Quality Assurance and Quality Improvement in U.S. Clinical Molecular Genetic Laboratories

Bin Chen1, C. Sue Richards2, Jean Amos Wilson3, Elaine Lyon4

1 Centers for Disease Control and Prevention, Atlanta, Georgia, 2 Oregon Health & Science University, Portland, Oregon, 3 Berkeley HeartLab, Alameda, California, 4 University of Utah School of Medicine, Salt Lake City, Utah
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 9.2
DOI:  10.1002/0471142905.hg0902s69
Online Posting Date:  April, 2011
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A robust quality‐assurance program is essential for laboratories that perform molecular genetic testing to maintain high‐quality testing and be able to address challenges associated with performance or delivery of testing services as the use of molecular genetic tests continues to expand in clinical and public health practice. This unit discusses quality‐assurance and quality‐improvement considerations that are critical for molecular genetic testing performed for heritable diseases and conditions. Specific discussion is provided on applying regulatory standards and best practices in establishing/verifying test performance, ensuring quality of the total testing process, monitoring and maintaining personnel competency, and continuing quality improvement. The unit provides a practical reference for laboratory professionals to use in recognizing and addressing essential quality‐assurance issues in human molecular genetic testing. It should also provide useful information for genetics researchers, trainees, and fellows in human genetics training programs, as well as others who are interested in quality assurance and quality improvement for molecular genetic testing. Curr. Protoc. Hum. Genet. 69:9.2.1‐9.2.26 © 2011 by John Wiley & Sons, Inc.

Keywords: molecular genetic testing; quality assurance; quality management; quality improvement; laboratory testing process; good laboratory practices; quality systems assessment; personnel competency

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Table of Contents

  • Introduction
  • Specific Considerations for Molecular Genetics Laboratories
  • Establishment and Verification of Performance Specifications for New Molecular Genetic Tests
  • Quality Assurance for the Total Testing Process
  • Personnel Qualifications, Responsibilities, and Competencies
  • Literature Cited
  • Tables
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Literature Cited

   American Association for Laboratory Accreditation. 2010. Available at http://www.a2la.org/.
   American Board of Medical Genetics (ABMG). 2010. Available at http://www.abmg.org/.
   American College of Medical Genetics (ACMG). 1995a. Points to consider: ethical, legal and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 57:1233‐1241.
   American College of Medical Genetics (ACMG). 1995b. Statement on storage and use of genetic materials. Am. J. Hum. Genet. 57:1499‐5000.
   American College of Medical Genetics (ACMG). 2008. ACMG Standards and Guidelines for Clinical Genetic Laboratories. Available at: http://www.acmg.net/AM/Template.cfm?Section=Laboratory_Standards_and_Guidelines&Template=/CM/HTMLDisplay.cfm&ContentID=2511.
   American Medical Association. 2010. Family medical history in disease prevention. Available at http://www.ama‐assn.org/ama1/pub/upload/mm/464/family_history02.pdf.
   Association for Molecular Pathology. 2010a. FDA‐approved molecular diagnostics tests. http://www.ampweb.org/FDAtable/FDAtablenov04.htm.
   Association for Molecular Pathology. 2010b. CHAMP listserv. Available at: http://www.amp.org/Membership/champ.htm.
   Burke, W., Atkins, D., Gwinn, M., Guttmacher, A., Haddow, J., Lau, J., Palomaki, G., Press, N., Richards, C.S., Wideroff, L., and Wiesner, G.L., 2002. Genetic test evaluation: information needs of clinicians, policy makers, and the public. Am. J. Epidemiol. 156:311‐318.
   Centers for Disease Control and Prevention. 2009. Good laboratory practices for molecular genetic testing for heritable diseases and conditions. Morbidity and Mortality Weekly Report (MMWR) Recommendations and Reports Vol. 58, No. RR‐6. 1‐37. Available at http://www.cdc.gov/mmwr/pdf/rr/rr5806.pdf.
   Centers for Disease Control and Prevention. 2010a. Evaluation of Genomic Applications in Practice and Prevention (EGAPP): Implementation and Evaluation of a Model Approach. Available at: http://www.cdc.gov/genomics/gTesting.htm.
   Centers for Disease Control and Prevention. 2010b. Genetic Testing Reference Materials Coordination Program (GeT‐RM). Available at http://wwwn.cdc.gov/dls/genetics/rmmaterials/default.aspx.
   Centers for Disease Control and Prevention. 2010c. Newborn Screening Quality Assurance Program. Available at: http://www.cdc.gov/labstandards/nsqap.htm.
   Centers for Medicare and Medicaid Services and Centers for Disease Control and Prevention. 2003. 42 CFR Part 493 Medicare, Medicaid, and CLIA Programs; Laboratory Requirements Relating to Quality Systems and Certain Personnel Qualifications; Final Rule. Federal Register 68[16]:3640‐3714.
   Centers for Medicare and Medicaid Services. 2010a. Clinical Laboratory Improvement Amendments (CLIA). Available at: http://www.cms.hhs.gov/CLIA/.
   Centers for Medicare and Medicaid Services. 2010b. APPENDIX C, Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services. Available at: http://www.cms.hhs.gov/CLIA/03_Interpretive_Guidelines_for_Laboratories.asp#TopOfPage.
   Clinical and Laboratory Standards Institute (CLSI). 2006. Clinical Laboratory Technical Procedure Manuals (GP02‐A5).
   Clinical and Laboratory Standards Institute (CLSI). 2007a. Molecular Diagnostic Methods for Genetic Diseases (MM01A); Approved Guideline‐Second Edition.
   Clinical and Laboratory Standards Institute (CLSI). 2007b. Nucleic Acid Sequencing Methods in Diagnostic Laboratory Medicine (MM09A); Approved Guideline.
   Clinical and Laboratory Standards Institute (CLSI). 2008. Verification and Validation of Multiplex Nucleic Acid Assays (MM17A).
   Clinical and Laboratory Standards Institute. 2010. Establishing Molecular Testing in Clinical Laboratory Environments; Proposed Guideline (MM19‐P). Available at: http://www.clsi.org/Content/NavigationMenu/Committees/MolecularMethods/ProjectsinDevelopment/Projects_in_Developm.htm. 2010.
   College of American Pathologists (CAP). 2010a. http://www.cap.org/apps/cap.portal.
   College of American Pathologists (CAP). 2010b. 2010 surveys & anatomic pathology education programs.
   College of American Pathologists (CAP). CAP Registry Service for Genetic Testing. 2010c. Available at: http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=laboratory_resources%2FExchangeRegistry%2FexchRegistry.html&_state=maximized&_pageLabel=cntvwr.
   EuroGenTest. 2010. http://www.eurogentest.org/testor/cgi‐bin/OTmain.php.
   Food and Drug Administration. 2004. Class II Special Controls Guidance Document: Factor V Leiden DNA Mutation Detection Systems: Guidance for Industry and FDA Staff. Available at: http://www.fda.gov/cdrh/oivd/guidance/1236.html.
   Food and Drug Administration. 2005. CFTR Gene Mutation Detection Systems: Guidance for Industry and FDA Staff: Class II Special Controls Guidance Document. Available at: http://www.fda.gov/cdrh/oivd/guidance/1564.html.
   Food and Drug Administration. 2007a. Guidance for Industry and FDA Staff: Pharmacogenetic Tests and Genetic Tests for Heritable Markers. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfggp/Results.CFM?Doc_Type=1&Doc_IsCur=1&Doc_OFFICE=OIVD&lookandfeel=1&SORT_ORDER=origin,documentdate%20desc.
   Food and Drug Administration. 2007b. Guidance for Industry and FDA Staff Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions. Available at: http://www.fda.gov/cdrh/oivd/guidance/1590.html.
   Food and Drug Administration. 2007c. Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays. Available at: http://www.fda.gov/cdrh/oivd/guidance/1610.html.
   Food and Drug Administration. 2007d. FDA News. FDA Clears Breast Cancer Specific Molecular Prognostic Test. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01555.html.
   GeneTests. 2010. Medical genetics information resource [database online]. Available at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests.
   HIPAA. 1996. Health Insurance Portability and Accountability Act of 1996. PUBLIC LAW, 104‐191. Available at: http://aspe.hhs.gov/admnsimp/pl104191.htm.
   Hofgartner, W.T. and Tait, J.F. 1999. Characteristics of clinical molecular‐genetic testing laboratories in the United States. Clin. Chem. 45:1288‐1290.
   Holtzman, N.A. 1999. Promoting safe and effective genetic tests in the United States: Work of the task force on genetic testing. Clin. Chem. 45:732‐738.
   Hudson, K.L., Murphy, J.A., Kaufman, D.J., Javitt, G.H., Katsanis, S.H., and Scott, J., 2006. Oversight of US genetic testing laboratories. Nat. Biotechnol. 24:1083‐1090.
   Human Genome Variation Society. 2010. Available at http://www.hgvs.org/rec.html.
   Intermountain Healthcare. 2010. Cross‐country transmission of genetic test results. Available at: http://intermountainhealthcare.org/services/genetics/research/Pages/home2.aspx?NewsID=240.
   International Organization for Standardization. 2005. ISO/IEC 17025: General requirements for the competence of testing and calibration laboratories. International Organization for Standardization, Geneva, Switzerland.
   International Organization for Standardization. 2007. ISO 15189 Medical laboratories: Requirements for quality and competence.
   International Organization for Standardization. 2009. ISO 9001: Quality management systems: Requirements. International Organization for Standardization Geneva, Switzerland.
   Kroese, M., Zimmern, R.L., Farndon, P., Stewart, F., and Whittaker, J. 2007. How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network. Eur. J. Hum. Genet. 15:917‐921.
   Lubin, I.M., McGovern, M.M., Gibson, Z., Gross, S.J., Lyon, E., Pagon, R.A., Pratt, V.M., Rashid, J., Shaw, C., Stoddard, L., Trotter, T.L., Williams, M.S., Amos Wilson, J., and Pass, K. 2009. Clinician perspectives about molecular genetic testing for heritable conditions and development of a clinician‐friendly laboratory report. J. Mol. Diagn. 11:162‐171.
   McGovern, M.M., Benach, M., Wallenstein, S., Boone, J., and Lubin, I.M. 2003. Personnel standards and quality assurance practices of biochemical genetic testing laboratories in the United States. Arch. Pathol. Lab Med. 127:71‐76.
   McGovern, M.M., Benach, M.O., Wallenstein, S., Desnick, R.J., and Keenlyside, R. 1999. Quality assurance in molecular genetic testing laboratories. JAMA 281:835‐840.
   McGovern, M.M., Elles, R., Beretta, I., Somerville, M.J., Hoefler, G., Keinanen, M., Barton, D., Carson, N., Dequeker, E., Brdicka, R., Blazkova, A., Ayme, S., Schnieders, B., Muller, C.R., Dalen, V., Martinez, A.A., Kristoffersson, U., Ozguc, M., Mueller, H., Boone, J., Lubin, I.M., Sequeiros, J., Taruscio, D., Williamson, B., Mainland, L., Yoshikura, H., and Ronchi, E. 2007. Report of an international survey of molecular genetic testing laboratories. Community Genet. 10:123‐131.
   Moore, C.A., Khoury, M.J., and Bradley, L.A. 2005. From genetics to genomics: Using gene‐based medicine to prevent disease and promote health in children. Semin. Perinatol. 29:135‐143.
   National Institutes of Health. 2010. Collaboration, Education, and Test Translation (CETT) program. Available at: http://www.cettprogram.org.
   New Jersey State Department of Health and Senior Services. 2010. Clinical Laboratory Improvement Service. http://www.state.nj.us/health/phel/clis.shtml.
   New York State Department of Health. 2010. Clinical Laboratory Evaluation Program. http://www.wadsworth.org/labcert/clep/clep.html.
   Office of Management and Budget. 1997. Federal Register notice: revisions to the standards for the classification of federal data on race and ethnicity. Available at: http://www.whitehouse.gov/omb/fedreg/1997standards.html.
   Organisation for Economic Co‐operation and Development (OECD). 2007. OECD Guidelines for Quality Assurance in Molecular Genetic Testing. Available at: http://www.oecd.org/document/24/0,3343,en_2649_34537_1885208_1_1_1_1,00.html.
   Richards, C.S., Bale, S., Bellissimo, D.B., Das, S., Grody, W.W., Hegde, M.R., Madhuri, R., Lyon, E., and Ward, B.E. 2008. Molecular Subcommittee of the ACMG. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.Genet. Med. 10:294‐300.
   Secretary's Advisory Committee on Genetic Testing (SACGT). 2007. Enhancing the Oversight of Genetic Tests: Recommendations of the SACGT. Available at: http://www4.od.nih.gov/oba/sacgt.htm.
   Secretary's Advisory Committee on Genetics, Health, and Society. 2008. U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and Human Services. Available at: http://www4.od.nih.gov/oba/sacghs/reports/SACGHS_oversight_report.pdf.
   Washington State Office of Laboratory Quality Assurance (LQA). 2010. Available at: http://www.doh.wa.gov/hsqa/FSL/LQA_Home.htm.
   Yoon, P.W., Chen, B., Faucett, A., Clyne, M., Gwinn, M., Lubin, I.M., Burke, W., and Khoury, M.J. 2001. Public health impact of genetic tests at the end of the 20th century. Genet. Med. 3:405‐410.
   Zimmern, R.L. and Kroese, M., 2007. The evaluation of genetic tests. J. Public Health 29:246‐250.
Internet Resources
  21 CFR Part 809. In Vitro Diagnostic Products for Human Use. Revised as of April 1, 2008.
  21 CFR Part 820. Quality System Regulation. Revised as of April 1, 2008.
  42 CFR Part 493. The Clinical Laboratory Improvement Amendments (CLIA) Regulations. As amended.
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