The rapid pace of discovery of genetic factors in disease has improved our ability to predict risks of disease in asymptomatic individuals. We have learned how to prevent the manifestations of a few of these diseases and treat some others. Gene therapy is being actively investigated.

Despite remarkable progress much remains unknown about the risks and benefits of genetic testing.

It is primarily in the context of their unknown potential risks and benefits that the Task Force considers genetic testing.

The Task Force was created by the National Institutes of Health (NIH)-Department of Energy (DOE) Working Group on Ethical, Legal, and Social Implications (ELSI) of Human Genome Research to review genetic testing in the United States and 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.

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. Principles and recommendations of the Task Force appear in bold-faced type.

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, and 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. Some, but not all, predictive genetic testing falls under the rubric "genetic screening," a search in a population for persons possessing certain genotypes.

For the most part, genetic testing in the United States has developed successfully, providing options for avoiding, preventing, and treating inherited disorders. However, problems arise as a result of current practices.

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 the benefits of testing can be fully realized undiluted by harm.

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 may arise from testing. Regarding these issues, the Task Force endorses the following principles.

Informed Consent. The Task Force strongly advocates written informed consent. The failure of the Task Force to comment on informed consent for other uses does not imply that it should not be obtained.

Prenatal and Carrier Testing. 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.

Testing of Children. 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.

Confidentiality. Protecting the confidentiality of information is essential for all uses of genetic tests. (1) Results should be released only to those individuals for whom the test recipient has given consent for information release. Means of transmitting information should be chosen to minimize the likelihood that results will become available to unauthorized persons or organizations. Under no circumstances should results with identifiers be provided to any outside parties, including employers, insurers, or government agencies, without the test recipient's written consent.

Discrimination. 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.

Consumer Involvement in Policy Making. Although other stakeholders are concerned about protecting consumers, they cannot always provide the perspective brought by consumers themselves, the end users of genetic testing. Consumers should be involved in policy (but not necessarily in technical) decisions regarding the adoption, introduction, and use of new, predictive genetic tests.

Providers and consumers cannot make a fully-informed decision about whether or not to use genetic tests unless their benefits and risks have been assessed. Although extensive use has eventually proved most tests to be of benefit, a few eventually proved unhelpful and were discarded. In the meantime, people were wrongly classified as at-risk and subjected to treatments that, in their case, proved unnecessary or sometimes harmful. Others, who could have benefited from treatment were classified as "normal" and denied treatment. The Task Force strongly recommends that the following criteria be satisfied.

(3) Data to establish the clinical validity of genetic tests (clinical sensitivity, specificity, and predictive value) must be collected under investigative protocols. In clinical validation, the study sample must be drawn from a group of subjects representative of the population for whom the test is intended. Formal validation for each intended use of a genetic test is needed.

(4) Before a genetic test can be generally accepted in clinical practice, data must be collected to demonstrate the benefits and risks that accrue from both positive and negative results.

Because of the length of time it can take to establish the appropriateness of a test for clinical use, it is all the more important to ensure the collection of data on safety and effectiveness in the course of test development. At present, no government policy requires the collection of data on clinical validity and utility for all predictive genetic tests under development.

Considering the structures for external review of research in the U.S. today, the Task Force is of the opinion that institutional review boards (IRBs) are the most appropriate organizations to consider whether the scientific merit of protocols for the development of genetic tests warrants the risk to subjects participating in the research.

The Task Force recommends that the Office of Protection of Human Subjects from Research Risks (OPRR) develop guidelines to assist IRBs in reviewing genetic testing protocols. The proposed Secretary's Advisory Committee should work with OPRR to accomplish this task. In developing guidelines for IRBs, OPRR should focus first on tests under development that require stringent scrutiny. The proposed Secretary's Advisory Committee or its designate, in cooperation with OPRR, should establish criteria for stringent scrutiny.

Conflict of Interest. The Task Force recommends strenuous efforts by all IRBs (commercial and academic) to avoid conflicts of interest, or the appearance of conflicts of interest, when reviewing specific protocols for genetic testing. OPRR should consider more stringent standards for all types of IRBs for avoiding conflict of interest situations.

Enforcement. Testing organizations should comply voluntarily with obtaining IRB approval of genetic test protocols. Other options the Task Force considered for enforcing the requirement for IRB approval included that: (1) the FDA use its authority to require all test developers to submit protocols to IRBs, (2) third-party payers refuse to reimburse for a genetic test unless the developer can show that it conducted validation/utility studies under an IRB-approved protocol, (3) clinical laboratory surveyors (see chapter 3) confirm that laboratories have received IRB approval of the new genetic tests that they developed, and (4) Congress enact legislation requiring submission of all research protocols, regardless of support, to an IRB.

Data Collection. To expedite data collection, collaborative efforts will often be needed. OPRR, with input from the proposed Secretary's Advisory Committee on genetic testing, should streamline the requirements for IRB review of multicenter collaborative protocols for genetic test development in order to reduce costs and get the studies quickly underway.

The Need for Post-market Surveillance. The Task Force recognizes that assessing the validity and utility of some genetic tests will take a long time. When preliminary data indicate a test is likely to have validity and utility, the test should be approved for marketing (see below) but developers must continue to collect data until more definitive answers are obtained. Options for encouraging collection of the requisite data include the following:

(1) Voluntary collection of data by developers after their tests enter clinical use.

(2) Reimbursement for, or coverage of, tests by third party payers during investigative stages in which data are being collected.

(3) Conditional premarket approval by the FDA of genetic test kits. In return for conditional approval, developers could include a profit markup in the price while they continue to collect data.

Test developers must submit their validation and clinical utility data to internal as well as independent external review. In addition, test developers should provide information to professional organizations in order to permit informed decisions about routine use. The Task Force recognizes that not all new genetic tests are in need of such review. The proposed Secretary's Advisory Committee should suggest criteria for external review, and recommend means of ensuring that review of tests requiring stringent scrutiny will take place. To accomplish the latter, the cooperation of various government and nongovernment groups to conduct reviews must be secured, as well as funds to support the reviews. A wide range of stakeholders should participate in reviews.

Local Review. The Task Force strongly suggests that any organization in which tests are developed conduct a structured review of the analytic and clinical validity and utility of new genetic tests before marketing them or otherwise making them available for clinical use. This structured review should be conducted by those not actually involved in developing the test and collecting the data. Some medical centers have standing committees that review tests proposed to be offered in the institution's clinical laboratories that could serve this function. For commercial organizations, a unit within the company, but independent of the laboratory that is actually developing the test, should review the data.

No clinical laboratory should offer a genetic test whose clinical validity has not been established, unless it is collecting data on clinical validity under either an IRB-approved protocol or conditional premarket approval agreement with FDA (one of the options presented in chapter 2. The service laboratory should justify and document the basis of decisions to put new tests into service. Regardless of where the test to be adopted was developed, clinical laboratory directors are responsible for ensuring the analytic validity of each genetic test their laboratory intends to offer before they make the test available for use in clinical practice (outside of an investigative protocol).

Because laboratories provide services to providers and patients in many states it is clearly more desirable to have a rigorous Federal standard for certification or accreditation than fifty different State standards. Moreover, interstate genetic testing is unavoidable when only one or a few laboratories in the country provide tests. A national accreditation program for laboratories performing genetic tests, which includes proficiency testing and onsite inspection, is needed to promote standardization across the country. Such an accreditation program can occur more readily if a genetics specialty were established under CLIA. Until such time as a genetics specialty is established under CLIA, laboratories performing DNA/RNA-based tests for predictive purposes should choose to voluntarily participate in the College of American Pathologists' (CAP) molecular pathology program, including the CAP/American College of Medical Genetics (ACMG) molecular genetics proficiency testing program. Laboratories performing genetic tests on analytes not covered in the CAP/ACMG program, such as Tay-Sachs carrier screening and newborn screening, should participate in the available proficiency programs.

Onsite Inspection. All CLIA-certified laboratories are routinely inspected on a two-year survey cycle by (1) HCFA regional offices and State agencies, (2) private non-profit organizations to which HCFA has given "deemed" status in recognition of their ability to provide reasonable assurance that the laboratories they accredit meet the conditions required by Federal law, or (3) State-exempt licensure programs.

Publishing the names of laboratories performing satisfactorily would advise users that labs not appearing on the list have either not submitted to external review or have not performed adequately. HCFA annually publishes a list ("Laboratory Registry") that identifies all poor performance laboratories. As CAP is not deemed to accredit in areas of genetics, it does not make the results of its assessments of genetic test performance public. The Task Force recommends that CAP/ACMG periodically publish, and make available to the public, a list of laboratories performing genetic tests satisfactorily under its voluntary program. Other PT programs should also publish the names of laboratories performing satisfactorily if they do not already do so. Directories of laboratories providing genetic tests should also publish information on listed laboratories' satisfactory participation in PT and other quality control programs specific to genetic tests. Managed care organizations and other third-party payers should limit reimbursement for genetic tests to the laboratories on published lists of those satisfactorily performing genetic tests.

The Task Force recommends that CAP and ACMG seek advice and input from consumer groups, such as the Alliance of Genetic Support Groups, as well as from the National Society of Genetic Counselors (NSGC), on educational, psychological, and counseling issues in pre- and post-analytic components of genetic testing that are of direct concern to consumers. CDC should consider how the pre- and post-analytic phases of predictive genetic testing can be given greater weight in CLIA standards and regulations.

Many clinical laboratories advertise the availability of tests directly to the public. Great care must be taken that information on genetic tests presented directly to the public is accurate and includes risks and limitations, as well as benefits. Consumers should discuss testing options with a health care provider competent in genetics prior to having specimens collected for analysis. The Task Force discourages advertising or marketing of predictive genetic tests to the public.

The Task Force recommends that efforts should be made to harmonize international laboratory standards to ensure the highest possible laboratory quality for genetic tests.

Greater Public Knowledge of Genetics. A knowledge base on genetics and genetic testing should be developed for the general public. Without a sound knowledge base, informed decisions are impossible and claims of autonomy and informed consent suspect. People who are more knowledgeable will grasp more readily the issues raised by providers when they offer tests. This could diminish the time needed for education and counseling without reducing consideration of the implications of testing. New models of providing education and counseling to patients and other consumers are needed.

Undergraduate and Graduate Medical Education. The Task Force encourages the development of genetics curricula in medical school and residency training to enable all physicians to recognize inherited risk factors in patients and families and appreciate issues in genetic testing and the use of genetic services. Those responsible for education and training have begun to recognize that most medical care is provided in ambulatory settings and that the delivery of care in those areas presents challenges for education. Genetic testing is a prime example. Moreover, teaching about genetic tests, including such issues as analytic and clinical validity, introduces students and residents to general problems of reliability and test sensitivity and specificity, which are important for a much wider range of clinical laboratory tests.

Licensure and Certification. The likelihood that genetics will be covered in curricula will improve if relevant genetics questions are included in general licensure and specialty board certification examinations, and if correctly answering a proportion of the genetics questions is needed to attain a passing score.

Continuing Medical Education. The full beneficial effects of improving medical school and residency curricula in genetics will not be felt for many years. Consequently, improving the ability of providers currently in practice to offer and interpret genetic tests correctly is of paramount importance. In addition to the basic curricula already considered, the Task Force recommends that each specialty involved with the care of patients with disorders with genetic components should design its own curriculum for continuing education in genetics.

Demonstrating Provider Competence. Hospitals and managed care organizations, on advice from the relevant medical specialty departments, should require evidence of competence before permitting providers to order predictive genetic tests defined as needing stringent scrutiny or to counsel about them. Periodic, systematic medical record review, with feedback to providers, should also be used to ensure appropriate use of genetic tests. In order to succeed, this policy requires, first, deciding which tests need evidence of competence, second, defining competence for those tests, and third, making educational modules readily available to enable providers to gain competence.

Screening could be offered in health department clinics, mobile vans or other sites, but not all segments of the population are likely to utilize them. A greater chance of breaching confidentiality is possible at community and health department sites than in the privacy of the traditional provider-patient relationship. Traditionally, health departments have been most involved in clinical care when there were well-accepted interventions (such as immunizations or tuberculosis control) without which the health of the public would be jeopardized. It might be difficult for public health personnel to appreciate that someone who refuses genetic screening is not jeopardizing the health of the public. Before these new models are investigated, additional training of the personnel involved is necessary. Schools of nursing, public health, and social work need to strengthen their training programs in genetics.

Between 10 and 20 million Americans may suffer from one or more of the several thousand known rare diseases over their lifetimes. With the discovery of the role of inherited mutations in common diseases, such as breast and colon cancer and Alzheimer disease (albeit in a small proportion of affected people), the development and maintenance of tests for rare genetic diseases must continue to be encouraged. A comprehensive system to collect data on rare diseases must be established. Multiple sources will almost always be needed to validate tests for rare diseases. CDC and the NIH Office of Rare Diseases (ORD) should work closely to develop the appropriate data-gathering and monitoring systems to assess the validity of genetic tests for rare diseases.

Unfortunately, the diagnosis of rare diseases is often delayed. One reason for the delay is inaccessibility of information. Physicians who encounter patients with symptoms and signs of rare genetic diseases should have access to accurate information that will enable them to include such diseases in their differential diagnosis, to know where to turn for assistance in clinical and laboratory diagnosis, and to locate laboratories that test for rare diseases.

Several private and public organizations, both professional and consumer-oriented, do provide information on rare diseases. The Task Force is concerned that there might be some unnecessary duplication of effort in compiling databases while, at the same time, some diseases or laboratories offering tests will not be included. In order to avoid redundancy and to use the expertise of these organizations more efficiently, NIH should assign its Office of Rare Diseases (ORD) the task of coordinating these efforts and provide ORD with sufficient funds to fulfill the Task Force's recommendations on rare diseases. ORD should periodically report to the proposed Secretary's Advisory Committee on the status of these activities. With CDC playing a greater role in genetics, it should be closely involved in activities in this area.

Research laboratories that provide physicians with results of genetic tests, which may be used for clinical decision making, must validate their tests and be subject to the same internal and external review as other clinical laboratories. Nevertheless, the proposed genetics subcommittee of CLIAC should consider developing regulatory language under the proposed genetics specialty that is less stringent, but does not sacrifice quality for laboratories that only occasionally and in small volume perform tests whose results are made available to health care providers or patients.

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% in some population groups;³ usually the combined frequency of all such mutations is under 5% 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% 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.

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.

To determine the state of the art of genetic testing in the U.S., 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 U.S. 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 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 (http://ww2.med.jhu.edu/tfgtelsi), 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.

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.

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% 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% said they were covering predictive tests for breast cancer and 42% 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 cancer^35,36 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.

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.

SCOPE OF THE REPORT

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.

OVERARCHING PRINCIPLES

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.

Prenatal and Carrier Testing

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.

(1) Results should be released only to those individuals for whom the test recipient has given consent for information release. Means of transmitting information should be chosen to minimize the likelihood that results will become available to unauthorized persons or organizations. Under no circumstances should results with identifiers be provided to any outside parties, including employers, insurers, or government agencies, without the test recipient's written consent. Consent given for minors should expire when the minor reaches adulthood.

Unless potential test recipients can be assured that the results will not be given to individuals or organizations they have not specifically named, some will refuse testing for fear of losing insurance, employment, or for other reasons. Aggregate results, stripped of identifiers, can be reported to government agencies for statistical and planning purposes.

The Task Force agrees with recommendations of The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research⁴⁹ and the Institute of Medicine²³ that disclosure by providers to other family members is appropriate only when the person tested refuses to communicate information despite reasonable attempts to persuade him or her to do so, and when failure to give that information has a high probability of resulting in imminent, serious, and irreversible harm to the relative, and when communication of the information will enable the relative to avert the harm. When test results have serious implications for relatives, it is incumbent upon providers to explain to people who are tested the reasons why they should communicate the information to their relatives and to counsel them on how they should convey the information so the communication itself does not result in undue harm. Great care must be taken to avoid inadvertent release of information.

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 others^55-58 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.

31. Council on Scientific Affairs: Maternal serum a-fetoprotein monitoring. JAMA 1982;247:1478-1481.

In developing genetic tests, scientists must first be confident that the DNA segments under investigation play a role in the disease in question. These segments might be apparently functionless markers that appear to be spatially linked on a chromosome to a disease-related gene. Linkage is demonstrated when, within families, one form of the marker is found in those with the disease more often than in blood relatives in whom the disease is absent. Because such associations might be due to chance, as was the case for the linkage claimed between bipolar affective disorder and markers on chromosome 11, and between schizophrenia and markers on chromosome 5,^1,2 stringent statistical standards must be satisfied before accepting linkage,³ and the findings must be confirmed in additional families with the disease. The method has proved successful in locating disease-related genes for Huntington disease, cystic fibrosis, b