3
Laboratory Issues in Human Genetics

The mapping of the human genome will lead to the identification of virtually all disease-causing genes and the development of tests to detect at least some of the mutations that are responsible for single-gene disorders and for susceptibility to many other common disorders. This proliferation of genetic tests will benefit those at risk of genetic and chromosomal disorders by permitting early treatment or, when treatment is not available, by providing prospective parents with options for avoiding the conception or birth of children affected with serious disorders. Consequently, errors in test performance and interpretation will detract from the benefit of genetic testing. Laboratory errors do occur. Errors have been documented in newborn screening (Holtzman et al., 1986; Hannon and Adam, 1991; Adam and Hannon, 1992), in biochemical genetic testing (Hommes et al., 1990), in karyotyping in cytogenetics* (Vockley et al., 1991), in linkage analysis, and in interpretation of results (P.M. Conneally, personal communication, February 1992).

Such errors in performance are likely to continue for the following reasons:

  • many clinical laboratories are unfamiliar with the recombinant DNA techniques used in most new genetic tests;

  • the use of very small samples with polymerase chain reaction (PCR) increases the chance of contamination with foreign DNA;

  • the large volume of tests increases the chance of unintentional switching of samples;

*  

 Martinez v. Long Island Jewish Hillside Center, 512 N.E.2d. 535, New York; 1987.



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Assessing Genetic Risks: Implications for Health and Social Policy 3 Laboratory Issues in Human Genetics The mapping of the human genome will lead to the identification of virtually all disease-causing genes and the development of tests to detect at least some of the mutations that are responsible for single-gene disorders and for susceptibility to many other common disorders. This proliferation of genetic tests will benefit those at risk of genetic and chromosomal disorders by permitting early treatment or, when treatment is not available, by providing prospective parents with options for avoiding the conception or birth of children affected with serious disorders. Consequently, errors in test performance and interpretation will detract from the benefit of genetic testing. Laboratory errors do occur. Errors have been documented in newborn screening (Holtzman et al., 1986; Hannon and Adam, 1991; Adam and Hannon, 1992), in biochemical genetic testing (Hommes et al., 1990), in karyotyping in cytogenetics* (Vockley et al., 1991), in linkage analysis, and in interpretation of results (P.M. Conneally, personal communication, February 1992). Such errors in performance are likely to continue for the following reasons: many clinical laboratories are unfamiliar with the recombinant DNA techniques used in most new genetic tests; the use of very small samples with polymerase chain reaction (PCR) increases the chance of contamination with foreign DNA; the large volume of tests increases the chance of unintentional switching of samples; *    Martinez v. Long Island Jewish Hillside Center, 512 N.E.2d. 535, New York; 1987.

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Assessing Genetic Risks: Implications for Health and Social Policy the vast majority of results will be in the normal range, a tendency that reduces the vigilance of those performing the test; the nature of genetic disorders increases the chance of errors in interpretation; tests at the DNA level may not detect all disease-causing or susceptibility-conferring mutations, resulting in false negative results; and a positive test result cannot always predict disease severity and, in some instances, may falsely predict the future occurrence of disease particularly in tests for predispositions to multifactorial disorders and disorders of variable expressivity. This chapter reviews current programs and regulations for assessing the quality of laboratories providing genetic tests, including the interpretation of test results, and current provisions for assessing the safety and effectiveness of genetic test kits and their critical components. For purposes of the committee's definition, genetic tests are those that are used primarily for predicting the risk of genetic or gene-influenced disease either in the person being tested or in his or her descendants. Tests that are used primarily for other purposes, but may contribute to diagnosing a genetic disease (e.g., blood smears, certain serum chemistries), would not be covered by this definition. Because the field of genetic testing is developing very rapidly, few systematic data are available on how many genetic tests are being done, who is doing them, or how well they are being done (Meaney, 1992). Some data are available on newborn screening (Holtzman et al., 1986; Hannon and Adam, 1991; Adam and Hannon, 1992; CORN, 1992). Similarly, few published data on genetic laboratory quality are available (Holtzman et al., 1986; Hommes et al., 1990; Hannon and Adam, 1991; Meaney, 1992). To assess the nature and extent of special laboratory issues in human genetics, therefore, the committee held an expert workshop to review existing voluntary, professional, and governmental regulatory efforts to ensure the quality of genetic laboratory testing (participants are listed in Appendix A of this report). Committee members also met with representatives of the Food and Drug Administration (FDA), the Health Care Financing Administration (HCFA), and the Centers for Disease Control and Prevention (CDC) to learn the agencies' current policies and plans for assessing the safety and effectiveness of genetic tests. Identifying problems of the quality of genetic tests is complicated because of the ways in which they are provided. A few are sold as kits, primarily to clinical laboratories; these have to undergo scrutiny by the FDA. An increasing number of tests are being marketed as laboratory services by commercial laboratories and a few academic laboratories. Many more are being provided for clinical decisionmaking purposes by research laboratories in academic medical centers. Although the critical reagents (which usually are not part of FDA-approved kits) used for testing in commercial and research laboratories, and the laboratories themselves,

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Assessing Genetic Risks: Implications for Health and Social Policy are subject to new federal regulations, many laboratories and investigators are unaware of them. Part of the reason is the federal government's failure to apply current regulations to genetic tests on a systematic and thorough basis. Were it not for the availability of tests through research laboratories, many people at risk for rare diseases could be deprived of an opportunity to use these tests; they are of such limited commercial value that manufacturers of in vitro diagnostics have little interest in them. One regulatory challenge is to ensure quality without diminishing the availability of these tests. The committee is concerned that the regulatory burden not impede further development of tests or the provision of genetic testing services by laboratories that currently provide them. PROGRAMS AND REGULATIONS FOR ASSESSING THE QUALITY OF LABORATORIES PROVIDING GENETIC TESTS Assessment of the quality of laboratories providing genetic tests is currently conducted by a few states and by voluntary participation in the proficiency testing programs of private organizations. At present, only 10 states have some form of specific requirements for the licensing of clinical laboratories providing genetic tests (M. Watson, personal communication to Congressman Ted Weiss, 1992). Only New York State has specific legislation and regulations dealing with laboratories providing the full range of genetic tests, including DNA tests. State Assessments of Laboratories Providing Genetic Tests New York State began mandatory regulation of genetic testing when it established the first program assessment for cytogenetics laboratories in the United States in 1972, with cytogenetics proficiency testing beginning in 1974 (Willey, 1992). Since 1990, New York has been the only state that has specific mandatory standards and permits for DNA genetics laboratories performing tests on its citizens. It has a list of DNA tests approved for testing, including tests for sickle cell anemia, cystic fibrosis (CF), Duchenne and Becker muscular dystrophy, Tay-Sachs, and the thalassemias (A. Willey, Director, Laboratory of Human Genetics, New York State Department of Health, personal communication, January 1993). To be included on this list of approved DNA tests, the disorders must meet identified criteria (e.g., no form of the disorder that is undetectable because a mutation at another locus is known to exist; the method must identify 90 to 95 percent of cases; reagents and processes must be generally available in the laboratory community—or must be made available; if linkage analysis is required, the markers must be a specified map distance from the disease gene). To be approved to perform DNA tests from this list, the laboratories must demonstrate that they successfully perform the accepted test methodologies. New York developed a special training program for all inspectors who survey laboratories that perform genetic testing. New York has also developed standards for proficiency testing for

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Assessing Genetic Risks: Implications for Health and Social Policy BOX 3-1 Congressional Oversight Hearing To focus attention on the special issues in genetic laboratory testing, congressional hearings were held in July 1992 to highlight unresolved laboratory issues in human genetics (House Subcommittee on Human Resources and Intergovernmental Relations, 1992). The hearing included testimony from two patients who had had significant problems with genetic testing. One woman experienced long delays (more than seven months), high cost, and problems with her referring physician—all without receiving any results from the first physician and laboratory, when she sought presymptomatic diagnosis for Huntington disease. A pregnant woman testified about the anxiety caused by two positive reports from maternal serum alpha-fetoprotein (MSAFP) screening tests indicating a high risk for Down syndrome; only weeks later was it determined by amniocentesis that the fetus she carried did not have Down syndrome (Hoyt, 1992). Anxiety of this type is observed frequently while women are awaiting MSAFP results but usually abates when a negative result is reported (Holtzman et al., 1991). The expert witnesses each presented cases of laboratory problems in various kinds of genetic diagnosis, testing, and screening. In one prominent medical center, the coordinator of the prenatal alpha-fetoprotein screening laboratory identified four significant problems over a two-month period, three involving commercial laboratories that provide MSAFP, and one problem of interpretation by a physician (Holtzman, 1992): In one case, a laboratory reporting an abnormally low MSAFP result, failed to recognize that the woman's age of 36 (considered "advanced maternal age" for purposes of prenatal diagnosis) warranted proceeding directly to a definitive cytogenetic test. Waiting for the results of the tests it recommended could have delayed diagnosis and reduced the woman's options had the confirmatory test been positive. In a second case, the laboratory director was uncertain whether the result had been adjusted for the patient's race and weight, key factors in interpreting test results. In a third case, there was not enough information supplied on the request form to determine that the woman was further into her pregnancy than thought; the laboratory reported that her result was abnormal when, in fact, it was normal for her true stage of pregnancy. In interpreting a woman's results, her physician correctly noted that she was not at increased risk for having a child with Down syndrome, but he failed to observe that she had an elevated MSAFP level and was, therefore, at increased risk for having a child with a neural tube defect. ____________ NOTE: Witnesses at the July 23, 1992, hearing included three panels: (1) Heidi Hoyt, Washington, D.C., and "Kim" of Illinois (both patients reporting their experiences with genetic testing); (2) specialized genetics personnel: Elizabeth Gettig, M.S., Director of Genetic Counseling, West Penn Hospital, Pittsburgh, Pa.; Paul Billings, M.D., Chief, Division of Genetic Medicine, California Pacific Medical Center, Assistant Clinical Professor of Medicine, University of California, San Francisco, Calif.; Neil A. Holtzman, Professor of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Md.; Patricia Murphy, Ph.D., Genica Pharmaceutical Corporation, Worcester, Mass.; and (3) representatives of U.S. Department of Health and Human Services agencies: William Toby, Acting Administrator of the Health Care Financing Administration (HCFA); Barbara Gagle, Acting Director, Health Standards and Quality Bureau, HCFA; Edward Baker, M.D., Director, Public Health Practice Program Office, Centers for Disease Control; Alan Anderson, M.D., Acting Director, Center for Devices and Radiological Health, Food and Drug Administration.

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Assessing Genetic Risks: Implications for Health and Social Policy DNA tests, but these standards have not yet been implemented (Murphy, 1992a). The reach of the New York State program extends beyond the geographic borders of the state, since any laboratory wishing to perform a genetic test on a citizen of New York must be certified just as if it were located in New York; thus, most large commercial genetic testing laboratories who accept specimens from around the United States are licensed to meet New York DNA laboratory standards. Currently, no other state has developed as rigorous a program for the quality control of genetic testing as New York. The California Department of Health Services contracts with private laboratories to provide newborn screening and maternal serum alpha-fetoprotein (MSAFP) testing. As part of the process it assesses the quality of the laboratories with whom it contracts. Since 1980, California has limited newborn screening to eight state-monitored laboratories, with centralized computer data collection, quality control, blind proficiency testing, and case follow-up. Fees for newborn screening are collected from the birth hospital or birth attendant. California also has centralized laboratory testing, quality control, and blind proficiency testing for its MSAFP screening program, which must be offered to every pregnant woman in California. California has developed draft regulations on DNA, cytogenetics, and microbiological testing, and for prenatal diagnosis centers and clinical centers; these draft regulations are awaiting public comment and public hearing (Cunningham, 1992). Maryland has regulations requiring genetic testing and screening laboratories to demonstrate "continuing satisfactory performance" in external proficiency testing programs where they exist. The only approved laboratory for newborn screening in Maryland is the state laboratory, which participates in the U.S. Centers for Disease Control proficiency testing program for newborn screening (see below). Fourteen laboratories (including the state laboratory) are approved for MSAFP screening. Maryland regulations require laboratories doing Tay-Sachs testing to participate successfully in the proficiency testing program of the International Tay-Sachs Disease Quality Control Reference Standards and Data Collection Center (M. Kaback, personal communication, November 1992). New Jersey requires its laboratories to comply with the New York system for genetic tests, and it now also recognizes College of American Pathology (CAP) proficiency testing for cytogenetics. Florida licenses cytogenetics laboratories using CAP guidelines and proficiency testing, but its legislation is now expiring. Iowa requires that MSAFP testing be done centrally in the state laboratory at the University of Iowa. In addition, states in the Pacific Northwest Region (PacNoRGG) of the Council of Regional Networks for Genetic Services (CORN), including Washington, Oregon, Idaho, and Alaska, have adopted PacNoRGG proficiency testing standards as a condition for state laboratory license as a cytogenetics laboratory. The PacNoRGG cytogenetics proficiency test involves the provision of blind samples and requires the interpretation of clinical information on individuals and families.

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Assessing Genetic Risks: Implications for Health and Social Policy Each round of proficiency testing gets more difficult as the proficiency of the participating laboratories improves. Voluntary Quality Assurance and Proficiency Testing in Genetics The Council of Regional Networks of Genetic Services, the College of American Pathologists, the Centers for Disease Control and Prevention, and several other organizations have developed specific genetic tests or tests for specific disorders. These include maternal serum alpha-fetoprotein, Tay-Sachs disease, and Huntington disease, for which the organizations have established voluntary proficiency tests (see Box 3-2). Other organizations interested in the quality of genetic tests include the Organization for Clinical Laboratory Genetics, the American Society for Histocompatibility and Immunogenetics, the American Association of Blood Banks, the Technical Working Group on DNA Analysis Methods (TWGDAM), the National Reference System for the Clinical Laboratory, the National Committee for Clinical Laboratory Standards (NCCLS), and the new American College of Medical Genetics (ACMG). Many of the voluntary quality assurance programs grew from the efforts of the American Society of Human Genetics (ASHG) (Punnett, 1992). CORN was established in 1985 as a coordinating body for state genetic services programs organized in 10 regions. CORN is funded by the Genetic Services Program of the Maternal and Child Health Program, Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services (DHHS). Laboratory quality assurance quickly became and remains a high priority for CORN. CORN has a Quality Assurance Committee (for laboratory services), as well as other committees on quality assurance and proficiency testing, and education. CORN's national proficiency testing programs include alpha-fetoprotein, biochemical genetics, hemoglobinopathies and newborn screening, and most recently, DNA-based tests. The College of American Pathologists developed guidelines, criteria, and methods for quality control and standards for clinical laboratories. CAP played a key role in the implementation of the Clinical Laboratory Improvement Act of 1967 (see below) when its quality assurance and proficiency testing standards and activities were recognized (''deemed") by the Secretary of Health and Human Services to fulfill the requirements of the law. Since 1967, CAP has worked to maintain itself and M.D.-pathologists as the appropriate professional group to judge the quality of clinical laboratories. CAP has voluntary proficiency testing programs for cytogenetics and MSAFP screening that are recognized by some states. With input from ASHG, CAP has spent two years developing guidelines for what it calls "molecular pathology." The ASHG role in setting standards for laboratory genetics will be assumed by the ACMG in 1993. ACMG laboratory standards for genetics are now under final revision and will be very important in quality assurance in genetic testing.

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Assessing Genetic Risks: Implications for Health and Social Policy BOX 3-2 Voluntary Quality Assurance and Proficiency Testing Programs New England Regional Genetics Group and the Foundation for Blood Research The New England Regional Genetics Group (NERGG) sponsored the first proficiency testing program for MSAFP screening in pregnant women. Since 1983, the Foundation for Blood Research (FBR) in Maine has served as the national testing and training resource for the use of MSAFP. The foundation provides quality control and proficiency training programs that include (1) bimonthly quality assessment; (2) assessment of the ability of laboratories to measure MSAFP levels reliably; (3) assessment of the laboratories' ability to interpret the AFP result, adjust for critical variables, and make screening recommendations to referring laboratories; (4) assessment of the quality of commercial test kits as well as individual laboratory performance; and (5) telephone consultation on laboratory problems. In 1986, the College of American Pathologists also began to offer proficiency testing for MSAFP; since 1988, FBR and CAP have offered such proficiency testing jointly. In addition, FBR now offers proficiency testing for so-called triple-marker screening for Down syndrome; and this program is also offered jointly with CAP (Haddow and McKnight, 1992). National Voluntary Biochemical Genetics Laboratory Proficiency Testing Program This voluntary program was established in 1985 by Frits Hommes and the Southeastern Region Genetics Group (SERGG) to provide quality standards and proficiency testing for biochemical genetic tests. It includes criteria for assessing adequate performance in (1) measuring inborn errors of metabolism of amino acids, organic acids, glycosaminoglycans, and oligosaccharides, as well as the assay of galactose-1-phosphate; (2) reporting analytical results; and (3) interpreting those results. A supervisory committee evaluates the results. Laboratories with unsatisfactory results are notified and offered a repeat test. Summary results of all participating laboratories are distributed after the supervisory committee has evaluated all the tests, including the repeat tests. Testing is performed twice a year, in February and September. Sixteen rounds of testing have been completed, with evidence of improved performance (Hommes, 1992). International Tay-Sachs Disease Quality Control Reference Standards and Data Collection Center A voluntary, international laboratory quality assurance and proficiency testing program for Tay-Sachs disease has existed since 1973 (Kaback et al., 1977). Laboratories that make an error on the first round of proficiency testing on 25 unknown samples are not accredited but have an opportunity to be retested with 10 additional samples. If the laboratory achieves 100 percent accuracy in the second round, it can still be accredited; if there is an error on the second round, the laboratory is not accredited. The list of accredited laboratories is widely disseminated to Jewish organizations by the National Tay-Sachs and Allied Diseases Association, Inc. Although the only leverage exerted is not to publish the names of laboratories that fail its proficiency programs, the system has effectively closed some laboratories, and

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Assessing Genetic Risks: Implications for Health and Social Policy has helped many others to improve their methodologies and quality in Tay-Sachs testing. The majority of laboratories doing Tay-Sachs identification have participated in this voluntary program, but new private laboratories can be started without meeting the requirements of this quality control program. Huntington Disease Pilot Projects The Huntington disease pilot projects also organized a voluntary laboratory quality assurance program. Early in the development of presymptomatic testing for Huntington disease, standards were developed for the original pilot studies to ensure the quality of the testing program, including rigorous laboratory standards. Once funding for the pilots ceased, and other centers and laboratories began presymptomatic testing for Huntington disease, it was no longer possible to enforce the standards developed for the original pilot studies. Since this quality assurance program is voluntary, and involved only the laboratories participating in the Huntington pilot projects, it does not reach all laboratories performing marker analysis and identification of Huntington disease. One recent study attempted to determine the accuracy of interpretation of complex linkage analysis for Huntington disease (Michael Conneally, personal communication, February, 1992). Selected family genetic linkage patterns (often called family "pedigrees") were distributed to a group of laboratories already performing complex linkage analysis for Huntington disease. Problems were found in the interpretation of inheritance patterns for Huntington disease by the responding laboratories. Presymptomatic testing for Huntington disease—like many late-onset disorders—is extremely complex. The significance of the findings is so great that the standard for testing can tolerate no errors. Thus, prospects for the expansion of testing for Huntington disease without enforceable standards raise concerns about the quality of future testing for this disorder. The recent clarification of the basic mechanism of Huntington disease (Collaborative Research Group, 1993) now provides the possibility of direct DNA testing. Laboratory standards will be needed to ensure the quality of this new, more accurate testing method. Although the Centers for Disease Control and Prevention attempted to establish its own cytogenetics proficiency testing program, it never progressed beyond a pilot program (Murphy, 1992a). CDC does run a voluntary proficiency testing program for newborn screening tests discussed below. Costs, Benefits, and Limitations of State and Voluntary Quality Assurance Programs In most state-run and voluntary programs, most of the costs of the quality control programs are paid by the participating laboratories. These costs could deter a research laboratory, or other small laboratory without cash reserves, from participating in the program. The costs of participation could be passed on to the

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Assessing Genetic Risks: Implications for Health and Social Policy consumer through higher laboratory prices, although the increases would not be a very large percentage of the current prices of most genetic tests. California now charges $40 for newborn screening and $55 for the MSAFP screening test, both of which include the cost of quality control and proficiency testing. Rigorous state licensing provides protection to the citizens of that state, but continued reliance on the states will not afford equal protection to citizens of all states. Separate programs in each state could result in duplication of effort or in competing and, in some instances, conflicting laboratory standards. Many diagnostic laboratories do not now participate in voluntary quality assurance and proficiency testing in genetics. One incentive for such participation would be to publish the results of voluntary quality evaluations by laboratory name, as is now done by the National Tay-Sachs Disease and Allied Disorders Association, Inc., which publishes results of the quality assessment conducted by the International Tay-Sachs Disease Quality Control Reference Standards and Data Collection Center. Federal Regulation of Clinical Laboratories History The Clinical Laboratory Improvement Act of 1967 (CLIA67) established federal control of laboratories providing more than 100 tests per year in interstate commerce for a profit. Only about 12,000 laboratories reimbursed by Medicare and Medicaid were covered. CLIA67 was originally administered by CDC, but authority was transferred to the Health Care Finance Administration in 1978. For laboratories under its purview, CLIA67 required the establishment of standards for laboratory directors and other laboratory personnel (CRS, 1990). The College of American Pathologists was recognized to set laboratory and personnel standards, and to develop a laboratory inspection system nationwide. The Clinical Laboratory Improvement Amendments of 1988 (CLIA88) were enacted in response to rising concern over media reports of serious errors and variability in laboratory results, and inadequate training and supervision of personnel performing clinical laboratory tests. In particular, so-called Pap mills were found to have serious deficiencies in their cytology analysis of Papanicolaou tests, intended to detect cervical cancer. Public concern had also intensified about the quality of the increasing amount of unregulated laboratory services provided in physicians' office laboratories and other laboratories reimbursed by Medicare and Medicaid. Laboratories Covered by CLIA88 With few exceptions, laboratories performing an "examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assess-

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Assessing Genetic Risks: Implications for Health and Social Policy ment of the health of, human beings" must obtain certification from HCFA under CLIA88 (Federal Register, 1992a). The exceptions are laboratories performing tests only for forensic purposes, research laboratories that do not report patient specific results for the purposes defined above, and laboratories of federal agencies to the extent excepted by the Secretary of Health and Human Services (Federal Register, 1992a). How a laboratory derives its revenues, or even whether it charges for tests, is no longer a determinant of coverage under CLIA88. Thus, any laboratory that provided a genetic test result on which a clinical decision was based is subject to regulation. More than 200,000 laboratories are estimated to be covered by CLIA88, over 100,000 of them in physicians' offices. Compliance with CLIA88, including CLIA certification is required for Medicare reimbursement of laboratory services, and many other third-party payers use Medicare certification as one criterion for reimbursement. However, HCFA may not know about laboratories that do not obtain certificates unless there is a complaint. CLIA88 Regulations In implementing CLIA88 the government sets standards for laboratories according to whether the tests they perform are of "moderate" or "high" complexity. The distinction between moderate and high complexity depends on a number of factors including knowledge needed to perform the test, characteristics of operational steps, judgment required, and interpretation of results. Thus far, CDC has classified 10,000 tests, approximately 25 percent as high complexity and 75 percent as moderate complexity (as of January 1993). Laboratories performing tests of moderate or high complexity must conform to general quality control standards as well as those of the "specialty" under which the tests they perform are classified. (Some specialties are microbiology, chemistry, pathology, and hematology.) Laboratories must participate in proficiency testing programs for each specialty in which they perform tests and for which proficiency programs have been established. By 1995, a laboratory that fails a proficiency test two consecutive times or two out of three times will be subject to sanctions and may not continue to perform that test under its CLIA certificate. Nor will it be eligible for Medicare reimbursement for that test (CDC, 1992). HCFA had approved 12 of the 19 proficiency testing programs that had applied as of December 1992. None of these is in genetics (see below). The absence of a complexity rating for a test does not exempt a laboratory performing only unrated tests from quality control. A laboratory test whose complexity has not been categorized "is considered to be a test of high complexity until PHS (Public Health Service), upon request, reviews the matter and notifies the applicant of its decision" (Federal Register, 1992b). In the meantime, "the laboratory must have a system for verifying the accuracy and reliability of its test results at least twice a year" (Federal Register, 1992c). Moreover, all laboratories

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Assessing Genetic Risks: Implications for Health and Social Policy filing a certificate of registration with HCFA will be inspected every two years, and the laboratory's quality control and internal proficiency test system will be assessed. HCFA has a training program for laboratory inspectors—many of whom are sent by states—provided by the Department of Laboratory Medicine of the Johns Hopkins University School of Medicine. HCFA may soon deem other organizations (CAP, Joint Committee on Accreditation of Health Organizations, specific states) as capable of conducting its surveys and accrediting laboratories. State accreditation can supplant HCFA accreditation when a state's program is deemed equivalent or more stringent than the federal program. Quality control under CLIA88 is funded by fees charged to laboratories. Compliance fees vary substantially from hundreds to thousands of dollars depending on how many different types of tests the laboratory performs, their complexity, and the volume of testing. Genetic Tests Under CLIA88 Very few genetic tests are on the list of tests whose complexity has been defined under CLIA88. Those that are listed have been classified as of moderate complexity including sweat chloride for CF, creatine kinase, and alpha-fetoprotein (AFP) for tumor marker (Federal Register, 1992d). A test subspecialty called "clinical cytogenetics" has been established, but there is no other genetic test subspecialty under CLIA88. Moreover, no proficiency testing for cytogenetic laboratories is required, although well-established programs (e.g., New York State and CAP) have been operating for years. Proficiency tests are not required for any other genetic tests, either. Few laboratories performing genetic tests as their sole or principal activity are yet complying with the CLIA88 regulations. Based on the committee's workshops and other information, it appears that few genetics laboratories have applied for certification from HCFA even though they provide genetic test information for clinical use. Committee staff also surveyed the directors of 12 genetics laboratories in academic centers to ask if their laboratory had applied for certification, and only I laboratory indicated that it had. Research Laboratories and Tests for Rare Disorders Research laboratories are covered under CLIA88 if they also provide tests on which clinical decisions are based. Some of these laboratories provide genetic tests as clinical services that are not directly related to the research they perform, and they may have limited expertise in performing or interpreting such tests. In many large academic hospitals, the central laboratory is not even aware of all the laboratories that provide services. This situation could be rectified either by having these laboratories obtain their own certificates from HCFA or by having them (and the tests they perform) listed under the central laboratory's certificate. Al-

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Assessing Genetic Risks: Implications for Health and Social Policy Nebraska 1     16 17d Nevada   Contracts with Oregon     0 New Hampshire   Contracts with Massachusetts     0 New Jersey 1       1 New Mexico 1       1 New York 1       1 North Carolina 1       1 North Dakota 1       1 Ohio 1       1 Oklahoma 1       1 Oregon 1       1 Pennsylvania 1e   1 1 3 Rhode Island 1f Contracts with Massachusetts     1 South Carolina 1       1 South Dakota   8 8   8 Tennessee 1       1 Texas 1       1 Utah 1       1 Vermont   Contracts with Massachusetts     0 Virginia 1       1 Washington 1       1 West Virginia   Contracts with S. Carolina     0 Wisconsin 1       1 Wyoming   Contracts with Colorado     0 Puerto Rico 1       1 TOTAL 36 13 21 20 84 a Eight private laboratories under contract to California. b 95% Central operated laboratory usage. c One laboratory does tests for and provides services to other New England states. d Plus some out of state laboratories. e State laboratory does confirmatory and Q/A tests. f Rhode Island state laboratory does some phenylketonuria tests. SOURCE: CORN, 1992.

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Assessing Genetic Risks: Implications for Health and Social Policy The regulation of laboratories under CLIA88 can only ensure that performance of the tests is as good as the intrinsic validity of the test. It does not address the inherent safety and effectiveness of the screening tests themselves. None of the current newborn screening tests has gone through the FDA's full premarket approval process. Tests for PKU and congenital hypothyroidism (for which all 50 states screen), sickle cell anemia (for which 42 states screen and 11 other states have limited screening or pilot studies), and galactosemia (for which 39 states screen) have been classified as Class II by FDA. It seems probable that the FDA has not even been notified of many of the "in vitro diagnostic devices" used in state laboratories for screening because they are not marketed outside that laboratory. It is also doubtful that in developing these devices, manufacturers (companies or individuals) have followed FDA requirements for investigational device exemption and use. Recently, mandatory newborn screening for CF has been undertaken in Colorado and Wyoming (Hammond et al., 1991). As far as the committee could determine, the immunoreactive trypsin assay used for CF screening by these states has not been submitted to FDA for premarket review for use in CF screening. An interesting policy dilemma arises if the organization performing the pilot study (e.g., a state laboratory) has no plans to market the test. It would then have no need to apply to FDA for premarket approval and could continue to handle the device as investigational even after screening becomes routine. FINDINGS AND RECOMMENDATIONS Ensuring the Quality of Laboratories The safety and effectiveness of genetic tests must be established before these tests are used routinely and, once that comes to pass, great care must be taken in performance of the tests and interpretation of the results. Laboratory quality control falls into three areas: The training and experience of the laboratory personnel: The nature of genetic tests and the implications of their interpretation suggest the need for special requirements for supervisory personnel (laboratory directors and technical supervisors) in laboratories involved in genetic testing. The structure and function of the laboratory itself: This requires inspectors with special training in assessing such laboratories. Proficiency testing: The most rigorous type should be conducted whenever possible, that is, external, blind proficiency testing in which an outside agency sends specimens to the laboratory under a fictitious patient's name. The laboratory has no way of knowing that the specimen is for assessing laboratory quality. Other types of proficiency testing involve the sending of coded samples from a central source. Proficiency testing should extend to all genetic laboratory tests and to the interpretation provided by the laboratory to referring physicians.

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Assessing Genetic Risks: Implications for Health and Social Policy Voluntary quality control programs have helped to establish criteria and standards for genetics laboratories and laboratory personnel. The committee finds the current state of voluntary laboratory quality control programs in human genetics to be beneficial, but generally inadequate to address the special issues posed by genetic testing, because these programs lack essential enforcement authority. The impact of these voluntary programs should be strengthened by the publication of the names of laboratories that have satisfied the proficiency and other requirements. Before names are withheld from a published list of "quality" laboratories, any laboratory not satisfying these requirements should be given an opportunity to rectify its deficiencies. The clinical implications of commonly performed prenatal tests, particularly the abortion of presumably affected fetuses, warrant that laboratories performing them participate in proficiency testing programs. The performance standard for genetic testing should be as close to zero error as possible. Laboratories with any error in proficiency testing should be placed on probation, with proficiency testing repeated using blinded methods. Unless the laboratory can attain the required standard in performing and interpreting any genetic test, its certification to perform that test should be removed. The existing CLIA88 regulations could ensure the quality of genetic laboratory testing were they to be fully implemented and applied to genetic testing. Action by DHHS would help to ensure the quality of the most frequently performed genetic tests by (1) establishing genetics as a subspecialty under the CLIA88 regulations; (2) rating specific genetic tests for complexity; and (3) requiring proficiency testing for genetic tests. The first step would be to require all laboratories providing any genetic test to obtain a certificate from HCFA. Next, would be development of a system for verifying the accuracy and reliability of the tests they perform. Third, laboratories performing genetic tests would be subject to inspection every two years. To make this approach meaningful, the laboratory inspectors would have to be well versed in the unique aspects of genetic tests, including the interpretation included in the report of results. A specific training unit on genetic testing should be included in HCFA's educational training program for inspectors, and the same training should be required of inspectors in agencies deemed by HCFA capable of performing inspections. In addition to these steps, HCFA could determine that existing proficiency programs for genetic tests satisfy its standards; HCFA could deem these proficiency testing programs to be required by laboratories providing those tests until such time as other programs are developed (see previous section on voluntary programs and Box 3-2 in this chapter). A laboratory that failed proficiency testing in a "deemed" program would be subject to HCFA sanctions even if that program was voluntary and did not itself impose sanctions. It is doubtful that adequate quality control can be ensured with voluntary proficiency testing. This holds for newborn and other types of screening as well. As with any genetic testing, participation in proficiency testing programs

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Assessing Genetic Risks: Implications for Health and Social Policy should be required of laboratories providing newborn screening tests. This could be accomplished by designating genetic screening tests as moderate or high complexity under CLIA88. HCFA should examine the proficiency testing programs for genetic screening tests described earlier in this chapter and, if they meet its criteria, deem them acceptable. The committee recommends that HCFA create a new specialty of clinical genetics into which it can incorporate the existing subspecialty of clinical cytogenetics, and also create new subspecialties of biochemical and molecular genetics. MSAFP testing and other methods of prenatal testing for birth defects should be incorporated into one of these three subspecialties. Most genetic tests should be classified as high complexity under CLIA88, primarily to ensure that supervisory personnel have adequate training in genetics. Although genetic tests might someday be simple enough to be feasible for home use, the difficulties of interpreting results would still render them of high complexity. Within its existing authorities, HCFA can take steps to enhance the quality of tests for rare disorders, for which specific requirements may never be established. According to a HCFA representative, requirements for proficiency testing are unlikely to be established for low-volume tests unless their clinical or public health implications are high (J. Yost, HCFA, personal communication, January 1992). The establishment of such requirements could be costly both to HCFA and to laboratories that must participate. The committee strongly recommends that the genetics community, under the leadership of its professional societies, designate a small number of laboratories as centralized facilities for tests for rare disorders . These organizations should establish and publicize a register of the tests performed by these central laboratories and encourage referral of specimens to them. The register should be easily accessible to a wide range of health care providers. It could also be included in the data bases of the National Library of Medicine. An external proficiency testing program should be established for the central laboratories. The genetics community should also study the possibility of setting a minimum volume of a genetic test that a laboratory must perform annually in order to obtain certification for that test and ensure the quality of test performance. With its informatics and data base capabilities, the National Library of Medicine should maintain a data base of centralized laboratories performing tests for rare disorders, genetic counseling centers, and support groups, which should be available to laboratories and providers at no charge. HCFA and CDC should give high priority to requiring established proficiency programs for genetic tests. The New York State program can be considered a model for many genetic tests, although high priority should also be extended to setting specific requirements for other frequently performed prenatal tests. HCFA should incorporate standards and procedures for assessing genetic tests in its training programs for current and new laboratory inspectors. Laboratories in academic health centers and elsewhere that conduct re-

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Assessing Genetic Risks: Implications for Health and Social Policy search, but that also perform genetic tests as a service (providing the results to referring laboratories or physicians, or directly to patients), should be subject to the same criteria, standards, and regulation as commercial genetic testing laboratories since they fall under the purview of CLIA88. The committee recommends that HCFA inform all hospitals of their legal responsibilities to register with HCFA every laboratory that provides results used in clinical decisions to physicians or patients. The committee recommends that genetics laboratories provide reports in an easily understandable form for referring physicians who are not genetic specialists. These reports, including interpretation of the results, should be reviewed by HCFA as part of its inspection of laboratories performing genetic tests. To ensure that physicians and patients receive consistent and accurate information, ''package inserts" (information and instructions both for physicians and patients) should be provided by the manufacturer of genetic test kits through the laboratory from which the physician orders the test. Ensuring the Safety of New Tests Because genetic tests seldom will have perfect sensitivity or specificity, particularly when used for predictive purposes, because of the novelty of some genetic testing technologies, and because of the possibilities of misinterpretation of test results, full premarket approval is needed for all new genetic tests; that is, genetic tests should be in Class III. The concerns of the committee will be addressed only if FDA uses criteria for review that address these issues. In its recent reply to the committee's inquiries, FDA indicated (Tsakeris and Yoder, 1992, p. 8) that a sponsor may be asked to provide information that includes when appropriate analytic sensitivity/limits of detection; analytic specificity/cross-reactivity/interference studies; accuracy studies; precision studies; reportable range; clinical sensitivity and specificity; and stability data. The committee believes that data on all of these areas should be provided in premarket approval submissions for genetic tests. Specifically, sponsors should present evidence of sensitivity in terms not only of the ability of the test to detect specific mutations (analytic sensitivity) but of the proportion of people with clinically significant disease that are detected by the test (i.e., who have the specific mutation detected by the test; clinical sensitivity). One area of concern, for

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Assessing Genetic Risks: Implications for Health and Social Policy example, is the possibility of FDA approval of a (hypothetical) test kit for CF carriers that detects six mutations and might have 100 percent analytical sensitivity, but only 85 percent clinical sensitivity. The determination of an acceptable clinical sensitivity should be on a test-by-test basis, by taking into consideration not only the benefits of making correct predictions but the risks of making wrong ones. The FDA should develop guidance to manufacturers for preparing premarket applications for genetic test devices. The application should include the intended and potential use(s) of the test (e.g., presymptomatic diagnosis or prediction, carrier screening, prenatal diagnosis); for each intended use, data on the sensitivity and specificity of the test, with clinical manifestations serving as an end point in the absence of a "gold standard" test; procedures to be used by clinical laboratories to demonstrate their reliability (precision and accuracy) and proficiency in performance of the test; and description to be given to health care providers and to patients regarding the objectives of the test and the interpretations of negative or positive findings. For very rare diseases, it may take a long time to collect sufficient data on specificity and sensitivity. For diseases of late onset, a long lag will occur between the time of the test and the appearance of disease, and it will be difficult for applicants to provide adequate data on safety and effectiveness for subjects of the type in whom the test would be applied (e.g., presymptomatic individuals). It may also be impossible to assess the sensitivity and specificity of prenatal tests by independent tests or histopathological examination of aborted fetuses. In all such cases, the committee recommends that data of the type described in the section "Collection of Data for Test Validation" be required. If these preliminary data suggest that the test is safe and effective for its intended use, the FDA should grant the applicant "provisional premarket approval" in order not to unduly delay submission for PMA. Under this category, the test could be made more widely available, but the manufacturer would be responsible for obtaining and submitting additional periodic postmarket data of an adequate sample of subjects, until sufficient data are available to warrant full premarket approval. These data would be collected from patients' physicians either directly by the manufacturer or by the laboratories to whom it sells the device. The protocol used in the investigational phase (before provisional approval) would still apply, and informed consent would still be needed. Once provisional premarket approval has been granted, however, the laboratories performing the test could charge a fair market price for the device or test kit. The committee recommends that people receiving the test during this provisional period be informed that the safety and effectiveness of the test have not

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Assessing Genetic Risks: Implications for Health and Social Policy been fully determined. If the manufacturer is to contact physicians directly, testees must be informed if the manufacturer will have their names. Once provisional premarket approval is granted, manufacturers should be allowed to charge a market price for the test. This process may require new legislation. Provisional premarket approval, with periodic postmarket study for which the sponsor would be responsible, could also be used to cover the development of tests for rare conditions (which is the intent of the humanitarian device exemption). The committee therefore recommends that Congress consider the need for legislation in the spirit of the Orphan Drug Act that would give manufacturers the incentive to develop diagnostic medical devices for genetic tests of limited marketability. The appearance of clinical disease is the only possible confirmation of many genetic tests, and that may not occur until many years after testing. Investigators should be permitted to convey the results of investigational tests to subjects who are aware of the investigational nature of the test. Thus, clinical decisions could be made on the basis of the results as long as the investigator has an approved investigational device exemption. FDA should make it clear that in such cases, with an approved IDE, results could be communicated to the patient or to his or her physician so that interventions can be instituted accordingly. Since many IRBs are not experienced in the review of investigational genetic testing protocols, the committee recommends that the National Institutes of Health (NIH) Office for Protection from Research Risks (OPRR) and the National Center for Human Genome Research Ethical, Legal, and Social Implications (ELSI) Program coordinate efforts to assist IRBs in coping with this responsibility, and ELSI should consider supporting efforts to assist IRBs in this task. Other federal agencies (such as the FDA) and professional groups should also consider developing guidelines to help IRBs cope with this added responsibility (such as the informed consent guidelines for research involving genetic testing developed by the Alliance of Genetic Support Groups and the ASHG). The formation of a national advisory body on genetic testing could also be helpful in educating IRBs concerning research involving genetic testing (see Chapter 9). IRBs used by commercial organizations should also have a broad, unbiased membership. Compliance with FDA requirements for premarket approval and approved investigational device exemption is essential to ensuring safe and effective use of a genetic test, just as compliance with CLIA88 is essential for any laboratory performing genetic tests for clinical purposes. The committee recommends that the FDA publicize widely to potential sponsors, including academic centers, that DNA probes and other reagents essential to the performance of genetic tests are medical devices. Consequently, whenever they are used for clinical purposes, genetic test devices (i.e., test kits, reagents, probes, etc.) either must be labeled "for investigational use only" (and must comply with FDA requirements for such use) or must have been approved or

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Assessing Genetic Risks: Implications for Health and Social Policy or cleared for marketing by FDA. When genetic test devices are used investigationally for clinical purposes, manufacturers—including commercial or academically based laboratories preparing their own devices—should apply for FDA approval of an investigational device exemption, including an IRB approved protocol, and periodic reports on the results of their investigations. To speed the widespread availability of investigational devices of limited marketability, FDA should grant provisional premarket approval, as described earlier, when adequate preliminary evidence of safety and effectiveness has been collected. In addition, the NIH and private funding agencies should support meritorious studies designed to assess the safety and effectiveness of investigational genetic testing devices. To speed the collection of data on tests of limited marketability, national collaborative studies should be encouraged. Funding agencies should also support long-term studies on safety and effectiveness of genetic test devices (through the phase of provisional premarket approval) for diseases in which a long lag will occur between the time of the test and the clinical appearance of the disease. The committee recommends that all genetic tests should either be designated as investigational devices—subject to IRB approval and FDA regulation—or be submitted to the FDA for premarket approval. FDA should clarify that when an approved IDE is obtained for a test for which no independent confirmatory test is available, the results may be given to the patient's health care provider or to the patient. When a device with an approved IDE is used to provide clinical information, the laboratory performing the test should be allowed to charge for the costs of testing, record keeping, and complying with reporting requirements. Because the investigational phase of new genetic tests may be prolonged, the laboratories performing these tests should be subject to external quality assessment. The committee recommends that HCFA inform every organization (e.g., academic health center or other hospital) that all laboratories in which investigational devices are being used for genetic testing are covered by CLIA88 and must register with HCFA to obtain CLIA88 certificates and be inspected. The FDA has taken important first steps to increase the pool of advisors expert in genetics by inviting applications for service as FDA advisors ("special government employees") under its Clinical Chemistry and Toxicology Devices Panel of Experts. The agency should also consider developing workshops on critical aspects of genetic testing technology for manufacturers and clinical laboratories. The committee is concerned that screening tests may become routine standard of care without adequate studies of their safety, effectiveness, or clinical utility. To ensure that adequate studies are conducted, the committee recommends that any new screening test should comply with FDA rules regarding investigational devices, including a protocol reviewed by an IRB. The committee recommends that the decision to move from "pilot" or "investigational" use to rou-

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Assessing Genetic Risks: Implications for Health and Social Policy tine practice involve review of data collected in the pilot study and elsewhere by both FDA and a policy-making body, usually at the state level, that is independent of the organization directly responsible for conducting the pilot study. A national oversight body (see Chapter 9) could facilitate collection and dissemination of data from pilot "investigational" studies. An adequately conducted pilot study in one or a few states need not be repeated in others as long as the other state(s) can maintain the same standards of the pilot study in routine operation. The committee also recommends that some mechanism be found to resolve the dilemma posed by the need to demonstrate that the device is safe and effective for its intended use, whether or not it will be commercially marketed. The preceding sections, as well as other chapters in this report, indicate that genetic tests for screening and other purposes differ in many respects from other laboratory tests. Some federal agencies, particularly FDA, have recognized this by planning special guidance for manufacturers of genetic tests and by inviting geneticists to participate on advisory groups. The committee welcomes such activity and encourages other agencies to do likewise. In particular, the committee recommends a Genetic Device Advisory Panel to provide FDA with continuing and timely access to expert advice. In addition, the Clinical Laboratory Improvement Advisory Council should appoint a subcommittee on genetics to make recommendations on improving the quality of laboratories performing genetic tests under CLIA88. REFERENCES Adam, B., and Hannon, W. 1992 (published in 1994). The Centers for Disease Control's infant screening quality assurance program: Overview, accomplishments, and initiatives. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Benn, P., et al. 1992. A rapid (but wrong) prenatal diagnosis. New England Journal of Medicine 326(24): 1638-1639. Centers for Disease Control (CDC). 1992. Morbidity and Mortality Weekly Report 41 (RR-2), February 28. Congressional Research Service (CRS). 1990. Clinical Laboratory Improvement Amendments of 1988. Washington, D.C. Collaborative Research Group for Huntington's Disease. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971983. Council of Regional Networks for Genetic Services (CORN). 1992. Newborn Screening Report: 1990 (Final report, February 1992). Cunningham, G. 1992 (published in 1994). California newborn screening program. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Federal Register. 1992a. 57 (40), February 28, 1992, Sec. 493.2, p. 7139; Sec. 493.3, p. 7140. Federal Register. 1992b. 57 (40), February 28, 1992, Sec. 493.17{C}{4}, p. 7141. Federal Register. 1992c. 57 (40), February 28, 1992, Sec. 493.1709, p. 7184).

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Assessing Genetic Risks: Implications for Health and Social Policy Federal Register. 1992d. 57 (131), July 8, 1992. Federal Register. 1992e. 57 (60491); 21 CFR 812, Docket 91N0404. Food and Drug Administration (FDA). 1992. Draft "accommodation list" for device tests essential to clinical practice, but not approved by FDA for those uses. Washington, D.C. (personal communication of draft for comment, May 3, 1992). Haddow J., and McKnight, G. 1992 (published in 1994). Quality of genetic laboratory procedures in the United States. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Hammond, K., et al. 1991. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. New England Journal of Medicine 325:769-774. Hannon, W., and Adam, B. 1991. Identified problems found in the voluntary newborn screening proficiency testing program conducted by the Centers for Disease Control. In An overview of the national infant screening quality assurance program: Update and future directions. In Proceedings of the Eighth Annual Neonatal Screening Symposium, Saratoga Springs, N.Y., April. Hoffman, E. 1991. Presentation at the Conference on Biotechnology and the Diagnosis of Genetic Disease: Forum on the Technical, Regulatory and Societal Issues. Program on Technology and Health Care, Department of Community and Family Medicine, Georgetown University Medical Center. Washington, D.C., April. Hofman, K., et al. 1993. Physicians' Knowledge of Genetics and Genetic Tests. Academic Medicine 68(8):625-631. Holtzman, C., et al. 1986. PKU newborn screening in descriptive epidemiology of missed cases of phenylketonuria and congenital hypothyroidism. Pediatrics 78(4):553-558. Holtzman, N. 1991. The interpretation of laboratory results: The paradoxical effect of medical training. Journal of Clinical Ethics 2(4): 1-2. Holtzman, N. 1992. Testimony on genetic testing before the Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Operations, U.S. House of Representatives, July 23. Holtzman, N., et al. 1991. Effect of education on physicians' knowledge of a new technology: The case of alpha-fetoprotein screening for neural tube defects . Journal of Clinical Ethics 2(4): 1-5. Hommes, F. 1992 (published in 1994). Laboratory quality assurance efforts in biochemical genetics. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Hommes, F., et al. 1990. Documented errors and improvements in biochemical genetic testing. In Proficiency testing for biochemical genetics laboratories: The first ten rounds of testing. American Journal of Human Genetics 46:1001-1004. House Subcommittee on Human Resources and Intergovernmental Relations. 1992. Committee on Government Operations, U.S. House of Representatives, hearing on genetic testing, July 23. Hoyt, H. 1992. Testimony on genetic testing before the Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Operations, U.S. House of Representatives, July 23. Kaback, M., et al. 1977. Tay-Sachs disease heterozygote detection: A quality control study. TaySachs disease: Screening and prevention. In Kaback, M. (ed.) Progress in Clinical and Biological Research 18:267-277. Klinger, K. 1992 (published in 1994). New developments in genetic testing. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Meaney, J. 1992 (published in 1994). Council of Regional Networks for Genetic Services data on laboratory procedures . In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Murphy, P. 1992a (published in 1994). New York City DNA Laboratory Quality Assurance. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press.

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Assessing Genetic Risks: Implications for Health and Social Policy Murphy, P. 1992b. Testimony on genetic testing before House Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Operations, U.S. House of Representatives, July 23. Punnett, H. 1992 (published in 1994). Quality assurance efforts of the American Society of Human Genetics. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Tsakeris, T., and Yoder, F. 1992 (published in 1994). FDA response to Institute of Medicine questions on regulation of human genetic devices. In Fullarton, J. (ed.)Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press. Vockley, J., et al. 1991. "Pseudomosaicism" for 4p- in amniotic fluid cell culture proven to be true mosaicism after birth. American Journal of Medical Genetics 39:81-83. Ward, B., et al. 1992. Response. New England Journal of Medicine 326(24):1639-1640. Willey, A. 1992 (published in 1994). New York State Genetic Quality Assurance Efforts. In Fullarton, J. (ed.) Proceedings of the Committee on Assessing Genetic Risks. Washington, D.C.: National Academy Press.