P. 1
Genetic Testing and Issues of Ethics, Accuracy, and Usefulness.pdf

Genetic Testing and Issues of Ethics, Accuracy, and Usefulness.pdf

|Views: 5|Likes:
Published by pieterinpretoria391
Genetic Testing and Issues of Ethics,
Accuracy, and Usefulness
Genetic Testing and Issues of Ethics,
Accuracy, and Usefulness

More info:

Categories:Types, Research
Published by: pieterinpretoria391 on Apr 08, 2013
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

11/01/2015

pdf

text

original

feature

Genetic Testing and Issues of Ethics, Accuracy, and Usefulness
Frances Katz

Despite continuing conversations about the pros and cons of genetic testing, a number of tests are in active use by clinicians ...

501

©

laboratorymedicine> july 2002> number 7> volume 33

̇ feature ̈
Many genetic tests are performed at specialized laboratories; by June 2002, there were 534 specialized laboratories that tested for 933 diseases.1 Most of this activity has been generated within the last decade and a half, beginning roughly with the determination in 1989 that tendencies for cystic fibrosis (CF) could be identified. In 1991, the American College of Medical Genetics (ACMG) was incorporated to give national representation to the providers of genetic services and patients with genetic disorders and to speak for the emerging specialty of medical genetics in organizations and agencies concerned with medical service, certification, and regulatory issues. By 1996, the ACMG had gained full membership in the American Medical Association (AMA) House of Delegates, and the AMA had passed the laboratory current procedural terminology (CPT) codes.2 Concerns about how genetic tests might be used triggered the formation of the Task Force on Genetic Testing, created by the National Institutes of Health - Department of Energy Working Group on Ethical, Legal, and Social Implications of Human Genome Research. This group started meeting in 1991 and published its final report in September of 1997. The 80-page report addressed the need for ensuring safety and effectiveness of new genetic tests, ensuring the quality of laboratories performing genetic tests, and improving providers’ understanding of genetic testing.3 The group was drawn from organizations with a stake in genetic testing. This group invited 5 agencies within the Department of Health and Human Services (HHS) to send nonvoting liaison members to the Task Force. One of the early realizations of the Task Force was that the gap between the cutting edge and the usefulness of genetics tests would have to be managed. The report states that “in the next few years, a greater burden for offering genetic testing will fall on providers who have little formal training or experience in genetics.” There are more providers with broader knowledge in 2002, and the understanding of the relationship between genes and disease has improved greatly since 1997. However, as the baseline knowledge moves rapidly, test development is under pressure to keep up. The focus of the Task Force was to recommend policies to reduce the likelihood of damaging effects from genetic tests. At the same time that the federal agencies were developing policies on genetics testing and the various concerns of their constituents were becoming clearer, advisory committees such as the SACGT (Secretary’s Advisory Committee on Genetic Testing) were also being formed. State governments were also becoming active, passing laws and recommendations across the spectrum of genetic testing and its impact on employment, insurance, and health care. In 1998, SACGT included 13 members and made recommendations on issues including the oversight of genetic testing, patent issues affecting genetic testing, and genetic nondiscrimination legislation. The report of the advisory committee was issued in July 2002, with requests for public comments published in the Federal Register on December 7, 2000. Thirty-four comments were received by the group and discussed at the February 2001 meeting; most questions dealt with the appropriateness of the criteria and issues regarding classification. The recommendations were made before the human genome mapping was completed. Genetic tests were defined by the Task Force to mean the analysis of human DNA, RNA, chromosomes, proteins, or other gene products to detect disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes. Such purposes include prediction of disease risks, identification of carriers, monitoring, diagnosis or prognosis, and establishing genetic identity. These clinical purposes do not include tests conducted purely for research. Although family history can be a very important screening tool to determine the need for genetic testing, this was not included in the definition of a genetic test. The Task Force expressed concerns about predictive uses of genetic tests performed in healthy or apparently healthy people or fetuses for the purpose of determining the presence of alterations that are associated with an increased risk of disease. Because many genetic tests to diagnose disease in symptomatic individuals can also be used to predict disease in healthy individuals, it was difficult to limit discussion about the validation, quality, or delivery of genetic tests only to their predictive uses. The Task Force recommended excluding tests for somatic cell mutations unless such tests are capable of detecting germline mutations. The SACGT developed a document, issued on August 4, 2000, titled “Development of a Classification Methodology for Genetic Tests: Conclusions and Recommendations of the Secretary’s Advisory Committee on Genetic Testing.”4 The document listed methodologies based on 4 criteria that would place genetic tests into 2 levels of review. The criteria were: test volume, whether the test would be used for population-based testing, whether the test is diagnostic or predictive; the availability of an intervention, the predictive value of the test, and the potential for medical or social harm associated with the test. During SACGT’s February 2001 meeting, the Food and Drug Administration’s (FDA) plans for pre-market review of genetic tests was presented. Further information on FDA’s pre-market activity for tests was presented during the May 2001 SACGT meeting, and the advisors concluded that the classification activity should remain inactive. Genetic Tests Today A large number of genetic tests are being used for a wide variety of applications. There are a number of consensus statements regarding certain tests that have been developed and published by the ACMG. These include: Statement on Use of Apolipoprotein E Testing for Alzheimer’s Disease The conclusion was that at the present time it is not recommended for use in routine clinical diagnosis nor should it be used for predictive testing. Studies to date indicate that the apolipoprotein E (APOE) genotype alone does not provide sufficient sensitivity or specificity to allow genotyping to be used as a diagnostic test. Because Alzheimer’s disease develops in the

502

laboratorymedicine> july 2002> number 7> volume 33

©

̇ feature ̈
absence of APOE epsilon-4 and because many with APOE epsilon-4 seem to escape disease, genotyping is not recommended for use as a predictive genetic test. The results of a collaborative study under way will clarify some of these issues. Whether APOE genotypes have other uses in the management of Alzheimer’s diesease will become apparent over the next few years. Published in JAMA, 1995. Genetic Susceptibility to Breast and Ovarian Cancer: Assessment, Counseling, and Testing Guidelines These Guidelines were published in 1999 by the ACMG, funded by a grant from the New York State Department of Health to the ACMG foundation. Laboratory Standards and Guidelines for PopulationBased Cystic Fibrosis Carrier Screening The committee recommends that CF carrier screening be offered to non-Jewish Caucasians and Ashkenazi Jews, and be made available to other ethnic and racial groups who will be informed of CF detection possibility through educational brochures, the informed consent process, and/or other efficient methods. For example, Asian-Americans and Native Americans without significant Caucasian admixture should be informed of the rarity of the disease and the very low yield of the test in their respective populations. Testing should be made available to African-Americans, recognizing that only about 50% of at-risk couples will be detected. An educational brochure and a consent form which recites this information, as well as a sign-off for those choosing not to be tested after reading these materials, was prepared by the Working Group on Patient Education and Informed Consent. The recommendation was that preconception testing be encouraged whenever possible, although it was also recognized that for practical purposes, testing will often only occur in the prenatal setting. Statement on Factor V Leiden Mutation Testing Which methodology should be used: factor V Leiden DNA testing or functional activated protein C (APC) resistance testing? When appropriate clinical care requires testing for the factor V Leiden allele, either direct DNA-based genotyping or a Leiden-specific functional assay is recommended. Patients who test positive by a functional assay should then be further studied with the DNA test for confirmation and to distinguish heterozygotes from homozygotes. Patients on heparin therapy or with known lupus anticoagulant should proceed directly to molecular testing if the modified functional assay is not used. When relatives of individuals known to have factor V Leiden are tested, the DNA method is recommended. Opinions and practices regarding factor V Leiden testing vary. Some physicians advocate testing of all patients with venous thrombosis except when active malignancy is present. Other physicians exclude testing of patients over the age of 60 in the absence of a family history of thrombosis or a previous thrombotic event. There is growing consensus that testing should be performed in at least the following circumstances (these are the same general recommendations

[I1] Scientist Viktor Barski of the Russian Engelhardt Institute of Molecular Sciences studies the computer data from an Argonne-developed microchip used to speed sequencing of the human genome. Photo courtesy of Argonne National Laboratory.

for testing for any thrombophilia): age <50; any venous thrombosis; venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins); recurrent venous thrombosis; venous thrombosis and a strong family history of thrombotic disease; venous thrombosis in pregnant women or women taking oral contraceptives; relatives of individuals with venous thrombosis under age 50; myocardial infarction in female smokers under age 50. Testing may also be considered in the following situations: venous thrombosis, age >50, except when active malignancy is present; relatives of individuals known to have factor V Leiden; or knowledge that they have factor V Leiden may influence management of pregnancy and may be a factor in decision-making regarding oral contraceptive use. Women with recurrent pregnancy loss, unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation, or stillbirth are recommended for testing. Knowledge of factor V Leiden carrier status may influence management of future pregnancies. Random screening of the general population for factor V Leiden is not recommended. Technical and clinical assessment of fluorescence in situ hybridization (FISH): an ACMG-ASHG position statement5 The conclusions of the Test and Technology Transfer Committee, accepted by the ACMG Board of Directors (March 2000), is that FISH testing be considered a highly useful and accurate test for the diagnosis of microdeletion and for the identification of unknown material in the genome. In disorders in which FISH testing provides results not possible from standard cytogenetic testing, the testing is stand-alone and should be accepted as such. Microduplication analysis can be a useful test for disorders in which tandem duplication is among the mutation

503

©

laboratorymedicine> july 2002> number 7> volume 33

̇ feature í
types. When validating such assays to establish reportable reference ranges, additional attention should be paid to background rates of target replication in controls. When using FISH testing in prenatal diagnosis or screening, positive FISH tests should be a part of the clinical decision-making along with confirmatory chromosome analysis or consistent clinical information. When used as a management tool in estimating reproductive risk in families in which a fetus is identified, positive results should be further characterized using traditional chromosome analysis to determine mutational mechanisms that may account for the positive FISH result. Fragile X Syndrome: Diagnostic and Carrier Testing The diagnosis of fragile X, the most common cause of inherited mental retardation seen in approximately 1 in 1,200 males and 12 in 2,500 females, was originally based on the expression of a folate-sensitive fragile site at Xq27.3, induced in cell culture under folate deprivation. In 1991, the fragile X gene FMR1 was characterized and found to contain a randomly repeated trinucleotide sequence (CUG) near its 5’end. The mutation that is responsible for fragile X syndrome involves expansion of this repeat segment as much as 200 times. Because premutation in both males and females do not cause symptoms and because the premutation are passed on and may expand during female meiosis, there is a risk of expansion in offspring. The recommendations for testing includes individuals of either sex who are mentally retarded, developmentally delayed, autistic, and especially if they have physical or behavioral characteristics of fragile X syndrome, a family history of fragile X syndrome, or relatives with undiagnosed mental retardation. Individuals seeking reproductive counseling with a family history of fragile X syndrome or undiagnosed mental retardation should be tested, as should be fetuses of known carrier mothers. Patients who have cytogenetic fragile X test results should be evaluated, particularly if the test results are discordant with their phenotype. The DNA test is very accurate, but the policy statement notes that effective means must be in place to inform tested individuals of the meaning and implications of the result. Dealing with Sampling Issues Diagnostic tests are currently being used to identify the causes of illness and to predict the possibility of disease that may be passed on to future generations. Testing for these conditions is actually relatively simple from the clinical laboratory standpoint. Samples are usually sent to laboratories who specialize in the tests. Annette Taylor is the president of Kimball Genetics. She noted that the specific DNA is either present or not. Therefore, bad samples do not give faulty results. Rather, they simply do not provide a result at all. With extremely careful directions for either blood samples (most hospitals use blood draws) or cheek cell collections (generally the method of choice for physicians offices), the number of bad samples is quite small. Blood samples can be sent room temperature or frozen. Enzymes are trickier, but with good sampling containers and fast shipping service, most samples can be transported to a central specialty laboratory in good condition. Room temperature samples (factor V Leiden mutation, factor V R2 polymorphism, prothrombin (factor II) mutation, fragile X, FRMP, FRAXE, Apo E, and hemachromatosis DNA testing) are sent in tubes in a Styrofoam container that is taped shut. The container is placed in a plastic bag with a closure. The completed test request form is attached and inserted into a cardboard box for shipping. Samples are sent by overnight mail. For FRMP testing, the laboratory must receive the sample within 24 hours of collection. For frozen samples, samples are processed according to specimen collection instructions. They must be frozen prior to shipping and kept frozen at all times. Shipping instructions are specific, including the request to call the laboratory before sending the sample to ensure that the sample arrives in good condition. Cheek cell collection is a simple procedure. Patients rinse their mouths twice with water. They are cautioned to avoid coffee for an hour prior to collection. Two small circular brushes individually wrapped are used. Cells are collected by rolling a brush firmly over the inside of each cheek and allowing the brush to dry for 30 minutes, packaging the brushes in the original packet, labeling according to instructions, completing the test forms, and sending the brushes to the laboratory in a padded envelope. Future Testing Gene testing has developed relatively quickly, and Taylor expects the pace to continue. An area of particular interest to her is pharmacogenetics. “I’ve been watching the general area since 1995. The number of papers has continued to increase, and it seems that this science can change patient care,” Taylor said. “Using tests to adjust dosing, and to select specific cancer treatments, for instance, will reduce the amount of pharmaceuticals and the related side effects that occur. The metabolism of drugs is often controlled by a patient’s specific genes, and selecting the dose and type of drug by using the genotype of the disease can be easier on the patient, as well as more effective.” There is a time lag between the understanding of how a test can be used and its clearance from the FDA. But the time lag is becoming shorter, and more tests are expected as the genome project feeds information to the companies and universities that develop the genetic tests.
1. GenTests-GeneClinics: Medical Genetics Information Resource [database online]. Copyright, University of Washington and Children’s Health System, Seattle. 1993-2001. Updated weekly. Available at: http://www.geneclinics.org, or http://www.genetests.org. Accessed May 30, 2002. 2. ACMG History. Available at: www.acmg.net. Accessed May 30, 2002. 3. Promoting safe and effective genetic testing in the United States, final report of the Task Force on Genetic Testing, Holtzman NA, Watson, MS, eds. Sept 1997. Available at: www.NHGRI.NIH.GOV.ELSI.TFGT_final/index.html. Accessed on May 30, 2002. 4. Development of a classification methodology for genetic tests: conclusions and recommendations of the Secretary’s Advisory Committee on Genetic Testing. 2000. Available at: www.4.od.nih.gov/oba/sacgt.htm. Accessed on May 30, 2002. 5. FISH2: FISH technical and clinical assessment of: An ACMG/ASHG position statement. Genet in Med. 2000;2:356-361.

504

laboratorymedicine> july 2002> number 7> volume 33

©

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->