ABSTRACTS FROM THE 1st ANNUAL CONFERENCE ON
GENETICS AND PUBLIC HEALTH
Claire Broome, Doris Barnett, Elizabeth Thomson, and Don Williamson
- Genetics and Public Health
Keynote for the CDC Conference on Translating Advances in Human Genetics into Disease Prevention and Health Promotion - Gilbert S. Omenn
CHALLENGES AND OPPORTUNITIES: A Framework for Genetics & Public Health
- A Framework for the Role of Genetics in Public Health and Preliminary Data from a Genetics and Public Health State Survey
Muin J. Khoury
- Ethical, Legal and Social Challenges in Genetics: Predictions, Precautions, and Public Health
- Challenges in Educating Primary Care Providers about Genetic Medicine
Robert M. Fineman
PANEL DISCUSSION: Integrating Genetics into Public Health through Partnerships
- Genetics and Managed Care
Mark A. Rothstein
- Industry/Academic Collaboration in the Development of New Genetic Tests
- The Academic Foundations of Public Health Genetics
John J. Mulvihill
MEETING THE CHALLENGES OF GENETICS AND PUBLIC HEALTH: State Perspectives on Program Activities
SHARING THE LATEST INFORMATION ON GENETICS AND PUBLIC HEALTH: Existing and Planned Information Resources
- The Human Genome Epidemiology Network (HuGE Net)
Muin J. Khoury
- Linking Public Health Professionals with Human Genetics Information
- The National Coalition for Health Professional Education in Genetics
PUBLIC HEALTH GENETICS: Ethical, Legal and Social Issues
- Balancing Individual Interests, Group Interests, and the Public Health: Addressing the Special Issues Raised by Genetics
Ellen Wright-Clayton, M.D.
- Genetic Screening in the Genome Era: A Minority Perspective
Robert F. Murray
- What Should We Mean by "Prevention" in Public Health Genetics?
Eric T. Juengst
- Public Health Genetics: Law and Ethics
Lawrence O. Gostin
GENETICS AND CHILD HEALTH
- Forecasting the Genetic Health of New York State: DNA Analysis of Newborn Screening Dried Blood Spots
- Mortality among Children with Sickle Cell Disease Identified by Newborn Screening: California, Illinois, and New York, 1990-1994
GENETICS AND CANCER
- Will Genetic Testing for Breast Cancer Risk Help Control Breast Cancer? Attitudes of At-Risk Women Offered BRCA1/2 Testing Toward Early Detection and Risk Reduction Behaviors
- Recent Discoveries in Colorectal Cancer Susceptibility Genes
Gloria M. Petersen
- Occupational Exposure and Genetic Markers
Paul A. Schulte
- Economic Implications of Genetic Screening for Cancer Susceptibility: The Case of Hereditary Nonpolyposis Colorectal Cancer
Scott D. Ramsey
GENETICS AND CHRONIC DISEASE
- Predicting and Preventing Alzheimer's Disease
- Genetics and the Prevention of Cardiovascular Disease
Roger R. Williams
- Hemochromatosis: Public Health Implications of Screening
PUBLIC HEALTH GENETICS AND TRAINING PRIORITIES
- Gene- Environment Interaction and the Environmental Genome Project
Jack A. Taylor
- Prevention Effectiveness: Demonstrating the Impact of Genetic Interventions
Steve M. Teutsch
- Training Future Public Health Professionals
Patricia A. Peyser
GENETIC TESTING PROCESS AND PUBLIC HEALTH
- Promoting Safe and Effective Genetic Testing in the United States: The Report of the Task Force on Genetic Testing
Neil A. Holtzman
- The FDA Review of In Vitro Diagnostic Devices - An Overview
Ginette Y. Michaud
GENETICS AND PUBLIC HEALTH IN THE NEW MILLENNIUM
James Marks and Deborah Klein-Walker
Claire Broome, M.D.
Centers for Disease Control and Prevention
Doris Barnett, A.C.S.W.
Principal Advisor to the Administrator
Health Resources and Services Administration
Elizabeth Thomson, R.N., M.S., C.G.C.
Program Director - Clinical Genetic Research
ELSI Research Program
National Human Genome Research Institute (NHGRI)
Don Williamson, M.D.
State Health Officer
State of Alabama Department of Public Health
As a result of the Human Genome Project and other research efforts in human genetics, most--if not all--of the estimated 100,000 human genes will be identified and mapped by the year 2005. Many of the genes identified thus far are associated with rare disorders. However, scientists are becoming increasingly aware of the role that genes play in the etiology of diseases that have significant public health impact --from cancer to coronary heart disease. As quickly as genes are being identified, genetic tests are being developed and marketed, with tests for approximately 600 genes being currently available. Scientific advances in genetics are creating both exciting opportunities and tremendous challenges for public health. Complex issues regarding genetic testing have emerged: the need for population-based data balanced against the ethical concerns of obtaining informed consent for genetic research, the rapid commercialization of genetic tests, the availability of and access to genetic services, and the potential discrimination against and stigmatization of individuals and groups based on their genetic makeup. The challenge in translating discoveries in genetics into public health action lies in ensuring the appropriate use of genetic information and new genetic technologies, while balancing these concerns with public health opportunities for disease prevention and health promotion. Public health leadership at the federal, state, and local levels is needed to respond to these unique challenges and opportunities. As the role of genetics in disease becomes better understood, and genetic tests become more widely used, it will be increasingly necessary to have leaders who can envision the impact of genetics across programs and activities, foster the partnerships needed to incorporate genetics into existing programs and activities, and create policy to address the many concerns. With the proper public health leadership and the formation of key partnerships among public health, medicine, industry, and academia, discoveries in human genetics can be translated into effective and efficient public health actions.
Genetics and Public Health: Keynote for the CDC Conference on Translating Advances in Human Genetics into Disease Prevention and Health Promotion
Gilbert S. Omenn, M.D., Ph.D.
Executive Vice-President for Medical Affairs
CEO of the University of Michigan Health System
Professor of Internal Medicine, Human Genetics, and Public Health
University of Michigan Gilbert S. Omenn, M.D., Ph.D.
Executive Vice-President for Medical Affairs
CEO of the University of Michigan Health System
Professor of Internal Medicine, Human Genetics, and Public Health
University of Michigan
Genetics is growing in importance in public health as the public becomes more knowledgeable and more demanding of genetic services and as knowledge of our genes and their functions permits more effective strategies for treatment and especially for prevention, the special responsibility of public health. The Human Genome Project is yielding vast information about sequences, mutations, and variation, all of which will require the public health sciences to interpret clinical significance in the context of environmental, metabolic, nutritional, and behavioral risk factors. Genetic epidemiology, statistical genetics, eco-genetics, host-pathogen gene-environment interactions, and ethical, cultural, political, legal, and organizational research on genetic services and their outcomes will become mainstream elements of academic public health and eventually of the practice of public health and preventive medicine.
CHALLENGES AND OPPORTUNITIES: A Framework for Genetics and Public Health
A Framework for the Role of Genetics in Public Health and Preliminary Data from a Genetics and Public Health State Survey
Muin J. Khoury, M.D., Ph.D.
Acting Director, Office of Genomics and Disease Prevention
Centers for Disease Control and Prevention
In this talk, I will focus on the challenges and opportunities that are facing the practice of public health as a result of advances in human genetics and progress in the Human Genome Project. I will present a general framework for the emerging role of genetics in public health. I will also summarize the preliminary results of a survey conducted by the Council for State and Territorial Epidemiologists on key issues, activities and concerns of state health departments related to the emerging role of genetics in public health practice.
In 1997, the Centers for Disease Control and Prevention created the Office of Genomics and Disease Prevention to highlight the emerging role of genetics in the practice of public health in the United States, and to provide internal coordination and promote external partnerships in activities related to genetics and disease prevention and health promotion. This action was recommended in an agency-wide strategic plan that outlines a conceptual framework for a public health program in genetics. The strategic plan is based on the assumption that, broadly defined, virtually all human diseases of important public health impact are the result of the interaction between human genetic variation and the environment. It is also based on the assumption that the use of genetic information in public health is appropriate in diagnosing, treating and preventing disease, disability, and death among people who inherit specific genotypes. Prevention includes the use of medical, behavioral, and environmental interventions to reduce the risk for disease among people susceptible because of their genetic makeup. The plan supports the responsible use of genetic tests and services, including adequate family history assessment and genetic counseling, for promoting health and preventing disease in different communities. The plan assumes that much of the delivery of genetic tests and services will be done within the context of the evolving health care system, including managed care organizations, rather than under public health agencies. Public health agencies will have an increasing role in assessing the health needs of populations, assuring the quality of genetic tests and services, and evaluating the impact of interventions.
The framework for the role of genetics in public health is based on an extension of the Institute of Medicine model of the Future of Public Health (1988). The framework identifies four essential public health genetics program components:
- Public health assessment using surveillance and population-based epidemiologic studies to assess how risk for disease and disability in different populations is influenced by the interaction of human genetic variation with modifiable risk factors.
- Evaluation of policies and quality of genetic testing to ensure the appropriateness and quality of population-based genetic testing.
- Intervention development, implementation, and evaluation to ensure that genetic tests and services are incorporated into population-based interventions that promote health and prevent disease and disability.
- Communication and information dissemination to provide timely and accurate information to both the general public and professional audiences on the role of genetics in the promotion of health and the prevention of disease and disability.
In order for these activities to be done, three cross-cutting critical issues that can affect each program component need to be addressed: partnerships and coordination, ethical, legal, and social issues, and training of the public health workforce and education of the general public.
Karen Rothenberg, J.D., M.P.A.
Marjorie Cook Professor of Law
Director, Law & Health Care Program
University of Maryland School of Law
The integration of genetic technologies into the public health model raises significant challenges for our society. The temptation will be to focus on linearly defined genes rather than their multi-dimensional context. The challenge will be to recognize the dangers of such an approach and to respond by designing public health strategies that do not isolate genetic information from environmental factors and social realities.
This presentation is designed to highlight the ethical, legal, and social implications of the CDC's framework for incorporating genetics into public health research and services. More specifically, what challenges will be raised by the integration of genetic information and technologies into public health surveillance and epidemiological studies? How can public health agencies meet their responsibility to assure the quality and accuracy of genetic technologies? What impact will these new technologies have on existing public health priorities and systems? Will public health professionals be able to effectively communicate genetic information without undermining competing public health messages?
Issues of autonomy, privacy, and confidentiality will require special consideration as genetic technologies and information begin to be integrated into public health. Will it be possible to obtain fully informed consent from large populations, when it may be possible to provide only limited information about the genetic information being sought? What should be the expectation for protecting privacy and maintaining confidentiality when genetic information is included in public health registries and databases? How can group stigmatization and discrimination be prevented when genetic epidemiologic research is subjected to subgroup analysis? How can we better translate the results of such genetic research to the public? None of these questions have easy answers, but they raise important challenges for the public health community.
Robert M. Fineman, M.D., Ph.D.
Medical Consultant, Office of Maternal and Child Health
Washington State Department of Health
Clinical Professor of Public Health
University of Washington, School of Public Health
The Washington State Genetic Education Project (GEP) aims to prevent premature death and disability caused by birth defects and genetic diseases by educating primary care providers (PCPs) and others about medical genetic services and interventions. Utilizing this information, it may be possible at this time to improve outcomes in a significant percent of patients seen by PCPs. During the past 2 1/2 years, our statewide GEP has utilized a train-the-trainers model and a curriculum entitled, "Genetics & Your Practice," to raise awareness in almost 2,000 PCPs, with an overall training satisfaction rate of 90+%. In order to create, implement, and maintain this GEP we have concentrated on POLITICS and four other major areas of interest:
- PUBLIC HEALTH - assessment, policy development, assurance, capacity, infrastructure, partnerships, and consensus
- GENETIC MEDICINE - subjective, objective, assessment, and plan (SOAP)
- BUSINESS - strengths, weaknesses, opportunities, and barriers (SWOB)
- MARKETING - price, place, product, and promotion (the Four Ps)
During the past year, we have added to this GEP a Web site and the development of a Genetics & Your Practice interactive CD-ROM to be released in the summer of 1998. In addition, we are attempting to replicate this GEP in twelve other states (locales) by the fall of 1998. This GEP is funded by the Genetic Services Branch, MCHB, HRSA, DHHS; Washington State DOH; March of Dimes; and the Institute for Child Health Policy, University of Florida.
PANEL DISCUSSION: Integrating Genetics into Public Health Through Partnerships
Mark A. Rothstein, J.D.
Cullen Distinguished Professor of Law
Director - Health, Law and Policy Institute
University of Houston
A wide range of important issues are raised as genetic testing and genetic services move from the experimental to the clinical stages of development. In health care reimbursement, medical claims will be denied for services that are "not medically necessary" or "experimental," and it is not well settled when medical tests or procedures, including those based on genetics, have gained sufficient acceptability as to be reimbursable. Reimbursement for genetic counseling and testing of extended families are other issues to be addressed.
Managed care holds the promise of improved compilation and utilization of genetic information. With large numbers of lives covered, data collection on the prevalence of rare disorders and treatment outcomes may be easier. Using genetic screening for prevention also may be easier to implement on a wide basis. On the other hand, if cost considerations of managed care drive clinical decisions, then the use of genetic information could result in several possible adverse effects. These include excluding at-risk individuals from coverage, limiting treatment options based on genetic factors, and even attempting to prevent the birth of severely impaired newborns as a cost control mechanism.
Brian Ward, Ph.D.
Vice President of Laboratory Operations
Myriad Genetics Laboratories, Inc.
Future development of new diagnostic genetic testing has a growing dependency on partnerships. The traditional pathway in the development of a new diagnostic test has three major phases: 1) research phase; 2) investigational diagnostic test; and 3) evolution of the diagnostic procedure into a generally accepted test.
The discovery for the scientific foundation for a new diagnostic test is performed in a research lab setting. Expansion of this research effort occurs in the investigational phase as the diagnostic procedure moves from research lab into clinical laboratory. In the research phase of a laboratory test, results are not provided to the patient. In addition, it is during this period of development that the specificity, sensitivity, and medical utility of a genetic test is determined. As the test moves in the direction of a generally accepted technology, mechanisms for health care delivery of information about tests to patients are developed and reimbursement issues are resolved. A generally accepted test is widely available, validated in a common platform by a number of labs and is regarded as a part of routine medical practice.
Prior to the advent of rapid growth in the biotech industry, the majority of genetic tests that proceeded through this pathway were developed in universities, became investigational tests in a comprehensive university medical center and evolved into an accepted test only after a diagnostic "kit" was developed. The biotechnology companies collaboration between biotech industry and university is rapidly changing the direction and duration of this path. Many new genes and genetic diagnostic procedures are being discovered in private settings or by close collaboration between industry and academia. For example, recent discovery of melanoma gene MMAC1 was the result of a university initiating a partnership with industry. The university had discovered the general location of the gene, but required the expertise and genetic research capabilities of a biotech company.
The investigational testing phase now occurs frequently in both academic and industrial settings. Often, the academic environment does not have access to resources and capitol required to develop diagnostic tests. Conversely, industry does not have broad access to patient populations for validation studies. The beginning of beneficial collaborations to address this issue has been demonstrated on numerous projects, such as clinical validation of clinical diagnostic tests for deleterious mutations in predisposed cancer genes BRCA1 and BRCA2.
The path from investigation to a generally accepted analysis is less clear. It is in this area that partnerships between industry, academia, and HMO/private consumer have great future potential. The formalization of this process will accelerate the final integration of reliable and efficient genetic services into public health.
John J. Mulvihill, M.D.
Professor of Human Genetics
University of Pittsburgh
Any academic discipline is defined by its professional personnel, their societies, meetings, publications, and training programs and, in the end, their corpus of research. The scope of academic public health genetics in the U.S. was articulated in a conference in Ann Arbor in 1963 and a seminar series at Johns Hopkins University that led to a monograph. Recent summaries address the principles, practices, and future strategy of the field. The journal Genetic Epidemiology, founded by D. C. Rao in 1984, has been a forum for methodologic advances, and a new British journal, Community Genetics, has been announced. Genetics has had little presence within the American Public Health Association, and comprehensive public health has no focused presence within the American Society of Human Genetics, the International Genetic Epidemiology Society, and the National Society of Genetic Counselors. Geneticists with public health interests exist at many universities and academic medical centers, but the only formal Department of Human Genetics in a public health school is at the University of Pittsburgh. The University of Michigan has a nationally funded training program, Public Health Genetics Interdepartmental Concentration; the University of Texas at Houston has a Genetics Center; the Johns Hopkins Medical Institutions has a Genetics and Public Policy Studies Unit; and, the University of Washington's School of Public Health and Community Medicine has a multidisciplinary graduate program in Public Health Genetics in the context of Law, Ethics, and Policy. Progress in public health genetics will require coalition building among public health administrators, consumers, and academicians (e.g., epidemiologists, human and medical geneticists, genetic counselors) and their societies. It is hoped that the acute disease care industry can be engaged in health maintenance and disease prevention efforts, including through genetics. Special attention is needed to 1) draw sharp distinction between old eugenics; 2) recognize and take advantage of international and intercultural variations in health care and disease prevention systems; and 3) maintain the scientific basis of public health genetics. One unifying scientific concept should be "ecogenetics," the notion that all human health and disease is the result of gene-environment interactions over time in individuals.
MEETING THE CHALLENGE OF GENETICS AND PUBLIC HEALTH: State Perspectives on Program Activities
Stephen Bowman, M.H.A., Acting Director, Chronic Disease Prevention, Washington Dept. of Health
Deborah Doyle, M.S., C.G.G., State Coordinator for Genetic Services, Washington Dept. of Health
Paul Stehr-Green, Dr.P.H., State Epidemiologist, Washington State Department of Health
In 1988, the Institute of Medicine significantly changed the direction of the Washington State Department of Health including the Genetic Services Section. This report clearly articulated the fact that many public health programs have become the safety, or the provider of last resort, particularly for low income families. While the Genetic Services Section continued to provide fiscal support for regional genetic clinic services, additional emphasis was placed on conducting core public health genetics activities. Examples of these activities include the statewide genetic needs assessment, the development of the 3-5 Year Statewide Genetics Plan, as well as the Genetics Education Plan. This presentation will focus on describing the public health genetics core public health functions as implemented in Washington State. Examples will be highlighted based on assessment, policy development, and assurance activities. Finally, a dialogue will be facilitated that addresses the numerous complex issues that pertain to potential public health policies and public health strategies for genetic services and genetics education.
Christopher Atchison, M.P.A., Director, Iowa Department of Health
Jean Anderson, R.N., M.A., C.P.N.P., State Coordinator for Genetic Services, Iowa Dept. of Health
Paul Stehr-Green, Dr.P.H., State Epidemiologist, Washington State Department of Health
An extensive system of statewide genetic health care services has been available in Iowa for many years. Most of the genetic programs are joint efforts of the Iowa Department of Public Health (IDPH) and The University of Iowa Department of Pediatrics. The public health focus of the programs has changed dramatically from the early years, when the only program was voluntary newborn screening for PKU done by 5 laboratories, to a comprehensive program with multiple components. The IDPH played a pivotal role in the development and organization of the various programs in the early years; however, until recently, this role gradually had become one primarily of financial support. Some of the genetic programs have been in existence for over 20 years, with only a few new services or programs initiated. Currently, the IDPH is renewing its commitment to state of the art genetic health care by assuming a more active and strengthened leadership role. This is being done in several ways, including establishing the position of State Coordinator for Genetic Services, strengthening relationships and clarifying expectations for the University based providers and programs, utilizing the Great Plains Genetics Services Network Guidelines for State Genetic Service Programs to evaluate services, defining and examining issues related to genetics and public health, and developing a plan to establish and incorporate new and existing genetic services into the framework of core public health functions. This presentation will describe where Iowa is today with respect to statewide genetic health care services, how this has been achieved, and what the goals are for preserving and expanding services in the future, given the constraints and demands of today's health care systems.
George Cunningham, M.D., Chief, Genetic Disease Branch, California Dept. of Health Services
Neil Kohatsu, M.D., M.P.H., Chief, Medicine and Public Health Program, CA Dept. of Health Services
James Stratton, M.D., M.P.H., Deputy Director, Prevention Services, CA Department of Health Services
Ray Neutra, M.D., Dr.P.H., Chief, Division of Environmental & Occupational Disease Control
California has the most comprehensive and integrated public health based genetic program in the nation. The legislature created a special unit, the Genetic Disease Branch, with broad authority to provide and regulate genetic services.
Prevention and Treatment
The Genetic Disease Branch (GD) has a staff of 129 persons and an annual budget of over $60 million in FY 97/98.
The Genetic Disease Branch operates two statewide fee supported screening programs using a public private partnership model. The State sets standards and cutoffs and then pays private vendors for laboratory and clinical services. The Newborn Screening Program screens 540,000 newborns for PKU, hypothyroidism, galactosemia, and hemoglobinpathies using automated state-of-the-art equipment and with 98% complete follow-up. The fee is $42. The prenatal screening is a triple marker based screening followed by comprehensive diagnostic testing. The fee is $105, with 350,000 women screened annually. In addition, the state supports Dr. Michael Kaback at UCSD in a statewide Tay Sachs screening. Rh screening is required of all pregnancies and monitored by GDB.
The Prevention Services division of the department provides additional programs in clinical prevention and applied research in areas such as ovarian, breast, cervical, and prostate cancer screening. Other programs in chronic disease prevention and control target cardiovascular disease, diabetes, and Alzheimer's disease.
Finally, promotion of reproductive health services by the Office of Women's Health, Maternal and Child Health Branch (MCH) and Women, Infants and Children Supplement Food Branch (WIC) program contribute to prevention of birth defects by promoting and providing prenatal care and improved prenatal nutrition.
Research and Policy Development
The Genetic Disease Branch maintains a registry of neural tube defects and chromosomal defects. There is also an extensive database on newborns and women who have been screened. A specimen bank is maintained for research in birth defect prevention.
The California Birth Defects Monitoring Program (CBDMP) collects data on birth defects from birth certificates, hospital discharge, prenatal diagnostic centers, and hospital abstracting in approximately 43% of births.
The Environmental and Occupational Disease Control Division conducts research in environmental gene interactions. A cancer registry in the Prevention Services Division is maintained to monitor cancer prevalence and prevention activities.
Education and Training
The Genetic Disease Branch provides public and professional education through an online library of approved materials called GeneHelp. GDB also trains and certifies sickle cell counselors via contract with UCB. A major effort in folate education is jointly conducted by GDB, Women, Infants and Children Supplement Food Branch (WIC), and Maternal and Child Health (MCH) with the March of Dimes, and professional group support. Newsletters on screening are regularly sent to all newborn and prenatal care providers.
Prevention Services units conduct public and professional education in prevention and control of chronic disease and injury.
MCH and WIC provide media grants to promote early prenatal care and better prenatal nutrition.
Quality Assurance Monitoring
GDB has standards for newborn screening follow-up, prenatal diagnostic centers, genetic counseling, amniocentesis, and ultrasound services. A licensing bill for genetic counselors is before the legislature. Site visits are made to the 29 area genetic centers. Private contractors for services are monitored by GDB by data collection and visits.
The Laboratory Field Service unit is implementing a CLIA waiver program, which separates genetics as a specialty with subspecialties in cytogenetics and molecular biology. Regulations for special licensing are in process.
The legislature has a Select Committee on Genetics and Public Policy and has authorized the department to establish an Advisory Committee on Cloning. An extensive body of law has been developed with respect to genetic clinical and laboratory services. The law also prohibits genetic discrimination and protects confidentiality of genetic data.
Eugene Lenegrich, Director, Office of Epidemiology North Carolina Dept. of Health and Human Services
Elizabeth Moore, North Carolina Department of Health and Human Services
Shu H. Chaing, Ph.D., Branch Head, Newborn Screening/Clinical Laboratory, NC State Laboratory
The State Board of Public Health, as it was referred to in the early 70's, took the initiative to develop what we consider a model genetic services network. Initial funding for the planning, development and implementation of the North Carolina service network was made possible through the Genetic Diseases Act of 1973. It is through these years of experience that we would like to share some of our successes and frustrations. We continue to be visionary, realizing that new technologies and advancements will cause us to constantly analyze and re-evaluate where we are going.
Organization and Administration
The Genetic Health Care Branch is located within the Division of Women's and Children's Health (MCH).
There are six administrative staff in the Genetic Branch.
Six regional public health genetic counselors and nine regional sickle cell educator counselors facilitate communication with the comprehensive clinical genetic and hemoglobinopathies services (medical centers, hospitals) in order to provide appropriate patient services.
The Genetics Branch administers 17 contracts with medical centers, community hospitals, and community based centers for the provision of comprehensive maternal serum screening services, clinical genetic services, sickle cell services and newborn screening follow-up.
The total genetics budget is 5.5 million dollars. The MCH Block Grant contributes 633,470 of the total budget with the remainder coming from state appropriations.
Newborn Screening Programs
The North Carolina Administrative Procedures Codes mandates that a newborn screening specimen be sent to the State Laboratory of Public Health. The state laboratory tests specimens for primary hypothyroidism, phenylketonuria, galactosemia, congenital adrenal hyperplasia, and hemoglobinopathy diseases. Strong partnerships have been established by the laboratory with the Division of Women's and Children's Health (MCH); medical centers; North Carolina Pediatric Society; and the North Carolina Newborn Screening Advisory Committee. A pilot effort was initiated in July, 1997 which involves sending a newborn specimen to NeoGen Laboratory Inc. Dr. Naylor's laboratory analyzes the specimen for twenty to thirty inborn errors of metabolism through the use of tandem mass spectrometry technology. The state is collecting data to determine whether this technology should be established in the state laboratory.
Team Building through Collaborative Efforts
The success of the public health genetic services network is due to the collaborative efforts developed with the medical centers, local communities, parent support groups, legislature and with other public health programs. The focus of these efforts have been on pediatric and prenatal genetic services. Obviously, the time has come that we must address adult diseases such as heart disease, hypertension, diabetes, and cancers all of which have a genetic component. In order to do this, we will need many more resources.
Barbara DeBuono, M.D., M.P.H., Commissioner of Health, New York State Department of Health
Susan True, Director, Bureau of Chronic Disease Services, New York State Department of Health
Simon Spivack, M.D., Research Physician, New York State Department of Health
Kenneth Pass, Ph.D., Chief, Laboratory of Newborn Screening and Genetic Services
New York State Genetics Programs
New York State has one of the most comprehensive and integrated genetic service programs in the country. Research and policy development, prevention and treatment programs, education, quality assurance, and legislation contribute to the Department's goals of ensuring access, availability, and quality of genetics services. Within these areas, New York has unique and interdependent components.
Research and Policy Development
New York collects genetic data through a variety of registries and research projects: the newborn screening program; registries for cancer and congenital malformations; and a chromosome registry. The registries serve to both track incidence retrospectively and to project future health care needs.
New York has also implemented the Life and Law Task Force, to make policy recommendations on genetic counseling and anonymous testing, insurance access and reimbursement, discrimination, and confidentiality.
The American College of Medical Genetics was funded by the Department to develop, disseminate, and evaluate clinical guidelines for screening and testing for genetic risk of breast and ovarian cancer. Those guidelines are currently under Department review. Clinical guidelines for the assessment of infants with congenital abnormalities are under development.
Other current research is focusing on genetic susceptibility in individuals vulnerable to environmental pollutants such as cigarette smoke and the long-term effects of perinatal AZT exposure, and on a cooperative agreement with CDC to study outcomes of newborns with sickle cell disease.
Prevention and Treatment Programs
The Early Intervention Program, the Prenatal Care Assistance Program, and the Medicaid Obstetrical and Maternal Services Program all direct efforts to specific services for pregnant women and infants.
The Dental Rehabilitation Program provides treatment for clients with congenital or acquired facial malformations such as cleft palate.
Screening programs are in place for breast, colorectal, and cervical cancers, as well as a recent collaboration with Harlem Project to survey and educate about prostate cancer in African-American men.
Education and Training
The Genetics Services Program oversees $2.6 million in grants to 24 genetic service providers, which enables them to provide culturally sensitive, and clinically accurate services and education about genetics to primary care providers and the lay public.
The Department is the recent recipient of a training grant from the Association of Schools in Public Health to provide genetics education to public health workers in New York.
Broad-based educational efforts include education about use of folic acid to prevent neural tube defects and activities to prevent fetal alcohol syndrome.
Wadsworth Center-based activities include the annual Legislative Workshops for New York State legislators, a Public Health Lecture Series for the lay community, and a quarterly newsletter.
Quality Assurance and Monitoring
Through the Wadsworth Center, the Department has regulatory oversight of all laboratories conducting genetic tests in New York, or whose specimens originate in NY, and maintains a comprehensive database on the operations of these labs.
New York Public Health Law Article 5 identifies genetic testing as an area requiring licensure.
Legislation enacted in 1996 and amended in 1997 ensures confidentiality of genetic information and discusses use of this information by employers and insurers.
Mary Scisney, M.S.N., C.P.N.P., Director, Children's Health Branch/Genetics Coordinator
William J. Callan, Ph.D., Director, Bureau Clinical Laboratories, Alabama Dept. of Public Health
Anita Cowden, Dr.P.H., Epidemiologist, Alabama Department of Public Health
Acknowledging the importance of genetics in health care and policy brings an added dimension to the Alabama Department of Public Health's (ADPH's) view of the Department's role in the current health care environment. ADPH's role in performing core public health functions is being redefined by dramatic changes in this environment. For example, as managed care systems gain in subscribers and geographic reach, these systems may assume greater responsibility for preventive services. To adapt to these changes and facilitate the continued integration of local health departments into the overall system of health care, ADPH will need to review services of and relationships among traditional public and private providers of care, systems providing managed care, providers of genetic health care services, and other components of the overall health care system. In this presentation, representatives from the ADPH will: 1) provide an overview of the state's demographics and health care priorities; 2) discuss genetic health care services and resources in Alabama; and 3) review ideas being considered for future action. A discussion with the audience will follow.
SHARING THE LATEST INFORMATION ON GENETICS AND PUBLIC HEALTH: Existing and Planned Information Resources
Muin J. Khoury, M.D., Ph.D.
Acting Director, Office of Genomics and Disease Prevention
Centers for Disease Control and Prevention
HuGE Net represents the collaboration of individuals and organizations from diverse backgrounds who are committed to the development and dissemination of population-based human genome epidemiologic information The goals of HuGE Net are to: 1) establish an information exchange network that promotes global collaboration in the development and dissemination of peer-reviewed epidemiologic information on human genes; 2) develop an updated and accessible knowledge base on the World Wide Web; and 3) promote the use of this knowledge base by health care providers, researchers, industry, government, and the public for making decisions involving the use of genetic tests and services for disease prevention and health promotion.
The term human genome epidemiology (HuGE) denotes an evolving field of inquiry that uses systematic applications of epidemiologic methods and approaches in population-based studies of the impact of human genetic variation on health and disease. The spectrum of topics addressed in human genome epidemiology range from basic to applied population-based research on discovered human genes:
- Assess the prevalence of gene variants in different populations.
- Assess the magnitude of disease risk associated with gene variants in different populations (relative and absolute risks).
- Assess the contribution of gene variants to the occurrence of the disease in different populations (attributable risks).
- Assess the magnitude of disease risk associated with gene-gene and gene-environment interaction in different populations.
- Assess the validity of genetic tests in different populations (disease positive and negative predictive values).
- Evaluate the magnitude and determinants of the utilization of genetic tests and services in different populations.
- Evaluate the impact of genetic tests and services on morbidity, disability, mortality and cost in different populations.
Given the massive amount of population-based epidemiologic data that will be generated on human genes over the next decades, HuGE Net will represent a coordinated global effort to disseminate human genome epidemiologic information in order to keep up with the progress of the Human Genome Project and its accompanying gene discoveries. HuGE Net will evolve as a collaboration among epidemiologists, clinical geneticists, basic scientists, medical and public health practitioners from government, professional, academic, industry and consumer organizations worldwide.
Marjorie Cahn, M.A.
Head, National Information Center on Health Services Research and Health Care Technology
National Library of Medicine
The Centers for Disease Control and Prevention (CDC), National Library of Medicine (NLM), National Network of Libraries of Medicine (NN/LM), Association of State and Territorial Health Officials (ASTHO) and the National Association of County and City Health Officials (NACCHO) have formed a partnership entitled, "Partners in Information Access for Public Health Professionals" to provide public health professionals timely, convenient access to information resources to aid them in improving the health of the American public.
Objectives of the project include increasing awareness and use of NLM, NN/LM and CDC distributed learning resources among public health professionals; assisting public health professionals in obtaining the hardware/software, Internet connection, and satellite reception needed for effective access to information resources; training public health professionals to use the technology required for effective access to information resources; training public health professionals to identify and use pertinent information resources and services; and increasing awareness of public health professionals' needs and resources among NN/LM members.
This session will discuss NLM's resources, the partnership, and approaches for linking public health professionals with human genetics information.
Karina Boehm, M.P.H.
Education Coordinator, Office of Policy Coordinator
National Human Genome Research Institute
The National Coalition for Health Professional Education in Genetics (NCHPEG) was established in 1996 by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute. NCHPEG members are leaders from approximately 100 diverse health care professional organizations, consumer and voluntary groups, government agencies, private industry, managed care organizations, and genetics professional societies. The concept of such a Coalition emerged in response to the growing need for exchange of information and coordination of genetics education activities at the national level. Accordingly, one of the Coalition's top priorities is the creation of a centralized source of information on genetics and genetics education resources for health care professionals from all disciplines. So that it will be both easy to update and cost-effective, this tool will be primarily Web-based initially. A database of high quality genetics-related WWW sites for health care professionals and patients is currently under development and will be accessible via the NCHPEG Web site. Plans for future genetics information modules will be discussed, as will efforts to capitalize on the collective expertise of Coalition members through the use of a password-protected, interactive members section of the NCHPEG Web site.
PUBLIC HEALTH GENETICS: Ethical, Legal and Social Issues
Balancing Individual Interests, Group Interests, and the Public Health: Addressing the Special Issues Raised by Genetics
Ellen Wright-Clayton, M.D., J.D.
Associate Professor of Pediatrics
Associate Professor of Law
Until recently, debates about the limits of the state's power to intrude on individuals' interests to promote the health of the public centered on two practices: efforts, ranging from immunization to quarantine, to prevent the spread of infectious disease from one individual to another, and measures directed to protection of large segments of the population, such as the fluoridation of water and pasteurization of milk. While the problems have remained much the same, this debate about the state's power has evolved greatly in recent years in response to such challenges as the emergence of HIV and the re-emergence of TB and growing concerns about privacy and stigmatization.
The focus of this presentation will be on the problems that may be presented by a new public health activity, namely, efforts in the public health context to more fully understand the impact of the interactions between genes and environment on the public health. Some of these problems, such as those of privacy and preservation of confidentiality, are raised by other aspects of public health practice as well. Greater understanding of genetics also poses unique problems. Learning which mutations contribute to ill health defines individuals who are unalterably at risk of becoming ill themselves; that their genetic makeup cannot be changed although environmental intervention may prevent them from developing disease. Their having a mutation, however, cannot make another person more susceptible to becoming ill. The question then is to define the extent to which the state can and should be able to obtain genetic information about individuals and groups in order to direct public health intervention. In this discussion, I will address both the arguments in favor of public health access to genetic information, which include cost efficiency and desires to avoid potential side effects of intervention to those not at risk, as well as the arguments against such access, including concerns about privacy and discrimination.
Robert F. Murray, M.D.
Chief, Division of Medical Genetics
Howard University College of Medicine
The public health approach to genetic screening places major emphasis on prevention of the occurrence or manifestation of a particular disorder. If that is not feasible, a secondary approach is to identify the high risk individual and institute a program of early presymptomatic screening followed by active and aggressive treatment to minimize any critical expression or manifestation of the condition. Newborn screening programs currently operating illustrate this latter approach.
This model works reasonably well and is ethically acceptable when the disorder to be treated will have serious, irreversible, or possible lethal effects in the individual who is affected. In this situation, the risk/benefit ratio will more than likely be to the benefit of the individual identified to be at risk or be affected.
The same cannot be said of the person screened when the disorder being identified will not manifest for a number of years, especially when the treatment available may be of questionable value or where there is no known effective intervention. The issue is even more complex when the identifier merely places the individual in a category of increased risk to develop the condition. The ethical and legal conflicts that will arise for individuals so identified are made more contentious and are likely to result in more serious negative consequences when the population of individuals tested are members of a minority group. In today's managed care and health insurance environment minority individuals are more likely to experience negative rather than positive consequences based on past experience. There is no clear cut or ready solution to this public health dilemma. Before embarking on any genome-based screening programs, however, it is imperative that one be found.
Eric T. Juengst, Ph.D.
Associate Professor of Biomedical Ethics
Cleveland Case Western Reserve University
The prevention of human disease is a time-honored and honorable goal of public health professionals. What might it mean, however, to use the special tools and authorities of public health agencies to attempt to prevent genetic disease? A number of different kinds of prevention are possible in this regard, but attempts to locate them within traditional public health categories like "primary, secondary and tertiary" prevention have been confusing. Carrier screening, for example, has been classified by different authorities as all three types! In this talk, I will offer another approach. I distinguish between two senses of "prevention" that are often conflated in public health genetics: "phenotypic prevention" and "genotypic prevention." Phenotypic prevention describes medical efforts to forestall the clinical manifestations of a genetic disease in an at-risk patient, like newborn screening and dietary prophylaxis for PKU. Genotypic prevention, on the other hand, describes efforts to avoid the transmission of particular genotypes to the next generation, like selective termination following intrauterine diagnosis. Genotypic prevention can either be performed on behalf of prospective parents as a reproductive risk reduction strategy, or as a public health intervention to reduce the incidence of a disease in the larger population. Conflating phenotypic and genotypic prevention in discussions of public health genetics is dangerous, because it blurs the line (well established in clinical genetics) between interventions appropriate to prescribe to individuals and families and reproductive choices that should be theirs alone to make. While reproductive risk reduction is a legitimate goal for individuals and families to pursue, I argue that public health officials should follow the lead of their colleagues in clinical genetics and eschew genotypic prevention as an overarching aim of their work.
Lawrence O. Gostin, J.D., LL.D (Hon.)
Professor of Law
Georgetown University Law Center
There exists a broad and rich literature on the ethical, legal, and social aspects of the human genome. Much of this literature focuses on decisions about the financing and delivery of care to individual patients, and the resulting ethical and legal problems. Thus, much of the public discourse concerns issues of testing and consent; disclosure of information and privacy; health care access and insurance discrimination; and occupational safety and employment discrimination.
These are highly appropriate issues to discuss and they effect individual relationships between physician and patient. What results would accrue if, instead of examining these issues from the perspective of physician and patient, we examined these issues from the perspective of whole populations? This paper will discuss the law, ethics and public policy relating to application of human genetic technologies on whole populations. The questions to be discussed will involve genetic screening of large populations, as well as privacy and discrimination concerns that ensue.
Genetic technologies have real promise for improving the health of populations in fundamental ways. These human goods have to be preserved while society seeks to determine the effects on constitutionally protected and other fundamental rights, including interests in autonomy, privacy, and anti-discrimination. This paper will examine the trade-offs between the fundamental importance of improved morbidity and mortality on the one hand, and diminution of liberty interests on the other.
GENETICS AND CHILD HEALTH
Forecasting the Genetic Health of New York State: DNA Analysis of Newborn Screening Dried Blood Spots
Michele Caggana, Sc.D
Director, Molecular Genetic Epidemiology Laboratory
New York Department of Public Health
As the Human Genome Project approaches completion, many more genes contributing to diseases that affect large segments of our population will be discovered and their functions elucidated. The utility of newborn screening programs as a successful mode of preventing the manifestations of some genetic diseases is already well established. These programs can also be an efficacious springboard for the development of epidemiological studies designed to help us understand genetic disease. The Molecular Genetic Epidemiology Laboratory (MGEL) at the New York State Department of Health has developed sensitive, high throughput DNA methods to analyze various genes which are relevant to the public health of New York. These DNA analyses are carried out on the material remaining on Guthrie cards after the routine newborn screening tests are complete. Examples of these techniques will be shown. MGEL has three goals. The first is to enhance the newborn screening program by providing detailed molecular analyses of particular specimens. For example, molecular techniques may be used to confirm the genotype of some of the hemoglobinopathies diagnosed by newborn screening. Furthermore, b-globin haplotypes can be studied to estimate the severity of sickle cell disease in newborns. A second goal is to assimilate population-based allele frequency data, which is used to design large scale consented molecular studies for common complex diseases. For example, preliminary studies on two putative asthma genes will be presented. The third goal is to provide these frequency data to policy makers whose task is improving public health. To illustrate this goal, studies of two variants of the HFE gene, which causes hereditary hemochromatosis, will be presented. The overall goal of these studies is to further our understanding of the mechanisms by which various genetic factors contribute to common multifactorial diseases. One major accomplishment arising from these studies will be the design of treatment methods that ameliorate the inherited genetic component of disease in individuals at risk before disease manifests or becomes more severe.
Mortality among Children with Sickle Cell Disease Identified by Newborn Screening: California, Illinois, and New York, 1990-1994
Richard Olney, M.D., M.P.H.
Birth Defects and Genetic Diseases Branch
National Center for Environmental Health
In a study of U.S. death certificates for 1968-1992, mortality among black children aged 1-4 years who had sickle cell disease declined significantly. This trend occurred at the same time as the establishment of newborn screening programs, more comprehensive care and parental education, widespread acceptance of penicillin prophylaxis, and new vaccinations. One of the Healthy People 2000 objectives (14.15) is to increase to 90% the proportion of newborns testing positive for sickle cell disease who receive appropriate treatment. To study the effectiveness and utilization of prevention programs among large populations of infants with sickle cell disease, several newborn screening programs in the United States are now attempting to determine rates of complications and actual use of early medical interventions (e.g., penicillin prophylaxis and pneumococcal vaccination). Findings from outcome studies in California, Illinois, and New York indicate low mortality rates among children born in the early 1990s (1% or 0.35 deaths per 100 person-years for children < 3 years old with hemoglobin SS). The rate of compliance with penicillin prophylaxis is unknown among the decedents and the survivors; a risk factor study is currently under way to analyze this and other factors potentially associated with death as well as other serious complications.
GENETICS AND CANCER
Will Genetic Testing for Breast Cancer Risk Help Control Breast Cancer? Attitudes of At-Risk Women Offered BRCA1/2 Testing Toward Early Detection and Risk Reduction Behaviors
Gail Geller, Sc.D.
Johns Hopkins Medical Institutions
Genetic testing technologies raise new questions about what it means to prevent or control disease. Drawing on public health perspectives of disease prevention and health services research, this paper will: (1) explore what it means to prevent or control inherited breast cancer; (2) discuss ways of evaluating prevention and control efforts; (3) present results of a survey of 403 women at increased risk for breast cancer regarding their attitudes toward possible interventions to lower their risk of breast cancer or detect cancer early; and (4) explore whether those who chose to undergo BRCA1/2 education, counseling and testing differ in their attitudes toward early detection and risk reduction behaviors from those who declined education and testing. One purpose of our survey was to assess the likelihood that at-risk women would alter their reproductive plans as a result of testing (i.e., engage in primary prevention), as well as what intervention(s) they would be likely to follow if they had a mutation (i.e., engage in secondary prevention efforts). Possible interventions included more intensive surveillance (mammography and clinical breast exam), prophylactic mastectomy, participation in chemoprevention trials and lifestyle changes such as diet and exercise. There is a significant reduction in interest in testing after women are educated about the limitations of testing and follow-up interventions (from 79% to 8%). Overall, only 9% of women would be discouraged from having children knowing that they would pass the abnormal gene on to them. Only 1% would be very likely to abort if they were pregnant and knew they were going to have a daughter with a breast cancer susceptibility mutation. These numbers were too small to see if they differed by actual interest in testing. In terms of attitudes toward various intervention(s), most women would undergo intensive surveillance. Most women also would reduce their intake of fatty foods and alcohol, despite the fact that less than half of respondents thought such environmental exposures could cause cancer. Only 7% would undergo prophylactic mastectomy and about 40% would participate in research on preventive drugs. Women who attended BRCA1/2 education and counseling would be more likely to participate in chemoprevention research than women who did not attend (54% vs. 36%, p<.01). Women who actually pursued testing by involving an affected relative would be more likely to have prophylactic mastectomy than women who did not pursue testing (15% vs. 2%, p=.03). These data suggest that, at the current time, genetic testing for breast cancer susceptibility is not likely to improve either primary or secondary efforts to prevent breast cancer. At-risk women do not seem very interested in predispositional or prenatal test utilization after being educated about the limitations of testing, including the efficacy (benefit) of preventive interventions. The paper will conclude with a discussion of how and why these parameters might change in the future.
Gloria M. Petersen, Ph.D.
Associate Professor, Department of Epidemiology
School of Hygiene and Public Health
and Department of Oncology, School of Medicine
The Johns Hopkins University
Since 1987, significant strides have been made in characterizing the genetic events that lead to colorectal cancer. This work has been based on detailed clinical-family studies and molecular genetic studies of colorectal tumors. Acquired genetic alterations seen in tumors include APC and MCC on chromosome 5q, K-RAS on chromosome 12p, DCC on chromosome 18q, GTBP on chromsome 2p, and p53 on chromosome 17p. In addition, an important strategy in identifying genes involved in colorectal neoplasia has been the study of colorectal cancer syndromes, through which we have discovered specific genes that are the basis of inherited cancer susceptibilities.
Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis (FAP), an autosomal dominant syndrome, clinically characterized by young onset (age 12-15 yr), hundreds of adenomatous polyps in the colon, and increased risk for gastric polyps, duodenal cancer, thyroid cancer, and desmoid tumors. We have recently discovered a missense mutation, APC I1307K, in the Ashkenazi Jewish population (Laken et al., Nature Genet 17:79, 1997).This particular mutation does not in itself cause polyposis or cancer, but instead is a true cancer predisposition gene because it creates an instability in the colon cell's gene that then may develop a more deleterious mutation that can lead to cancer. We have found the APC I1307K mutation to occur in about 6% of the Ashkenazi Jewish population, and among 10% of Ashkenazi Jews with colorectal cancer. Among such patients with a family history of colon cancer, the proportion who have the mutation is even higher (28%). The novel mechanism for cancer predisposition may partially explain the reduced penetrance of this mutation.
Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with specific somatic alterations in the tumor, characterized by high microsatellite instability (MSI-H). HNPCC is characterized by young onset colorectal cancer (mean age 42-45 yr), proximal colon location, multiple primary cancers, and increased risk of endometrial cancer, transitional cell cancer of the ureters, small bowel cancer, gastric cancer, bile duct cancer, and ovarian cancer.
Cancer gene discoveries have led to clinical application in the form of improved cancer genetic risk assessment and genetic testing. We have shown that molecular diagnostic testing can better characterize syndromes, diagnose and potentially improve management of mutation carriers, and allow presymptomatic diagnosis of mutation carriers in at risk persons to whom interventions will be more accurately directed, along with concomitant improvement in adherence to cancer prevention recommendations.
Paul A. Schulte, Ph.D.
Director, Education and Information Division
National Institute for Occupational Safety and Health
Centers for Disease Control and Prevention
Of most concern with occupational cancer are genes which have multiple alleles and are sometimes referred to as "metabolic polymorphisms." These are genes which specify enzymes involved in metabolism or detoxification of xenobiotic carcinogens. They generally do not confer risk on their own but only in combination with specific exposure. These genetic markers may be used as effect modifiers in epidemiologic studies, to gain mechanistic insight in laboratory studies, as candidates for screening workers for job placement, and for assessing life and health insurance risks. In research, the ethical, legal, and social issues pertain to how and why biologic specimens are obtained from participating workers, how the results of studies are interpreted and communicated to participants, and the extent to which privacy and confidentiality are maintained. For genetic screening for job placement, no metabolic polymorphisms have yet to meet the criteria of strong predictive value for occupational disease. Additionally for workers already employed, genetic screening needs to be considered in conjunction with established approaches to control the workplace. For insurance purposes, metabolic polymorphisms have been rarely mentioned in the literature but would be subject to meeting criteria for high predictive value and attributable proportion. Genetic marker information is useful in assessing occupational cancer risks. Study of gene-environment interactions may increase the ability to characterize relatively low cancer risks if a substantial proportion of the population cancer burden is attributed to high risk in a smaller group of genetically susceptible members exposed to the compound of interest. On the horizon is the capacity to analyze many genetic markers using high throughput technologies. The expectations of researchers is that genes will be measured before and after exposure. This is the leading edge of batteries of biomarkers to assess exposure, effect, and susceptibility and gene-environment interactions. The ability to make sense of complex arrays of genetic expression data has little precedent and will likely raise additional ethical issues.
Economic Implications of Genetic Screening for Cancer Susceptibility: The Case of Hereditary Nonpolyposis Colorectal Cancer
Scott D. Ramsey, M.D., Ph.D.
Departments of Medicine and Health Services
University of Washington
Colorectal cancer is the third most common non-skin cancer in the United States and the world, accounting for 9% of all malignancies. As many as 5-10% of all colorectal cancers occur in individuals who have hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal dominant disorder linked to germline defects in at least four mismatch repair genes. Individuals who carry the HNPCC mutation(s) have a 65%-95% lifetime risk of developing colon cancer, with a median age of onset of 42 years, compared to an average age of onset of over 60 and a lifetime risk of 6% for the general population. The genetic mutations responsible for HNPCC could have a frequency as high as 1 carrier per 200 in the general population.
A fundamental issue related to genetic screening for HNPCC is selecting a screening strategy that balances the desire to identify and intervene to reduce colon cancer-related mortality and morbidity against the direct and indirect costs of testing. Although almost every screened individual will experience some degree of anxiety and worry before and after the test, only a fraction of those tested will be found to carry mutations for HNPCC, and not all carriers detected will benefit from surveillance and treatment. Furthermore, widespread use of costly genetic tests could consume a tremendous amount of societal resources. Finally, HNPCC mutation carriers who are otherwise healthy may be at risk for experiencing employment problems and difficulty obtaining health and life insurance. Although the costs of screening will be incurred soon after the genetic tests for HNPCC become widely available, the benefits of screening will not be known for years. Therefore, it is critically important to apply the best available techniques for estimating costs and benefits so that rational screening policies for HNPCC can be implemented while waiting for more complete data.
Cost-effectiveness analysis is a useful technique when the goal is to identify the strategy that produces the most health benefit per dollar spent from a set of options that produce a common effect, such as alternative genetic screening strategies for HNPCC. This analysis can also be useful when information is incomplete, as is the case with genetic screening for HNPCC, because the process gives structure to the problem, allows open consideration of all relevant effects of decisions, and forces explicit treatment of key assumptions. Information from modeling can be used to help guide genetic screening policies by improving the benefit/harm ratio resulting from application of this technology.
GENETICS AND CHRONIC DISEASES
Richard Mayeux, , M.D.
Director, Sergievsky Center
The risk of Alzheimer's disease increases steadily from approximately 1% per year between the ages of 60 to 65 years to about 10% after age 85 years. The risk differs only slightly for men and women, but the risk is significantly higher for those with a parent or sibling affected with Alzheimer's disease. The risk is also significantly higher for African-Americans and possibly some Hispanic ethnic groups.
Alzheimer's disease is best considered an example of a "complex" disorder. By definition, complex disorders result from the variable contributions of one or more genes and from environmental influences. Early-onset familial Alzheimer's disease has already been associated with mutations in three distinct genes: the amyloid precursor protein on chromosome 21, presenilin I on chromosome 14 and presenilin II gene on chromosome 1. The 4 allele of the APOE gene is the first major "genetic" risk factor for both sporadic and familial late onset Alzheimer's disease. However, the APOE-,4 is neither necessary or sufficient to cause Alzheimer's disease. Age and the number of years of formal education have been consistently associated with increased risk, while parental age, a family history of Down Syndrome or Parkinson Disease and traumatic head injury have been found to be inconsistently related to the risk of Alzheimer's disease.
Nonetheless, it is now possible to identify individuals at high risk, but effective strategies to prevent the disease limit the usefulness of this potential. Results of recent observational studies may change this perspective. Estrogen use by postmenopausal women, steroidal and nonsteroidal anti-inflammatory agents, and possibly antioxidants and other dietary supplements have been associated with a lower risk of Alzheimer's disease, suggesting possible therapeutic strategies.
Primary prevention of Alzheimer's disease will require treatments or interventions that would be used by a large number of individuals, such as most elderly, who may or may not be at higher than average risk for the disease. In contrast, secondary prevention will target individuals at highest risk, such as asymptomatic gene carriers. Minimal adverse effects would be a necessity for primary prevention, but less a concern in secondary prevention where disease risk is highest. Clearly, the goals of any "preventive" treatment will be to reduce the overall incidence of disease, but as a first step, simply delaying the onset of Alzheimer's disease for several years may prove to be very effective.
Roger R. Williams, M.D.
University of Utah
Molecular geneticists are collaborating with genetic epidemiologists and clinicians to identify many different genetic variants that promote coronary heart disease (CHD), strokes, and their risk factors (dyslipidemia, hypertension, obesity, diabetes, etc). Helping millions of patients who carry these genes now requires more effective and better coordinated efforts by primary care physicians, specialists, and public health professionals. Genetic factors proven or suspected to contribute to mechanisms promoting early CHD and stroke include familial dyslipidemias, hypertension-stroke syndromes and hyperhomocyst(e)inemia. Practical concepts are presented for preventing early deaths from CHD and strokes due to genetic factors that offer opportunities for more effective diagnosis, early treatment and prevention!
The most common familial lipid disorders can be divided into three major categories: lDL disorders (FH, FDB, and PH); triglyceride associated disorders (FCHL and Type III); and HDL disorders (isolated low HDL or predominantly low HDL). Making an accurate diagnosis is important because methods of treatment are different. However, medical records seldom contain these specific diagnoses or diagnosis-specific approaches to treatment. Making an accurate diagnosis usually requires collecting clinical and blood lipid data from index cases and their close relatives. The basic components of an informative and useful family history (FHx) are presented in conjunction with a sample FHx form for use in clinical practice. A screening FHx takes less than 5 minutes but a complete and detailed FHx required for accurate genetic diagnosis may take 6 months to collect from relatives. Effective diet can drop cholesterol 10-20% without nutritional imbalance with the help and follow up of a trained dietician (RD). In many persons with serious familial lipid disorders the effect of genes promoting dyslipidemia is often more than double the practical effect achievable with diet, and thus medication is generally required for inherited dyslipidemias.
Severe dominant forms of hypertension leading to very early strokes include glucocorticoid remediable aldosteronism (GRA), Liddle's Syndrome, and multiple endocrine adenopathy type II (MEA-II). Without proper diagnosis and treatment these disorders lead to severe hypertension (e.g. 220/120) in early adult life and death from stroke in the 4th decade of life. Specific causal genes have been identified for each of these disorders. Normal blood pressures can be achieved with spironolactone or dexamethasone therapy for GRA, triamterene or amiloride for Liddle's Syndrome, and detection of tumors with MRI or CT scans and surgical removal for pheochromocytomas in those with MEA-II.
Common genes promoting hypertension are now being detected. The best characterized is angiotensinogen. A common variant at this locus (M235T/G-6A) seems to promote salt-sensitive hypertension in the homozygous TT/AA carriers. Two clinical trials suggest that risk of hypertension is much higher while prevention of hypertension using sodium restriction is more effective in those with this "susceptible genotype," which is found in about 20% of Caucasians and 72% of African Americans.
Hyperhomocyst(e)inemia promotes early CHD probably by promoting thrombogenic aspects of atherogenesis. It can result from lower than average vitamin intake (folate, B12, and B6) and genetic enzyme deficiency (methylene tetrahydrofolate reductase MTHFR, or cystathionine beta synthase CBS). Detection and treatment are both feasible.
Relative screening should be performed for all first degree relatives of persons with early CHD, for siblings of persons with polygenic hypercholesterolemia (PH), recessive Type III hyperlipidemia, and MTHFR with CHD. Extended relatives including cousins on the affected side of the family should be screened in families with heterozygous familial hypercholesterolemia (FH), familial defective apo B (FDB), familial combined hyperlipidemia (FCHL), dominant type III, dominant low HDL with CHD, and dominant hypertension-stroke syndromes (GRA, Liddle?s Syndrome, and MEA-II).
Long term compliance with both diet and medication are often poor even in persons with deadly but treatable serious disorders, such as heterozygous FH. Family and peer support, freedom from side effects, and simple treatment regimen are some of the main predictors of long term compliance physicians should understand and apply. To recruit spouse support of compliance it is suggested patients bring spouses to each follow up visit. Here are simple summary phrases to emphasize important concepts:
- A treatable lipid is usually familial.
- Help families and not just individuals.
- The spouse is a key to compliance.
- Helping high risk families often requires contacting relatives.
- Successful family risk reduction is not a do-it-yourself project.
- Involve patients with MD, RD, RPh, RN, spouse, and other relatives!
Wylie Burke, M.D., Ph.D.
Associate Professor of Medicine
University of Washington
Centers for Disease Control and Prevention
National Center for Chronic Disease Prevention and Health Promotion
Hemochromatosis (HH) is an autosomal recessive disease of iron regulation, resulting in excessive iron absorption and ultimately in iron overload, leading to end organ disease. Complications of HH include cirrhosis, primary liver cancer, cardiomyopathy, arthritis and diabetes. Screening studies using serum iron measures suggest a prevalence of 1/200-1/400. The rate of symptomatic diagnosis is much lower; likely contributors to this discrepancy include both underdiagnosis and lack of disease progression in some affected individuals. In all clinical series, males outnumber females. HH is much rarer in Asians and African-Americans than in people of European descent. A different iron overload syndrome, probably genetic, has been described in African-Americans and sub-Saharan Africans. In 1996, a candidate gene for HH was identified adjacent to the major histocompatibility locus. The gene has been designated HFE (it was referred to as HLA-H in some initial studies). The function of the HFE protein is not yet known. Two HFE mutations have been defined: C282Y and H63D. Most affected individuals in clinical series reported to date have been homozygous for C282Y. However, the carrier rate in control populations was 2-14% for C282Y and 4-24% for H63D. Low penetrance of H63D is thus suggested by the low percentage of H63D homozygotes among cases, despite a higher carrier rate for H63D than for C282Y. Incomplete penetrance of C282Y is likely as well, because C282Y homozygotes without evidence of iron overload have been documented among siblings of individuals known to be affected with HH. Both alcohol and high dietary intake of iron are thought to increase the likelihood of clinical disease in HH. Hepatitis C infection or other liver insults may increase the likelihood of liver disease. Loss of iron through menstruation and pregnancy is postulated to be protective, accounting for the lower incidence of clinical disease in women. No data are yet available on interactions between HH genotypes and modifiable risk factors. Removal of iron by phlebotomy increases survival in symptomatic patients. In a small cohort, institution of regular phlebotomy (3-4 times per year) prior to the development of cirrhosis or diabetes was associated with an apparently normal life expectancy. However, the likelihood of clinical symptoms in asymptomatic people (i.e. the penetrance of HFE mutations) is unknown. Transferrin saturation (TS=serum iron/total iron binding capacity X 100) has been used in screening trials to identify presumptively affected people, with confirmation of diagnosis by liver biopsy. This screening approach has been estimated to have a positive predictive value of 60-70%. Reliable sensitivity, specificity and predictive value for tests for HH genotypes cannot yet be determined, because of the absence of population-based data correlating genotype, serum iron measures and disease status. Individuals with HH are not currently considered suitable blood donors in the US, because phlebotomy is done for other than altruistic reasons; this policy represents a potential barrier to adequate treatment of individuals identified in screening programs.
There have also been anecdotal reports of loss of insurance after a diagnosis of HH, suggesting a potential for discrimination on the basis of a genetic disease diagnosis. Thus, a number of questions need to be resolved before public health screening programs are considered, including the efficacy of phlebotomy in asymptomatic individuals and the effect of an HH diagnosis on self-perception, family relationships, access to health care, employment, and insurance. Before screening occurs, population-based research is needed to define genotype-phenotype correlations and to assess both clinical and social outcomes of screening programs. The relative merits of screening with TS vs. a test for HFE mutations will be determined not only by predictive value of the tests but also by individual and public perceptions of the meaning of genetic information.
PUBLIC HEALTH GENETICS RESEARCH AND TRAINING PRIORITIES
Jack A. Taylor, M.D., Ph.D.
Head, Molecular and Genetic Epidemiology Section
National Institute of Environmental Health Sciences
Disease risk is a consequence of both an individual's genotype and their environmental exposure. In the past these two areas largely have been studied independently of one another. With the advent of rapid sequencing technologies and the polymerase chain reaction (PCR), rapid genotyping of large numbers of individuals is now practical. Population-based studies of genetic susceptibility and environmental exposure are important for identifying both the alleles and agents that cause disease and in quantifying the risk of disease. Although about 7,000 of the estimated 60,000 genes in the human genome have been identified and sequenced, there is to date no systematic effort to identify polymorphisms in these genes. The National Institute of Environmental Health Science's (NIEHS) Environmental Genome Project is being designed to search for common functional polymorphisms in 200 known genes that are important in environmentally-associated diseases. This project will take place in three overlapping phases. Phase 1 includes population and candidate gene selection; Phase 2 includes gene resequencing and web-based database reporting; and Phase 3 includes functional and epidemiologic studies of polymorphisms. The ultimate goal of the project is to provide a better scientific basis for risk assessment and regulation of environmental exposures and for the protection of susceptible subgroups.
Steve M. Teutsch, M.D., M.P.H.
Senior Research Scientist
Outcomes Research and Management
Merck and Company, Inc.
Prevention effectiveness studies provide answers to key questions for developing and implementing public health interventions and facilitating choices of alternative strategies for achieving public health goals and establishing priorities. Genetics provides new methodologic challenges for prevention effectiveness research. To establish the value of genetic interventions we need to provide answers to basic questions:
- How big is the problem?
- What can an intervention accomplish?
- What does an intervention accomplish in actual practice?
- What are the benefits and harms?
- What is the value of the benefits and harms?
- What does the intervention cost?
- What would additional resources produce?
- What do we recommend?
Our challenge is to formulate critical policy issues and to conduct the necessary studies. These require skills in descriptive and analytic epidemiology, economics, outcomes research, decision analysis, quantitative policy analysis, and evidence-based medicine.
Patricia A. Peyser, Ph.D.
Professor of Epidemiology
Director, Public Health Genetics-Interdepartmental Concentration
University of Michigan
The University of Michigan School of Public Health has initiated a new program, the Public Health Genetics Interdepartmental Concentration. This program is offered to graduate students seeking M.P.H., M.S., Dr.P.H., or Ph.D. in all five departments in the school. The focus is genetics in Public Health: students gain knowledge of how genes, together with the environment and behavior, influence health and disease. The objective is to enable students to apply genetic information into their areas of public health practice. Faculty from throughout the University participated in establishing the requirements and goals for the program.
This program does not extend training time or alter degree requirements. The curriculum consists of twelve credits distributed among three core courses and an elective. The first core course, Introduction to Genetics in Public Health, provides the basic scientific understanding of human genetics, as well as applications, current research, and anticipated scientific advances. The second course, Genetics in Epidemiology, relates genetics to the core public health discipline of epidemiology, emphasizing the use of genetics to help describe disease frequency and distribution and to gain insight into disease etiologies. The third course, Issues in Public Health Genetics, analyzes ethical, legal, social, and policy issues arising from the increasing application of genetic technology to the health of individuals and populations. The core courses and electives are open to all public health students as well as others. For students in the program, departmental required internships and independent studies are directed towards areas related to public health genetics.
Seventeen students enrolled in the program in the Fall of 1996. They will graduate in Spring of 1998. These students were joined by an additional 13 students in the Fall of 1997. Currently, every department in the school is represented among the students. The program has increased interdisciplinary collaboration among both students and faculty from different departments and schools.
Several different initiatives at other institutions are underway to bring genetics into Public Health. It has even been suggested that genetics should be one of the core fields for public health training. The new programs provide future public health professionals training opportunities that enable them to function at the cutting edge of this important new area of Public Health.
GENETIC TESTING PROCESS AND PUBLIC HEALTH
Promoting Safe and Effective Genetic Testing in the United States: The Report of the Task Force on Genetic Testing
Neil A. Holtzman, M.D., M.P.H.
Professor, Johns Hopkins Medical Institute
Genetic testing has been transformed over the past twenty years from essentially a not-for-profit service provided by academic medical centers (karyotyping and biochemical testing) and state health departments (newborn screening) to a largely for-profit service of biotechnology companies. Commercial organizations have encroached on services provided by the academic centers. Recently, they show interest in assuming a greater role in newborn screening. They also provide most testing for common, gene-influenced disorders, such as breast and colon cancer. Even before this transition, problems of ensuring the validity and utility of genetic tests and their performance in laboratories of assured quality, were evident. For instance, health departments sometimes added tests to their newborn screening repertoire without adequate evidence of their value, and proficiency testing sometimes revealed laboratories performing outside of acceptable ranges of variation. The introduction of the profit motive introduces another challenge. Tests are sometimes rushed to market in a lax regulatory environment and without adequate consideration of the ability of health care providers and consumers to understand their indications and implications.
The Task Force on Genetic Testing was created by the NIH-DOE Working Group on Ethical, Legal, and Social Implications of Human Genome Research to examine genetic testing in the U.S. and to make recommendations to ensure the safety and effectiveness of genetic tests. Safety and effectiveness encompass validity and utility, laboratory quality, and appropriate use by health care providers and consumers. Task Force members represented a range of stakeholders in genetic testing as well as federal agencies that play a role in genetic testing and education. To meet its objectives the Task Force recommended that before tests are introduced into the clinical arena evidence must be collected on their utility and validity under IRB-approved protocols and that the findings be reviewed by a body independent of the test developer. It also recommended the creation of a genetics specialty under the Clinical Laboratory Improvement Amendments of 1988, and suggested the need for demonstration of competence by providers who ordered predictive genetic tests. At the request of the Secretary of Health and Human Services, a federal inter-agency working group is actively considering the Task Force's recommendations.
Ginette Y. Michaud, M.D.
Food and Drug Administration
The FDA is working cooperatively with CDC, HCFA, and other groups within the department of Health and Human Services to develop better mechanisms for responding to the recommendations of the Task Force on Genetic Testing. Regulatory and scientific issues raised by genetic tests present a unique challenge to the agency. Options for oversight range from the current application of the Clinical Laboratory Improvement Amendments (CLIA) statutes to the more intensive oversight of the traditional FDA regulatory process. The Division of Clinical and Laboratory Devices is responsible for the premarket review of in vitro diagnostic devices (laboratory tests). We currently process over 1000 diverse applications per year. The nature of review is dependent on the novelty of the product. New versions of old devices are handled as premarket notifications or so-called 510(k) submissions. The review objective is to establish that the new product is "substantially equivalent" to its predicate. Fundamentally new devices are handled as premarket applications or PMA submissions. Since no predicate is identified, the review objective for these is to establish de novo that the product is "safe and effective." A central regulatory issue over the past several years has been the development of a standardized model for sound scientific review. More recently, the agency has also concentrated on introduction of management initiatives to direct and prioritize review resources. The agency recognizes that while it plays a key role in safeguarding the public from poor devices, its role in fostering new technologies and providing timely review and introduction of these is also critical to public health. The FDA is committed to determining the best approach for accomplishing this in the area of genetic testing.
James Marks, M.D., M.P.H.
Director, National Center for Chronic Disease Prevention and Health Promotion
Centers for Disease Control and Prevention
Deborah Klein-Walker, Ed.D.
Assistant Commissioner, Bureau of Family and Community Health
Massachusetts Department of Public Health
The remarkable research achievements of the Human Genome Project present public health with a host of possibilities for the future. Almost daily, news media report the discovery of genes involved in diseases affecting the health of children (e.g., cystic fibrosis, sickle cell disease, birth defects, asthma), as well as those affecting millions of adult Americans (e.g., cancer, Alzheimer's disease, liver disease, cardiovascular disease, AIDS, and occupational diseases). However, it will take more than the identification of genes for human genetics to benefit the health of the public. Such discoveries require translation if they are to aid in reducing morbidity and mortality. Public health must assume a leadership role in the translation process. Transforming discoveries in human genetics into public health action will require the collection of population-based data (on the scope and population distribution of specific genes, gene-environment interactions, the impact of genetic testing, laboratory practices and quality assurance issues, availability of effective and acceptable interventions, etc.), the training and education of public health professionals, and effective communication and information dissemination. Translation will also require meeting the challenges presented by ethical, legal and social issues and strong partnerships between states, academia, federal agencies, and the private sector. With effective public health leadership, the next millennium will see a new paradigm of individualized preventive medicine.