AN EVIDENCE
FRAMEWORK FOR
GENETIC TESTING
Committee on the Evidence Base for Genetic Testing
Board on the Health of Select Populations
Board on Health Care Services
Health and Medicine Division
A Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by Contract No. HHSP233201400020B between the National Academy of Sciences and the Department of Defense. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-45329-5
International Standard Book Number-10: 0-309-45329-1
Digital Object Identifier: 10.17226/24632
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2017. An evidence framework for genetic testing. Washington, DC: The National Academies Press. doi: 10.17226/24632.
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COMMITTEE ON THE EVIDENCE BASE FOR GENETIC TESTING
ALFRED O. BERG (Chair), Professor and Chair Emeritus, Department of Family Medicine, University of Washington School of Medicine
JONATHAN S. BERG, Associate Professor, Department of Genetics, University of North Carolina at Chapel Hill
CHESTER W. BROWN, Professor and Division Chief of Genetics, Department of Pediatrics, University of Tennessee Health Science Center
WYLIE BURKE, Professor, Department of Bioethics and Humanities, University of Washington
BRUCE N. CALONGE, President and CEO, The Colorado Trust
WENDY K. CHUNG, Kennedy Family Associate Professor of Pediatrics and Medicine, Department of Pediatrics, Columbia University
THOMAS W. CLINE, Professor Emeritus, Department of Molecular and Cell Biology, University of California, Berkeley
SEAN P. DAVID, Associate Professor of Medicine, Division of Primary Care and Population Health, Stanford University School of Medicine
JUDY E. GARBER, Director, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School
ROBERT C. GREEN, Associate Professor of Medicine, Division of Genetics, Brigham and Women’s Hospital, Broad Institute and Harvard Medical School
JULIAN A. MARTINEZ-AGOSTO, Associate Professor, Department of Human Genetics, Division of Medical Genetics, David Geffen School of Medicine, University of California, Los Angeles
MARGARET A. PIPER, Senior Medical Research Analyst, Genetic Test Evaluation Program, Hayes, Inc.
NEIL J. RISCH, Lamond Family Foundation Distinguished Professor in Human Genetics and Director, Institute for Human Genetics, University of California, San Francisco
J. SANFORD SCHWARTZ, Leon Hess Professor of Medicine, Health Management and Economics, Perelman School of Medicine and Wharton School of Business, University of Pennsylvania
DAVID VALLE, Henry J. Knott Professor and Director, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
DAVID L. VEENSTRA, Professor, Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington
NANCY S. WEXLER, President, Hereditary Disease Foundation, and Higgins Professor of Neuropsychology, College of Physicians and Surgeons, Columbia University
Study Staff
CAROLYN FULCO, Scholar
CARY HAVER, Program Officer
SARAH BEACHY, Senior Program Officer
JOSEPH GOODMAN, Senior Project Assistant
Editor
NORMAN GROSSBLATT
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REVIEWERS
This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise. The purpose of the independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of the report:
Jose Fernandez, University of Alabama at Birmingham
Bruce Gelb, Icahn School of Medicine at Mount Sinai
Stephen Gruber, University of Southern California
Mehdi Hatamian, 2Pi-Sigma Corporation
Barbara A. Koenig, University of California, San Francisco
Edward R McCabe, March of Dimes Birth Defects Foundation
Hope Northrup, University of Texas Health Sciences Center
Susan P. Pauker, Harvard Medical School
Aleksander Rajkovic, Magee-Womens Research Institute
Stephen S. Rich, University of Virginia
Sean Tunis, Center for Medical Technology and Policy
Janet Williams, University of Iowa
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Harold C. Sox, Patient-Centered Outcomes Research Institute, and Maxine Hayes, University of Washington. They were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the authoring committee and the institution.
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CONTENTS
Ethical, Legal, and Social Implications
Overview of the Proposed Framework
Genetics and Medicine: A Brief Historical Perspective
Genomic Features and Genetic Variation
Genetic Variation and Health Outcomes
Additional Complexity of Monogenic Disorders
Methods for Evaluating Genetic Tests
Comparative Analysis of Evaluation Methods
Integration Between Genetic Test Assessment Methods and Relevant Outcomes
ACRONYMS AND ABBREVIATIONS
| ACA | Patient Protection and Affordable Care Act |
| ACCE | analytic validity, clinical validity, clinical utility, and associated ethical, legal, and social implications |
| ACMG | American College of Medical Genetics and Genomics |
| AHRQ | Agency for Healthcare Research and Quality |
| ASCO | American Society of Clinical Oncology |
| CAP | College of American Pathologists |
| CDC | Centers for Disease Control and Prevention |
| CED | coverage with evidence development |
| CFTR | cystic fibrosis transmembrane conductance regulator |
| CLIA | Clinical Laboratory Improvement Amendments |
| CMS | Centers for Medicare & Medicaid Services |
| CNV | copy number variant |
| CPG | Clinical Practice Guideline |
| CPIC | Clinical Pharmacogenetics Implementation Consortium |
| CU | clinical utility |
| CV | clinical validity |
| DHA | Defense Health Agency |
| DNA | deoxyribonucleic acid |
| DoD | Department of Defense |
| EGAPP | Evaluation of Genomic Applications in Practice and Prevention |
| ELSI | ethical, legal, and social implications |
| EPC | Evidence-Based Practice Center |
| EWG | EGAPP Working Group |
| FDA | Food and Drug Administration |
| GETT | Genetic testing Evidence Tracking Tool |
| GINA | Genetic Information Nondiscrimination Act |
| GRADE | Grading of Recommendations Assessment, Development and Evaluation |
| GTR | Genetic Testing Registry |
| LDT | laboratory-developed test |
| MAF | minor allele frequency |
| MHS | Military Health System |
| NBS | newborn screening |
| NF1 | neurofibromatosis, type 1 |
| NGC | National Guideline Clearinghouse |
| NGS | next-generation sequencing |
| NIH | National Institutes of Health |
| NSGC | National Society of Genetic Counselors |
| OMIM | Online Mendelian Inheritance in Man |
| PCORI | Patient-Centered Outcomes Research Institute |
| RCT | randomized controlled trial |
| RNA | ribonucleic acid |
| SNP | single nucleotide polymorphism |
| SNV | single nucleotide variant |
| USPSTF | US Preventive Services Task Force |
| VUS | variant of uncertain significance |
| WES | whole-exome sequencing |
| WGS | whole-genome sequencing |
