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Preface for Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease

“The findings and conclusions in this book are those of the author(s) and do not
necessarily represent the views of the funding agency.”


These chapters were published with modifications by Oxford University Press (2004)

Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease

Edited by

Muin J. Khoury, M.D., Ph.D.
Director, Office of Genomics and Disease Prevention
Centers for Disease Control and Prevention
Atlanta, Georgia

Wylie Burke, M.D., Ph.D.
Chair, Department of Medical History and Ethics
University of Washington
Seattle, Washington

Julian Little Ph.D.
Chair of Epidemiology
Department of Medicine and Therapeutics University of Aberdeen
Aberdeen, Scotland




Advances in human genetics are expected to play a central role in medicine and public health in the 21st century by providing genetic information for disease prediction and prevention. Although human gene discoveries generate excitement and expectations, the translation of gene discoveries into meaningful actions to improve health and prevent disease depends on scientific information from multiple medical and public health disciplines. The field of epidemiology plays a central role in this effort. Epidemiology is often viewed as the scientific core of public health and involves the study of the distribution and determinants of health-related states or events in populations and the application of this study to control health problems.  Epidemiologists determine risk factors for various diseases, identify segments of the population with highest risk to target prevention and intervention opportunities, and evaluate the effectiveness of health programs and services in improving the health of the population.

In this book, we show how the epidemiologic approach will play an important role in the continuum from gene discovery to the development and applications of genetic tests. We call this continuum human genome epidemiology  (or HuGE) to denote an evolving field of inquiry that uses systematic applications of epidemiologic methods to assess the impact of human genetic variation on health and disease. Since most gene discoveries are based on studies of high-risk families or selected population groups, once disease gene(s) are found, well-conducted epidemiologic studies are needed to quantify the population impact of gene variants on the risk for health outcomes and to identify and measure the impact of modifiable risk factors that interact with gene variants. Epidemiologic studies are also required in the process of clinical validation of new genetic tests, and to monitor population use of genetic tests and determine the impact of genetic information on the health and well being of different populations. The results of such studies will help medical and public health professionals integrate genetics into practice.

As more epidemiologic investigations of human genes are conducted and published, evidence needs to be integrated from different studies.  Given the large numbers of genes that will be examined in relation to numerous diseases, many spurious findings are likely to emerge. Variation in study designs and execution will make difficult the synthesis of information across studies. The increasing number of human genome epidemiologic studies has uncovered the need for guidelines for synthesizing results of the increasing number of such studies, particularly for assessing prevalence of gene variants, gene-disease associations, gene-environment and gene-gene interactions, and evaluation of genetic tests.

Although none of the material presented here is novel, we have structured the book to allow readers to proceed systematically from the fundamentals of genome technology and discovery, to epidemiologic approaches to gene characterization, to evaluation of genetic tests and health services. We then illustrate these concepts in several disease-specific case studies.  The book focuses on post-gene discovery (what do you do with a gene when you find one?) with an overview of emerging analytic methods for gene discovery. Section I  describes genomic technologies and their applications, evolving methods of gene discovery, and summarizes the current status of the ethical, legal and social issues for conducting epidemiologic studies of the human genome (with emphasis on informed consent issues).  Section II addresses epidemiologic approaches to the study of genotypes in populations and their relation to diseases, including the assessment of gene-gene and gene-environment interaction.  This section also addresses issues of synthesis of these studies, including some methodologic standards. Section III deals with the application of epidemiologic methods to assessing genetic information for clinical and public health applications. The section lays an epidemiologic foundation for using population level information to assess individual risk for clinical use. We explore population-based concepts of the usefulness of genetic tests in populations, and discuss the evaluation of genetic tests from a combined clinical-laboratory approach. We also explore an epidemiologic framework for the interface between genetics, pharmacology and medicine. Lastly, we explore the integration of genetics into controlled clinical trials and the role of genetics in the development of clinical practice guidelines. Finally, section IV uses case studies to illustrate concepts discussed in the first three sections in relation to specific disease examples, including gene-environment interactions (pesticides and oral contraceptive use), chronic diseases (colon cancer, Alzheimer disease, cardiovascular disease, breast cancer and iron overload), occupational exposures (berylliosis), newborn screening issues (fragile X syndrome and hearing loss), and infectious disease (HIV infection). These examples are by no means exhaustive, but they do illustrate the spectrum from single gene disorders to complex conditions, and the need for epidemiologic research to obtain population level information for developing health policy and practice. Indeed, for many of the case studies, the lack of solid epidemiologic data represents a primary barrier to developing appropriate health policies related to the use of genetic risk information. Because our knowledge is rapidly evolving for each one of these examples, most likely, the case studies will be outdated soon. Nevertheless, the basic methodologic foundation for translating gene discovery into usable clinical information will still apply.

Ultimately, a multidisciplinary approach is needed to fulfill the promise of the Human Genome Project in improving health. At the core of these disciplines, the epidemiologic approach will begin to fill immense gaps in our knowledge of population risk of various diseases in relation to genetic variation. This information is a necessary first step in the long road from gene discovery to medical and public health practice.

Atlanta, GA                         MJK
Aberdeen, UK                      JL
Seattle, WA                        WB


We are grateful to the following individuals for reviewing drafts of selected book chapters:  Harry Campbell, David FitzPatrick, Seymour Garte, Scott Grosse, James E. Haddow, Robin Harbour, Craig Hooper,  Rolv T. Lie, Zosia Miedzybrodzka, Arno Motulsky, Thomas O'Brien,  Sonja Rasmussen, Duncan Shaw, Michael Steel, Karen Steinberg, Donna Stroup, Emmanuela Taioli, Paolo Vineis, and Paula Yoon.  In addition, we thank Karen Foster, Pamela Gillis Watson, Elizabeth Fortenberry and Patti Seikus, with the Centers for Disease Control and Prevention editorial staff, for their literary support to this book; and, thanks also to Thelma Brown without whom the book would have never been completed.

Table of Contents

Links are provided to selected chapters that were published with modifications...


Human Genome Epidemiology:  Scope and Strategies
Muin J. Khoury, Julian Little and Wylie Burke

Emerging Genomic Technologies and Analytic Methods for Population-and Clinic-Based Research
Darryl L. Ellsworth and Christopher J. O'Donnell

Approaches to Quantify the Genetic Component of and Identify Genes for Complex Traits
Patricia Peyser and Trudy Burns


PART II    METHODS AND APPROACHES 1: Assessing Disease Associations and Interactions

Assessing Genotypes in Human Genome Epidemiology Studies
Karen Steinberg and Margaret Gallagher

Statistical Issues in the Design and Analysis of Gene-Disease Association Studies
Duncan C. Thomas

Facing the Challenge of Complex Genotypes and Gene-Environment Interaction:  The Basic Epidemiologic Units in Case-Control and Case-Only Designs
Lorenzo D. Botto and Muin J. Khoury

Inference Issues in Cohort and Case-Control Studies of Genetic Effects and Gene-Environment Interactions
Montserrat Garcia-Closas, Sholom Wacholder, Neil Caporaso, and Nathaniel Rothman

Applications of Human Genome Epidemiology to Environmental Health
Samir N. Kelada, David L. Eaton, Sophia S. Wang, Nathaniel Rothman, and Muin J. Khoury
PART III   METHODS AND APPROACHES 2:  Assessing Genetic Tests for Disease Prevention

Epidemiologic Approach to Genetic Tests:  Population-Based Data for Preventive Medicine
Marta Gwinn and Muin J. Khoury

Genetic Tests in Populations:  An Evidence-Based Approach
Paolo Vineis

ACCE:  A Model Process for Evaluating Data on Emerging Genetic Tests
James E. Haddow and Glenn E. Palomaki

The Interface Between Epidemiology and Pharmacogenomics
David L. Veenstra

Integrating Genetics Into Randomized Controlled Trials
John P.A. Ioannidis and Joseph Lau

Developing Guidelines for the Clinical Use of Genetic Tests -A U.S. Perspective
Linda E. Pinsky, David Atkins, Scott Ramsey, and Wylie Burke

Using Human Genome Epidemiologic Evidence in Developing Genetics Services:  The U.K. Experience
Brenda J. Wilson, Jeremy Grimshaw, and Neva Haites


PART IV    CASE STUDIES:  Using Human Genome Epidemiology Information to Improve Health

Paraoxonase Polymorphisms and Susceptibility to  Organophosphate Pesticides: Implications for Pesticide Applicators
Kathryn Battuello, Clement Furlong, Richard Fenske, Melissa A. Austin and Wylie Burke

Interaction Between Factor V Leiden and Oral Contraceptives:  New Etiologic Insights in Deep Vein Thrombosis
Jan P. Vandenbroucke, Frits R. Rosendaal, and Rogier M. Bertina

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene (MTHFR) Folate and Colorectal Neoplasia
Linda Sharp and Julian Little

Apolipoprotein-E and the Epidemiology of Alzheimer's Disease
Richard Mayeux

Immunogenetic Factors in Chronic Beryllium Disease
Erin McCanlies, Michael E. Andrew, and Ainsley Weston

From Epidemiology to Clinical Practice:  The Connexin Connection
Aileen Kenneson and Coleen Boyle

Genetic and Environmental Factors in Cardiovascular Disease
Molly Bray

BRCA1/2 and the Prevention of Breast Cancer
Jenny Chan-Claude

The Role of Chemokine and Chemokine Receptor Genes in HIV-1 Infection
Thomas R. O'Brien

Hereditary Hemochromatosis
Giuseppina Imperatore, Rodolfo Valdez, and Wylie Burke

Address correspondence to Dr. Khoury at
Office of Genomics and Disease Prevention
Centers for Disease Control and Prevention
6 Executive Park, Mail Stop E-82
Atlanta, Georgia 30329