Genomic and Personalized Medicine. Volumes I & II

1480 Pages·2009·80 MB·English

by  Ph.D., Huntington F. Willard, and Geoffrey S. Ginsburg, M.D., Ph.D. (Eds.)

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A cknowledgements
We wish to express our appreciation and gratitude to our We acknowledge our Advisory Board for their suggestions
many colleagues, especially in the Duke Institute for Genome and support and especially thank the nearly 300 authors of the
Sciences & Policy, who have shared their knowledge and ideas 112 chapters that comprise these volumes. Needless to say, with-
about genomic and personalized medicine and who, by doing out their efforts, this project could never have come to fruition.
so, inspired this project. We particularly thank our fi rst edi- We also thank Secretary Mike Leavitt for providing a Foreword
tor at Academic Press/Elsevier, Luna Han, who encouraged us for this book, as well as for his enthusiastic support of the con-
to develop the concept of a text on genomic and personalized cept of genomic and personalized medicine.
medicine. We are also grateful to Sally Cheney, Kirsten Funk, It gives us pleasure to give special thanks to Kathy Hay and
and Christine Minihane, our Senior Editors at Academic Press/ to Lynne Skinner, whose tireless efforts kept us on track and saw
Elsevier; to Rogue Shindler, our Developmental Editor; and this project through to completion. Lastly, we thank our fam-
to Ganesan Murugesan, our Production Project Manager, for ilies for their patience and understanding for the many hours
their patience, advice, and professionalism in all stages of the we spent creating this, the inaugural edition of Genomic and
project. Personalized Medicine.
xxix
A dvisory Board
P aul R. Billings President and Chief Executive Offi cer, R aju Kucherlapati Center for Genetics and Genomics,
CELLPOINT DIAGNOSTICS, 265 N. Whisman Road, Harvard Medical School, 77 Avenue Louis Pasteur, Ste 250,
Mountain View, CA 94043 Boston, MA 02115
Robert Cook-Deegan Center for Genome Ethics, Law & E lizabeth G. Nabel National Heart, Lung and Blood
Policy, Duke Institute for Genome Sciences and Policy, Box Institute, 31 Center Drive MSC 2486, Building 31, Room
90141, Durham, NC 27708 5A52, Bethesda, MD 20892
K ay E. Davies Department of Human Anatomy and Genetics, R obert L. Strausberg Human Genomic Medicine, J. Craig
Oxford University, South Parks Road, Oxford, QX1 3QX, UK Venter Institute, 9704 Medical Center Drive, Rockville, MD
20850
B rian Druker Department of Medicine, Oregon Health &
Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Robert I. Tepper Third Rock Ventures, LLC, 29 Newbury
Oregon 97239 St., Boston, MA 02116
V ictor Dzau Offi ce of the Chancellor, Duke University J anet A. Warrington External RNA Controls Consortium,
Health System, Box 3701, Durham, NC 27710 Affymetrix, 3380 Central Expressway, Santa Clara, CA 95051
E ric Green National Institutes of Health, National Human R alph Weissleder Molecular Imaging Research Center,
Genome Research Institute, 50 South Drive, Room 5222, Massachusetts General Hospital, 149 13th Street, Room 5406,
Bethesda, MD 20892-8002 Charlestown MA 02129
J anet Woodcock Food and Drug Administration, 5600
M uin J. Khoury Offi ce of Genomics & Disease Prevention,
Fishers Lane, Parklawn Buildling, Rm 14-71, Rockville, MD
Centers for Disease Control and Prevention, 1600 Clifton Road,
20857
Atlanta, GA 30333
M ary-Claire King University of Washington, 1705 Northeast
Pacifi c Street, Box 357720, Seattle, WA 98195-7720
xxxix
F oreword
In the health care fi eld today, there are high expectations for a The shift will require development of new capacities that
paradigm shift in care delivery over the coming years. According will enable us to differentiate among the needs of individual
to this view, we have the opportunity to achieve fundamental patients. In turn, these new capacities will depend on data to be
change and improvement in the delivery of care, with better derived, analyzed, and employed on a new scale. Such informa-
health outcomes across the board, led by advances in genomics tion demands will surely need to be supported by sophisticated
and molecular medicine. electronic data networks that are yet to be created, informatics
The prospect is exciting: a continuum of health mainte- tools that are yet to be invented, and clinical decision-support sys-
nance and medical care that is truly tailored to the individual, tems that are yet to be devised or adopted. Finally, at the bedrock,
based on his or her individual biology. We could know our own the trust and understanding of the medical community and of
genetic profi les from birth. Prevention could be more individu- society at large must be won even as the edifi ce is being created.
ally charted, based on individual genetic factors. Disease could This is the work of a generation. It is work that spans profes-
be detected and treated earlier through molecular diagnostics. sions, economic sectors, and even nations. It is driven by science –
Health care dollars might be spent to much better effect. And but it makes new demands for the rapid translation of scientifi c
our lives could be healthier, longer. discovery into clinical practice and improved health outcomes.
The stepping stones to such a future are now widely One part of the work before us is continued discovery.
known. Building on the work of the Human Genome Project Phenomenal achievements have been made in mapping the
and its offspring, medical care can be expected to acquire pow- human genome, and a rush of fi ndings is occurring today in
erful new tools, especially in diagnosis, that could render care understanding associations between genomic factors and health.
much more effective by making it more precise, more individu- Yet vast areas still remain to be explored. That work is underway
ally targeted, and more predictive. on a global scale.
We should be able to prescribe drugs more safely because Another part of our work might be called the engineering.
genetic or other characteristics would help clinicians identify This includes the development of interoperable health informa-
which patients would respond well to a given therapy. As dis- tion technology, with all the implications of that goal: develop-
eases come to be understood at a new level, we should be better ment of technical and clinical standards, adoption of health IT
able to achieve the right diagnosis and the right treatment for across the health sector, and security of personal health informa-
each person, without the trial-and-error process that has long tion. In the long term, it should also include the use of health
characterized medical treatment. As biomarkers are identifi ed, IT to enable us to make faster progress in medical research –
we should be able to intervene in disease at much earlier stages. and then to feed back what we’ve learned into clinical practice,
And when we are able to know our personal genomic profi les, using IT decision-support tools that are physician-, nurse-, and
we should be able to better pinpoint our individual health sus- consumer-friendly.
ceptibilities. Our physicians could give more individualized pre- Another element of our task is less defi ned but equally chal-
vention advice – and perhaps it will even come to pass that we lenging: the collaboration and cooperation needed to bring this
will be more motivated to follow it. vision to reality. Personalized medicine means care that is infor-
I am a believer in this view of the possible future – and I mation-based at a new level. Gathering that information and
am confi dent it is not just wishful thinking. The pace of discov- using it successfully will transcend many disciplines and make
ery in the genomic fi eld today is unprecedented. Furthermore, new demands on a health system that is often characterized as
enough successful applications of this paradigm already exist “ f ractured.” It may seem ironic that delivery of individualized
to give us reason to look toward a new era of effectiveness in care depends on standardization, partnerships, and networks. But
medical care, with new information and new tools for both the these kinds of collaboration are among the most important ele-
clinician and the consumer. ment of the work that lies ahead.
At the same time, we must be realistic in our assessment of Finally, in today’s health care environment, the success of
this future, especially the extent of the efforts that will be needed new products, services, and models of care will depend more
to achieve it. However desirable the idea of this “paradigm shift” than ever on the value that is delivered. At its core, personalized
may be, the realization of such a shift rests on a foundation that medicine is about care that can achieve new levels in predicting,
is still very much under construction. preventing, and detecting disease. Medical effectiveness of this
xxv
xxvi ■ Foreword
kind should translate into cost effectiveness as well. Achieving contributors to this text help us appreciate the breadth of these
and demonstrating high value expectations will be challenging, issues, challenges, debates, and opportunities that lie ahead.
but this discipline will serve the success of personalized medi-
cine over the long term.
The paradigm shift of personalized medicine depends on an M ichael O. Leavitt
extensive foundation of scientifi c knowledge, professional leader- Secretary
ship, health information technology, and a spirit of cooperation, Department of Health and Human Services
collaboration, and dialogue. The many perspectives offered by the Washington, DC
P reface
It seems just yesterday that we were fi rst getting used to the mechanism and the role that genetic and genomic factors
notion of introducing the seemingly freshly uncovered con- play in the individual response to drugs.
cepts of genetics into the practice of medicine. And yet, with
This revolution in genomic and personalized medicine was
the completion of the Human Genome Project and the rapid
anticipated nearly three decades ago by Nobel laureate Paul
development and application of new advances in our ability to
Berg, who stated so presciently:
understand and query the human genome and its gene set, it is
time already to anticipate and outline the early stages of what J ust as our present knowledge and practice of medicine
must be called a transformation of medicine. We are beginning relies on a sophisticated knowledge of human anatomy,
to see the fi rst signs of a fundamental shift in how we behold physiology, and biochemistry, so will dealing with dis-
human physiology and pathology, how we view the concept of ease in the future demand a detailed understanding of the
what is “ normal,” how we consider individuals and their pros- molecular anatomy, physiology, and biochemistry of the
pects for lifelong health, and how we design healthcare systems human genome. . . . We shall need a more detailed knowl-
that are equally adaptable to the demands of population-wide edge of how human genes are organized and how they
epidemics and the opportunities for personalized care that uti- function and are regulated. We shall also have to have phy-
lizes genome-based information to consider individual suscepti- sicians who are as conversant with the molecular anatomy
bility to disease and therapeutic options. and physiology of chromosomes and genes as the cardiac
Genome-based data, information, knowledge, and eventu- surgeon is with the structure and workings of the heart.
ally wisdom will make possible the kind of healthcare that has
That time has come. This book is intended to lay out the
been dreamed of since the advent of disease-based medicine
foundations of this new science, to outline the early opportuni-
early in the 20th century. A system of healthcare that harnesses
ties for the practice of medicine to incorporate genome-based
the might of the genome and its derivatives, along with imaging,
analysis into healthcare, and to anticipate the many conditions
clinical and environmental information, will empower physi-
to which genomic and personalized medicine will apply in the
cians and other healthcare providers to do what they have always
years ahead. The chapters in these volumes are designed to be
aspired to do – make medical care as individualized as possible.
read either sequentially – introducing the scientifi c underpin-
But this newfound information and knowledge will also allow
nings of this revolution, exploring aspects of translational medi-
each of us as consumers of healthcare to take more control of
cine and genomics that will be critical for bringing about this
our futures and to develop a more strategic and a prospective
revolution, and presenting practical aspects of the fi rst applica-
approach to health. We stand at the dawn of a profound change
tions of genomic and personalized medicine in the context of
in science and medicine’s predictive nature and in our under-
specifi c medical conditions – or one-at-a-time for those inter-
standing of the biological underpinnings of health and disease.
ested in particular disorders or approaches.
Even in this early light, we can see the outlines of a coming
These volumes also describe a fi eld in its infancy, with
ability to:
many challenges for society at large, in addition to those associ-
● p redict individual susceptibility to disease, based on genetic, ated with healthcare systems strife with ineffi ciencies and het-
genomic and other factors; erogeneity in their ability to deliver the basics of healthcare .
● p rovide more useful tools and individualized programs There are “grand challenges” for the visionary science and the
for disease prevention, based on knowledge of one’s clinical care highlighted in these pages. Such challenges include
susceptibility; the potential for these innovations to exaggerate existing health
● d etect the onset of disease earlier and before it is clinically disparities, information technology systems that have been
evident, based on newly discovered biological markers that described as a “tower of Babel,” an unprepared healthcare work
arise from changes at the molecular level; force, and economic incentives that are inadequately aligned for
● p reempt disease progression, as a result of early detection; the various stakeholders to fully embrace genomic and personal-
● t arget medicines and their dose more precisely and safely to ized medicine. Nonetheless, we are optimistic that the appropri-
each patient, on the basis of a deep understanding of disease ate delivery models and economic incentives will be developed
xxvii
xxviii ■ Preface
in a trustworthy framework that will be embraced by societies Our intended audience is broad, ranging from medical stu-
around the globe. dents (and even the intrepid undergraduate eager to explore this
As an indicator of the importance of personalized medicine, new era of personalized and prospective medicine) to residents
international communities are working together on strategies to and fellows to practitioners in any of the healthcare professions –
overcome these obstacles. In the United States, the Department physicians in any of the medical specialties, surgeons, nurses,
of Health and Human Services has played a leadership role genetic (and genomic) counselors, and laboratory directors –
in this area and a plan was published in 2007 (P ersonalized and, fi nally, to members of the genomic and personalized
Healthcare: Opportunities, Pathways, Resources; see http://www. medicine research communities who will, we trust, help write
hhs.gov/myhealthcare/) . Other governments (in the United future editions of this text.
Kingdom, Iceland, Estonia, Luxembourg, and Singapore – to In times of transformation, we are all students. We hope
name just a few) have funded initiatives that will secure their that this book will help usher in this new era of genomic and
place in developing genome-based knowledge and its translation personalized medicine and will provide a useful and thorough
into day-to-day patient care. A collective and global approach to introduction to the science and practice of this new approach to
what might be arguably one of the most complex scientifi c and human health.
clinical undertakings in the history of healthcare is undoubtedly
what is required. Our international collective of contributors to
this work refl ects the early adopters and members of a global H untington F. Willard, Ph.D.
community of physicians, scientists, and policy makers who will G eoffrey S. Ginsburg, M.D., Ph.D.
make this happen.
T erminology
Throughout this book, the terms “ g enetics” and “g enomics” are used medicine approach clinical care largely through consideration of
repeatedly, both as nouns and in their adjectival forms. Although individual genes and their effects on patients and their families.
these terms seem similar, they in fact describe quite distinct (though G enomic medicine, by contrast, refers to the use of large-scale
frequently overlapping) approaches in biology and in medicine. genomic information and to consideration of the full extent of an
Here, we provide operational definitions to distinguish the various individual’s genome, proteome, transcriptome, or metabolome in
terms and the subfields of medicine to which they contribute. the practice of medicine and medical decision-making. The princi-
The field of genetics is the scientific study of heredity and of ples and approaches of genomic medicine are relevant well beyond
the genes that provide the physical, biological, and conceptual bases the traditional purview of individual medical specialties and include,
for heredity and inheritance. To say that something – a trait, a dis- as examples, gene expression profiling to characterize tumors or to
ease, a code or information – is “ g enetic” refers to its basis in genes define prognosis in cancer, genotyping variants in the set of genes
and in DNA. involved in drug metabolism or action to determine an individual’s
H eredity refers to the familial phenomenon whereby traits correct therapeutic dosage, scanning the entire genome for millions
(including clinical traits) are transmitted from generation to genera- of variants that influence one’s susceptibility to disease, or analyzing
tion, due to the transmission of genes from parent to child. multiple protein biomarkers to monitor therapy and to provide pre-
G enomics is the scientific study of a genome, the complete dictive information in presymptomatic individuals.
DNA sequence, containing the entire genetic information of a gam- Finally, p ersonalized medicine refers to a rapidly advancing
ete, an individual, a population or a species. The word “g enome” field of healthcare that is informed by each person’s unique clinical,
was first used as an analogy with the earlier term “ c hromosome,” genetic, genomic, and environmental information. The goals of per-
referring to the physical entities (visible under the microscope) that sonalized medicine are to take advantage of a molecular understand-
carry genes from one cell to its daughter cells or from one genera- ing of disease to optimize preventive healthcare strategies and drug
tion to the next. Over the past two decades, “g enomics” has given therapies while people are still well or at the earliest stages of dis-
birth to a series of other “ - omics” that refer to the comprehen- ease. Because these factors are different for every person, the nature
sive study of the full complement of, for example, proteins (hence, of disease, its onset, its course, and how it might respond to drug or
proteomics), transcripts (t ranscriptomics), or metabolites other interventions are as individual as the people who have them.
(metabolomics). The essential feature of the “ - omes” is that they For personalized medicine to be used by healthcare providers and
refer to the complete collection of genes, proteins, transcripts, or their patients, these findings must be translated into precision diag-
metabolites, not just to the study of individual entities. nostic tests and targeted therapies. Since the overarching goal is to
M edical genetics is the application of genetics to medicine and optimize medical care and outcomes for each individual, treatments,
is one of the 24 medical specialties recognized by The American medication types and dosages, and/or prevention strategies may dif-
Board of Medical Specialties, the preeminent medical organization fer from person to person – resulting in unprecedented customiza-
overseeing physician certification in the United States. tion of patient care.
G enetic medicine is a term sometimes used to refer to the The principles underlying g enomic and personalized medi-
application of genetic principles to the practice of medicine and cine and their applications to the practice of clinical medicine are
thus overlaps medical genetics. Both medical genetics and genetic presented throughout the chapters that comprise this volume.
C ontributors
M ichael J. Ackerman Mayo Clinic, Windland Smith Mark Boguski Harvard Medical School, Center for
Rice Sudden Death Genomics Laboratory, Rochester, Biomedical Informatics, 10 Shattuck St., Boston, MA 02115
MN 55905, USA.
S tefano Bonassi Unit of Molecular Epidemiology, National
M atthew L. Anderson Departments of Obstetrics and Cancer Research Institute, Genova, Italy.
Gynecology and Pathology, Baylor Colege of Medicine, B rigitta Bondy Section Psychiatric Genetics and
Houston, Texas, USA. Neurochemistry, Psychiatric Hospital of University Munich,
F elicita Andreotti Institute of Cardiology, Catholic Munich, Germany.
University Medical School, Rome-Italy. J . Martijn Bos Mayo Clinic, Windland Smith Rice Sudden
Death Genomics Laboratory, Rochester, MN 55905, USA.
B rian H. Annex Division of Cardiovascular Medicine and
Department of Medicine, Duke University Medical Center, R oger E. Breitbart Department of Cardiology, Children’s
Durham, NC 27710, USA. Hospital Boston, Boston, MA 02115, USA.
A nthony Antonellis Genome Technology Branch, National J erome Brody Department of Medicine, Boston University
Human Genome Research Institute, National Institutes of School of Medicine, Boston, MA 02118, USA.
Health, Bethesda, MD, USA. M atthew P. Brown Omics Consulting LLC, Clayton, CA,
USA.
D mitri Artemov Department of Radiology – MR
Research, Johns Hopkins University School of Medicine, Lars Bullinger Department of Internal Medicine III,
Baltimore, MD 21205, USA. University of Ulm, Ulm, Germany.
J ames R. Bain Departments of Radiology and Internal S hawn C. Burgess Sarah W. Stedman Nutrition and
Medicine, Advanced Imaging Research Center, University of Metabolism Center, Department of Pharmacology and Cancer
Texas Southwestern Medical Center, Dallas, TX 75235, USA. Biology, Duke University Medical Center, Durham, NC
27704, USA.
P eter J. Barnes National Heart and Lung Institute, Section
of Airway Disease, London, SW3 6LY, UK. A tul J. Butte Department of Medicine and Department of
Pediatrics, Stanford Center for Biomedical Informatics Research,
J .S. Barnholtz-Sloan Case Comprehensive Cancer Stanford University School of Medicine, Stanford, CA 94305, USA.
Center, Case Western Reserve University School of Medicine;
D avid J. Carey Weis Center for Research/Geisinger Clinic,
Department of Epidemiology and Biostatistics, Case Western
Danville, PA 17822-2607, USA.
Reserve University School of Medicine, Cleveland, Ohio, USA.
G eorge Carlson McLaughlin Research Institute, Great Falls,
R ichard C. Becker Department of Medicine – MT, USA
Cardiovascular Thrombosis Center, Duke University Medical
Center, Durham, NC 27705, USA. J uan C. Celedón Channing Laboratory, Brigham and
Women’s Hospital, Boston, MA; Division of Pulmonary and
I vor J. Benjamin Division of Cardiology, Center for Critical Care, Brigham & Women’s Hospital, Boston, MA;
Cardiovascular Translational Biomedicine, University of Utah Harvard Medical School, Boston, MA; Center for Genomic
Health Sciences Center, Salt Lake City, UT, USA. Medicine, Brigham and Women’s Hospital, Boston, MA.
Paul R. Billings President and Chief Executive Offi cer, S ubhashini Chandrasekharan Center for Genome
CELLPOINT DIAGNOSTICS, 265 N. Whisman Road, Ethics, Law and Policy, Duke Institute for Genome Sciences and
Mountain View, CA 94043 Policy, Durham, NC 27708, USA.
S imon C. Body Department of Anesthesiology, Periopera- W ing C. (John) Chang Department of Pathology, Center
tive & Pain Medicine, Brigham and Women’s Hospital, Harvard for Lymphoma and Leukemia Research, University of Nebraska
Medical School, Boston, MA 02115, USA. Medical Center, Omaha, NE, USA.
xli
xlii ■ Contributors
Y an Chen Department of Chemistry, Shands Cancer Center D irk Elewaut Department of Rheumatology, Ghent
and UF Genetics Institute, University of Florida, Gainesville, FL University Hospital, Ghent, Belgium.
32611, USA.
C harles J. Epstein Department of Pediatrics and Institute
A ntonio Chiocca Department of Neurological Surgery, for Human Genetics, University of California, San Francisco,
Dardinger Laboratory for Neuro-oncology and Neurosciences, CA 94143, USA.
The Ohio State University Medical Center and Comprehensive
A yman H. Fanous Washington VA Medical Center,
Cancer Center, Columbus, OH 43210, USA.
Washington, DC, 20422, USA.
T heresa Puifun Chow Agency for Science, Technology and
P hillip G. Febbo Institute for Genome Sciences and Policy,
Research, Singapore Tissue Network, Singapore.
Department of Medicine – Oncology, Duke University Medical
W endy K. Chung Department of Pediatrics, Division Center, Durham, NC 27710, USA.
of Molecular Genetics, Columbia University, New York, NY
R obert J. Feezor Division of Vascular Surgery and
10032, USA.
Endovascular Therapy, University of Florida College of
R obert Cook-Deegan Center for Genome Ethics, Law and Medicine, Gainesville, FL.
Policy, Duke Institute for Genome Sciences and Policy, Durham,
Y onmei Feng Department of Pathology and the Arizona
NC 27708, USA.
Cancer Center, University of Arizona, Tucson, AZ, USA.
D olores Corella Nutrition and Genomics Laboratory, Jean
Z eno Földes-Papp ISS, National Center of Fluorescence,
Mayer–U.S. Department of Agriculture, Human Nutrition
Champaign, Illinois 61822, USA.
Research Center on Aging at Tufts University, Boston, MA,
USA; Genetic and Molecular Epidemiology Unit, School of H idehiko Fujinaka Institute for Clinical Research, Niigata
Medicine, University of Valencia, Valencia, Spain. National Hospital, Niigata 951-8585, Japan.
S usan Cottrell Amgen, Inc., Seattle, WA 98119, USA. D avid J. Galas Institute for Systems Biology, Seattle, WA,
USA; Battelle Memorial Institute, Columbus, OH, USA.
N ancy J. Cox Departments of Medicine and Human
Genetics, University of Chicago, Chicago, IL 60637, USA. L ouis, P. Garrison Department of Pharmacy, University of
Washington, Seattle, WA 98195, USA.
N igel P.S. Crawford CCR/NCI/NIH, Laboratory of
Cancer Biology and Genetics, National Cancer Institute, G lenn S. Gerhard Weis Center for Research/Geisinger
Bethesda, MD 20892-4264, USA. Clinic, Danville, PA 17822-2607, USA.
A . Jamie Cuticchia Bioinformatics Group, Duke G eoffrey S. Ginsburg Center for Genomic Medicine,
Comprehensive Cancer Center, Durham, NC 27708, USA. Duke Institute for Genome Sciences and Policy, Durham, NC
27710, USA.
D ieter Deforce Laboratory of Pharmaceutical
Biotechnology, Faculty of Pharmaceutical Sciences, Ghent B jorn T. Gjertsen Institute of Medicine, Hematology,
University, Ghent, Belgium. Haukeland University Hospital, University of Bergen, Bergen,
Norway.
M ario C. Deng Columbia University, New York, NY, USA.
M ichael Glass Newborn Screening Program, Washington State
G ayathri Devi Department of Surgery, Duke University
Department of Health, Shoreline, WA 98155, USA.
Medical Center, Durham, NC 27710, USA.
D avid B. Goldstein Center for Population Genomics and
T heo deVos Epigenomics, Inc, Seattle, WA, USA.
Pharmacogenetics, Duke Institute for Genome Sciences and
J uergen Distler Epigenomics, AG, Berlin, Germany. Policy, Durham, NC 27710, USA.
H armut Dohner Department of Internal Medicine III, E rynn S. Gordon Division of Pediatric Genetics, University
University of Ulm, Germany. of Maryland School of Medicine, Baltimore, MD 21201, USA.
A yotunde O. Dokun Division of Endocrinology T ucker Gosnell Massachussetts General Hospital Cancer
Metabolism and Nutrition. Center, Boston, MA, USA.
M ark R. Edbrooke Pharmacogenetics, GlaxoSmithKline, P eter Grass Biomarker Development, Novartis Pharma AG,
Durham, NC 27709, USA. Basel, Switzerland.
L ucas B. Edelman Department of Bioengineering E ric D. Green Genome Technology Branch, National
and Institute for Genomic Biology, University of Illinois, Human Genome Research Institute, National Institutes of
Urbana-Champaign. Health, Bethesa, MD 20892, USA.
Contributors ■ xliii
I ris Grossman Pharmacogenetics, Research and Develop- C hunhwa Ihm Department of Pathology, Brigham and
ment, GlaxoSmithKline, Research Triangle Park, NC 27709, Women’s Hospital, Harvard Medical School, Boston, MA 02115,
USA. USA.
M arta Gwinn National Offi ce of Public Health Genomics, O lga Ilkayeva Sarah W. Stedman Nutrition and Metabolism
Centers for Disease Control and Prevention, Atlanta, GA 30341, Center, Department of Pharmacology and Cancer Biology,
USA. Duke University Medical Center, Durham, NC 27704, USA.
C arolina Haefl iger Epigenomics, AG, Berlin, Germany. R afael Irizarry Department of Biostatistics, Johns Hopkins
Bloomberg School of Public Health.
S usanne B. Haga Duke Institute for Genome Sciences and
S hushant Jain Laboratory of Neurogenetics, National
Policy, Durham, NC 27710, USA.
Institute on Aging, National Institutes of Health, Bethesda,
P er Hall Department of Medical Epidemiology and
MD, USA; Reta Lila Weston Institute of Neurological Studies,
Biostatistics, Karolinska Institute, Stockholm, Sweden.
University College London W1T 4JF, UK; Department of
Molecular Neuroscience, Institute of Neurology, University
J oshua M. Hare Division of Cardiology and
College London, London, UK.
Interdisciplinary Stem Cell Institute, University of Miami, Miller
School of Medicine, Miami FL 33136, USA. M elissa D. Johnson Department of Medicine – Infectious
Diseases, Duke University Medical Center, Durham, NC 27710,
A hmad Hariri Developmental Imaging Genetics Program,
USA.
University of Pittsburgh, Pittsburgh, PA 15213, USA.
P hilip W. Kantoff Dana-Farber Cancer Institute, Department
J ames R. Heath Department of Chemistry, California
of Medical Oncology, Boston, MA, USA.
Institute of Technology, Los Angels, CA, USA.
S ekar Kathiresan Massachusetts General Hospital,
R obert A. Hegele Robarts Research Institute, Blackburn
Cardiovascular Disease Prevention Center, Boston, MA,
Genetics Laboratory, London, ONT, Canada.
02114, USA.
B ettina Heidecker Division of Cardiology and
H asmeena Kathuria Department of Medicine, Boston
Interdisciplinary Stem Cell Institute, University of Miami, Miller
University School of Medicine, Boston, MA 02118, USA.
School of Medicine, Miami, FL, USA.
K ensaku Kawamoto Division of Clinical Informatics,
S hona Hislop Department of Pathology, Brigham and
Duke University Medical Center, Durham, NC 27710, USA.
Women’s Hospital, Boston, MA 02115, USA.
F ilip De Keyser Department of Rheumatology, Ghent
E ric P. Hoffman Research Center for Genomic Medicine,
University Hospital, Ghent, Belgium.
Children’s National Medical Center, Washington, DC 20010,
A sif Khalid Division of Gastroenterology, Hepatology
USA.
and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213,
J ohn Holton Centre for Infectious Diseases and USA.
International Health, Windeyer Institute of Medical Sciences,
M uin Khoury National Offi ce of Public Health Genomics,
Royal Free and University College London Medical School,
Centers for Disease Control and Prevention, Atlanta, GA 30341,
London, W1T 4JF, UK.
USA.
L eroy Hood The Institute for Systems Biology, Seattle, WA
S tephen F. Kingsmore National Center for Genome
98103-8904, USA.
Resources.
A ndrew T. Huang Koo Foundation Sun Yat-Sen Cancer
M ichelle M. Kittleson Division of Cardiology, UCLA
Center, Taiwan.
School of Medicine, Los Angeles, CA, USA.
E rich S. Huang Duke University Medical Center, Durham,
B eena T. Koshy Pharmacogenetics, GlaxoSmithKline, Durham,
NC, USA.
NC 27709, USA.
C arlos A. Hubbard Southern Medical Group, Tallahassee,
R anga Krishnan Department of Psychiatry and Behavioral
FL 32308, USA.
Science, Duke University Medical Center, Durham, NC 27710,
USA.
K ent Hunter CCR/NCI/NIH, Laboratory of Cancer
Biology and Genetics, National Cancer Institute, Bethesda, MD R obert S. Krouse Southern Arizona Veterans Affairs Health
20892-4264, USA. Care System, Tucson, AZ, USA.
C ourtney Hyland Department of Pathology, Brigham and V ikas Kundra Diagnostic Radiology, University of Texas
Women’s Hospital, Boston, MA 02115, USA. MD Anderson Cancer Center, Houston, TX 77030, USA.