The remarkable advances in genetics in recent decades are the fruition of almost a century of basic research. Our ability to identify the underlying defects in single-gene (Mendelian) diseases, most of which are rare, has improved diagnosis in symptomatic individuals, and the prediction of risks of future disease in asymptomatic individuals. We have learned how to prevent a few of these diseases by early intervention and how to treat a few others after symptoms appear. Gene therapy, in which a normal gene is introduced into cells of patients with defective genes, is being investigated in over 1,000 individuals, including some with Mendelian disorders such as cystic fibrosis and adenosine deaminase deficiency.2
We now know that a small percentage of people with common disorders have inherited rare, single mutations that make them much more susceptible to developing the disease. Occasionally, single mutations that markedly increase susceptibility to disease reach frequencies as high as 1 percent in some population groups;3 usually the combined frequency of all such mutations is under 5 percent of all those who will develop the disease. More common genetic variants (polymorphisms) less markedly increase susceptibility.
Over the past half century, scientists have discovered the existence of DNA polymorphisms in which the most common form (allele) occurs in no more than 99 percent of the population. We are beginning to learn that some of these polymorphisms are associated with increased risks of common diseases, but usually not to the same degree as the rare variants. Conversely, some forms of polymorphisms convey resistance to disease. Before disease develops in people with either predisposing rare variants or polymorphisms, other genetic and environmental factors must be present.
Genetic discovery can benefit people in other ways than by discovering the inherited components. In the case of cancer, scientists have learned that acquired (somatic) mutations play a significant role.16 By comparing the molecular genetic profiles of cells from diseased organs and tissues to the comparable normal cells, scientists are beginning to learn which gene functions have been altered and how they might affect the development of chronic conditions like osteoporosis and arthritis.17 With this knowledge, interventions can be devised to avert or treat the triggering events or treat the disease effectively in its early stages.
Despite this remarkable progress much remains unknown. The unknowns have a strong impact on genetic testing, particularly when it is used predictively in healthy or apparently healthy people.
It is primarily in the context of their unknown potential risks and benefits that the Task Force considers genetic testing.
Research and discovery in the first century of the next millennium will reduce the uncertainties, but the nature of human variation is such that it will never be possible to have genetic tests that are perfect predictors of disease. Even today, however, tests for the disorders for which these problems have not been solved can be of benefit.
Nevertheless, problems will remain, especially as long as the means of preventing or treating genetic disease in those born with it are not fully at hand. The Task Force was created to make recommendations to ensure that genetic tests are safe and effective in view of the persistence of problems in the foreseeable future.
In 1994, the National Institutes of Health (NIH)-Department of Energy (DOE) Working Group on Ethical, Legal and Social Implications (ELSI) of Human Genome Research reviewed the report of the Institute of Medicine's Committee on Assessing Genetic Risks.23 Among the concerns raised in that report were the imperfect predictability of tests, the quality of laboratories providing clinical genetic tests, the lack of proven interventions for many disorders (see Chapter 3 ), and the limited ability of many health care providers to explain genetic tests accurately and nondirectively to patients (see Chapter 4). To consider these problems further, the Working Group convened the Task Force on Genetic Testing. It asked the Task Force to review genetic testing in the United States and, when necessary, make recommendations to ensure the development of safe and effective genetic tests. The Task Force has defined safety and effectiveness to encompass not only the validity and utility of genetic tests, but their delivery in laboratories of assured quality, and their appropriate use by health care providers and consumers.
How the public in general should be educated in genetics and genetic testing is beyond the purview of the Task Force, although it is critically important. So too, are policy recommendations - other than for improving genetic tests themselves--for reducing the harms that can result from some forms of genetic testing and can deter some people from being tested. Nevertheless, later in this chapter, the Task Force enunciates principles related to these harms.
The Working Group invited organizations with a stake in genetic testing to submit nominations from which it selected members of the Task Force. In addition, the Working Group invited five agencies in the Department of Health and Human Services (HHS) to send nonvoting liaison members to the Task Force. (Task Force members and their affiliations are listed at the front of this report.)
To determine the state of the art of genetic testing in the United States, a survey of organizations likely to be engaged in genetic testing was undertaken for the Task Force early in 1995. Following completion of the survey, in-depth interviews were conducted at 29 of the 463 organizations that indicated they were developing or providing genetic tests. Informational materials for providers and patients that were distributed by respondents who were performing genetic tests were collected and analyzed. Appendix 3 of the final report is a summary of the survey and interview findings, and Appendix 4 is a summary of the analysis of the informational materials. The Task Force also commissioned papers on some of the more frequent genetic screening programs in the United States. These appear in appendices 5 and 6. With the help of liaison representatives of relevant agencies and others, Task Force staff prepared analyses of various Federal statutes and regulations, most importantly those dealing with clinical laboratories and medical devices. Through notices in various genetics journals, an announcement on its World Wide Web page, and requests to consumer organizations, the Task Force asked professionals and consumers to report their experiences with various aspects of genetic testing. A small number of genetic counselors, physicians, and affected patients or their relatives responded. Some of these responses appear as sidebars throughout this report.
In this report, all principles and recommendations of the Task Force appear in bold-faced type. Unfamiliar terminology can be found in the Glossary.
The Task Force recognizes the tremendous potential of benefits from genetic testing. Its goal is to make recommendations that will assure the public that genetic tests will be safe and effective but will not stifle progress in this exciting field. It is particularly concerned about the continued availability of tests for rare inherited diseases.
The Task Force held seven meetings, all of which were open to the public. Halfway through its deliberations, the Task Force published Interim Principles,24 made them available on its World Wide Web site, invited public comments, and held a public hearing on them. Taking these comments into consideration, the Task Force turned to developing recommendations to implement its principles. These were published in the Federal Register and also made available on the Web site.25 Once again, the public was given an opportunity to comment. A list of all organizations and persons commenting on the Interim Principles and Proposed Recommendations appears in Appendix 1 of this report. The Task Force has taken these comments into consideration in preparing its final principles and recommendations.
The Task Force could not make recommendations on genetic tests without first defining them. After hearing considerable comment and much deliberation, the Task Force developed the following definition.
Genetic test--The analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes. Such purposes include predicting risk of disease, identifying carriers, establishing prenatal and clinical diagnosis or prognosis. Prenatal, newborn, and carrier screening, as well as testing in high risk families, are included. Tests for metabolites are covered only when they are undertaken with high probability that an excess or deficiency of the metabolite indicates the presence of heritable mutations in single genes. Tests conducted purely for research are excluded from the definition, as are tests for somatic (as opposed to heritable) mutations, and testing for forensic purposes.
The Task Force is primarily concerned about predictive uses of genetic tests performed in healthy or apparently healthy people. Predictive test results do not necessarily mean that the disease will inevitably occur or remain absent; they replace the individual's prior risks based on population data or family history with risks based on genotype. The Task Force divides predictive tests into presymptomatic tests, which are performed to detect highly "penetrant" conditions, and predispositional tests, which are performed for incompletely penetrant conditions. The Task Force cannot limit its definition to predictive tests because some tests intended for diagnostic use can also be used predictively. The Task Force also decided that it cannot limit genetic tests only to those for which the analyte is DNA. Clinical laboratories will continue to use protein and enzyme and metabolite analyses for the purposes listed in the definition, including prediction.
Some, but not all, predictive genetic testing falls under the rubric "genetic screening." The Task Force follows the definition used in a National Research Council report: "Genetic screening may be defined as a search in a population for persons possessing certain genotypes that (1) are already associated with disease or predispose to disease, (2) may lead to disease in their descendants, or (3) produce other variations not known to be associated with disease." 26 (p. 9) Under this definition, testing an asymptomatic person in a family with several relatives affected with disease does not constitute screening but predictive genetic testing.
The Task Force rejected the suggestion from the College of American Pathologists (CAP) that, "The definition of genetic tests should focus on germ line mutations that require genetic counseling with respect to the development of diseases." Neither the Task Force nor any other body has stated which tests require genetic counseling. The Task Force did acknowledge the concerns of CAP and The American Society of Clinical Pathologists that too many tests in standard use would be covered by limiting its definition to tests for metabolites only when they are "undertaken with high probability that an excess or deficiency of the metabolite indicates the presence of heritable mutations in single genes". Under the definition, cholesterol screening in the general population would not be covered, but cholesterol testing in a family with a documented low density lipoprotein receptor defect would be covered. Newborn screening tests for metabolites whose excess or deficiency require followup to rule out a heritable disorder would be covered.
It is not the intention of the Task Force that all of its recommendations be applied to all tests that meet its definition. A system is needed to classify genetic tests according to the scrutiny they need. Later in this chapter, the Task Force suggests how such a system can be developed.
Over 500 commercial, university, and health department laboratories provide tests for inherited and chromosomal disorders, and genetic predispositions in the United States. Virtually every newborn is screened for phenylketonuria and congenital hypothyroidism and many are screened for sickle cell disorders.27 Screening for carriers of Tay-Sachs and sickle cell is performed among populations at risk. Based on the recommendations of a recent consensus panel,28 cystic fibrosis carrier screening might increase. Approximately 2.5 million pregnant women are screened each year to see if their fetuses are at high risk of neural tube defects or Down syndrome.29 Of 467 organizations who responded fully to the survey conducted for the Task Force, 56.7 percent indicated that they were testing for at least one of 44 inherited conditions that were listed in the questionnaire (see Appendix 3). A few commercial and university laboratories were offering tests for inherited susceptibility mutations to breast and colon cancer. Of 197 health maintenance organizations who responded to a recent survey, 45 percent said they were covering predictive tests for breast cancer and 42 percent were covering for colon cancer for some of their subscribers.30
For the most part, genetic testing in the United States has developed successfully, providing options for avoiding, preventing, and treating inherited disorders. However, there are some problems, which are spelled out in greater detail later in this report and in the appendices.
In the past few years, scientific and professional societies, as well as consumer groups, have felt impelled to publicly express concern when predictive tests were introduced with insufficient evidence of safety and effectiveness. These included prenatal screening with alpha-fetoprotein and other markers,31,32 carrier screening for cystic fibrosis,33,34 testing for susceptibility to cancer35,36 and breast cancer in particular,37,38 and Alzheimer disease.39,40 These statements often expressed a reaction to the imminence or appearance of a test and undoubtedly reduced inappropriate use of tests. The publication of each statement depended on mobilizing individuals with interest and expertise and then getting ratification by the sponsoring organization, tasks not easily accomplished in a short period without extraordinary effort. This becomes an impossible task as the number of tests expands but the problems persist.
Although professional societies must play a major role in solving problems of genetic testing, they are only one of several stakeholders, some of whose interests conflict with others'. The Task Force believes that all stakeholders must be involved. As this report demonstrates, they often will succeed in resolving disagreements and reaching consensus.
Except for neonatal and prenatal screening and diagnosis, the volume of testing has not been great and much of the testing has been performed in genetic centers or in consultation with highly-trained geneticists and genetic counselors. In the next few years, the use of genetic testing is likely to expand rapidly while the number of genetic specialists remains essentially unchanged. A greater burden for making genetic testing decisions will fall on providers who have little formal training or experience in genetics and are less equipped to deal with the complex and special problems raised by some predictive genetic tests. Consulted primarily by people who are sick, and who expect doctors to tell them what to do to get better, many physicians adopt a directive stance when asked how they would deal with genetic tests and results that have reproductive implications.
Until the 1980s most genetic and cytogenetic testing was performed in the laboratories of non-profit organizations, most of them in academic medical centers. These labs were often directed by the same professionals who cared for patients. In the last decade, genetic testing has been commercialized. As a result, providers who were close to patients and families at risk of illness might not have as much influence on testing policy as they once did.
Although formal comparisons have not been made, there is little evidence that the problems encountered in the development and delivery of genetic testing technologies have been more frequent or severe than for other medical technologies. Some problems encountered in other specialties have not been trivial. Amendments to the Food, Drug and Cosmetic Act, and to the Clinical Laboratory Improvement Act were passed by Congress because of problems in the clinical use of some new medical technologies.41-45 In 1996, recognizing the challenge posed by genetic tests, two Congressional committees held hearings related to the validity and quality of genetic tests.46,47
The ELSI component of the Human Genome Project was founded on the concept that the new technologies of gene identification will engender problems that can be minimized if anticipated and dealt with promptly. The recommendations of the Task Force are very much in this vein. In this report, the Task Force does not recommend policies for specific tests but suggests a framework for ensuring that new tests meet criteria for safety and effectiveness before they are unconditionally released, thereby reducing the likelihood of premature clinical use.
The focus of the Task Force on potential problems in no way is intended to detract from the benefits of genetic testing. Its overriding goal is to recommend policies that will reduce the likelihood of damaging effects so testing's benefits can be fully realized undiluted by harm.
The Task Force has tried to stay within the limits of its charge and to use past and current genetic testing as its guide. In the remainder of this chapter we consider the need for a central advisory body on genetic testing, and enunciate overarching principles on problems that are not integral to genetic testing per se but impinge on, or that may arise as a consequence of, genetic testing. The next chapter considers criteria for the development of new genetic tests. It presents policies to ensure that sufficient evidence of the safety and effectiveness of new genetic tests is collected and is reviewed before tests are unconditionally made available for clinical use. In Chapter 3, we consider how the quality of the laboratories that provide genetic testing to health care providers in clinical practice can be ensured. Because new tests are often developed in clinical laboratories, the chapter begins with a consideration of laboratories' responsibilities in developing new tests. In Chapter 4, the expanding role of non-genetic health care providers in genetic testing is considered, followed by discussion of some of the obstacles to their providing testing appropriately. The chapter describes policies to ensure that providers who use genetic testing have an adequate understanding of the indications for genetic tests and their limitations. Chapter 5 raises several concerns about rare genetic diseases, which constitute the largest number of genetic diseases. Collectively rare diseases represent the most frequent indication for genetic testing. Policies for ensuring that providers include rare diseases when they consider the causes of some of their patients' problems and that they know how and where to obtain information about rare diseases, including where to obtain diagnostic and predictive clinical laboratory tests are considered. The chapter concludes with recommendations for ensuring the continuity and quality of clinical laboratory tests for rare diseases.
This report does not contain a separate chapter on genetic testing under public health auspices. The Task Force spent considerable time discussing this issue and concluded that its recommendations for genetic tests in clinical practice also apply to tests included in health department screening programs. Some members of the Task Force and several who submitted comments questioned the need for informed consent in public health programs that are undertaken only when the benefits to the individual markedly outweigh the risks. Task Force principles on this issue are presented later in this chapter. A public health role is discussed briefly in Chapter 4.
Policies related to genetic testing involve several different Federal agencies, as well as the private sector. Such policies can best be formulated and implemented by having input from many different sources in order to achieve the single goal: the availability of safe and effective genetic tests.
The Task Force calls on the Secretary of Health and Human Services to establish an advisory committee on genetic testing in the Office of the Secretary. Members of the committee should represent the stakeholders in genetic testing, including professional societies (general medicine, genetics, pathology, genetic counseling), the biotechnology industry, consumers, and insurers, as well as other interested parties. The various HHS agencies with activities related to the development and delivery of genetic tests should send nonvoting representatives to the advisory committee, which can also coordinate the relevant activities of these agencies and private organizations. The Task Force leaves it to the Secretary to determine the relationship of this advisory committee to others that may be created in the broader area of genetics and public policy, of which genetic testing is only one part.
The committee would advise the Secretary on implementation of recommendations made by the Task Force in this report to ensure that (a) the introduction of new genetic tests into clinical use is based on evidence of their analytical and clinical validity, and utility to those tested; (b) all stages of the genetic testing process in clinical laboratories meet quality standards; (c) health providers who offer and order genetic tests have sufficient competence in genetics and genetic testing to protect the well-being of their patients; and (d) there be continued and expanded availability of tests for rare genetic diseases.
The Task Force recognizes the widely inclusive nature of genetic tests. It is therefore essential that the advisory committee recommend policies for the Secretary's consideration by which agencies and organizations implementing recommendations can determine those genetic tests that need stringent scrutiny. Stringent scrutiny is indicated when a test has the ability to predict future inherited disease in healthy or apparently healthy people, is likely to be used for that purpose, and when no confirmatory test is available. The advisory committee or its designate should define additional indications.
In order to carry out its functions, the advisory committee should have its own staff and budget.
The Task Force further recommends that the Secretary review the accomplishments of the advisory committee on genetic testing after 2 full years of operation and determine whether it should continue to operate.
NOTE: Hereafter, the advisory committee on genetic testing is referred to as the proposed Secretary's Advisory Committee.
In making recommendations on safety and effectiveness, the Task Force concentrated on test validity and utility, laboratory quality, and provider competence. It recognizes, however, that other issues impinge on testing, and problems can arise from testing. Regarding these issues, the Task Force endorses the following principles.
The Task Force strongly advocates written informed consent, especially for certain uses of genetic tests, including clinical validation studies and predictive testing. The failure of the Task Force to comment on informed consent for other uses does not imply that it should not be obtained.
Test Development. Informed consent for any validation study must be obtained whenever the specimen can be linked to the subject from which it came. As long as identifiers are retained in either coded or uncoded form, the possibility exists to contact subjects even if the intent of the original protocol was not to do so. As part of the disclosure for consent, individuals must be informed of possible future uses of the specimen, whether identifiers will be retained and, if so, whether the individual will be recontacted.
Testing in Clinical Practice. (1) It is unacceptable to coerce or intimidate individuals or families regarding their decision about predictive genetic testing. Respect for personal autonomy is paramount. People being offered testing must understand that testing is voluntary. Their informed consent should be obtained. Whatever decision they make, their care should not be jeopardized. Information on risks and benefits must be presented fully and objectively. A non-directive approach is of the utmost importance when reproductive decisions are a consequence of testing or when the safety and effectiveness of interventions following a positive test result have not been established. Obtaining written informed consent helps to ensure that the person voluntarily agrees to testing.
(2) Prior to the initiation of predictive testing in clinical practice, health care providers must describe the features of the genetic test, including potential consequences, to potential test recipients. Individuals considering genetic testing must be told the purposes of the test, the chance it will give a correct prediction, the implications of test results, the options, and the benefits and risks of the process. The responsibility for providing information to the individual lies with the referring provider, not with the laboratory performing the test.
Newborn Screening. (1) If informed consent is waived for a newborn screening test, the analytical and clinical validity and clinical utility of the test must be established, and parents must be provided with sufficient information to understand the reasons for screening. By clinical utility, the Task Force means that interventions to improve the outcome of the infant identified by screening have been proven to be safe and effective. Using newborn screening to identify couples who are at risk of having a future child with sickle cell anemia or other disorder because their screened infant is found to be a carrier (heterozygote) is not of primary benefit to the infant screened. Using newborn screening to identify parents at risk should only be done after this intention is communicated to parents (prior to screening) and their written consent is obtained. The Task Force recognizes that newborn screening programs have succeeded in significantly reducing the burden of a number of inherited disorders by timely diagnosis and institution of preventive therapies. Sometimes, however, newborn screening is undertaken before tests are validated and interventions are established to prevent or reduce clinical problems (see Appendix 5). A recent consensus development conference on cystic fibrosis concluded that the evidence to warrant routine screening of newborns for cystic fibrosis was insufficient.28
(2) For those disorders for which newborn screening is available but the tests have not been validated or shown to have clinical utility, written parental consent is required prior to testing. The Task Force also recognizes that specimens collected for newborn screening become an important resource for developing new tests. When the infant's name or other identifying information is retained on these specimens, the Task Force believes that parental informed consent is needed.
Respect for an individual's/couples' beliefs and values concerning tests undertaken for assisting reproductive decisions is of paramount importance and can best be maintained by a nondirective stance. One way of ensuring that a non-directive stance is taken and that parents' decisions are autonomous, is through requiring informed consent.
Genetic testing of children for adult onset diseases should not be undertaken unless direct medical benefit will accrue to the child and this benefit would be lost by waiting until the child has reached adulthood. The Task Force agrees with the American Society of Human Genetics and the American College of Medical Genetics that "Timely medical benefit to the child should be the primary justification for genetic testing in children and adolescents."48 Although sympathetic to the considerable difficulties inherent in living with uncertainty about the health status of the child, the Task Force does not feel that these warrant foreclosing the child's right to make an independent decision in regard to testing in adulthood. We are aware, however, that there are situations (e.g., testing for inherited mutations in the ademomatous polyposis coli gene) in which the benefit of avoiding medical surveillance (if the test result is negative) is sufficient to warrant testing even though no treatment will usually be undertaken until a later age (if the test result is positive). In addition, the Task Force realizes that legal adulthood is a somewhat arbitrary concept. For example, in families with a considerable burden of disease and in which several adults are undergoing genetic testing, older teenagers might request testing for themselves in order to reduce uncertainty and anxiety. It is unfortunate that almost no research evidence currently exists on the risks and benefits of genetic testing to teenagers and younger children. We believe that such psychosocial research must be pursued as vigorously as research on issues of analytic validity or utility of tests. However, unless and until such time as contradictory research findings emerge, testing of minors for presumed psychological benefits should be avoided.
Protecting the confidentiality of information is essential for all uses of genetic tests.
Recently, a subcommittee of the American Society of Human Genetics50 endorsed these same principles for disclosure to relatives, but suggested that "the health care professional should be obliged to inform the patient of the implications of his/her genetic test results and potential risks to family members. Prior to genetic testing and again upon refusal to communicate results, this duty to inform the patient of familial implications is paramount. (emphasis added)." The Task Force is of the opinion that, as part of this duty, providers must make clear that they will not communicate results to relatives, except in extreme circumstances, which the provider should define. If left with the impression that the provider will inform relatives when the person considering testing does not want them informed, some people will decline testing. This would have the effect not only of denying information to the relative but to the person offered testing as well. Providers should be explicit in describing the extreme situations in which they would inform other relatives.
Harm can also result when relatives communicate genetic information. Strategies to assist individuals in communicating information to relatives should be developed.
No individual should be subjected to unfair discrimination by a third party on the basis of having had a genetic test or receiving an abnormal genetic test result. Third parties include insurers, employers, and educational and other institutions that routinely inquire about the health of applicants for services or positions. Discrimination can take the form of denial or of additional charges for various types of insurance, employment jeopardy in hiring and firing, or requirements to undergo unwanted genetic testing. Protection from unfair discrimination has been the subject of legislation at both the State and Federal levels.51 The problem has not been completely solved.52,53
Although other stakeholders are concerned about protecting consumers, they cannot always provide the perspective brought by consumers themselves, the end users of genetic testing. Clearly, there are technical issues that cannot be decided primarily by consumers, but consumers must be involved in decision making on matters of policy in test development and in clinical use that directly affects their well-being. Consumers should be involved in policy (but not necessarily in technical) decisions regarding the adoption, introduction, and use of new, predictive genetic tests.
There are aspects of genetic testing with which we have not dealt. Several respondents asked the Task Force to comment on genetic testing for non-medical conditions, such as homosexuality or other behavioral traits, or for gene enhancement. Although the Task Force has drawn upon examples of past and current testing, it has not made pronouncements about specific types of testing. As already stated, its intent is to develop generic policies that cover predictive testing for a wide range of medical conditions.
The Task Force recognizes that patenting and licensing can have a profound effect on the costs of medical tests. The payment of license fees is likely to be passed on to third-party payers or to consumers if they do not have or wish to use their health insurance. This issue has been highlighted recently by lawsuits by a patent holder to force laboratories performing prenatal screening for Down syndrome to pay royalties.54 The issue of patenting and licensing needs further exploration but is beyond the scope of the Task Force.
The Task Force has not dwelled in depth on the use of stored tissues for genetic research, including the development of genetic tests. Recommendations on this issue have been made by others55-58 and are still being actively discussed and modified.
Undoubtedly, others would have liked us to comment on additional issues. We reiterate that our main concern is the safety and effectiveness of genetic tests in both the developmental phase and the clinical-use phase. We turn now to these major topics.
|Top of page|
Last Reviewed: October 2005