VALIDATION OF TOXICOGENOMIC TECHNOLOGIES

A Workshop Summary

Committee on Validation of Toxicogenomic Technologies: A Focus on Chemical Classification Strategies

Committee on Emerging Issues and Data on Environmental Contaminants

Board on Environmental Studies and Toxicology

Board on Life Sciences

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Validation of Toxicogenomic Technologies: A Workshop Summary VALIDATION OF TOXICOGENOMIC TECHNOLOGIES A Workshop Summary Committee on Validation of Toxicogenomic Technologies: A Focus on Chemical Classification Strategies Committee on Emerging Issues and Data on Environmental Contaminants Board on Environmental Studies and Toxicology Board on Life Sciences Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C., www.nap.edu

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Validation of Toxicogenomic Technologies: A Workshop Summary THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW 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. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract No. G-NAG 9-1451 between the National Academy of Sciences and the National Aeronautics and Space Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-10413-5 International Standard Book Number-10: 0-309-10413-0 Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2007 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Validation of Toxicogenomic Technologies: A Workshop Summary THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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 Academy 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf 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 Institute 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 Sciences 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 Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Validation of Toxicogenomic Technologies: A Workshop Summary COMMITTEE ON VALIDATION OF TOXICOGENOMIC TECHNOLOGIES: A FOCUS ON CHEMICALCLASSIFICATION STRATEGIES Members JOHN QUACKENBUSH (Co-Chair), Harvard School of Public Health, Boston, MA KENNETH S. RAMOS (Co-Chair), University of Louisville, KY CYNTHIA A. AFSHARI, Amgen, Inc., Thousand Oaks, Louisville, CA LINDA E. GREER, Natural Resources Defense Council, Washington, DC CASIMIR A. KULIKOWSKI, Rutgers University, New Brunswick, NJ GEORGE ORPHANIDES, Syngenta Central Toxicology Laboratory, Cheshire, UK LAWRENCE M. SUNG, University of Maryland School of Law, Baltimore, MD RUSSELL D. WOLFINGER, SAS Institute Inc., Cary, NC Staff KARL E. GUSTAVSON, Project Director MARILEE K. SHELTON-DAVENPORT, Project Director JENNIFER E. SAUNDERS, Associate Program Officer RUTH E. CROSSGROVE, Senior Editor MIRSADA KARALIC-LONCAREVIC, Research Associate RADIAH A. ROSE, Senior Editorial Assistant LUCY V. FUSCO, Senior Project Assistant Sponsor NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

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Validation of Toxicogenomic Technologies: A Workshop Summary COMMITTEE ON EMERGING ISSUES AND DATA ON ENVIRONMENTAL CONTAMINANTS Members KENNETH S. RAMOS (Chair), University of Louisville, Louisville, KY PATRICIA A. BUFFLER, University of California, Berkeley JAMES S. BUS, Dow Chemical Company, Midland, MI GREGORY J. CARR, The Procter & Gamble Company, Cincinnati, OH JOSEPH J. DEGEORGE, Merck Research Laboratories, West Point, PA DAVID J. GALAS, Battelle Memorial Institute, Columbus, OH LINDA E. GREER, Natural Resources Defense Council, Washington, DC ROBERT J. GRIFFIN, Marquette University, Milwaukee, WI AMY D. KYLE, University of California, Berkeley PETER G. LORD, Johnson & Johnson, Raritan, NJ WILLIAM B. MATTES, Critical Path Institute, Poolesville, MD AUBREY MILUNSKY, Boston University School of Medicine, Boston, MA GILBERT S. OMENN, University of Michigan Medical School, Ann Arbor GEORGE ORPHANIDES, Syngenta Central Toxicology Laboratory, Cheshire, UK FREDERICA P. PERERA, Columbia University, New York, NY JOHN QUACKENBUSH, Harvard School of Public Health, Boston, MA MARK A. ROTHSTEIN, University of Louisville School of Medicine, Louisville, KY LEONA D. SAMSON, Massachusetts Institute of Technology, Cambridge MARTHA S. SANDY, California Environmental Protection Agency, Oakland TODD SHERER, Emory University, Atlanta, GA PETER S. SPENCER, Oregon Health and Science University, Portland LAWRENCE M. SUNG, University of Maryland, Baltimore MAHLET G. TADESSE, University of Pennsylvania School of Medicine, Philadelphia CHERYL L. WALKER, University of Texas, Smithville Staff KARL E. GUSTAVSON, Project Director MARILEE K. SHELTON-DAVENPORT, Project Director JENNIFER E. SAUNDERS, Associate Program Officer RUTH E. CROSSGROVE, Senior Editor RADIAH A. ROSE, Senior Editorial Assistant LUCY V. FUSCO, Senior Project Assistant

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Validation of Toxicogenomic Technologies: A Workshop Summary BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members JONATHAN M. SAMET (Chair), Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX JOHN M. BALBUS, Environmental Defense, Washington, DC DALLAS BURTRAW, Resources for the Future, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC MARY R. ENGLISH, University of Tennessee, Knoxville J. PAUL GILMAN, Oak Ridge Center for Advanced Studies, Oak Ridge, TN SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA WILLIAM P. HORN, Birch, Horton, Bittner and Cherot, Washington, DC JAMES H. JOHNSON, JR., Howard University, Washington, DC WILLIAM M. LEWIS, JR., University of Colorado, Boulder JUDITH L. MEYER, University of Georgia, Athens DENNIS D. MURPHY, University of Nevada, Reno PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON (retired), Chicago, IL DANNY D. REIBLE, University of Texas, Austin JOSEPH V. RODRICKS, ENVIRON International Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta ROBERT F. SAWYER, University of California, Berkeley LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Massachusetts Institute of Technology, Cambridge MONICA G. TURNER, University of Wisconsin, Madison MARK J. UTELL, University of Rochester Medical Center, Rochester, NY CHRIS G. WHIPPLE, ENVIRON International Corporation, Emeryville, CA LAUREN ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering KULBIR BAKSHI, Senior Program Officer for Toxicology EILEEN N. ABT, Senior Program Officer for Risk Analysis KARL E. GUSTAVSON, Senior Program Officer K. JOHN HOLMES, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer STEVEN K. GIBB, Program Officer for Strategic Communications RUTH E. CROSSGROVE, Senior Editor

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Validation of Toxicogenomic Technologies: A Workshop Summary BOARD ON LIFE SCIENCES Members KEITH YAMAMOTO (Chair), University of California, San Francisco ANN M. ARVIN, Stanford University School of Medicine, Stanford, CA JEFFREY L. BENNETZEN, University of Georgia, Athens RUTH BERKELMAN, Emory University, Atlanta, GA DEBORAH BLUM, University of Wisconsin, Madison R. ALTA CHARO, University of Wisconsin, Madison JEFFREY L. DANGL, University of North Carolina, Chapel Hill PAUL R. EHRLICH, Stanford University, Stanford, CA MARK D. FITZSIMMONS, John D. and Catherine T. MacArthur Foundation, Chicago, IL JO HANDELSMAN, University of Wisconsin, Madison ED HARLOW, Harvard Medical School, Boston, MA KENNETH H. KELLER, University of Minnesota, Minneapolis RANDALL MURCH, Virginia Polytechnic Institute and State University, Alexandria GREGORY A. PETSKO, Brandeis University, Waltham, MA MURIEL E. POSTON, Skidmore College, Saratoga Springs, NY JAMES REICHMAN, University of California, Santa Barbara MARC T. TESSIER-LAVIGNE, Genentech, Inc., San Francisco, CA JAMES TIEDJE, Michigan State University, East Lansing TERRY L. YATES, University of New Mexico, Albuquerque Senior Staff FRANCES E. SHARPLES, Director KERRY A. BRENNER, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer EVONNE P.Y. TANG, Senior Program Officer ROBERT T. YUAN, Senior Program Officer ADAM P. FAGEN, Program Officer ANN H. REID, Senior Program Officer ANNA FARRAR, Financial Associate ANNE F. JURKOWSKI, Senior Program Assistant TOVA G. JACOBOVITS, Senior Program Assistant

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Validation of Toxicogenomic Technologies: A Workshop Summary PREFACE Toxicogenomics has been described as a discipline combining expertise in toxicology, genetics, molecular biology, and environmental health to elucidate the response of living organisms to stressful environments. It includes the study of how genomes respond to toxicant exposures and how genotype affects responses to toxicant exposures. As the technologies for monitoring these responses rapidly develop, it is critical that scientists and regulators are confident that the technologies are reliable and reproducible and that the data analyses have been validated. To discuss these issues in a public forum, the Committee on the Validation of Toxicogenomic Technologies designed a workshop to consider the current practice and advances in the validation of toxicogenomic technologies. The workshop focused on the technical aspects of validation, recognizing it as a prerequisite for considering other important issues, such as biological validation (e.g., validating the use of microarray “signatures” to describe a toxic effect). This workshop summary has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s (NRC) 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 workshop summary as sound as possible and to ensure that the summary 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 wish to thank the following people for their review of this workshop summary: Federico Goodsaid, William Mattes, Gavin Sherlock, and Mahlet Tadesse. Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of the workshop summary was overseen by Timothy R. Zacharewski, of Michigan State University. Appointed by the NRC, he was responsible for making certain that an independent examination of the workshop summary was carried out in accordance with institutional procedures and that all review com-

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Validation of Toxicogenomic Technologies: A Workshop Summary ments were carefully considered. Responsibility for the final content of the workshop summary rests entirely with the committee and the institution. The committee gratefully acknowledges the following for making presentations at the workshop: Kevin K. Dobbin, National Cancer Institute; Hisham K. Hamadeh, Amgen, Inc.; Wherly P. Hoffman, Eli Lily & Company; Rafael A. Irizarry, Johns Hopkins University Bloomberg School of Public Health; Kyle L. Kolaja, Iconix Pharmaceuticals; Leonard M. Schechtman, Food and Drug Administration; Guido Steiner, F. Hoffmann-La Roche AG; and Weida Tong, FDA National Center for Toxicological Research. The committee is grateful for the assistance of the NRC staff in preparing this workshop summary: Karl Gustavson and Marilee Shelton-Davenport, program directors; James Reisa, director of the Board on Environmental Studies and Toxicology; Fran Sharples, director of the Board on Life Sciences; Jennifer Saunders, associate program officer; Ruth Crossgrove, senior editor; Mirsada Karalic-Loncarevic, research associate; Radiah Rose, senior editorial assistant; and Lucy Fusco, program associate. Finally, we thank the members of the committee for their dedicated efforts throughout the development of this workshop summary. John Quackenbush Kenneth S. Ramos Co-Chairs, Committee on Validation of Toxicogenomic Technologies

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Validation of Toxicogenomic Technologies: A Workshop Summary CONTENTS SUMMARY OF THE WORKSHOP         Introduction   1     Workshop Summary   3     References   34 ATTACHMENTS     1   Experimental Objectives of DNA Microarray Studies by Kevin K. Dobbin   41 2   Comparison of Microarray Data from Multiple Labs and Platforms by Rafael Irizarry   49 3   Statistical Analysis of Toxicogenomic Microarray Data by Wherly Hoffman and Hui-Rong Qian   58 4   Diagnostic Classifier—Gaining Confidence Through Validation by Weida Tong   66 APPENDIXES     A Workshop Planning Committee Biographical Information   75 B Workshop Agenda   79 C Federal Liaison Group for the NRC Committee on Emerging Issues and Data on Environmental Contaminants   82

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Validation of Toxicogenomic Technologies: A Workshop Summary VALIDATION OF TEXICOGENOMIC TECHNOLOGIES A Workshop Summary

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