Genetic Testing and Screening: V. Predictive Genetic Testing

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In June 2000 international leaders of the Human Genome Project (HGP) confirmed that the rough draft of the human genome had been completed a year ahead of schedule. In February 2001 special issues of Science and Nature published the working draft sequence and analysis. A complete, high-quality DNA reference sequence was announced in April 2003, two years earlier than the originally projected completion date. Although a major goal of the HGP is to provide tools to treat, cure, and ultimately prevent genetic disease, the immediate outcome has been a surge in the number of genetic tests that can be used to determine an individual's risk for developing an ever-increasing number of genetic diseases.

The ability to provide currently healthy individuals with DNA-based risk assessments for diseases that will manifest in the future, especially in the absence of effective treatment for those diseases, presents challenges for those at risk, health professionals, and society. This entry explores some of those challenges, concentrating on tests that can detect mutations associated with adult-onset disorders.

Available Tests

The beginning of the era of genetic prediction can be dated to 1983, when Huntington's disease (HD) became the first disease to be mapped to a previously unknown genetic location through the use of restriction enzymes that cleave deoxyribonucleic acid (DNA) at sequence-specific sites (Gusella et al.). Huntington's disease is a late-onset autosomal dominant neuropsychiatric disorder. The child of an affected parent has a 50 percent chance of inheriting the genetic mutation that causes HD. Disease onset usually occurs in the fourth decade of life and is marked by a movement disorder, alterations in mood, and cognitive decline. There is no treatment or cure.

Inherited variations of these DNA sequences, which also are known as restriction fragment length polymorphisms (RFLPs), can be used as genetic markers to map diseases on chromosomes and to trace the inheritance of diseases in families. The discovery of these markers represented a significant advance in HD research. Not only did the markers provide a possible clue for finding the HD gene and understanding the mechanism by which the gene causes brain cells to die, this discovery meant that predictive testing for some individuals at risk for HD was possible through the use of a technique called linkage. Linkage testing requires the collection and analysis of blood samples from affected and elderly unaffected relatives of the at-risk individual who asks for testing to trace the pattern of inheritance of the HD gene in a specific family. Linkage testing is labor-intensive and expensive and can result in erroneous conclusions caused by incorrectly attributed paternity, misdiagnosis, and the distance between the gene and the markers used for testing. The discovery of the HD gene in 1993 (Huntington's Disease Collaborative Research Group) made testing more accurate, less expensive, faster, and possible for every person at risk for HD.

Since that time new discoveries in molecular genetics have shifted the focus from relatively rare single-gene disorders such as HD to common adult-onset disorders that cause substantial morbidity and mortality. Examples include the identification of mutations in the BRCA1 and BRCA2 genes as causes of susceptibility to breast and ovarian cancers (Miki et al.; Wooster et al.), the discovery of multiple genetic mutations associated with the risk of colorectal cancer (Laken et al.; Lynch and Lynch), the reported association between the APOE e4 allele and late-onset Alzheimer disease (Strittmatter et al.), associations between factor V Leiden and thromboembolic disease (Hille et al.; Ridker et al.; Simioni et al.), and the identification of the HFE gene for hereditary hemochromatosis (Beutler et al.; Edwards et al.). In the second decade of the twenty-first century it has been predicted that genetic tests will be available for diabetes, asthma, dyslexia, attention deficit hyperactivity disorder, obesity, and schizophrenia. These discoveries point to the potential use of genetic tests for population screening in adult populations and an increasing role in public health for genetic testing.

Evaluating New Tests

The National Institutes of Health–Department of Education–Department of Energy (NIH–DOE) Task Force on Genetic Testing stated in 1998 that any proposed initiation of population-based genetic screening requires careful attention to the parameters of both analytical and clinical validity. For DNA-based tests analytical validity requires establishing that a test will be positive when a particular sequence is present (analytical sensitivity) and establishing the probability that that test will be negative when the sequence is absent (analytical specificity). Clinical validity involves establishing measures of clinical performance, including the probability that the test will be positive in people with the disease (clinical sensitivity), the probability that the test will be negative in people without the disease (clinical specificity), and the positive and negative predictive value (PV) of the test. The positive PV is the probability that people with a positive test eventually will get the disease. The negative PV is the probability that people with negative test results will not get the disease.

Two features of most of the genetic diseases discussed as candidates for population-wide screening also affect the clinical validity of any test designed to screen for those diseases. The first is heterogeneity, or the fact that the same genetic disease may result from the presence of any of several different variants of the same gene (an example would be cystic fibrosis, with over 900 mutations found in the CF gene) or of different genes (such as the genes for breast cancer BRCA1 and BRCA2). The second is penetrance, the probability that disease will appear when the disease-related genotype is present. Both heterogeneity and penetrance may differ in different populations, causing difficulties in the interpretation of test results. The final Report of the Task Force on Genetic Testing stated that "clinical use of a genetic test must be based on evidence that the gene being examined is associated with the disease in question, that the test itself has analytical and clinical validity, and that the test results will be useful to the people being tested" (Task Force on Genetic Testing).

From a public health perspective the value of implementing these tests on a population-wide basis will depend to a large extent on whether early treatment of diseases discovered through screening improves the prognosis (Burke et al.). That can be determined only through randomized clinical trials, an expensive process for the array of tests likely to be developed in the near future. However, experience with hormone replacement therapy (HRT) for healthy postmenopausal women in which HRT was found to cause more health problems than a placebo (Writing Group for the Women's Health Initiative Investigators) and a widely used knee surgery technique for osteoarthritis that was found to be ineffective (Moseley et al.) suggests that such trials may be a necessary component of any proposed large-scale screening effort.

Critics of this approach say that the prospective studies necessary to gather this type of information can take years. If widespread use of a test is withheld until the positive predictive value is determined fully and the risks and benefits of testing are known clearly, manufacturers and laboratories could be inhibited from developing tests, and consequently, people will be denied the benefits of being tested. Even without an effective treatment these benefits might include a reduction in uncertainty, the ability to avoid the conception or birth of a child carrying the disease-causing mutation, escape from frequent monitoring for signs of disease or prophylactic surgery, and freedom from concerns about employment or insurance discrimination.

In the absence of a consensus on the public health benefits of widespread screening, tests continue to be developed and in some cases marketed directly to physicians and consumers. For example, in June 2002 Myriad Genetics, based in Salt Lake City, Utah, announced that it would market genetic tests for familial cancers to the general public despite the fact that those tests were appropriate only for a very small percentage of the population. This practice has been the subject of some controversy (Holtzman and Watson), especially in cases in which predictive tests have become available without adequate assessment of their positive predictive value or benefits and risks. Without this information it is difficult for providers or consumers to make thoughtful and fully informed decisions about whether to offer or to use the tests. In another case a test based on the association of the APOE e4 allele with late-onset Alzheimer's disease was marketed directly to physicians just months after the first paper about that association was published. The genetics community decried this development, asserting that the actual interpretation of those associational data for any single individual could not be determined and that any test result based on it would be misleading if not worthless.

The public outcry was so great that the test was withdrawn from the market in a matter of months.

The Testing Process

Requests for testing can arise from a variety of circumstances and for a number of reasons. For example, although genetic test results can be used to guide individual healthcare and reproductive decisions, genetic testing often is sought to fulfill familial, domestic, or vocational responsibilities (Burgess and d'Agincourt-Canning). For this reason healthcare professionals must be adept at presenting and discussing the potential ramifications of testing in light of the at-risk individual's reason for requesting testing. Genetics practice also calls for pretest and posttest counseling and formal informed consent procedures to ensure that people deciding whether to undergo genetic testing are informed about the risks and potential harms, benefits, and limitations of the test, as well as alternatives and treatment options (National Advisory Council for Human Genome Research; Holtzman and Watson).

At the beginning of the twenty-first century, the volume of genetic testing was not great and the vast majority of testing occurred in genetic centers or in consultation with highly trained geneticists and genetics counselors. As the number of tests increases, the demand for testing may outstrip the capacity of genetics-trained individuals to respond. This scenario suggests that it is likely that more and more testing decisions will be made by physicians with little formal training or experience in genetics. Some question the ability of physicians to perform this function and continue to recommend referrals to health professionals with specific training in genetics to ensure proper counseling, informed consent, and correct interpretation of test results (Giardello et al.).

A related issue is the fear that physicians will be more likely to take a directive approach to decisions about testing. This approach is antithetical to the concept of the value-neutral nondirective counseling that is a main tenet of all genetic counseling. Historically, this commitment to nondirective counseling can be understood as a moral stance designed to disassociate modern genetics from the eugenics movements of the first half of the twentieth century, which often advocated forced sterilization for individuals deemed to be genetically abnormal (Paul).

Philosophically, nondirective counseling also reflects the centrality of respect for autonomy (the right to self-determination or self-governance) in modern bioethics. Because decisions about genetic testing often involve reproduction and/or an individual's most personal desires and fears, the genetics community has adopted the view that the role of the genetics professional is to help an individual make a decision about testing that is consistent with that person's most strongly held values. Genetic counselors in training are taught specifically not to let their own opinions and attitudes influence the information that is given to people or recommendations for a course of action.

The Decision to Be Tested

The process of genetic testing can challenge traditional concepts of autonomy and privacy. The desire to be tested on the part of one individual can place pressure on other family members if their cooperation is required for the test to be done. In testing for familial cancers, for example, it is often necessary for a family member who is already affected to be tested first to identify the specific disease-associated mutation in the family. If the affected family member refuses to cooperate, that refusal can frustrate the desire of other family members to learn about their risk. This need to identify an index case also makes it difficult for an individual who wishes to be tested to keep that decision private.

Some authors have advanced the concept of relational responsibility as playing a key role in decisions regarding testing (Burgess and d'Agincourt-Canning). This ethical concept emphasizes that decisions about genetic testing occur within complex social relationships that are embedded in and shaped by notions of responsibility to specific others. Thus, although testing guidelines often emphasize that the decision whether to undergo genetic testing should be solely that of the individual for his or her own purposes and free from coercion by a spouse or another family member, research suggests that in reality people often make decisions about testing on the basis of the wishes and desires of others, primarily close family members, about whom they care deeply. Rosamund Rhodes has taken the notion of relational responsibility further, arguing that individuals have a moral duty to pursue genetic information about themselves, especially in cases in which that information has ramifications for others, such as spouses or children (Rhodes).

Ordering Tests

Once the decision has been made to pursue testing, tests for relatively common disorders usually are obtained from commercial laboratories (GeneTest). Blood is drawn and mailed to the laboratory, and the test results are conveyed back to the healthcare professional who ordered the test. That person then has the responsibility of conveying the results, usually in person, to the individual who has been tested. Genetic tests for rare disorders sometimes are available only from laboratories in academic medical centers that have a particular interest in the disease in question. Those laboratories may not have satisfied the ongoing quality and proficiency assessments required of commercial laboratories, thus raising questions about the reliability of testing obtained from this source.

Sharing Genetic Information

When a test has been performed and a result has been obtained, other considerations come into play. Perhaps the most vexing is whether and when a person has a moral duty to share genetic information. Genetic test results for a specific individual also reveal information about that person's relatives. Parents and children share half their genes, as do siblings. If a woman learns that she carries a gene associated with breast cancer, does she have a responsibility to share that information with her sister? Many writers agree that that responsibility exists, with Dorothy Wertz and colleagues suggesting that at the level of the person genetic information, although individual, should "be shared among family members" as a form of shared familial property (Wertz et al.). Indeed, most people, once they are aware of the implications of genetic information for other family members, willingly share the information with those for whom it is especially relevant.

However, what if a woman with a breast cancer mutation does not wish to share that information? May her physician breach her confidentiality and warn her sister? Several groups have addressed this issue in depth (President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research; Andrews et al.). Guidelines published by the American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure in 1998 state that the legal and ethical norm of patient confidentiality should be respected, with breaches of confidentiality permitted only in exceptional cases. Those exceptions are (1) when attempts to encourage disclosure by the patient have failed, when the harm is highly likely to occur and is serious and foreseeable, when the at-risk relative or relatives are identifiable, and when the disease is prevent-able/treatable or medically accepted standards indicate that early monitoring will reduce the genetic risk and (2) when the harm that may result from failure to disclose outweighs the harm that may result from disclosure (Knoppers et al.). At least one author has argued that knowledge about the risk for conceiving a child with a deleterious gene does not pose the type of serious, imminent harm that generally would require disclosure (Andrews).

In regard to the issue of disclosure Ruth Macklin suggests the institution of a patient "Miranda" warning so that before genetic testing occurs, a patient would be warned about the circumstances that would result in the disclosure of genetic information to other family members regardless of the patient's intentions to disclose (Macklin).

Two court decisions appear to indicate an increasing trend toward disclosure. In Pate v. Threkel, Florida, 1995, a physician was held to a duty to warn patients of the familial implications of a genetic disease. In Safer v. Estate of Pack, New Jersey, 1996, the court held that a physician has a duty to warn relatives known to be at risk for a genetic disorder regardless of potential conflicts between the duty to warn and the obligations of confidentiality. The courts have not yet addressed a physician's obligation to disclose information concerning individuals whose occupations may place the lives of others in danger, such as pilots and air traffic controllers.

The completion of the Human Genome Project will result in a proliferation of genetic tests for a wide variety of disorders. Some public health advocates argue for a broader role for population-based testing, whereas critics believe that further work needs to be done to understand the value of testing on a widespread basis. Concerns exist about the ability of consumers and physicians to make informed decisions about whether to use genetic tests and are exacerbated by a growing trend on the part of commercial laboratories to market the tests directly to consumers. Once a test has been ordered and the results have been obtained, questions remain about the duties of both individuals and healthcare professionals regarding disclosure of test results.

kimberly a. quaid

SEE ALSO: Autonomy; Cancer, Ethical Issues Related to Diagnosis and Treatment; Children: Mental Health Issues; Dementia; Genetic Counseling, Ethical Issues in; Genetic Counseling, Practice of; Genetic Discrimination; Genetics and Human Self-Understanding; Health Insurance;Informed Consent; and other Genetic Testing and Screening subentries


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Genetic Testing and Screening: V. Predictive Genetic Testing

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Genetic Testing and Screening: V. Predictive Genetic Testing