Good Laboratory Practices for Biochemical Genetic Testing and Newborn Screening for Inherited Metabolic Disorders
Good Laboratory Practices for Biochemical Genetic Testing and Newborn Screening for Inherited Metabolic Disorders
Recommendations and ReportsApril 6, 2012 / 61(RR02);1-37
The material in this report originated in the Laboratory Science, Policy, and Practice Program Office, May Chu, PhD, Director, and the National Center for Environmental Health/Agency for Toxic Substances and Disease Registry, Christopher J. Portier, PhD, Director.
Corresponding preparer: Bin Chen, PhD, Division of Laboratory Science and Standards, 1600 Clifton Rd., NE, MS G-23, Atlanta, GA 30329. Telephone: 404-498-2228; Fax: 404-498-2215; E-mail: email@example.com .
SummaryBiochemical genetic testing and newborn screening are essential laboratory services for the screening, detection, diagnosis, and monitoring of inborn errors of metabolism or inherited metabolic disorders. Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized on the basis of the level of testing complexity as either waived (i.e., from routine regulatory oversight) or nonwaived testing (which includes tests of moderate and high complexity). Laboratories that perform biochemical genetic testing are required by CLIA regulations to meet the general quality systems requirements for nonwaived testing and the personnel requirements for high-complexity testing. Laboratories that perform public health newborn screening are subject to the same CLIA regulations and applicable state requirements. As the number of inherited metabolic diseases that are included in state-based newborn screening programs continues to increase, ensuring the quality of performance and delivery of testing services remains a continuous challenge not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories. To help ensure the quality of laboratory testing, CDC collaborated with the Centers for Medicare & Medicaid Services, the Food and Drug Administration, the Health Resources and Services Administration, and the National Institutes of Health to develop guidelines for laboratories to meet CLIA requirements and apply additional quality assurance measures for these areas of genetic testing. This report provides recommendations for good laboratory practices that were developed based on recommendations from the Clinical Laboratory Improvement Advisory Committee, with additional input from the Secretary's Advisory Committee on Genetics, Health, and Society; the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; and representatives of newborn screening laboratories. The recommended practices address the benefits of using a quality management system approach, factors to consider before introducing new tests, establishment and verification of test performance specifications, the total laboratory testing process (which consists of the preanalytic, analytic, and postanalytic phases), confidentiality of patient information and test results, and personnel qualifications and responsibilities for laboratory testing for inherited metabolic diseases. These recommendations are intended for laboratories that perform biochemical genetic testing to improve the quality of laboratory services and for newborn screening laboratories to ensure the quality of laboratory practices for inherited metabolic disorders. These recommendations also are intended as a resource for medical and public health professionals who evaluate laboratory practices, for users of laboratory services to facilitate their collaboration with newborn screening systems and use of biochemical genetic tests, and for standard-setting organizations and professional societies in developing future laboratory quality standards and practice recommendations. This report complements Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions (CDC. Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR 2009;58 [No. RR-6]) to provide guidance for ensuring and improving the quality of genetic laboratory services and public health outcomes. Future recommendations for additional areas of genetic testing will be considered on the basis of continued monitoring and evaluation of laboratory practices, technology advancements, and the development of laboratory standards and guidelines.
IntroductionInherited metabolic diseases, often referred to as inborn errors of metabolism, comprise a large class of genetic diseases involving disorders of metabolism; collectively, these diseases have an incidence of at least one in 1,500 persons in the United States (1). Biochemical genetic testing and newborn screening tests are essential for early recognition of and timely intervention for these disorders to reduce morbidity and mortality rates and improve health outcomes. Biochemical genetic tests encompass a diverse spectrum of laboratory analyses of metabolites, enzyme activities, and functional assays for evaluation, diagnosis, treatment monitoring, disease management, and assessing a person's risk for carrying a specific disease trait (i.e., carrier status assessment), such as inborn errors of metabolism. Newborn screening is a vital state-based public health system in the United States that aims to test all newborns for an increasing number of inherited metabolic diseases and other congenital disorders, many of which require immediate treatment (2). The nationwide implementation of a recommended uniform screening panel of inherited metabolic diseases (Table 1) (3) and the consideration of additional conditions by state newborn screening programs present continuing quality assurance challenges for public health laboratories and other newborn screening facilities as well as for biochemical genetic testing laboratories that perform subsequent diagnostic testing. As advances in laboratory technology and knowledge of the genetic basis of disease increase the necessity of accurate and reliable laboratory testing in the screening, diagnosis, classification, and treatment of inherited metabolic diseases, guidelines are necessary for quality assurance and quality improvement in these areas of laboratory testing.
CDC has collaborated with the Centers for Medicare & Medicaid Services (CMS), the Food and Drug Administration (FDA), and other federal agencies; state programs; professional organizations; standard-setting institutions; and federal advisory committees to promote the quality of genetic testing and provide guidance for appropriate use of genetic tests in clinical and public health practices. In the 2009 report Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions, CDC provided recommendations for good laboratory practices in molecular genetic testing and indicated the need for recommendations in other areas of genetic testing, such as biochemical genetic testing, molecular cytogenetic testing, and testing of acquired genetic variations (4 ). This report complements the 2009 CDC recommendations by providing recommendations for good laboratory practices for biochemical genetic testing and newborn screening for inherited metabolic diseases. Recommendations for additional areas of genetic testing will be considered based on continued monitoring and evaluation of laboratory practices, technology advancements, and the development of professional practice guidelines.
The purposes of this report are to 1) clarify CLIA requirements that are applicable to biochemical genetic testing and newborn screening for inherited metabolic diseases and 2) provide recommendations for additional quality assurance practices that are not specifically addressed by CLIA requirements. The recommended practices address the benefits of the quality management system (QMS) approach, factors to consider before introducing new biochemical genetic tests, establishment and verification of test performance specifications, the total laboratory testing process (which consists of the preanalytic, analytic, and postanalytic phases), confidentiality of patient information and test results, and laboratory personnel qualifications and responsibilities for laboratory testing for inherited metabolic diseases. These recommendations provide a comprehensive guide for laboratories that perform biochemical genetic testing for ensuring the quality of laboratory services and highlight laboratory practices critical for quality improvement in newborn screening for inherited metabolic diseases. This report also is intended as a resource for users of laboratory services (e.g., authorized persons under applicable state law, health-care professionals, patients, and referring laboratories) to aid in their collaboration in newborn screening systems and effective use of biochemical genetic tests. This report also might assist standard-setting organizations and professional societies with development of future laboratory quality standards and practices, federal and state agencies with strategies and policies related to genetic testing, medical and public health professionals with evaluating laboratory practices, manufacturers of in vitro diagnostics with developing new testing products, and patients and families with improving their knowledge of good laboratory practices for genetic testing. Incorporation of these recommended practices into laboratory systems can improve the quality and appropriate use of genetic testing services, leading to better health outcomes for patients and their families. Abbreviations and a glossary of terms used in this report are provided (Appendices A and B).
BackgroundInborn errors of metabolism are inherited genetic disorders that affect one or more of the hundreds of biochemical pathways in the human body. Patients with these disorders are unable to properly use or synthesize certain compounds, such as fatty acids, amino acids, organic acids, or macromolecules, because of defects in the enzymes or other components of various metabolic pathways. These conditions frequently are identified in infants and young children with acute or chronic symptoms. When possible, early diagnoses with timely and effective interventions are essential for preventing permanent neurologic sequelae, disabilities, and other severe adverse outcomes.
Biochemical genetic testing is a critical discipline in laboratory medicine for the evaluation, diagnosis, treatment monitoring, clinical management, and in some cases, carrier status assessment, of inherited metabolic diseases. These tests comprise highly complex and specialized laboratory procedures performed for evaluating enzyme activity, functional status of proteins, and levels of metabolites such as amino acids, organic acids, and fatty acids using a wide variety of specimen types including urine, whole blood, plasma, serum, cerebrospinal fluid, muscle biopsy, and other tissue types. Biochemical genetic tests also are among the critical follow-up procedures for diagnosing presumptive cases detected during newborn screening.
Both the number of laboratories in the United States that perform biochemical genetic tests and the numbers of tests being performed are not certain. Although a nationwide survey identified laboratories that performed biochemical genetic testing in 2003 (5), more recent comprehensive data are not available, and information from voluntary laboratory directories are likely to be underestimates (6). However, information from the College of American Pathologists (CAP) Biochemical Genetic Testing Proficiency Survey Program indicated that the number of participating laboratories increased by 15% in 6 years, from 93 laboratories in 2002 to 107 laboratories in 2010 (7). Despite the limited nationwide data, biochemical genetic tests are performed for approximately 270 metabolic disorders spanning diverse disease categories (Table 2). As advances in biomedical research and laboratory technology lead to better understanding of the effects of genetic variations in biochemical pathways and metabolic diseases, the use of biochemical genetic tests in diagnosis, classification, and management of inherited metabolic diseases will likely continue to increase.
Newborn screening is a state-based public health system that tests infants shortly after birth for serious or life-threatening metabolic and other conditions that, when detected early, might be managed or treated to prevent death, disability, or other severe consequences such as mental retardation. The newborn screening programs test almost all (≥97%) of the 4 million babies born in the United States each year. These tests are conducted by public health laboratories using a few drops of blood, often collected from newborns before hospital discharge, that are spotted on filter paper cards (2). Most states collect a fee for newborn screening, which varies depending on the state and can be paid by third-party payers. Although newborn screening programs are primarily funded by user fees, state and federal public health system funding often is necessary to support the comprehensive programs, which include education, laboratory screening, follow-up and tracking, diagnosis, treatment and management, and evaluation. Over the last decade, the increasing use of tandem mass spectrometry in newborn screening has substantially increased the number of metabolic disorders that can be detected from dried blood spot specimens (3,8,9). In 2010, the Secretary of the U.S. Department of Health and Human Services (HHS) adopted the recommendation of the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) for a uniform screening panel (including screening for 30 core conditions and reporting 26 secondary conditions) as a national standard for newborn screening programs together with the recommendation to facilitate the inclusion of this recommended panel into all state newborn screening programs (10). The expansion of inherited metabolic conditions screened by newborn screening programs has presented challenges to ensuring the quality of performance and delivery of testing services not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories that perform subsequent diagnostic testing (11).