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, breast cancer, and other disorders.

Further research leads scientists from the linked, functionless marker to a nearby gene suspected of being causally related to the diseases in question. The proof depends on finding mutations in the gene that are only present (in gene dosage sufficient to cause disease) in family members with disease.^a Further proof that a gene is causally related to disease comes from demonstrating that the protein encoded by the gene is absent, not synthesized in adequate amounts, or manifests a structural or functional aberration that plausibly accounts for symptoms and signs of the disease.

The DNA segments associated with a disease might be functional, common, polymorphic gene variants. Recently, attention has been given to the association between the apolipoprotein E polymorphism and Alzheimer disease (AD).⁷ A higher proportion of people with apoE4 will develop AD than those with other forms of the polymorphism. Some people with AD, however, will not inherit apoE4 and others with apoE4 will never develop AD;⁸ the polymorphism is neither a necessary nor sufficient cause for the disease. It is not clear whether polymorphic variants themselves predispose to the disease, whether the association is spurious (unlikely in the case of apoE4 and AD), or whether a marker linked to both the polymorphic gene and the disease-related gene is responsible.^b The following criterion must be satisfied before either linked markers or putative disease-related mutations are used as the basis of a genetic test. The genotypes to be detected by a genetic test must be shown by scientifically valid methods to be associated with the occurrence of a disease. The observations must be independently replicated and subject to peer review.

For DNA-based tests, analytical validity requires establishing the probability that a test will be positive when a particular sequence (analyte) is present (analytical sensitivity) and the probability that the test will be negative when the sequence is absent (analytical specificity).^c In contrast to DNA-based tests, enzyme and metabolite assays measure continuous variables (enzyme activity or metabolite concentration). One key measure of their analytical validity is accuracy, or the probability that the measured value will be within a predefined range of the true activity or concentration. Another measure of analytical validity is reliability, or the probability of repeatedly getting the same result.

Analytical validation of a new genetic test includes comparing it to the most definitive or "gold standard" method. The first genetic test to be used clinically might, however, be the gold standard; for example, a test that employs sequencing to detect disease-related mutations. In either case, validation includes performing replicate determinations to ensure that a single observation is not spurious, and "blind" testing of coded positive samples (from patients with the disease in whom the alteration is known to be present) and negative samples (from controls). Organizations engaged in new test development should have access to a sufficient number of patient samples to have statistical confidence in the validation. In validating a new test analytically, the laboratory techniques should be as similar as possible to those used when the test will be performed clinically once it is validated.

Penetrance. The probability that disease will appear when a disease-related genotype is present is the penetrance of the genotype. When penetrance is incomplete, PPV is reduced. Penetrance is incomplete when other genetic or environmental factors must be present. In high-risk breast cancer families, 10 to 15 percent of women with inherited susceptibility mutations of the BRCA1 gene will never develop breast cancer. Environmental factors and possibly other inherited factors are required as well. In women without a family history of breast cancer, the penetrance of a BRCA1 or BRCA2 mutation is even lower.¹⁰ Alleles at other gene loci and similar environments are more likely to be shared by relatives than by people in the general population.

Sensitivity can be estimated by determining the proportion of all known (symptomatic) patients with the disease in whom the test is positive. For direct DNA tests for inherited mutations whose causal role has been established, the mutation is not an effect of the disease. Therefore, determining the sensitivity in symptomatic people is a valid measure of its sensitivity among asymptomatic people. This might not be the case for tests of enzyme activity or metabolite concentration, however. They might be "effects" rather than "causes." Moreover, substances might interfere with their detection. Consequently, validation entails performing the test in healthy individuals. This can be accomplished in pilot screening programs discussed further in chapter 3.

Prospective studies can take years. If widespread use of a genetic test is withheld until PPV is fully determined, manufacturers and commercial laboratories could be inhibited from developing tests and, consequently, people denied the benefits that might accrue as a result of being tested. Later in this chapter we discuss solutions to this problem.

Parameters of clinical validity will depend in part on the group or population in which the test will be used. For instance, the frequency of disease-related alleles might differ between ethnic groups, making it difficult if not impossible to extrapolate test sensitivity from one group to another. This is the case for cystic fibrosis and breast cancer in which certain alleles can predominate in one ethnic group or geographical area but not in others.^11,12 Penetrance can also differ among ethnic groups. The prevalence of allele frequencies will have a marked effect on PPV; the greater the prevalence, the higher the PPV. Age will also affect allele prevalence; in a population older than the age at which the disease usually causes death, the allele frequency will be lower than in a younger population. For all these reasons, validation studies should be conducted in a group representative of the one in which the test is intended for clinical use.

When tests developed for one purpose are used for another, there is no assurance that the sensitivity or PPV will be the same. The maternal serum alpha-fetoprotein (MSAFP) test was formally validated and approved by the Food and Drug Administration (FDA) as a screening test for open fetal neural tube defects. When it was subsequently discovered that a low MSAFP could predict an increased probability of Down syndrome in the fetus, it quickly was used for this purpose without systematic formal validation. The sensitivity and PPV of the MSAFP test for Down syndrome and other chromosome abnormalities are lower than for neural tube defects.¹³ Data on a particular intended use of a test is needed before that use becomes generally accepted clinical practice.^d

The development of tests to predict future disease often precedes the development of interventions to prevent, ameliorate, or cure that disease in those born with genotypes that increase the risk of disease. Even during this therapeutic gap, benefits might accrue from testing as discussed in chapter 1, such as the ability to avoid the conception or birth of an affected child, reduction of uncertainty and, in those with negative results, escape from frequent monitoring for signs of disease or prophylactic surgery and fear of insurance or employment discrimination. In the absence, however, of definitive interventions for improving outcomes in those with positive test results, the benefits will be limited and not everyone will want to be tested. To improve the benefits of testing, efforts must be made as tests are developed to investigate the safety and effectiveness of new interventions. In the absence of such interventions, studies must be mounted to ensure that testing is beneficial and, particularly, does not inflict psychological harm. The balance of benefits to risks will sometimes depend on how the information is presented and who presents it. These issues are candidates for study. The effect of testing on people with negative, as well as positive results, is important to assess. In high-risk families, people with negative results might have assumed they would be affected and are unprepared to cope with a negative result. They might feel guilt for not having the problem afflicting their affected relatives.¹⁴ For genetic susceptibility testing, people with negative results might gain the false impression that they have no chance of getting the disease and persist in or undertake unhealthful behaviors possibly to their future detriment. Ways should be sought to present information and explanations to minimize inappropriate or erroneous interpretations (see chapter 4). Learning why people who are offered testing decide not to be tested might also help improve understanding of people's perceptions of genetic testing.

The scientists and laboratories developing genetic tests might not have the expertise to explore a number of issues related to communication and counseling. Collaboration with clinical geneticists, genetic counselors, and psychologists can improve the quality of studies looking into these aspects of test development.

ENSURING COMPLIANCE WITH CRITERIA

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. Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), any laboratory providing tests on which clinical decisions are based must demonstrate the tests' analytical validity to outside surveyors, but CLIA has no provision for review of clinical validity or utility. Under the Medical Device Amendments to the Food, Drug, and Cosmetic Act, the safety and effectiveness or substantial equivalence (to devices marketed prior to passage of the Medical Device Amendments in 1976) of clinical diagnostic testing devices, which include genetic testing devices,^e must be demonstrated prior to marketing. FDA considers clinical validity in assessing safety and effectiveness of clinical laboratory testing devices, but generally not data on followup interventions. The FDA's requirements for demonstrating safety and effectiveness are limited to developers who plan to market genetic testing kits.^f The FDA has acknowledged to the Task Force that it has the authority to regulate genetic tests marketed as services but is not doing so. (Personal communications from D. Bruce Burlington, M.D. Director, Center for Devices and Radiological Health, FDA, April 3, 1996) Organizations applying for Federal grants to develop genetic tests must submit their research proposals to peer review "study sections." Institutional review boards (IRBs) must also approve protocols submitted to study sections for Federal funding. Many genetic tests, particularly for common disorders, are being developed without Federal funds for research and are not, therefore, subject to peer review. Under FDA regulations, organizations developing new medical devices must have their investigational protocols approved by an IRB. If test results are reported for clinical use and there is no confirmatory test available, the developer must comply with FDA's Investigational Device Exemption regulations. The FDA has not enforced this regulation for developers planning to market tests as services. A number of organizations developing or offering genetic tests, including those who market their own tests (home brews), have never submitted a protocol to an IRB or contacted FDA.

Protocols for the development of genetic tests that can be used predictively must receive the approval of an institutional review board (IRB) when subject identifiers are retained and when the intention is to make the test readily available for clinical use, i.e., to market the test. IRB review should consider the adequacy of the protocol for: (a) the protection of human subjects involved in the study, and (b) the collection of data on analytic and clinical validity, and data on the test's utility for individuals who are tested. IRB review is not needed for minor changes in tests (e.g., detection of additional mutations) as long as the original test was reviewed by an IRB. IRBs may request notification of such changes, however.

In the early stages of test development, analytical validity and clinical sensitivity can be established using specimens from which identifiers have been removed. (For clinical sensitivity, it need only be known whether the specimen came from someone with disease; identity need not be known.) Using specimens stripped of identifiers prevents contacting subjects. In this case, IRB approval is not needed, although some IRBs might want to know of such studies.¹⁵ It would be more problematic to remove identifiers (anonymizing) in an attempt to estimate PPV. Positive test results on specimens from people who were healthy at the time the specimen was collected need to be followed up to see if disease subsequently appeared. Plans to contact the people or examine their medical records require IRB review and approval. Although recontact might be needed to establish PPV, it might not be appropriate to inform people of results. Informing of results would be appropriate only at a stage when the clinical validity of the test has been fairly well established and when some benefit accrues to the subject from knowing the result. Protocols should spell out what subjects will be told when they are invited to participate in the study, if and under what circumstances they will be recontacted and how recontact will be made, and under what circumstances they will be given results.

Institutional review boards were established to protect human subjects from the risks of participating in research.^g Genetic test development entails a quest for information in order to advance medical practice and clearly falls under the rubric of research. Any research involving humans entails some risk. Even for research in which the risk to subjects is minimal, the risk should not be taken unless the research has scientific merit. OPRR has commented "if a research project is so methodologically flawed that little or no reliable information will result, it is unethical to put subjects at risk or even to inconvenience them through participation in such a study (emphasis added).^{18( p. 4-1)} As part of their duty to protect, IRBs must assess the scientific merit of protocols. Most protocols for the development of genetic tests will have scientific merit if they satisfy the criteria enumerated above. In order to protect human subjects in the development of genetic tests, IRBs must recognize the risks posed by genetic test development and determine that investigators have taken adequate steps to apprise subjects of these risks and reduce the chance of harm from those risks.^19,20

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. OPRR and the Advisory Committee should consider how they can be kept apprised of protocols being submitted, in order for them to formulate relevant advice. One possibility is that IRBs submit a one page summary of each genetic testing protocol to OPRR or the group that is developing guidance. The information could include the name of the investigator and his/her institution, the disease for which the test is being developed, intended use, method proposed, and population being studied. Based on these brief reports, the group developing guidance could request protocols for further study but would have no authority to interfere with local IRB review. The protocols would help the group develop general guidance criteria for local IRBs in future reviews.

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. In addition to the three criteria mentioned in chapter 1--(1) tests that have the ability to predict future disease in healthy or apparently healthy people; (2) tests that are likely to be used for predictive purposes; and (3) tests for which no independent confirmation is available--others should be considered. These criteria include: (4) tests likely to have low sensitivity (due to genetic heterogeneity) and low positive predictive value (due to incomplete penetrance); (5) tests for which no intervention is available or proven to be effective in those with positive test results; (6) tests for disorders of high prevalence; (7) tests likely to be used for screening; and (8) tests likely to be used selectively in ethnic groups with higher incidence or prevalence of the disorder.^h

Enforcement. As previously mentioned, organizations that are developing genetic test kits would be expected to submit their investigative protocols to IRBs. FDA can decline to consider applications containing data from clinical investigations that have not been approved by an IRB. Organizations using Federal research funds for genetic test development are also required to obtain IRB approval. Tests developed without Federal funds, either commercially, in academic clinical laboratories, or in some health departments, are not, at the moment, in legal jeopardy if they do not obtain IRB approval.ⁱ 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 ensuring that: (1) the FDA use its authority to require all test developers, regardless of whether they plan to market tests as services or kits, 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,^j (3) clinical laboratory surveyors (see chapter 3) confirm that laboratories have received IRB approval of the new genetic tests they developed, and (4) Congress enacts legislation requiring submission of all research protocols, regardless of support, to an IRB.

Compliance with all of the criteria for assessment of genetic test validity and utility might be difficult. It can take years to determine whether a disease will appear in healthy people with positive test results or to establish whether an intervention is safe and effective in preventing or ameliorating the disease in question. The Task Force is concerned that the requirements for prolonged data collection might inhibit test development, especially if commercial firms cannot secure a profit until a test is recognized as being suitable for clinical use.^k Adoption of the recommendations in the following section would facilitate rapid introduction with collection of the data necessary for assessing validity and utility.

Over 500 clinical laboratories in the United States perform chromosomal, biochemical, and/or DNA-based tests for genetic diseases (see appendix 3). These laboratories must comply with regulations under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), which include biennial inspection, some proficiency testing, and requirements of the specialty in which the laboratory is certified. Although clinical cytogenetics is a specialty under CLIA, there is no broader genetics specialty and, consequently, no special requirements for laboratories performing DNA-based and other types of genetic tests. No proficiency testing programs in genetics or cytogenetics are required under CLIA. New York State requires any laboratory performing tests on New York residents (even if those laboratories are outside of New York) to participate in its quality assurance programs in DNA-based and biochemical genetics. These programs involve onsite inspection but not formal proficiency testing.^a A number of organizations have voluntary programs for quality control of genetic tests; they are described later in this chapter. In a survey conducted for the Task Force in early 1995, 11% of biotechnology companies that provide genetic tests and 16% of nonprofit (primarily university-based) molecular (DNA) labs reported that they neither participated in a formal proficiency testing program nor shared samples informally for quality control (see appendix 3). According to the survey, about 15% of laboratories performing clinical DNA-based tests were not registered under CLIA (see chapter 5 for further discussion of this problem).

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. In accord with the recommendations in chapter 2, a clinical laboratory that develops a genetic test would have to submit its data on analytical and clinical validity to external review before offering the test for clinical practice.^b If the test has been developed elsewhere, clinical laboratories should carefully review evidence for test validity. If external review by professional societies has led to the publication of indications and guidelines for use, laboratories should adhere to them. 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). (Methods for assessing analytical validity are summarized in chapter 2.)

Before routinely offering genetic tests that have been clinically validated, a laboratory must conduct a pilot phase in which it verifies that all steps in the testing process are operating appropriately. In establishing the pilot phase, the laboratory should define endpoints, such as number of tests to be performed,^c and the procedures to be used to review the findings, including the organizational body that will review them. If the outcome of this review reveals that the laboratory is not as competent as other laboratories in performing the test, or the test does not detect as many people with the genetic alteration as anticipated, the laboratory should not proceed to report patient-specific results without attempting to rectify the problems. If demand is not sufficiently high to be able to maintain a high level of quality, the laboratory should institute special procedures to ensure quality.

During the pilot phase, confidence in the analytic validity of the test can be gained by splitting specimens with another laboratory.^d This phase can be used to detect and correct problems in test requisitions, specimen transport, data analysis and transcription, reporting of results, and user satisfaction. It can also be used to establish that laboratory staff are capable of deciding whether each requisition for the test meets established criteria, and the staff is capable of performing the tests and interpreting the results correctly. The pilot phase should employ laboratory practices as similar as possible to those planned when the test becomes routinely available.

Over 17,000 clinical laboratory tests have been assigned a complexity level.^e Any test for which CDC has not determined test complexity is considered to be high complexity by default.^f Any home-brew method, or change in procedure that can affect laboratory performance (sensitivity, specificity, accuracy, precision) falls under the high complexity category until it is rated differently by CDC. Under the rating scheme, a genetic test that can be used predictively might receive a rating of moderate complexity despite the importance of ensuring that the provider and the patient understand the uncertainty of the prediction and the implications for decision-making. Both the creatine phosphokinase test, which can be used as a screening test for Duchenne muscular dystrophy, and alpha-fetoprotein (AFP), which is used as a predictive prenatal test for neural tube defects and Down syndrome, are rated as moderate complexity. Despite multiple uses, a test method gets only one rating based on the seven criteria (see box entitled Complexity Determinations under CLIA) that reflect the complexity of performing the test. All cytogenetic tests are rated high complexity, which seems appropriate. The Task Force recommends that tests that can be used for purposes of predicting future disease be given a rating of high complexity.

requirements of the specialties to which tests are assigned. Laboratories can perform tests only in specialties for which they are certified. Although there is a cytogenetics specialty, there is no genetics specialty.^g The specialty categories under CLIA are based on traditional laboratory practice; each specialty tends to involve somewhat similar technologies, although this is not the case in all instances. Each analyte is assigned to only one specialty.

Under CLIA, a laboratory director must possess a current license as a laboratory director in the state in which the laboratory is located and be either (1) a pathologist; (2) a physician licensed to practice medicine or osteopathy; or (3) a board-certified doctoral scientist (Ph.D.).^h The Task Force recommends that for laboratories performing high complexity tests in the proposed specialty of molecular genetics, as well as in biochemical genetics and cytogenetics, personnel serving as directors or technical supervisors must have formal training in human and medical genetics, as documented by holding certification from an organization that assesses knowledge of human and medical genetics as part of its certification process, such as the American Board of Medical Genetics.

CLIA imposes minimal academic qualification requirements for testing personnel.ⁱ This is reasonable in the area of genetics because most current medical technology training programs include little, if any, exposure to genetics or molecular biology. Several formal training programs for cytogenetics technical staff are available, but there are very few certificate- or diploma-track genetics training programs for technicians or technologists in the U.S. Consequently, most technicians in molecular genetic testing laboratories are trained on the job. Broad backgrounds in genetics are unlikely, as is a familiarity with specialized methodologies involved in molecular genetics testing. Training programs for laboratory technicians/technologists need more human and medical genetics content than are currently available in the U.S.

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 on-site 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 CAP molecular pathology program including the CAP/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.

Proficiency testing (PT) is mandated by CLIA to externally evaluate the quality of a laboratory's performance. For PT, a laboratory is provided with specimens whose composition of an analyte is known to the supplier but not to the recipient laboratories. They are expected to analyze the specimen the same way they would a patient's specimen. Each laboratory performing moderate or high complexity tests is required to enroll in an approved PT program for all specialties/subspecialties, analytes, or tests for which the laboratory is certified and for which a PT program has been recognized by HCFA. Any laboratory that fails a proficiency test must take corrective action.^j HCFA takes an educational approach to PT and works with the laboratories that have problems to help improve performance. Sanctions can be applied to those laboratories repeatedly unable to perform satisfactorily. These include suspension of the CLIA certificate to perform that test or specialty. If its certificate is suspended, the laboratory is not eligible for Medicare/Medicaid reimbursement, since such reimbursement requires a CLIA license with no restrictions.

So far, the Department of Health and Human Services has approved 19 PT programs under CLIA. It has not approved proficiency testing programs for genetic tests because such tests do not measure regulated analytes for PT purposes as currently listed in the regulations. New York State and a few regions have cytogenetics PT programs. CAP and ACMG jointly administer PT in cytogenetics, fluorescent in situ hybridization, biochemical genetics, and molecular genetics. In collaboration with the Foundation for Blood Research (FBR), CAP has a PT program for prenatal screening of neural tube defects and Down syndrome. CDC has a PT program for newborn screening tests, including hemoglobinopathies. PT is also available for laboratories worldwide performing Tay-Sachs screening. Responding to a survey conducted for the Task Force in July 1997, CAP, FBR, CDC, and the International Tay-Sachs program reported that most laboratories known to them were participating in their respective programs.^k

Proficiency testing programs should be broadly based since the number of genetic disorders is very large and the analytical approaches to testing are numerous. It is unlikely that proficiency challenges will ever be constructed for every rare disease or every rare mutation in common diseases for which a given laboratory might test. Because of the similarity of techniques used in biochemical genetics, proficiency in these techniques applied to one or a few analytes is a reasonably good indicator of proficiency in other uses of the technique. CAP/ACMG is expanding the PT offering in molecular genetics to a greater number of disorders in order to get more complete demonstrations of proficiency.

All CLIA-certified laboratories are routinely inspected on a two-year survey cycle^l by one of three types of organizations: (1) HCFA regional offices and State agencies; (2) private non-profit organizations that have applied for and received deemed status because they provide reasonable assurance that the laboratories they accredit, which enables the laboratory to obtain a CLIA certificate, meet the conditions required by Federal law and regulation;^m (3) State-exempt licensure programs. States that have programs that license laboratories and provide HCFA with reasonable assurance that their criteria are equivalent to or more stringent than those specified under CLIA can apply for exempt status. So far New York, Oregon, and Washington (state) have exempt status. California, Florida, and Georgia are under review (as of July 1997). Regardless of the organization under whose auspices inspections are conducted, the surveyors are laboratory professionals who are trained to determine compliance with CLIA regulations (or a program that is determined to be equal to or more stringent than CLIA). Even though genetics is not a specialty, surveyors are expected to examine the quality of genetic tests. This should include inspection of the records of how the laboratory performed on genetic PT programs in which it participated voluntarily. It is not clear, however, that all CLIA surveyors currently are sufficiently knowledgeable to assess the performance of molecular genetics laboratories.ⁿ

CAP has deemed status to conduct inspections in several specialties, but since genetics is not a specialty under CLIA, the CAP program does not have deemed status in genetics. In the CAP genetics program, laboratories who voluntarily (and for a fee) participate in the program are inspected. The surveyors use a checklist covering all aspects of quality assurance and quality control, from specimen accessioning to final sign-out. Compliance with some items on the checklist is optional; for others, compliance is mandatory.^o Following inspection, the laboratory receives a written report and is expected to respond to CAP in writing regarding correction of any deficiencies in the mandatory categories. In areas in which it does not have deemed status, such as genetics, CAP has no authority to grant accreditation for CLIA purposes.

HCFA annually publishes a list ("Laboratory Registry") that identifies all poor performance laboratories, the reason enforcement actions were taken and type of enforcement, and the name of the laboratory director. The Registry is available to the public upon request, and will soon be accessible on the Internet at http://www.hcfa.gov. Survey findings are also available through the Freedom of Information Act, once the laboratory has the opportunity to respond with its Plan of Action. CAP reports PT results for regulated analytes (i.e., those for which CLIA requires PT) to HCFA. It does not report PT results directly to the public because it maintains that PT alone is insufficient to demonstrate laboratory quality. CAP does make accreditation status available through its toll-free hotline (1-800-LAB-5678), and a CAP-published list of accredited laboratories.^p 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.

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. Directories of laboratories providing genetic tests (e.g.. HELIX--see chapter 5) should also publish information on listed laboratories' satisfactory participation in PT and other quality control programs specific for genetic tests. The Association for Molecular Pathology publishes information on the quality of laboratories, and the National Organization for Rare Diseases and the Alliance of Genetic Support Groups make it publicly available. 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. Implementation of this recommendation is especially important as more managed care organizations move to restrict access to laboratory services for their members to a single laboratory with whom each organization contracts. Such a laboratory might not have participated or performed satisfactorily in a quality control program.

Making cell lines or DNA containing disease-related mutations available to many laboratories would be useful in the validation of new tests, calibration, standardization, and quality control. To accomplish this, appropriate specimens from patients, carriers, and controls should be available through a centralized repository in order to facilitate their availability to aid in analytical validation, improving quality, and other needs. Resources such as the National Institute of General Medical Sciences' Human Genetic Mutant Cell Repository (housed at the Coriell Institute for Medical Research) and the American Type Culture Collection should be utilized. It should be impossible to trace samples in a repository to the individuals from whom they were obtained. The samples should not be used for any purpose from which a profit could be derived, such as the sale of unusual probes. A central repository of analytes for standardizing biochemical and other types of tests, including those used for screening, is also needed. Some mechanism for ensuring the composition and concentration of these standards, such as FDA review, is needed.

In the pre-analytic phase, laboratories sometimes give information about the test to providers and consumers. Informed consent can be obtained, and data are requested from those to be tested. In the post-analytic phase, test results are given to the provider and patient, often with an interpretation. Genetic counseling services can be provided or arranged by laboratories, but are the responsibility of the referring provider.

Increasingly, genetic tests will be requested by providers without much or any training in genetics. (Recommendations on ensuring provider competence appear in chapter 4.) Accurate and comprehensible interpretation of genetic test results by the clinical laboratories is critical to ensure that the provider understands the implications and can explain them to the persons who were tested. Genetic test results must be written by the laboratory in a form that is understandable to the non-geneticist health care provider. The quality of laboratories' written interpretations of genetic test results should be included in the overall assessment of laboratories providing genetic tests.

One way of improving laboratory performance is to have more rigorous standards with which laboratories must comply. The Task Force is of the opinion that not enough emphasis is placed on the pre- and post-analytic phases in CAP's molecular pathology and special chemistry programs. 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.

Under CLIA, the rating system used to establish the complexity of tests does not give sufficient weight to these phases (see box entitled Complexity Determinations under CLIA). 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 (see appendix 4). 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. The informational material should be sensitive to the knowledge level of the general public. In addition to describing the benefits and risks of the genetic test(s), including discrimination issues and the potential emotional impact on individuals and family members, the material should describe those for whom testing is appropriate (e.g., couples planning to have children for carrier tests, and individuals with a family history of a late-onset disorder for which genetic predispositions can be detected), and should emphasize that all genetic testing is voluntary, often requiring informed consent. Consumers should discuss testing options with a health care provider competent in genetics prior to having specimens collected for analysis.

In accord with laws in most States, clinical laboratories in the U.S. require that specimens for the vast majority of tests come from a physician or are reported to a physician. A few laboratories accept specimens for predictive genetic testing directly from consumers without the intervention of their own physician. In such cases, a physician affiliated with the testing laboratory, who is a specialist but may be previously unknown to the patient, can order the test. As DNA can be isolated and amplified from cells in saliva or scraped from the buccal mucosa, it is possible for lay people to collect their own specimens. FDA has the authority to regulate this practice if the laboratory supplies or requires use of a specially designated collection device or container to send specimens from the person's home to the laboratory. The Task Force discourages advertising or marketing of predictive genetic tests to the public.

The question can be asked, why not simply screen everyone for disease-related alleles and bypass the family and past history? First, relatively few predictive tests applied on a population basis meet the criteria of validity and utility described in chapter 2. Second, even if they did, it would be extremely costly to test everyone. As the cost of the technology is reduced, this reason becomes less important. Third, the process of offering predictive genetic screening takes time. In accord with the principles of autonomy presented in chapter 1, people must be informed of the benefits and risks of screening and given an opportunity to decline it. Although this might be accomplished simply by brochures and other audio-visual aids, the effectiveness of these methods has not yet been established. Unless and until they are, providers will have to spend time explaining screening to potential users. Fourth, when the results come back, they have to be interpreted. As discussed in chapter 2, many genetic tests are not perfect predictors. The probability that disease will occur when the test result is negative, or that disease will not occur when the result is positive, both of which will be greater when populations rather than at-risk individuals are tested, must be explained.

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. Policies for improving public understanding of genetics and genetic tests are beyond the scope of the Task Force. A number of private and public organizations have, through public statement and program investment, strongly endorsed the need for large-scale educational programs.^a Educating the public in genetics presents enormous challenges. Many people's views of how traits are inherited are inconsistent with Mendelian inheritance.²⁰ New models of providing education and counseling to patients and other consumers are needed.

Ethnic groups differ in their perceptions of disease origins and what should be done to avert disease.^21-23 Moreover, identifying a genetic variant that has a much higher frequency in some ethnic groups than in others could have a stigmatizing effect on that group. In keeping with the overarching principles described in chapter 1, sensitivity to cultural differences is of paramount importance. Unfortunately, minorities are seriously under-represented in the field of genetics.

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. A committee of the American Society of Human Genetics has published a list of objectives for medical school courses and the skills and attitudes they should engender in medical students.²⁴

As provider-patient communication is critical in offering genetic tests and counseling about them, consumers should be involved in the planning and implementation of new curricula in genetics. The Partnership for Genetic Services Pilot Program, just launched by the Alliance of Genetic Support Groups, and supported by public and private funds, has, as its goal, improving medical student and provider understanding, sensitivity, and competence in delivering genetic services. It will do this by exposing medical students and physicians-in-training to relevant community resource systems and illustrative presentations by consumers. Partnerships between consumers and clinical genetics providers, primary care practitioners, medical school faculty, and managed care administrators have been established.

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. Medical school curriculum and residency review committees, which exist at both the local medical school and hospital levels and at the national level, define teaching content based on core material needed for clinical practice, recent advances, and questions on board examinations. Those who prepare board examinations, the National Board of Medical Examiners for medical students, and the various specialty boards for specialty certification, derive questions from material they think important, yet questions involving genetics are sparse and sometimes inappropriate. The American Council of Graduate and Medical Education (ACGME), is the umbrella organization for boards and residency review committees, and also contributes importantly to residency training content. The Task Force encourages ACGME, as well as residency review committees, to consider the importance of graduate training in genetics. The Task Force is pleased that the American Board of Obstetrics and Gynecology and the Society of Perinatal Obstetricians have acknowledged the importance of teaching genetics, including ethical aspects, by including questions on the basic obstetrics and gynecology exams, as well as on the subspecialty board exams of Maternal-Fetal Medicine.^b

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. The Task Force vigorously debated the question of whether this goal could best be accomplished by a "carrot" or "stick" approach. An early position taken by the Task Force was: "Some documentation of continuing education in the area of human and medical genetics should be required for physicians offering genetic tests, including primary care providers."^{26 (p.24)} As the Task Force deliberated, it developed doubts as to whether continuing education could accomplish this goal and whether a requirement would accomplish the Task Force's objective. The Task Force was also concerned that such a requirement would be difficult to enforce. The need to demonstrate competence is discussed further in the next section, but the point the Task Force wishes to emphasize is the need for each specialty to recognize that all of those who are certified in that specialty appreciate the importance of genetics and genetic tests relevant to that specialty. In addition to 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.

The Task Force endorses the recent establishment of a National Coalition for Health Professional Education in Genetics (NCHPEG) by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute. The Coalition should work in consultation with non-genetic professional societies, such as the Association of American Medical Colleges, the American Council on Graduate and Medical Education, and genetic societies, such as the American College of Medical Genetics, the National Society of Genetic Counselors, the International Society of Nurses in Genetics, and appropriate consumer groups to encourage the development of core curricula in genetics. It should encourage input by consumers in the development of these curricula. In order to avoid duplication, the Coalition should serve as a registry and clearinghouse for, and disseminator of, information about various curricula and educational programs, grants, and training pilot programs in genetics education. It should encourage professional societies to track the effectiveness of their respective educational programs.

In 1994, the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration, through its Genetic Services Branch, began soliciting grant applications to strengthen genetics in primary care. Thus far nine programs have been funded and several more are expected to be funded in 1998.^c At least one educational module is available on the World Wide Web under MCH NetLink (http://www.ichp.ufl.edu?mch-netlink/). Others will appear shortly. Another MCHB grantee, the Council of Regional Networks for Genetic Services (CORN) has recently issued its Guidelines for Clinical Genetic Services for the Public's Health.²⁶ MCHB has also asked CORN to prepare national guidelines that can be used for comprehensive followup care of children and families with rare metabolic disorders that can be used by purchasers and service providers in negotiating contracts with managed care plans. CDC has developed a Public Health Training Network that can be adapted to provide information about genetics. The network often employs satellite broadcasting to multiple receiving sites with phone communication from the sites to permit two-way communication. The Network also develops material for Internet presentations and self-study, computer-based training modules. A wide range of subjects have been presented, including basic epidemiology, specific disease management, immunizations, and managing laboratories under CLIA. The format includes lectures, panel discussions, and videos.

A major problem in all educational endeavors is finding the "teachable moment," the time at which people, including health care providers, are receptive to new information and are most likely to retain it. These moments arise when providers are asked questions about genetic tests or when charts are flagged because the patient fulfills criteria for being offered a genetic test. Clearly, more people are asking providers questions about genetic tests. Computerized medical records or self-completing questionnaires (see box entitled Educational Module to Assist Physicians in Recognizing Genetic Risks) can generate flags to advise providers to offer genetic tests to people at risk. Printouts of background information, when flags are raised, could assist the provider. A 1-800 hotline that providers (and the public, perhaps,) can call to learn more about specific genetic tests, including availability and indications for their use, should be established by NCHPEG or some of its governmental and private constituent organizations.

The overall time that physicians spend talking with patients on all subjects is usually less than the time that genetic counselors spend informing people about genetic tests and their implications. The nursing profession has recognized that nurses have much to offer in helping people appreciate the benefits and risks of genetic testing.^27,28 Nurses can not only counsel (when trained) but also perform a wide range of activities in health care that genetic counselors are not qualified to do. Nurses are also in much greater supply. Nurses have been shown to be effective in providing education for testing for genetic susceptibility to cancer.²⁹ Oncology nurses increasingly view themselves as genetic health care professionals.^d One nursing organization told the Task Force, "We see genetic education as core content in nursing education at both the undergraduate and advanced levels."^e Nurses have played a large role in genetic counseling in the United Kingdom for many years.³⁰ A study currently under way in the U.S. is comparing the ability of nurse practitioners and genetic counselors in educating and counseling about testing for genetic susceptibility to breast cancer. (G. Geller, work in progress) Nurses should be provided with additional education and training that can increase their effectiveness in providing education for people undergoing genetic testing.

Many other disorders are spread throughout diverse communities and it would be a Herculean task to organize community-based screening. 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. Informed consent might not always be obtained.³³ 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 can be 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.^f

28. Anderson GW: The evolution and status of genetics education in nursing in the United States 1983-1995. Image The Journal of Nursing Scholarship 1996;28:101-106.

29. Lerman C, Biesecker B, Benkendorf JL, et al: Controlled trial of pretest education approaches to enhance infomed decission-making for BRCA1. Journal of the National Cancer Institute 1997;89:148-157.

30. Williams A: Genetic counseling. A nurse's perspective. In Clarke A (ed): Genetic Counseling. Practice and Principles. New York, Routledge; 1994:44-62.

31. Hiller EH, Landenburger G, Natowicz MR: Public participation in medical policy making and the status of consumer autonomy: The example of newborn screening programs in the United States. American Journal of Public Health 1997;87:1280-1288.

32. Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B: Newborn screening for sickle cell disease: Effect on mortality. Pediatrics 1988;81:749-755.

33. Farfel MR, Holtzman NA: Education, consent, and counseling in sickle cell screening programs: Report of a survey. American Journal of Public Health 1984;74:373-375.

There is no uniform definition of a rare disease. The Orphan Drug Act (ODA) defines orphan disease as one affecting less than 200,000 persons in the U.S., or approximately 1 in 1,250 Americans. For devices (which include genetic tests), the 1988 ODA Amendments define rare disease as "any disease or condition that occurs so infrequently in the United States that there is no reasonable expectation that a medical device...will be developed without [financial] assistance."^a As already noted, the Humanitarian Device Exemption of the Safe Medical Devices Act of 1990 applies to diseases or conditions that affect fewer than 4,000 persons in the United States (1 in 62,500 Americans). It is silent on what constitutes a disease or condition (e.g., whether rare variants of a common genetic disease constitute a separate disease, or whether carriers are excluded). The carrier (heterozygote) frequency for autosomal recessive disorders with an incidence of 1 in 10,000 is 1 in 50.

A major concern of the Task Force is that as tests to diagnose and, in many cases, to predict, rare diseases are developed, data will not be systematically compiled on their clinical, as well as analytical validity. A comprehensive system to collect data on rare diseases must be established. As discussed in chapter 2, the Center for Disease Control and Prevention (CDC) can and should play a role in coordinating data collection from multiple sources to facilitate the review of new genetic tests, particularly for rare diseases. Multiple sources will almost always be needed to validate tests for rare diseases. CDC and 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. The commonly encountered symptoms and signs with which rare diseases present and the process of evaluating them should be taught to medical students and residents. It would be too much to expect health care providers to retain information on all the unusual presentations, but they should be taught where to seek information. Although textbooks and medical journals are the classical starting points, and referrals to specialists may help, computerized databases in which a user could search by the patient's presenting finding would be more expeditious and effective. Most available information is organized by disease, not by presenting findings. The National Organization of Rare Diseases, Inc. (NORD) publishes The Physician's Guide to Rare Diseases, which includes an atlas of visual diagnostic signs. NORD also maintains the rare disease database containing entries on over 1,100 rare diseases. The database is logically organized by a description of the disorder, symptoms, causes, affected population, related disorders, diagnostic procedures, status of treatment (investigational or standard of care), resource referral for further information and support, and references from peer-reviewed medical literature. The database is available on the World Wide Web at http://www.nord-rdb.com/~orphan.

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 addition to the databases mentioned so far, several other organizations, including the Alliance of Genetic Support Groups, some of its member organizations, and other independent genetic disease interest groups maintain databases and, in some cases, patient registries. The American Academy of Pediatrics provides information periodically on newborn screening and other disorders. The Society for Inherited Metabolic Disorders is compiling information for providers about diagnostic evaluations of rare disorders, and ACMG is developing databases on tests that should be used to diagnose specific disorders. 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.

Some research laboratories have complained of the difficulty and expense of obtaining CLIA approval for tests that constitute a small part of their activity and will only be performed occasionally. A laboratory performing 2,000 or fewer tests a year can register for $100 and obtain certification for $300 (including onsite inspection for its first 2 years.)^b

The Task Force recognizes the important contribution that research laboratories make to clinical testing, particularly for rare diseases. The type of skills that are needed for research, including a willingness to modify experimental conditions, are not necessarily the skills for maintaining the quality of a service laboratory, in which consistency of performance ensures reliability. 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.^c