THE VALUE OF GENETIC AND GENOMIC TECHNOLOGIES

WORKSHOP SUMMARY

Theresa Wizemann and Adam C. Berger, Rapporteurs

Roundtable on Translating Genomic-Based Research for Health

Board on Health Sciences Policy

INSTITUTE OF MEDICINE
OF THE ACADEMIES PRESS

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
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The Value of GeneTic and Genomic TechnoloGies Workshop summary Theresa Wizemann and Adam C. Berger, Rapporteurs Roundtable on Translating Genomic-Based Research for Health Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This project was supported by contracts between the National Academy of Sciences and the American College of Medical Genetics (unnumbered contract); American Medical Association (unnumbered contract); American Nurses Association (unnumbered contract); Blue Cross and Blue Shield Association (unnumbered contract); Centers for Disease Control and Prevention (Contract No. 200-2005-13434); College of American Pathologists (unnumbered contract); Department of Veterans Affairs (Contract No. V101(93) P-2238); Eli Lilly and Company (Contract No. LRL-0028-07); Genetic Alliance (unnumbered contract); Genomic Health, Inc. (unnumbered contract); Health Resources and Services Administration; Johnson & Johnson (unnumbered contract); Kaiser Permanente (unnumbered contract); National Cancer Institute (Contract No. N01-OD-4-2139, TO#189); National Heart, Lung, and Blood Institute (Con- tract No. N01-OD-4-2139, TO#189); National Human Genome Research Institute (Contract No. N01-OD-4-2139, TO#189); National Institute of Child Health and Human Development (Contract No. N01-OD-4-2139, TO#189); National Society of Genetic Counselors (unnum- bered contract); Pfizer Inc. (Contract No. 140-N-1818071); and the Secretary’s Advisory Committee on Genetics, Health, and Society (Contract No. N01-OD-4-2139, TO#189). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-15771-1 International Standard Book Number-10: 0-309-15771-4 Additional copies of this report are available from The National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2010 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2010. The value of genetic and genomic technologies: Workshop summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE* BRUCE BLUMBERG, Co-Chief of Medical Genetics, Kaiser Permanente, and Institutional Director of Graduate Medical Education, Northern California Kaiser Permanente, The Permanente Medical Group, Oakland, CA DENISE E. BONDS, Medical Officer, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD RALPH J. COATES, Associate Director for Science, Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA SHARON KARDIA, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Co-Director, Center for Genomics & Public Health, University of Michigan School of Public Health, Ann Arbor MUIN KHOURy, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA MICHELE LLOyD-PURyEAR, Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD CATHERINE A. WICKLUND, Past President, National Society of Genetic Counselors; Director, Graduate Program in Genetic Counseling; Assistant Professor, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL MARC S. WILLIAMS, Director, Clinical Genetics Institute, Intermountain Health Care, Inc., Salt Lake City, UT IOM Staff ADAM C. BERGER, Project Director ERIN HAMMERS, Research Associate ALEx REPACE, Senior Project Assistant * Institute of Medicine (IOM) planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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ROUNDTABLE ON TRANSLATING GENOMIC-BASED RESEARCH FOR HEALTH* WyLIE BURKE (Chair), Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle BRUCE BLUMBERG, Co-Chief of Medical Genetics, Kaiser Permanente, and Institutional Director of Graduate Medical Education, Northern California Kaiser Permanente, The Permanente Medical Group, Oakland, CA DENISE E. BONDS, Medical Officer, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD C. THOMAS CASKEy, Director and Chief Executive Officer, The George & Cynthia Mitchell Distinguished Chair in Neurosciences, Executive Vice President of Molecular Medicine and Genetics, University of Texas Health Science Center at Houston STEPHEN ECK, Vice President, Translational Medicine & Pharmacogenomics, Eli Lilly and Company, Indianapolis, IN ANDREW N. FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD GEOFFREy GINSBURG, Director, Center for Genomic Medicine, Institute for Genomic Sciences & Policy, Duke University, Durham, NC R. RODNEy HOWELL, Special Assistant to the Director, National Institute of Child Health and Human Development, Bethesda, MD SHARON KARDIA, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Co-Director, Center for Genomics & Public Health, University of Michigan School of Public Health, Ann Arbor MOHAMED KHAN, American Medical Association; Associate Director of Translational Research, Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY MUIN KHOURy, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA ALLAN KORN, Chief Medical Officer, Senior Vice President, Clinical Affairs, Blue Cross and Blue Shield Association, Chicago, IL * Institute of Medicine Forums and Roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vi

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DEBRA LEONARD, College of American Pathologists; Professor and Vice Chair for Laboratory Medicine, Director of the Clinical Laboratories, Weill Cornell Medical Center of Cornell University, New York, NY MICHELE LLOyD-PURyEAR, Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD ELIZABETH MANSFIELD, Director of Personalized Medicine, Food and Drug Administration, Silver Spring, MD GARRy NEIL, Corporate Vice President, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ ROBERT L. NUSSBAUM, Chief, Division of Medical Genetics, Department of Medicine and Institute of Human Genetics, University of California–San Francisco School of Medicine KIMBERLy POPOVITS, President and Chief Executive Officer, Genomic Health, Inc., Redwood City, CA AIDAN POWER, Vice President and Global Head of Molecular Medicine, Pfizer Inc., New London, CT RONALD PRZyGODZKI, Associate Director for Genomic Medicine, Biomedical Laboratory Research and Development, Department of Veterans Affairs, Washington, DC AMELIE G. RAMIREZ, Dielmann Chair, Health Disparities and Community Outreach Research; Director, Institute for Health Promotion Research, University of Texas Health Science Center at San Antonio LAURA LyMAN RODRIGUEZ, Senior Advisor to the Director for Research Policy, National Human Genome Research Institute, Bethesda, MD ALLEN D. ROSES, Jefferson-Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology); Director, Deane Drug Discovery Institute; Senior Scholar, Fuqua School of Business, R. David Thomas Executive Training Center, Duke University, Durham, NC KEVIN A. SCHULMAN, Professor of Medicine and Business Administration; Director, Center for Clinical and Genetic Economics; Associate Director, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC SHARON TERRy, President and Chief Executive Officer, Genetic Alliance, Washington, DC STEVEN TEUTSCH, Chair, Secretary’s Advisory Committee on Genetics, Health and Society; Chief Science Officer, Los Angeles County Department of Public Health, Los Angeles, CA MARTHA TURNER, Assistant Director, American Nurses Association Center for Ethics and Human Rights, Silver Spring, MD vii

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MICHAEL S. WATSON, Executive Director, American College of Medical Genetics, Bethesda, MD CATHERINE A. WICKLUND, Past President, National Society of Genetic Counselors; Director, Graduate Program in Genetic Counseling; Assistant Professor, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL IOM Staff ADAM C. BERGER, Project Director ERIN HAMMERS, Research Associate ALEx REPACE, Senior Project Assistant ANDREW POPE, Director, Board on Health Sciences Policy viii

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this 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 for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: Felix W. Frueh, Vice President, R&D Personalized Medicine Medco Health Solutions Inc, Bethesda, MD J. Jay Gargus, Professor of Pediatrics, Human Genetics Division & Metabolism, Professor of Physiology & Biophysics, University of California, Irvine Eric J. Topol, Director, Scripps Translational Science Institute, The Gary and Mary West Chair of Innovative Medicine; Chief Academic Officer, Scripps Health, La Jolla, CA Marc S. Williams, Director, Clinical Genetics Institute, Intermountain Health Care, Inc., Salt Lake City, UT Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not endorse the final draft of the ix

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x REVIEWERS report before its release. The review of this report was overseen by Elena O. Nightingale, Scholar-In-Residence, Institute of Medicine, Washington, DC. Appointed by the Institute of Medicine, she was responsible for mak- ing certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authors and the institution.

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Acknowledgments The support of the sponsors of the Institute of Medicine Roundtable on Translating Genomic-Based Research for Health was crucial to the plan- ning and conduct of the workshop, The Value of Genetic and Genomic Technologies. Federal sponsors are the Centers for Disease Control and Prevention; Health Resources and Services Administration; National Can- cer Institute; National Heart, Lung, and Blood Institute; National Institute for Child Health and Human Development; National Human Genome Research Institute; the Secretary’s Advisory Committee on Genetics, Health, and Society; and the Department of Veterans Affairs. Non-federal spon- sorship was provided by the American College of Medical Genetics, the American Medical Association, the American Nurses Association, Blue Cross and Blue Shield Association, the College of American Pathologists, Eli Lilly and Company, Genetic Alliance, Genomic Health, Inc., Johnson & Johnson, Kaiser Permanente, the National Society of Genetic Counselors, and Pfizer Inc. The Roundtable wishes to express its gratitude to the expert speakers whose presentations examined the value that genomic and genetic technolo- gies play in existing clinical practice. These speakers were Bruce Blumberg, Marc Boguski, Wylie Burke, Roy Gandolfi, Anna Garrett, Karen Kaplan, Arthur Lurvey, Don Lyman, Elizabeth Mansfield, Dennis Salisbury, Andrew Spiegel, Vance Vanier, David Veenstra, Catherine Wicklund, Janet Williams, Marc S. Williams, David Witt, and Steven Woolf. xi

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xii ACKNOWLEDGMENTS The Roundtable also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. Planning committee members were Bruce Blumberg, Denise Bonds, Ralph Coates, Sharon Kardia, Muin Khoury, Michele Lloyd-Puryear, Catherine Wicklund, and Marc S. Williams. Thanks also go to Marc S. Williams for moderating the entire workshop.

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Contents ABBREVIATIONS AND ACRONyMS xv 1 INTRODUCTION 1 2 TUMOR-BASED SCREENING FOR LyNCH SyNDROME 5 Colorectal Cancer and Lynch Syndrome Screening, 5 Panel Reaction, 8 Open Discussion, 13 3 PHARMACOGENOMIC TESTING TO GUIDE WARFARIN DOSING 19 Warfarin Pharmacogenomics, 19 Panel Reaction, 23 Open Discussion, 30 4 GENOMIC PROFILING 35 Genomic Screening for Health Risk Assessment, 35 Panel Reaction, 37 Open Discussion, 46 5 CLOSING REMARKS 49 Research Systems, 49 How Much Data Are Enough?, 50 xiii

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xiv CONTENTS Personal Versus Clinical Utility, 51 Roundtable Activities, 52 Chair’s Summary, 53 REFERENCES 55 APPENDIxES A WORKSHOP AGENDA 57 B SPEAKER BIOGRAPHICAL SKETCHES 61 C LYNCH SYNDROME TOPIC BRIEF 71 D WARFARIN TOPIC BRIEF 77 E GENOMIC PROFILING TOPIC BRIEF 83 BOxES 1-1 Definitions, 2 4-1 Definitions, 36

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Abbreviations and Acronyms ACMG American College of Medical Genetics CLIA Clinical Laboratory Improvement Amendments CMS Centers for Medicare and Medicaid Services COAG Clarification of Optimal Anticoagulation Through Genetics DRG diagnosis-related group EGAPP Evaluation of Genomic Applications in Practice and Prevention FDA U.S. Food and Drug Administration FDAAA U.S. Food and Drug Administration Amendments Act FISH Fluorescence In Situ Hybridization GAPPNet Genomics Applications in Practice and Prevention Network GINA Genetic Information Nondiscrimination Act of 2008 GWAS genome-wide association study HMS Harvard Medical School HNPCC hereditary non-polyposis colorectal cancer IHC immunohistochemistry INR International Normalized Ratio IWPC International Warfarin Pharmacogenetics Consortium xv

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