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

ACRONYMS AND ABBREVIATIONS

SUMMARY

Statement of Task

Approach to the Task

Uses of Genetic Testing

Ethical, Legal, and Social Implications

Assessment of Genetic Tests

Evidence

Research Recommendation

Overview of the Proposed Framework

Framework Recommendation

1 INTRODUCTION

Genetics and Medicine: A Brief Historical Perspective

Statement of Task

Approach to the Task

Organization of the Report

2 GENETIC TESTING

Genomic Features and Genetic Variation

Genetic Variation and Health Outcomes

Additional Complexity of Monogenic Disorders

Genetic Tests

3 GENETIC TEST ASSESSMENT

Evaluating Genetic Tests

Methods for Evaluating Genetic Tests

Comparative Analysis of Evaluation Methods

Integration Between Genetic Test Assessment Methods and Relevant Outcomes

Summary

4 EVIDENCE

Analytic Validity

Clinical Validity

Clinical Utility

Evaluation of Evidence on Genetic Tests

Recommendation

5 AN EVIDENCE FRAMEWORK FOR GENETIC TESTING

Overview of the Proposed Framework

Recommendation

APPENDIXES

A UNDERSTANDING GENETIC VARIANCE AND PHENOTYPE EXPRESSION

B THE GETT CHECKLIST

C USING EVIDENCE TO INFORM CLINICAL AND POLICY DECISIONS

REFERENCES

GLOSSARY

ACRONYMS AND ABBREVIATIONS