GENETIC TESTING 

Comment Period and Submission of Comments 

Decades of research in genetics have brought about many important medical and public health benefits. Gene discoveries have provided a better understanding of the genetic basis of disease and opened new avenues for diagnosis, treatment, and prevention of disease. The pace of the discovery of new genes and the development of new genetic tests is expected to increase in the future. The Human Genome Project, a major international collaborative effort established and supported by public and private groups, including the U.S. Department of Energy (DOE) and the National Institutes of Health (NIH), is expected to complete the sequencing of the human genome by the year 2003. The unprecedented amount of genetic information produced by the Human Genome Project will enable scientists to make more rapid progress in understanding the role of genetics in many common complex diseases and conditions--such as heart disease, cancer, and diabetes--and to increase knowledge that may lead to the development of individually tailored medical treatments. These scientific and technological advances are expected to bring about revolutionary changes in clinical and public health practice and to have a significant impact on society.

The Secretary's Advisory Committee on Genetic Testing (SACGT) was established to advise the Department of Health and Human Services (DHHS) on the medical, scientific, ethical, legal, and social issues raised by the development and use of genetic tests. The formation of SACGT was recommended by the NIH-DOE Task Force on Genetic Testing and the Joint NIH-DOE Committee to Evaluate the Ethical, Legal and Social Implications Program of the Human Genome Project. At SACGT's first meeting in June 1999, the Assistant Secretary for Health and Surgeon General asked the Committee to assess, in consultation with the public, the adequacy of current oversight of genetic tests.

Advances in knowledge about the structures and functions of human genes and the development of new laboratory technologies for the analysis of genetic material are helping to produce many new genetic tests for a wide range of conditions and purposes. Genetic tests can be used to diagnose disease, confirm a diagnosis, provide prognostic information about the course of disease, confirm the existence of a disease in individuals who do not yet have symptoms, and, with varying degrees of effectiveness, predict the risk of future disease in healthy individuals. Currently, several hundred genetic tests are in clinical use, with many more under development, and their number and variety are expected to increase rapidly over the next decade. These advances stem in large part from research funded and conducted by agencies within DHHS, especially NIH.

The Task Force on Genetic Testing, which was charged to review genetic testing in the United States and to make recommendations to ensure the development of safe and effective genetic tests, began its work in 1995 and published its final report two years later. In its final report, the Task Force concluded that although genetic testing is developing successfully in the United States, some concerns about it exist. These can be grouped into four main areas:

• the way in which tests are introduced into clinical practice;

• the adequacy and appropriate regulation of laboratory quality assurance;

• the understanding of genetics on the part of health care providers and patients; and

• the continued availability and quality of testing for rare diseases.

 

The Task Force recommendations were intended primarily to enhance the way in which tests are developed, reviewed, and used in clinical practice. The Task Force explored the question of how tests should be assessed, considered how comprehensive data gathering efforts could incorporate new data, and made suggestions about the need for external review of tests. Although the Task Force recommended that revisions to the current review process may be needed to assess the effectiveness and usefulness of genetic tests, it did not specify how the review of laboratory-based genetic tests should be changed.

DHHS requested that SACGT build on the work of the Task Force by assessing whether current programs for assuring the accuracy and effectiveness of genetic tests are satisfactory or whether other measures are needed. This assessment requires consideration of the potential benefits and risks (including socioeconomic, psychological, and medical harms) to individuals, families, and society, and, if necessary, the development of a method to categorize genetic tests according to these benefits and risks. Considering the benefits and risks of each genetic test is critical in determining its appropriate use in clinical and public health practice. If, after public consultation and analysis, SACGT finds that other oversight measures for genetic tests are warranted, it has been asked to recommend options for such oversight.

It is important to note that although this paper focuses on Federal oversight of genetic tests in laboratory and clinical settings, the training and education of health care providers and the promotion of greater public understanding of genetics are also critical issues. More genetics training and education of health care providers who prescribe genetic tests and use the results for clinical decision-making is widely regarded as another way in which to enhance the safe and effective development and use of genetic tests. It is helpful to keep training and education of health care providers and promotion of public understanding in mind while considering the Federal role in oversight. SACGT intends to address the training and education issue after this current assignment is completed.

Much of the information presented in the following sections regarding genes, genetics research, and genetic testing is adapted from Understanding Gene Testing, a booklet produced by the National Cancer Institute and the National Human Genome Research Institute. The booklet is available at http://www.accessexcellence.org/AE/

AEPC/NIH/index.html.

Genes are made of DNA, a long, threadlike molecule coiled inside cells. Within the cell, the DNA is packaged into 23 pairs of chromosomes. Each chromosome, in turn, contains thousands of genes. Genes, which are segments of DNA, are packets of instructions that tell cells how to behave. They do so by specifying the instructions for making particular proteins. The gene instructions are written in a four-letter code, with each letter corresponding to one of the chemical constituents, or bases, of DNA: A, G, C, T. The number of bases in the human genome (the complete sequence of the DNA molecule) is estimated to be 3 billion to 4 billion. The human genome is estimated to contain 100,000 to 140,000 genes.

If the DNA sequence, the order of the four-letter code, becomes altered in any way, the cell may make the wrong protein, or too much or too little of the right one-mistakes that often result in disease. In some cases, such as sickle cell anemia, just a single misplaced base is sufficient to cause the disease. Genetic mistakes can be inherited (called an inherited mutation) or they can develop during an individual's lifetime (an acquired mutation). Inherited mutations are found in every cell of the body, while acquired mutations occur sporadically in individual cells.

Mutations in genes are responsible for an estimated 3,000 to 4,000 clearly hereditary diseases and conditions. Some of these-including Huntington disease, cystic fibrosis, neurofibromatosis, Duchenne muscular dystrophy-are caused by the mutation of a single gene. Gene mutations also play a role in cancer, heart disease, diabetes, and many other complex diseases. Genetic alterations may increase a person's risk of developing one of these more complex disorders, although it is the cumulative effects of the interaction of genetic and environmental factors, such as diet and smoking, that result in the development of disease.

 The process of discovering and understanding genetic mutations is an extremely complex one. Reaching a complete understanding of the relationship between a mutation and a disease or condition can involve many years of investigation, and the discovery of a mutation usually is only the first step. Scientists looking for a gene that contributes to a particular disease or condition typically begin by studying DNA samples from members of families in which many relatives over several generations have developed the same illness--colon cancer, for example. Scientists start looking for detectable traits or distinctive segments of DNA (called genetic markers) that are consistently inherited by relatives with the disease or condition but that are not found in relatives who do not have it. Then, scientists work to narrow down the target DNA area, identify possible genes, and look for specific mutations within those genes.

Because the genome is vast, discovering a specific disease gene has, up to now, been a difficult and time consuming effort. In the case of Huntington disease, for example, scientists worked for ten years before they found the gene that causes the disease. The Human Genome Project combined with new developments in technology, such as tandem mass spectrometry, microarrays, and gene chips, will speed up the pace of the discovery of disease genes and mutations.

Once the entire sequence of the human genome has been mapped, scientists will have the tools they need to better understand the contribution of each gene to the development and function of the human body. Even then, however, the role played by a specific gene mutation in disease will not be completely understood because of complicating factors such as gene-gene interactions and environmental influences (for example, smoking and diet). As a result, understanding what gene mutations mean for a person's future health and well-being will require more research, including population-based studies that focus on clarifying the significance of gene-gene and gene-environment interactions.

 Genetic testing involves the analysis of chromosomes, genes, and/or gene products to determine whether a mutation is present that is causing or will cause a certain disease or condition. It does not involve treatment for disease, such as gene therapy, although test results can sometimes suggest treatment options.

 Genetic tests are performed for a number of purposes, including prenatal diagnosis, newborn screening, carrier testing, diagnosis/prognosis, presymptomatic testing, and predictive testing. Prenatal diagnosis is used to diagnose a genetic disorder or condition in a developing fetus. Newborn screening is used to detect certain genetic diseases in newborns, and it is performed on a public health basis by the States. The disorders screened for are those that, if detected early, have significant treatment or prevention benefits. Carrier screening is performed to determine whether an individual carries a copy of a mutated gene for a recessive disease (recessive means that the disease will occur only if both copies of a gene are mutated). Carriers are not affected with the disease, but they have a 50 percent risk of passing the mutation on to their children. If the partner of a carrier is screened and found also to be a carrier, each child they conceive will have a 25 percent risk of being affected with the disorder. Diagnostic testing is used to identify or confirm the diagnosis of a disease or condition in an affected individual. Diagnostic testing can also be used for prognostic purposes to help determine the course of a disease. Presymptomatic testing is used to determine whether individuals who have a family history of a disease, but no current symptoms, have the gene mutation. Predictive testing determines the probability that a healthy individual with or without a family history of a certain disease might develop that disease.

 Several standard terms are used in discussing the accuracy and effectiveness of laboratory tests. These terms--analytical validity, clinical validity, and clinical utility--apply not only to genetic tests but also to other kinds of tests, such as cholesterol or pap smear tests. An understanding of these terms is helpful in considering the possibilities for oversight of genetic tests.

Analytical validity is an indicator of how well a test measures the property or characteristic it is intended to measure. (In the case of a genetic test, the property can be DNA, proteins, or metabolites.) An analytically valid test would be positive when the relevant gene mutation is present (analytical sensitivity) and negative when the gene mutation is absent (analytical specificity). Another element of the test's analytical validity is reliability--meaning that the test obtains the same result each time. During the process of validating a new genetic test, how well it performs will be compared to how well the best existing method or "gold standard" performs. Sometimes, if a gold standard does not exist for a new genetic test, the test's performance must be based on how well it performs in samples from individuals known to have the disease.

Clinical validity is a measurement of the accuracy with which a test identifies or predicts a clinical condition. A clinically valid test would be positive if the individual being tested has the disease or predisposition (clinical sensitivity) and negative if the individual does not have the disease or predisposition (clinical specificity). To be clinically valid, a test would be positive if the individual being tested has or will get the disease or condition (positive predictive value) and negative if the individual being tested does not have or will not get the disease or condition (negative predictive value). Determining the clinical validity of a test may be more challenging when different mutations within the same gene cause the same disease and different mutations can result in different degrees of disease severity. In addition, gene mutations may or may not lead to disease depending on how "penetrant" or completely expressed they are.

Clinical utility refers to the degree to which benefits are provided by positive and negative test results. If a test has utility, it means that the results--positive or negative--provide information that is of value to the person who is tested. The availability of an effective treatment or preventive strategy, for example, would make such information valuable. However, even if no interventions are available to treat or prevent the disease or condition, there may be benefits associated with knowledge of a result. On the other hand, social, psychological, and economic harms can result from such knowledge, particularly in the absence of privacy and discrimination protections. Thus, determining the clinical utility of a test requires obtaining information about the benefits and risks of both positive and negative test results.

A final point can be made about the challenge of assessing the clinical validity and utility of genetic tests used for predictive purposes and for rare diseases. For genetic tests used for predictive purposes in diseases or conditions whose effects do not become apparent for many years, clinical validity and utility will need to be evaluated over time. For genetic tests for rare diseases, gathering sufficient data to assess clinical validity and utility may never be possible because of the low prevalence of the diseases. Consequently, different approaches to the evaluation of clinical validity and utility for predictive tests and for rare disease tests may be necessary.

Genetic tests currently have certain limitations that are relevant to the issue of oversight. One important limitation is that a test may not detect every mutation a gene may have. A single gene can have many different mutations, and they can occur anywhere along the gene. Moreover, not all mutations have the same effects. For example, more than 800 different mutations of the cystic fibrosis gene have been identified, some of which cause varying degrees of disease severity and some of which appear to cause no symptoms at all. This means that a positive test for a specific cystic fibrosis mutation may not provide a clear picture of how the disease is likely to affect the individual. A negative test result cannot completely rule out the disease because the test will usually focus only on the more common mutations and will not detect rare ones. Furthermore, because of varying genetic and environmental factors, even the same mutations may present different risks to different people and to different populations. The same mutation in the cystic fibrosis gene in individuals from different populations may have different clinical effects as a result of variations in genetic and environmental factors. In addition, the frequency of common cystic fibrosis mutations varies among population groups. Determining the clinical validity of a genetic test requires a thorough analysis of all these factors without which the likelihood of error may be high.

Another current limitation of genetic tests, especially if used for predictive purposes, relates to the complexities of how diseases develop. Diseases and conditions can be caused by the interaction of many genetic and environmental factors. Thus, predictive tests cannot provide certain answers for everyone who might be at risk for a disease such as breast or colon cancer. For example, mutations in the breast cancer 1 gene (BRCA1) occur in about half of families with histories of multiple cases of breast and ovarian cancer. If a woman with no family history of the disease has the BRCA1 mutation, it may not mean that she will develop breast or ovarian cancer. Likewise, if she does not have the mutation, she still cannot be sure she will never develop breast cancer.

Another important consideration related to the limitations of genetic testing is that effective treatments are not available for many diseases and conditions now being diagnosed or predicted through genetic testing, and, in some instances, they may never be available--a situation sometimes called the "therapeutic gap." While knowledge that a disease or condition will or could develop may not provide any direct clinical benefit, it may lead to increased monitoring which could help manage the disease or condition more effectively. At the same time, information about risk of future disease can have significant emotional and psychological effects and, in the absence of privacy and anti-discrimination protections, can also lead to discrimination or other forms of misuse of personal genetic information.

Information provided by genetic tests has potential benefits and risks. Understanding the benefits and risks of a genetic test is critical in determining its appropriate use in clinical and public health practice. The benefits and risks of any particular test to individuals or particular populations may change over time as more information is gathered.

 Potential Benefits. Individuals with a family history of a disease live with troubling uncertainties about their and their children's futures. Having a genetic test may relieve some of those uncertainties. If the test result is positive, it can provide an opportunity for counseling and for the introduction of risk-reducing interventions such as regular screening practices and healthier lifestyles. Early interventions (for example, annual colonoscopies to check for precancerous polyps, the earliest signs of colon cancer) could prevent thousands of colon cancer deaths each year. If the test result is negative (they do not have the mutation), in addition to feeling tremendous relief, individuals may also no longer need frequent checkups and screening tests, some of which may be uncomfortable and/or expensive.

Genetic tests can sometimes provide important information about the course a disease may take. For example, certain cystic fibrosis mutations are predictive of a mild form of the disease. Other gene mutations may identify cancers that are likely to grow aggressively.

Genetic tests can provide information to improve treatment strategies. Because genetic factors may affect how individuals respond to drugs, the knowledge that an individual carries a particular genetic mutation can help health care providers tailor therapy. For example, individuals with Alzheimer disease (AD) who have two copies of a certain gene mutation do not respond to the drug Tacrine. In individuals with AD who do not have both copies of the mutation, however, the drug seems to slow progression of the disease.

Potential Risks. Genetic testing poses potential physical, medical, psychological, and socioeconomic risks to individuals being tested and to members of their families. For the most part, the physical risks of genetic testing are minimal because most genetic tests are performed on blood samples or cells obtained by swabbing the lining of the cheek. The procedures required to carry out prenatal genetic testing can, in rare circumstances, cause miscarriage.

The medical risks of genetic testing relate to actions taken in response to the results of a genetic test. Positive test results can have an impact on a person's reproductive and other life choices. Individuals with positive test results may choose not to have children. They may opt to take extraordinary preventive measures, such as surgical removal of the breasts to prevent the possible development of cancer. Individuals with negative test results may forgo screening or preventive care because they mistakenly believe they are no longer at risk for developing a given disease. Incorrect test results or misinterpretation of test results have substantial risks. False negative test results can mean delays in diagnosis and treatment. False positive results can lead to follow-up testing and therapeutic interventions that are unnecessary, inappropriate, and sometimes irreversible.

Genetic test results have potential psychological risks. The emotional impact of positive test results can be significant and can cause persistent worry, confusion, anger, depression, and even despair. Individuals who have relatives with a disorder have a fairly clear, and perhaps frightening, picture of what their own future may hold. Negative test results also can have significant emotional effects. While most people will feel greatly relieved by a negative result, they may also feel guilty (survivor guilt) for escaping a disease that others in the family have developed. A negative test result may provide a false sense of security because the individual may still bear the same risk of disease as the general population.

Because genetic test results reveal information about the individual and the individual's family, test results can shift family dynamics in pronounced ways. For example, if a baby tests positive for sickle-cell trait during newborn screening, it means that one of the parents is a carrier. It is also possible for genetic tests to inadvertently disclose information about a child's paternity.

Genetic test results present potential socioeconomic risks for individuals. Some people have reported being denied health insurance and losing jobs or promotions as a result of genetic test results. People have reported being rejected as adoptive parents because of their genetic status. Some people seeking adoptions have requested genetic testing for the child before finalizing the adoption.

Genetic test results can pose risks for groups if they lead to group stigmatization and discrimination. Concerns about the potential risks of discrimination and stigmatization are particularly acute among minority groups who have experienced other forms of discrimination. Regrettably, the African American experience with sickle cell anemia screening provides an example of the potential for and consequences of discrimination and is one of the reasons why the particular risks of genetic testing for minority groups must be considered. In the 1970s, a major effort was made in many States, with Federal Government support, to screen African American children and young adults for sickle cell disease. Many of the screening programs were based on an inadequate knowledge of the genetics of sickle cell disease, and in some instances, the accuracy and validity of the test itself was in question. Also, many programs were implemented without sufficient sensitivity to ethnocultural issues and the potential for misuse of personal test results. Individuals who were actually carriers of the mutation were incorrectly identified as having sickle cell disease. Carriers were ostracized, deprived of employment and educational opportunities, and denied health and life insurance.

It is important to point out that the potential risks described above relate to genetic testing for conditions that are solely health-related. In the future, it may be possible to develop tests that could be used to diagnose conditions that are related to certain predispositions, such as to obesity, alcohol abuse, or nicotine addiction, or to predict future behavior. Although the assumption that single genes, or even many genes, can predict complex human actions is simplistic, the possibility of such tests raises profound concerns because their potential psychological and socioeconomic harms are so significant and the potential misuse of such information is so great.

 After a gene has been shown to cause or play a role in a specific disease or condition (through analysis of DNA from affected individuals), the function of this gene in both healthy and disease states must then be understood. Each step along the research path adds to and reshapes existing knowledge in this constantly evolving area of study. In the following sections, seven case studies are provided to illustrate the different kinds of genetic testing that are performed, the way in which genetic tests evolve from research to clinical and public health practice, and some of the difficulties that can arise when a test moves from research to clinical use due to limitations in the data on clinical validity and utility. Although each example primarily describes one use of the test, it is possible that the same test could be used for other purposes. For example, a diagnostic test also may be used for predictive purposes. Indeed, the fact that tests may be used for multiple and overlapping purposes is one of the significant challenges of any effort to identify distinct categories of genetic tests.

Prenatal diagnosis of Tay-Sachs disease was first achieved in 1970. The test involves measuring the activity of a particular enzyme in cells from a developing fetus. The fetal cells are obtained through two principal methods--chorionic villus sampling (CVS) and amniocentesis. CVS, which is performed at 10 to 12 weeks of pregnancy, involves examining a sample of fetal cells taken from the placenta. Amniocentesis is a procedure, done at 16 to 18 weeks of pregnancy, in which a sample of the fluid surrounding the fetus (the amniotic fluid) is withdrawn from the womb and examined. These procedures carry a risk of miscarriage (1 case in 100 for CVS and 1 case in 200 to 300 for amniocentesis). When the results of the Tay-Sachs test are positive, many couples face an agonizing decision about whether to continue the pregnancy. Most, but not all, elect to terminate the pregnancy. Although prenatal diagnosis for Tay-Sachs disease initially was used only for couples to whom affected children had already been born, it is now also offered to couples who are identified by carrier screening to be at risk.

Over the last two decades, the analytical validity and clinical validity of prenatal testing for Tay-Sachs disease have been established, and the clinical utility of the test is now also fairly well understood. Tay-Sachs disease testing is limited primarily to populations in which the disease is known to be prevalent, including people of Ashkenazi Jewish or French Canadian descent. The incidence of Tay-Sachs disease in the Ashkenazi Jewish population is approximately 1 in 4,000 births; in the general population the incidence is one hundred-fold less (1 in 400,000).

In 1963, a simple, inexpensive test to screen for elevated phenylalanine in the blood of newborns became available. A trial test was conducted on a group of individuals with mental retardation, and it identified correctly all persons who were previously diagnosed with PKU. After publication of the test method, the PKU screening test was accepted by the medical and scientific communities and became part of routine neonatal screening programs across the country. In fact, PKU was the first genetic disease for which newborn screening was developed. Newborn PKU screening is required by law in nearly all States.

The gene responsible for the major form of PKU was found in 1986, and since then more than 100 different mutations in the gene have been identified. Because DNA analysis of the PKU gene cannot always be correlated with disease severity, analysis of enzyme function and measurement of phenylalanine metabolites are more reliable indicators of clinical severity.

In the nearly 40 years since the PKU screening test was first used, a significant amount of data has been collected to establish its analytical and clinical validity and clinical utility. The test's clinical utility is especially significant because the most serious consequence of untreated PKU--mental retardation--can be prevented through a phenylalanine-restricted diet.

The CF gene was identified in 1989. Seventy percent of affected individuals carry the same mutation in the CF gene, and about 30 other mutations account for another 20 percent of CF cases. The remaining 10 percent have been found to have one of at least 800 additional mutations, and new mutations are still being identified. More than 85 percent of individuals with CF are born to parents who have no family histories of the disorder.

Results from a CF carrier test can only reduce--not eliminate--the risk that one may be a carrier, because it is not practical to test for all of the possible rare mutations. Carrier screening is recommended for those individuals with family histories of CF or for those who have a relative identified as a CF carrier. An NIH consensus development conference in 1997 concluded that carrier screening should be offered to all pregnant women and couples contemplating pregnancy, but this recommendation is in the early stages of implementation. Further research is needed to correlate the many different gene mutations with disease severity, population differences, and penetrance. Information from these studies may aid in an assessment of the clinical validity and clinical utility of broader based carrier screening.

The majority of new genetic tests are being developed by laboratories for their own use. These are referred to as in-house tests or "home brews." The FDA has stated that it has authority, by law, to regulate home brew laboratory tests, but the agency has elected, as a matter of enforcement discretion, not to exercise that authority. However, the FDA has taken steps to establish a measure of regulation of home brew tests by instituting controls over the active ingredients (analyte-specific reagents) used by laboratories to perform genetic tests. This regulation subjects reagent manufacturers to certain general controls, such as good manufacturing practices. However, with few exceptions, the current regulatory process does not require a premarket review of the reagents. (The exceptions involve certain reagents that are used to ensure the safety of the blood supply and to test for high-risk public health problems such as HIV and tuberculosis.) The regulation restricts the sale of reagents to laboratories capable of performing high-complexity tests and requires that certain information accompany both the reagents and the test results. The labels for the reagents must, among other things, state that "analytical and performance characteristics are not established." Also, the test results must identify the laboratory that developed the test and its performance characteristics and must include a statement that the test "has not been cleared or approved by the U.S. FDA." In addition, the regulation prohibits direct marketing of home brew tests to consumers.

The mission of NIH is to support and conduct medical research to improve health. This research encompasses basic, clinical, behavioral, population-based, and health services research. In addition to funding a substantial amount of genetics research, including the Human Genome Project, and assuring that the research is conducted in accordance with human subjects regulations and other pertinent guidelines, NIH supports a number of other programs that have an important role in disseminating knowledge and technology to the public and private sectors. These activities help promote the appropriate integration and application of scientific knowledge into clinical and public health practice. The following are examples of research, dissemination, and integration activities supported wholly or in part by NIH that might specifically contribute to a better understanding of the validity and utility of genetic tests.

• The Ethical, Legal, Social Issues (ELSI) Program, a major program established as an integral part of the Human Genome Project, supports research on the ethical, legal, and social implications of human genetics research.

 

• A five-year epidemiologic study of iron overload and hereditary hemochromatosis is beginning to gather data on the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of the disorder. The knowledge gained from this study will be used to determine the feasibility, benefits, and risks of a broad-based screening program.

 

• The Cancer Genetics Network, a consortium of academic cancer centers around the country, serves as a national resource to support multi-center investigations into the genetic basis of cancer susceptibility, to integrate new research data into medical practice, and to identify psychological, ethical, legal, and public health issues related to cancer genetics.

 

• GeneTests, a directory of clinical laboratories providing testing for genetic disorders, disseminates information about diseases and diagnostic and treatment options to health care providers and the public.

 

• The National Coalition for Health Professional Education in Genetics promotes genetics education and information dissemination to health professionals.

NIH also produces consensus statements and technology assessment statements on issues important to health care providers, patients, and the general public. Topics related to genetic testing have included newborn screening for sickle cell disease, genetic testing for cystic fibrosis, and screening for and management of PKU.

State health agencies, particularly state public health laboratories, have an oversight role in genetic testing, including the licensure of personnel and facilities that perform genetic tests. State public health laboratories and State-operated CLIA programs, which have been deemed equivalent to the Federal CLIA program, are responsible for quality assurance activities. A few States, such as New York, have promulgated regulations that go beyond the requirements of CLIA. States also administer newborn screening programs and provide other genetic services through maternal and child health programs.

It is likely that no single agency or organization will be able to address all the issues raised by genetic tests. Instead, the combined expertise of all entities may be needed.

The CDC, NIH, the Health Resources and Services Administration (HRSA), and the Agency for Health Care Policy and Research (AHCPR) are beginning to collaborate more closely to promote and support the development of genetic knowledge and technology and to ensure that this knowledge and technology is used appropriately to improve the health and well being of the Nation. The goal of this collaboration is to enhance agency programs involving technical assistance, professional and public education, data collection and surveillance, applied genetic research and assessment, policy development, and quality assurance.

SACGT has been asked to assess, in consultation with the public, whether current programs for assuring the accuracy and effectiveness of genetic tests are satisfactory or whether other oversight measures are needed for some or possibly all genetic tests. This assessment requires consideration of the potential benefits and risks (including socioeconomic, psychological, and medical harms) to individuals, families, and society, and, if necessary, the development of a method to categorize genetic tests according to these benefits and risks. Considering the benefits and risks of each genetic test is critical in determining its appropriate use in clinical and public health practice. If, after public consultation and analysis, SACGT finds that other oversight measures are warranted, it has been asked to recommend options for such oversight. The advantages and disadvantages of each option must be considered carefully before a final determination is made.

SACGT has been asked to address five specific issues (see box at right). These five issues are discussed in more detail below. This discussion is provided in order to foster public discussion and deliberation. Following the discussion of each major issue, SACGT presents a number of related questions. SACGT encourages public comment on all or any one of the major issues and approaches and on the related questions. SACGT presents a sixth set of other related questions relevant to genetic testing and encourages public input on these as well.

Issue 3: What process should be used to collect, evaluate, and disseminate data on single tests or groups of tests in each category?

Issue 4: What are the options for oversight of genetic tests and the advantages and disadvantages of each option?

Issue 5: What is an appropriate level of oversight for each category of genetic test?

In considering this issue, SACGT identified three primary criteria that could be used to assess the benefits and risks of a genetic test. One criterion is clinical validity, which refers to the accuracy of the test in diagnosing or predicting risk for a health condition. Clinical validity is measured by the sensitivity, specificity, and predictive value of the test. The second criterion is clinical utility, which involves identifying the outcomes associated with positive and negative test results. Because clinical validity and clinical utility of a genetic test may vary depending upon the health condition and the population to be tested, these criteria must be assessed on an individual basis for each test. The third criterion relates to the social context within which genetic testing is performed.

Because clinical validity considers many aspects of genetics that make genetic testing complex, it is a measure that is essential to the assessment of the benefits and risks of genetic tests. A test's clinical validity is influenced by a number of factors beyond the laboratory, including the purpose of the test, the prevalence of the disease or condition tested for, and the adequacy of relevant information.

Purpose of test. Genetic tests have a number of purposes, and some are used for more than one purpose. The acceptable level of a predictive value of a genetic test may vary depending on the purpose for which the test is used (for example, for diagnosing or predicting a future health risk). In addition, a higher predictive value may be required of a stand-alone test than of a test that is used to confirm other laboratory or clinical findings.

Prevalence. Clinical validity, particularly predictive value, is influenced by the prevalence of the condition in the population. Assessing clinical validity may be particularly challenging in the case of tests for rare diseases. This is because gathering statistically significant data may be difficult, as relatively few people have these diseases. Thus, prevalence may be a factor in determining how much data on test performance should be available before a test is offered in patient care.

Adequacy of information. For many genetic tests, particularly those used for predicting risk, knowledge of the test's clinical validity may be incomplete for many years after the test is developed. When information that may affect clinical validity is incomplete, the potential harms of the test may increase and must be considered more carefully.

Clinical utility is the second criterion that is critical to assessing the benefits and risks of genetic tests. Clinical utility takes into account the impact and usefulness of the test results to the individual, the family, and society. The benefits and risks to be considered include the social and economic consequences of testing as well as the implications for health outcomes. Decisions about the use of a genetic test should be based upon a consideration of the risks of any follow-up tests required to confirm an initial positive test, of the degree of certainty with which a diagnosis can be made, and of the potential for adverse socioeconomic effects versus beneficial treatment if a diagnosis is made. Factors affecting clinical utility include the potential benefits and risks of test results, the nature of the health condition and its potential outcomes, the purpose of the test, uncertainties of genetic test results, the provision of information concerning other family members, and the quality of evidence for assessing outcomes.

Potential benefits and risks of genetic test results. There are a number of potential benefits and risks of genetic testing. The benefits and risks of true positive and negative test results must be considered, as must the risks of false positive and negative results (see list of benefits and risks below). A true positive result means that the test result is positive, and the condition or predisposition is actually present. A true negative result means that the test result is negative, and the condition or predisposition is not present. False results can also be both positive and negative. A false positive occurs when the test indicates a positive result when in fact the condition or predisposition is not present. A false negative occurs when the test indicates a negative result but the condition or predisposition is present.

Potential benefits of a positive test result:

• May provide knowledge of diagnosis or risk status.

• May allow preventive steps or treatment interventions to be taken.

• May identify information about risk status in other family members (also a potential harm).

Potential benefits of a negative test result:

• May rule out specific genetic diagnosis or risk.

• May eliminate the need for unnecessary screening or treatment.

Potential risks of a positive test result:

• May expose individuals to unproven treatments.

• May cause social, psychological and economic harms, including stigmatization and potential exclusion from health insurance and employment.

• May identify information about risk status in other family members (also a potential benefit).

• For false positive test results, individuals may be exposed to unnecessary screening and treatment.

Potential risks of a negative test result:

• May give false reassurance regarding risk due to nongenetic causes.

• May have psychological effects, such as "survivor guilt."

• For false negative test results, may delay diagnosis, screening, and treatment.

Nature of health condition and health outcomes. The nature (severity, degree of associated disability, or potentially stigmatizing characteristics) of the health condition being tested for is an important factor in assessing clinical utility. For example, a genetic test for periodontal disease may raise less concern than a test for cancer, and genetic tests developed for conditions such as alcoholism or mental illness might cause even greater concern. Health outcomes, as measured by such indicators as morbidity and mortality, are important in assessing clinical utility of genetic testing, and they can be affected by both the nature of the health condition as well as the availability, nature, and efficacy of treatment. As uncertainties increase about the health outcomes associated with a test result, so do the potential harms of the test. This is an important consideration in genetic testing for common health problems such as cancer and cardiovascular disease, since health outcomes typically are the result of the combined effects of genetic, environmental, and behavioral risk factors.

Purpose of the genetic test. The purpose of the test is an important factor in assessing clinical utility. Genetic tests used to predict a disease or condition will have different risks and uncertainties associated with it as compared to a diagnostic test. For example, the use of a test to aid in the diagnosis of cystic fibrosis in a person who has symptoms has different implications than the use of a test to determine whether a woman with no symptoms has a risk for breast and ovarian cancer because she possesses a BRCA1 or BRCA2 mutation. Tests used for diagnostic purposes will most likely be conducted as part of a clinical evaluation to diagnose a specific disease or will be used for clearly inherited diseases or conditions.

Genetic tests used for predictive purposes in healthy persons are associated with greater uncertainties and risks. Currently, tests used for predictive purposes will give an estimate of the risk a person may have of developing a particular disease or condition. Due to incomplete knowledge, however, the risk assessment may be inaccurate because of other genetic and environmental factors that have not been accounted for or are not yet known. Predictive genetic tests may have profound effects on the lives of otherwise healthy individuals. Even though degree of risk is uncertain, a positive test result for breast cancer may affect treatment, reproductive, and lifestyle plans. A negative test result for a BRCA1 mutation does not eliminate the risk of breast cancer, because BRCA1 mutations account for only a small percentage of breast cancer cases overall. A woman with a negative test result still carries, at minimum, the breast cancer risk of the average woman and she should still continue with preventive screening measures.

The use of a genetic test in population screening may raise greater concern than the use of the same test in an individual seeking information about his or her health. In population screening, a large number of healthy people may receive unexpected test results that may or may not provide definitive information. Decisions about whether to use genetic tests for screening should take into account the prevalence of the condition. The higher the prevalence of the genetic condition, the greater the number of people who will be subjected to false positive and false negative results. On the other hand, if treatment options are available, screening for highly prevalent diseases may have significant public health value.

Uncertainties of genetic test results. The assessment of a test's clinical utility is affected by the accuracy of test results. False negative results are more common in the early stages of the development of diagnostic tests, including genetic tests. Genetic tests in early development may identify only a portion of mutations associated with a given health outcome. If a woman is from a family in which multiple cases of early breast cancer have occurred, she is likely to be at risk for an inherited susceptibility to breast cancer even if genetic testing has failed to identify a specific cancer-associated mutation in her family.

Information about family members. Because genetic information may have implications for family members, the potential of the test to reveal information about family members is another factor to be considered in assessing a test's clinical utility. For example, DNA-based tests for cystic fibrosis, sickle cell anemia, or other conditions will identify carriers for the condition as well as those who are affected. If a woman with breast cancer tests positive for a BRCA1 mutation, her first-degree relatives are then known to have a 50 percent chance of carrying the same mutation. Some of these relatives may not wish to discover their risk, while others may wish to use the test results of their relatives to make a decision about their own genetic testing.

Quality of evidence for outcomes assessment. The quality of evidence for assessing outcomes of genetic test results is a factor in the clinical utility of a genetic test. Often, evidence to assess relevant factors, especially those related to potential social or economic harms, is limited or lacking. In assessing potential risks under these circumstances, incomplete information and the potential for harms that have not yet been documented must be considered. Established methods for evaluating the quality of the evidence should be used to assess outcomes.

Genetic stigmatization. Genetic test results can change how people are viewed by their family, friends, and society, and how they view themselves. People diagnosed with or at risk for genetic diseases or conditions may be affected by the way others begin to see and interact with them. Having or being at risk for a disease or condition that is viewed by society in a negative light can result in stigmatization, and emotional and psychological harms. In addition to changes in how they are seen by others, social influences can affect self-perception and have a profound impact on life decisions.

Genetic discrimination. Diagnostic or predictive genetic information about an individual may lead to discrimination in health insurance, life insurance, and education and employment. The potential for discrimination may be particularly acute for people with, or at risk for, diseases or conditions that are chronic, severely disabling, and lack effective or affordable treatments. Educational opportunities may be restricted, further limiting future life possibilities. Fears of genetic discrimination have made the establishment of Federal privacy and confidentiality protections a high priority for many.

As important as legal protections are, however, they cannot prevent all adverse consequences of genetic information. For example, the stigma associated with certain genetic diseases or conditions can affect personal choices, such as marriage and child bearing.

Special considerations for U.S. populations. Significant social concerns have grown out of the strong memories of the American eugenics movement and the painful history of programs that tested minority populations for conditions such as sickle cell disease. In some cases, these programs heightened discrimination against those tested. Given this history, tests developed for use in particular population groups, whose incidence of a condition may be higher, or in circumstances where the meaning of the test could be interpreted only within a certain population, may carry higher risks. This issue is of great concern in the United States because of the exceptional diversity of the population. Specific genetic diseases or conditions occur with different frequencies in different populations. As genetic testing becomes more common, the potential for stigmatization of groups increases. Educational programs, legal protections, and the involvement of ethnocultural group representatives in assessing the risks and benefits of genetic tests are needed to reduce the risk of stigmatization of groups.

In addition, social categories used to classify ethnocultural differences often do not accurately reflect actual genetic variation within a population. For example, since the categories "Hispanic" and "Asian" encompass populations from different parts of the world, genetic variations are likely to exist within these populations. Thus, care should be taken in determining the ethnocultural background of individuals in order to ensure accurate interpretation of genetic test results. A further note of caution is also necessary. In developing genetic tests, it will be important to assure their accuracy when used in different populations. In so doing, however, the erroneous assumption that there is a straightforward, one-to-one relationship between one's genes and one's ethnocultural identity may be inadvertently reinforced. This could result in stigmatization because even accurate tests could reinforce misguided cultural notions about genetic determinism.

Tests for conditions not commonly regarded as medical or health-related. In the future, it may be possible to develop genetic tests that could be used to identify predispositions to certain patterns of behavior, such as risk-taking, shyness, or other complex features of personality. Although the assumption that single genes, or even many genes, can predict complex human actions is simplistic, the possibility of such tests raises profound ethical questions and concerns because their potential psychological and socioeconomic harms are so significant and the potential misuse of such information is so great. The boundaries between "health-related" and "non-health related" are not clear cut and shift over time. Genetic tests could also be used to identify health conditions for non-health related purposes, such as determining child custody cases based on the parent's/guardian's future risk of disease. It will, therefore, be difficult to avoid harm from genetic tests simply by limiting their use to situations of diagnosing or predicting disease. For example, genetic tests might be used to predict susceptibility to conditions that are health-related but where a strong behavioral component exists, such as obesity, alcohol abuse, or nicotine addiction.

Individuals identified as at risk for stigmatized conditions such as these may suffer special harms.

1.1 What are the benefits/risks of having a genetic test?

1.2 What are the major concerns regarding the different genetic tests that are currently available?

1.3 What expectations do individuals have about genetic tests, such as whether they have a high level of accuracy and can be used to help make health or important personal decisions?

1.4 In deciding whether to have a genetic test, does it matter whether a treatment exists for the condition or disease being tested for? Is the information provided by the test important or useful by itself?

1.5 Do concerns about the ability to keep genetic test results confidential influence an individual's decision to have a genetic test?

1.6 Are genetic tests different from other medical tests, such as blood tests for diabetes or cholesterol? Should genetic test results be treated more carefully with more confidentiality than other medical records?

In attempting to address this issue, SACGT considered whether the criteria of clinical validity and clinical utility could be used to characterize the potential risks associated with a given test, which would allow tests to be grouped according to the risks that are associated with them. Using this information, tests might be organized into categories such as "high risk" and "low risk." Such a categorization would not be simple or straightforward, however, because it would depend upon a combination of factors, including test characteristics, availability of safe and effective treatments, and the social consequences of a diagnosis or identification of risk status. For example, a test of high predictive value that identifies a nonstigmatizing condition with a safe and effective treatment might fall into a low-risk category, while a test that has high predictive value and that identifies a genetic risk for a serious condition for which treatment is unproven might fall into a high-risk category.

As these general examples illustrate, categorizing tests will require the weighing of several different aspects of the test and of the disease that the test is used to diagnose or predict. Developing an appropriate mechanism for this process poses a challenge, and it is likely that such a mechanism will involve at least three steps. In the first step, data concerning the test would be collected perhaps using a standardized format to ensure that all of the required data are reported. In the second step, the data would be analyzed to determine risk category. One possible approach would be to initially sort tests into a readily identifiable low-risk category (possibly tests with well-defined characteristics that meet a previously defined low-risk threshold). For tests not falling within the low-risk category (possibly tests for rare diseases or complex, common diseases), a third step involving a more detailed evaluation of available data would be required to make a final determination of risk category.

Thus, determining the risk category of a test will involve evaluating the data available regarding the analytical and clinical validity of the test and the outcomes of positive and negative test results. This evaluation should consider socioeconomic factors, such as the potential for stigmatization and other social risks, including the likelihood that a test would be used in particular population groups. For tests that are determined to be high risk or potentially high risk, the analysis likely will require a diverse range of technical expertise and input.

Data on clinical application of a test could be collected and evaluated by a number of sources, including professional organizations, individual laboratories, academic institutions, and/or governmental agencies. One option is to continue to rely on the current practice of allowing laboratories to base decisions on information they collect and analyze, including their own data or data they glean from other sources, such as research publications or consensus conferences. A second option is to make each laboratory that offers a test responsible for collecting and analyzing the information that is required to support its claims for the test according to national standards. A third choice would be for a Government agency, possibly the CDC, to coordinate the creation and collection of information on clinical applications of tests that detect particular mutations and perhaps to define appropriate claims for tests as well. (See Part IV for a discussion of CDC's current efforts in this area.) A fourth option, discussed as part of Issue 4, would be to form a consortium of government, professional associations, and industry that would create, collect, and analyze information about clinical applications. More than likely, data on any genetic test will be incomplete and must be collected on a continuous basis. If the data available at the time of the initial evaluation suggest benefit of the test in clinical practice, the test may be approved on the condition that data will continue to be collected and will be reviewed again at a future date.

Another approach to data collection on validity and utility of genetic tests could be modeled after tumor registries. Tumor registries document and store information about a patient's history, diagnostic findings, treatment, and outcome. Information within a tumor registry may be used to generate a variety of reports on topics such as patient quality of care and long-term results of specific treatments.

Regardless of the option chosen for data collection, once the data have been collected and evaluated, they must be disseminated to health care practitioners and the public. This must include not only data generated prior to offering the test for clinical use, but also data generated as part of any postmarket evaluation. One option is to require laboratories to release summaries of data on clinical application as part of the process of offering the test. Such summaries could be directed to health care professionals, to the general public, or to both. In addition, different methods of collection and distribution of information may be used for different tests. Guidelines or regulations might be required to make those distinctions. One method would be to rely upon publications and professional societies to inform readers and members, with the expectation that practitioners will inform the public over time. Alternatively, the Federal Government or a consortium could be responsible for ensuring that relevant data are available for both professional and public use.

3.1 Given that collection of data is an ongoing process, what type of system or process should be established to collect, evaluate, and disseminate data about the analytical validity, clinical validity and clinical utility of genetic tests?

3.2 How can the system or process for data collection, evaluation, and dissemination be structured in such a way as to protect the privacy and confidentiality of the data that is collected?

SACGT has been asked to focus on oversight of the accuracy and effectiveness of genetic tests-especially, the development, use, and marketing of genetic tests developed by clinical laboratories. SACGT recognizes that there are many areas beyond test development, use, and marketing that might have an equally important impact in assuring the safety and effectiveness of a genetic test. For example, the training and education of health care providers who prescribe genetic tests and use their results for clinical decision making is a critical issue, in particular as it relates to their ability to stay abreast of new information on the uses, capabilities, and limitations of these tests. The effect that gene patenting is having on the cost, accessibility, and quality assurance of genetic tests is another critical issue, as is the potential for workplace and insurance discrimination that could result from genetic testing. Oversight of genetic tests that provide non-health related information is another area of inquiry. SAGCT will focus its attention on these other high priority oversight issues once it completes its current work.

Under the medical device regulations, the FDA requires that genetic tests packaged and sold as kits to laboratories require premarket approval or clearance by the FDA. The premarket review would evaluate the test's accuracy and analytical validity. For devices in which the link between clinical performance and analytical performance has not been well established, the FDA requires that additional analyses be conducted to determine the test's clinical characteristics, or its clinical sensitivity and specificity. In some cases, the FDA requires that the predictive value of the test be analyzed for positive and negative results. The FDA has not attempted to extend its authority to regulate home brew tests (tests developed by laboratories for their own use). All of the genetic tests described in Part II are home brew tests. FDA has implemented regulation of the active ingredients of genetic tests, or analyte-specific reagents (ASRs). Manufacturers of ASRs are required to comply with good manufacturing practices, restriction of sales to laboratories capable of performing complex tests, and requirements that certain information accompany both the reagents and the test results.

Additional oversight protections are provided by professional organizations and state health departments. Organizations such as CAP, ACMG, and NCCLS have developed guidelines and standards for the development and use of genetic tests. State health departments may require laboratory facilities and personnel that perform genetic tests be licensed.

Introducing Laboratory-Developed Tests into Clinical Practice

Analytical Validity. It seems clear that a genetic test should not be used in clinical practice (i.e., for other than research purposes) unless it has been shown to detect reliably the mutation that it is intended to detect. CLIA now requires a laboratory that offers a test to determine the analytical validity of the test before it is used in clinical practice. In the current system, the laboratory intending to offer a test decides when it has met CLIA's requirement, a judgment that may later be audited during a CLIA inspection. Most believe that the current system needs review. Some have suggested that voluntary or mandatory standards should be enhanced to assist laboratories in deciding when a test's analytical validity has been determined and is acceptable, or that laboratories should be required to obtain the concurrence of an independent third party before a test is offered for use in clinical practice.

Clinical Validity. Similar questions arise with respect to the appropriate level of knowledge about a test's ability to generate information about the presence, or possibility of future occurrence, of a disease. Determining a genetic test's clinical validity is a complex and usually long term process (often requiring decades of work). At the same time, many people want to see gene discoveries translated into practical use as soon as the discoveries are made, often before the clinical validity of the test is fully established. The use of the test is then refined as new information becomes available. No Federal standards guide laboratory decision making with respect to when enough is known about a genetic test for it to be used in clinical practice or the extent to which uncertainties about a test's characteristics must be disclosed.

Clinical Utility. Also important is the degree to which benefits are provided by positive and negative test results. Some have argued that genetic tests should not be available unless they can provide information useful in making health-related decisions and that consumers are likely to assume that a test would not be made available unless it has a health benefit. For example, a negative genetic test result may provide a useful basis of information for informed decision-making. Others have argued that access to information, even it if does not lead to an health-related intervention, is itself useful. There is currently no requirement that the clinical utility of a genetic test be assessed before it is used in clinical practice, and some observers have suggested that additional oversight is needed to ensure greater awareness of the utility of the test.

Changes in Test Methodology. When test manufacturing methods and materials change, either deliberately or inadvertently, the performance characteristics of a test can change as well, which can change the analytical validity, clinical validity, and clinical utility of the test. Some have suggested that stronger incentives should be created to re-qualify tests when methods and materials change.

Patient Safeguards

Informed consent in the research phase of development. In some cases, laboratories that are developing genetic tests for eventual use in clinical practice conduct studies using identifiable patient samples. Unless the study is conducted with Federal funding or is intended for submission to FDA, there is no Federal requirement that laboratories obtain informed consent from a patient participating in that study.

Informed consent for tests used in clinical practice. Even after a test has been accepted into clinical practice, some observers have suggested that due to the predictive power of genetic tests and the impact test results may have on the individual and their families, tests should not be administered unless the individual has been fully informed of the test's risks and benefits and a written informed consent obtained. There is currently no requirement for such an informed consent.

Availability of genetic education and counseling. Current oversight does not specifically address whether genetic education and qualified counseling should be made available for all genetic tests. Genetic test results may be difficult to interpret and present in an understandable manner, raise important questions related to disclosure of test results to family members, and sometimes involve difficult treatment decisions. Because of these intricate issues, some have suggested that those who offer genetic tests should be encouraged or required to make genetic education or counseling available to individuals.

Post Market Data Collection

Many tests are put into clinical use before full information about their validity and utility has been obtained. Virtually everyone agrees that it is critical that data continue to be collected after such tests reach the market. Yet, no comprehensive method for data collection now exists. Many observers believe that ongoing mechanisms to collect data need to be put in place. A number of potential mechanisms to accomplish data collection are outlined in the discussion of Issue 3.

Information Disclosure and Marketing

Data disclosure. There is no current requirement that data about a test's analytical validity, clinical validity, or clinical utility, or lack thereof, be disclosed to health care providers or patients. Some observers believe that laboratories should be encour