people will be facing the possibility of undergoing many more genetic tests in their lifetimes, the disclosure of information to parents about newborn screening prior to the event can be an important tool for education about genetics. Informed Consent Obtaining informed consent should be the method of ensuring that genetic testing is voluntary. By informed consent the committee means a process of education and the opportunity to have questions answered—not merely the signing of a form. The patient or client should be given information about the risks, benefits, efficacy, and alternatives to the testing; information about the severity, potential variability, and treatability of the disorder being tested for; information about the subsequent decisions that will be likely if the test is positive (such as a decision about abortion); and information about any potential conflicts of interest of the person or institution offering the test (see Chapters 1, 3, and 8). Research should therefore also be undertaken to determine what patients want to know in order to make a decision about whether or not to undergo a genetic test. People often have less interest in the label for the disorder and its mechanisms of action than in how certainly the test predicts the disorder, what effects the disorder has on physical and mental functioning, and how intrusive, difficult, or effective any existing treatment protocol would be. Research is also necessary to determine the advantages and disadvantages of various means of conveying that information (e.g., through specialized genetic counselors, primary care providers, single disorder counselors, brochures, videos, audiotapes, computer programs). Confidentiality All forms of genetic information should be considered confidential and should not be disclosed without the individual's consent (except as required by state law, or in rare instances discussed in Chapters 4 and 8). This includes genetic information that is obtained through specific genetic testing of a person, as well as genetic information about that person that is obtained in other ways (e.g., physical examination, past treatment, or a relative's genetic status). The confidentiality of genetic information should be protected no matter who obtains or maintains that information. This includes genetic information collected or maintained by health care professionals, health care institutions, researchers, employers, insurance companies, laboratory personnel, and law enforcement officials. To the extent that current statutes do not ensure such confidentiality, they should be amended.

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Assessing Genetic Risks: Implications for Health and Social Policy Codes of ethics for professionals providing genetic services should contain specific provisions to protect autonomy, privacy, and confidentiality. The committee endorses the 1991 National Society of Genetic Counselors (NSGC) statement of guiding principles on confidentiality of test results: The NSGC support individual confidentiality regarding results of genetic testing. It is the right and responsibility of the individual to determine who shall have access to medical information, particularly results of testing for genetic conditions. Confidentiality should be breached and relatives informed about genetic risks only when (1) attempts to elicit voluntary disclosure fail, (2) there is a high probability of irreversible harm that the disclosure will prevent, and (3) there is no other reasonable way to avert the harm. When disclosure is to be attempted over the patient's refusal, the burden should be on the person who wishes to disclose to justify to the patient, to an ethics committee, and perhaps in court that the disclosure was necessary and met the committee's test. Thus, the committee has determined that the disadvantages of informing relatives over the patient's refusal generally outweigh the advantages, except in the rare instances described above (see Chapters 4 and 8). The committee recommends that health care providers not reveal genetic information about a patient's carrier status to the patient's spouse without the patient's permission, and that information on misattributed paternity should be given to the mother, but not be volunteered to her partner. As a matter of general principle, the committee believes strongly that patients should disclose to relatives genetic information relevant to ensuring the health of those relatives. Patients should be encouraged and aided in sharing appropriate genetic information with spouses and relatives. To facilitate the disclosure of relevant genetic information to family members, accurate and balanced materials should be developed to assist individuals in informing their families, and in providing access to further information, as well as access to testing if relatives should choose to be tested. Under those rare circumstances where unauthorized disclosure of genetic information is deemed warranted, the genetic counselor should first try to obtain the permission of the person to release the information. The committee also endorses the principles on the protection of DNA data and DNA data banking developed in 1990 by the ASHG Ad Hoc Committee on Identification by DNA Analysis. In short, patients' consent should be obtained before their names are provided to a genetic disease registry, and their consent should also be obtained before information is redisclosed. Each entity that receives or maintains genetic information or samples should have procedures in place to protect confidentiality. Information or samples should be kept free of identifiers and instead use encoding to link the information or sample to the individual's name. Finally, any entity that releases genetic information about an

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Assessing Genetic Risks: Implications for Health and Social Policy individual to someone other than that individual should ensure that the recipient of the genetic information has procedures in place to protect the confidentiality of the information. Genetic Discrimination in Health Insurance Legislation should be adopted to prevent medical risks, including genetic risks, from being taken into account in decisions on whether to issue or how to price health care insurance. Because health insurance differs significantly from other types of insurance in that it regulates access to health care—an important social good—risk-based health insurance should be eliminated. Access to health care should be available to every American without regard to the individual's present health status or condition; in particular, the committee recommends that insurability decisions not be based on genetic status (see Chapters 7 and 8). Some of the committee's concerns about genetic discrimination in health insurance would be obviated by current proposals for national health insurance reform that would eliminate most, if not all, aspects of medical underwriting. The committee recommends that insurance reform preclude the use of genetic information in establishing eligibility for health insurance. As health insurance reform proposals are developed, those concerned with genetic disorders will need to assess whether they adequately protect genetic information and persons with genetic disorders from health insurance discrimination and discrimination in the provision of medical services (see Chapters 7 and 8). Genetic Discrimination in Employment Legislation should be adopted that forbids employers to collect genetic information on prospective or current employees unless it is clearly job related. Sometimes employers will have employees submit to medical exams to see if they are capable of performing particular job tasks. If an individual consents to the release of genetic information to an employer or potential employer, the releasing entity should not release specific information, but instead answer only yes or no regarding whether the individual was fit to perform the job at issue. The committee urges the Equal Employment Opportunity Commission to recognize that the language of the Americans with Disabilities Act (ADA) provides protection for presymptomatic people with genetic risks for late-onset disorders, unaffected carriers of disorders that might affect their children, and individuals with genetic profiles indicating the possibility of increased risk of a multifactorial disorder. State legislatures should adopt laws to protect people from genetic discrimination in employment. In addition, ADA should be amended (and similar state statutes adopted) to limit the type of medical testing employers can request and to ensure that the medical information they can collect is job related.

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Assessing Genetic Risks: Implications for Health and Social Policy RESEARCH AND POLICY AGENDA In its efforts to complete a comprehensive overview of issues in genetic testing and screening, the Committee on Assessing Genetic Risks identified significant gaps in data, research, and policy analysis that impede informed policy making for the future. Surprisingly few data exist on the extent of genetic testing and screening today, for example, and no system is in place to gather data or to assess practices in relation to the committee's principles and recommendations for the future. The committee's review of the key data, research, and policy needs in genetic testing and screening has generated recommendations addressed to the Ethical, Legal, and Social Implications Program of the Human Genome Project, and several recommendations are addressed to other relevant agencies, including other components of the National Institutes of Health, the Agency for Health Care Policy and Research (AHCPR), the Centers for Disease Control and Prevention, the Food and Drug Administration, the Public Health Service (PHS), the Health Care Financing Administration, the Department of Health and Human Services (DHHS), the Department of Energy (DOE), the National Science Foundation (NSF), and a broad range of private organizations. Policy Oversight The committee strongly believes that effective oversight will be essential as genetic testing develops to ensure that genetic tests are validated and used appropriately, with respect for the potential harms such testing may pose. For effective overall and continuing policy oversight, the majority of the committee recommends the creation of a broadly representative National Advisory Committee and Working Group on Genetic Testing to oversee professional practices and determine when new genetic tests are ready for wide-scale use in medical practice (see Chapters 1 and 9). Although the American Society of Human Genetics, National Society of Genetic Counselors, American Academy of Pediatrics, American College of Obstetricians and Gynecologists, and other professional organizations have developed policy statements on key policy issues in genetic testing, genetic testing has moved beyond the domain of genetics specialists alone. There is also a need for broad public involvement in the development of public policy concerning genetic testing and screening. As discussed throughout this report, genetic testing has broad health and social implications of both immediate and future concern to individuals and families with genetic disorders, genetic support groups, and the public at large. Increased public education will be required to equip the public to make informed personal and policy decisions in genetic testing (see Chapter 5). The proposed National Advisory Committee on Genetic Testing and its Working Group are intended to provide the essential broadly based scientific and public oversight for genetic testing and screening.

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Assessing Genetic Risks: Implications for Health and Social Policy The committee also sees a need for broadly representative advisory bodies at the state level (see Chapters 1 and 9). These advisory bodies should be guided by the principles outlined in this report. They should guide state health departments and legislatures on such issues as when tests should be added to state-run screening programs and how to ensure that the offering, testing, and associated education and counseling are conducted in accord with the principles outlined in this report. State statutes affecting genetic testing should not be unduly prescriptive or restrictive, and should provide latitude to such advisory bodies to modify state-run genetic testing programs. Research Policy Much of current genetic testing grew out of the context of research studies, and some genetic testing is still being done in research settings. Research initiatives involving genetic testing are being supported and developed not only within the Human Genome Project, but also within the research programs of various components of the National Institutes of Health (including the National Institute of General Medical Sciences, National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Child Health and Human Development, National Institute of Diabetes and Digestive and Kidney Diseases) and the Human Genome Program of the Department of Energy. In developing and approving research protocols, the committee recommends that the NIH and the DOE consider the recommendations of this committee within the context of their research programs, including study of the psychosocial issues and implications of genetic testing and the potential for harm from the use and misuse of genetic information. This is especially significant where there is no treatment available for the disorders, as will often be the case in the near future. In developing requests for proposals and requests for applications and in reviewing research, demonstration projects, pilot studies, clinical trials, and family studies in genetics, funding agencies should pay particular attention to psychosocial issues and should assess the availability of appropriate genetic counseling and follow-up services as elements of study design. Need for Additional Standards The committee identified several areas for which additional standards were needed concerning who should be tested, for what disorders, and at what age. While existing standards may have been adequate for the past, new standards must be developed in response to rapid developments in genetic testing methods that are now experimental. In particular, additional standards are needed for prenatal diagnosis, predispositional testing, and multiplex testing (see Chapter 9). Research and policy analysis is needed in prenatal genetic diagnosis to address problems such as the complexities of identifying fetal cells in maternal blood, maternal serum alpha-fetoprotein screening, notions of ''perfect-

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Assessing Genetic Risks: Implications for Health and Social Policy ibility," use of prenatal diagnosis and selective abortion to choose the sex of the fetus, the special impact of prenatal diagnosis on women, and carrier detection in pregnancy rather than prior to conception (see Chapters 2 and 9). Reproductive genetic decisions raise some of the most deeply personal and troubling issues in genetic testing. Professional groups need to work together and develop innovative methods for involving the public in the development of standards for the use of these technologies (see Chapters 2, 3, 4, and 9). Standards are also needed for genetic testing for predisposition to late-onset disorders. There is an important "window of opportunity" for considering these issues now, before predispositional genetic testing becomes widespread. Tests for predisposition to common disorders will be of great commercial interest, and could have substantial potential for harm to individuals and families in terms of insurability and employability, as well as substantial benefit from the potential of early preventive and therapeutic interventions. Strict guidelines for efficacy will be necessary to prevent premature introduction of this technology (see Chapters 1, 2, and 9). The committee believes that population screening for late-onset diseases should be considered only for treatable or preventable conditions of relatively high frequency and only after appropriate, reliable, sensitive, and specific tests become available; and such tests should be voluntary. In general, because of the significant medical and psychosocial consequences of predictive testing, the committee believes that testing of minors should be discouraged. Instead, research should be undertaken to determine the appropriate age for testing and screening for genetic disorders in minors in order to maximize the benefits of therapeutic intervention. Multiplex testing—multiple genetic tests on a single blood or other tissue sample—represents one of the most likely innovations in genetic testing. Consequently, the committee also recommends the development of standards for multiplex genetic testing. Innovative methods are needed to group tests by related types of disorders that raise similar issues (including the availability of effective treatment and how soon treatment needs to be instituted), as a basis for appropriate education, informed consent, and genetic counseling. This will allow potential screenees (or parents) to choose which, if any, group of tests they feel is appropriate for them. Tests for untreatable disorders should not be multiplexed with tests for disorders that can be cured or prevented by treatment or by avoidance of particular environmental stimuli. Multiplex testing is also an area in which more research is needed to develop ways to ensure that patient autonomy is recognized (see Chapters 1, 2, 3, 4, and 8). Policy Research Needs The committee identified significant data and policy research needs related to genetic testing (see Chapter 9). In addition to its other recommendations, the committee identified several areas in which policy research is needed, including

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Assessing Genetic Risks: Implications for Health and Social Policy pilot studies of new tests before wide-scale introduction; cost-effectiveness analysis of genetic testing; critical deficiencies in data on genetic services; research on population distribution and heterogeneity of traits involved in genetic or genetically influenced disease; and assessment of what has been learned thus far from ELSI research and policy studies.