Nazneen Aziz, Qin Zhao, Lynn Bry, Denise K. Driscoll, Birgit Funke, Jane S. Gibson, Wayne W. Grody, Madhuri R. Hegde, Gerald A. Hoeltge, Debra G. B. Leonard, Jason D. Merker, Rakesh Nagarajan, Linda A. Palicki, Ryan S. Robetorye, Iris Schrijver, Karen E. Weck, and Karl V. Voelkerding (2014) College of American Pathologists' Laboratory Standards for Next-Generation Sequencing Clinical Tests. Archives of Pathology & Laboratory Medicine In-Press.

Early Online Release

College of American Pathologists' Laboratory Standards for Next-Generation Sequencing Clinical Tests

Nazneen Aziz, PhD; Qin Zhao, PhD; Lynn Bry, MD, PhD; Denise K. Driscoll, MS, MT(ASCP)SBB; Birgit Funke, PhD; Jane S. Gibson,PhD; Wayne W. Grody, MD; Madhuri R. Hegde, PhD; Gerald A. Hoeltge, MD; Debra G. B. Leonard, MD, PhD; Jason D. Merker, MD, PhD; Rakesh Nagarajan, MD, PhD; Linda A. Palicki, MT(ASCP); Ryan S. Robetorye, MD; Iris Schrijver, MD; Karen E. Weck, MD; Karl V. Voelkerding, MD

From Molecular Medicine (Dr Aziz), Laboratory Improvement Programs (Dr Zhao and Ms Palicki), and Laboratory Accreditation and Regulatory Affairs (Ms Driscoll), College of American Pathologists, Northfield, Illinois; the Department Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr Bry); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (Dr Funke); the Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando (Dr Gibson); the Divisions of Medical Genetics and Molecular Diagnostics, Department of Pathology & Laboratory Medicine, Pediatrics, and Human Genetics, UCLA School of Medicine, UCLA Institute for Society and Genetics, Molecular Diagnostic Laboratories and Clinical Genomics Center, UCLA Medical Center, Los Angeles, California (Dr Grody); the Department of Human Genetics, Emory University School of Medicine, Decatur, Georgia (Dr Hegde); Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio (Dr Hoeltge); the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Leonard); the Departments of Pathology (Drs Merker and Schrijver) and Pediarics (Dr Schrijver), Stanford University School of Medicine, Stanford, California; the Department of Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri (Dr Nagarajan); the Department of Laboratory Medicine & Pathology, Mayo Clinic in Arizona, Phoenix (Dr Robetorye); the Departments of Pathology & Laboratory Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill (Dr Weck); and ARUP Laboratories Institute for Clinical and Experimental Pathology, and Department of Pathology, University of Utah School of Medicine, Salt Lake City (Dr Voelkerding). Dr Aziz is now with Phoenix Children's Hospital, Phoenix.

Context.— The higher throughput and lower per-base cost of next-generation sequencing (NGS) as compared to Sanger sequencing has led to its rapid adoption in clinical testing. The number of laboratories offering NGS-based tests has also grown considerably in the past few years, despite the fact that specific Clinical Laboratory Improvement Amendments of 1988/College of American Pathologists (CAP) laboratory standards had not yet been developed to regulate this technology.

Objective.— To develop a checklist for clinical testing using NGS technology that sets standards for the analytic wet bench process and for bioinformatics or “dry bench” analyses. As NGS-based clinical tests are new to diagnostic testing and are of much greater complexity than traditional Sanger sequencing–based tests, there is an urgent need to develop new regulatory standards for laboratories offering these tests.

Design.— To develop the necessary regulatory framework for NGS and to facilitate appropriate adoption of this technology for clinical testing, CAP formed a committee in 2011, the NGS Work Group, to deliberate upon the contents to be included in the checklist.

Results.— A total of 18 laboratory accreditation checklist requirements for the analytic wet bench process and bioinformatics analysis processes have been included within CAP's molecular pathology checklist (MOL).

Conclusions.— This report describes the important issues considered by the CAP committee during the development of the new checklist requirements, which address documentation, validation, quality assurance, confirmatory testing, exception logs, monitoring of upgrades, variant interpretation and reporting, incidental findings, data storage, version traceability, and data transfer confidentiality.