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Meeting Report
Applying Genetics and Public Health Strategies to Primary Immunodeficiency Diseases
November
8-9, 2001
Atlanta,
Georgia
Prepared
by:
Office of
Genomics and Disease Prevention
Centers
for Disease Control and Prevention
Department of Health and Human Services
Executive
Summary
Overview On November 8-9, 2001, the Centers for Disease Control and Prevention (CDC), convened a panel of more than 50 experts in clinical immunology, public health, genetics, and communication from state and federal agencies, academic centers, public health laboratories, professional organizations, and advocacy foundations to identify genetic and public health strategies that can be applied to primary immunodeficiency (PI), a diverse group of more than 95 disorders, many of which result from single-gene defects. The defects may affect one or more components of the immune system and lead to a characteristic increased susceptibility to recurrent and persistent infections. Recent advances in molecular biology and genetics have led to the identification of the genetic defects for many of these diseases and prompted the development of promising new diagnostic tools and therapies. During the meeting, experts outlined a framework for a public health approach to PI diseases, as a model for a public health approach to other single-gene disorders. Participants assessed the public health impact of PI and examined public health interventions to prevent morbidity, disability, and mortality and to improve health outcomes. They reviewed data available for a public health assessment of PI diseases; examined uses of laboratory tests-particularly genetic tests-and their role in clinical practice; and discussed potential public health interventions, including enhanced early clinical recognition, population-based screening, and education and outreach to increase awareness of these diseases. Background The public health framework is based on a combined genetic-epidemiologic approach with four components: (1) public health assessment; (2) evaluation of genetic testing; (3) development, implementation, and evaluation of population interventions; and (4) communication and information dissemination. Each of these components requires (1) partnerships and coordination of genetic and public health activities; (2) attention to the ethical, legal, and social issues that can arise when applying genetics to health promotion and disease/disability prevention, and (3) education and training of providers and the public and provision of timely and accurate information. I. Public Health Assessment Public health assessment is the application of traditional public health methods-surveillance, epidemiology, and laboratory science-to assess the impact of discovered genes on community health. In order to translate genetic research into clinical and public health practice, ongoing population-based epidemiologic studies are needed to assess the impact of gene variants on the risk for disease, disability, and death; to identify modifiable risk factors; and to evaluate interventions. At the meeting, presenters reviewed current efforts to assess the burden and impact of PI diseases, including estimates derived from national and regional disease registries and surveys of PI disease prevalence. They reported on data from U.S. disease-specific registries for chronic granulomatous disease and seven other PI diseases and from the PI disease registry of the European Society for Immunodeficiency Diseases (ESID). ESID has also established web-based immunodeficiency mutation databases. One such database, BTKbase, provides information about mutations in the BTK gene that cause X-linked agammaglobulinemia. Presentations highlighted the potential for using existing population-based data (e.g., national mortality data, hospital-discharge data, state-based data, health maintenance organization [HMO] data) to assess PI disease prevalence and health outcomes. The goals and methods of ongoing public health surveillance were presented, using birth defects surveillance as an example. Efforts to collect epidemiologic and surveillance data on patients with other genetic diseases, including the Cystic Fibrosis Patient Registry and the Comprehensive Prevention Program for Persons with Bleeding Disorders, were presented as models that may help assess PI diseases. II. Laboratory Issues/Evaluation of Genetic Testing The Secretary's Advisory Committee on Genetic Testing provides recommendations to enhance the oversight of genetic testing. Criteria to assess the benefits and risks of genetic tests include analytical validity, clinical validity, clinical utility, and ethical, legal, and social consequences. Speakers
discussed current diagnostic tests for PI diseases, including genetic tests;
reviewed evaluation criteria for diagnostic and screening tests, including
analytic validity, clinical validity, and clinical utility, with a focus on
early clinical recognition and the potential role of III. Developing, Implementing, and Evaluating Population Interventions The intervention component of the public health framework involves developing intervention strategies for diseases with a genetic component; implementing pilot demonstration projects; and evaluating the impact of interventions on morbidity, disability, health care costs, and mortality. Timely and effective public health interventions can reduce complications from genetic diseases, including PI diseases. These strategies include enhanced early clinical recognition in early symptomatic populations or population-based screening in asymptomatic populations. Early diagnosis, combined with effective therapy such as bone marrow transplantation, intravenous immunoglobulin, and antibiotics, can reduce the burden of these diseases. A. Strategies to increase early clinical recognition Meeting participants discussed the development and assessment of early
recognition systems and initial laboratory tests; considered which B. Potential role for population-based newborn screening
Population-based screening is the systematic application of a test to a
population that has not sought medical attention for symptoms. Both IV. Communication and Information Dissemination Effective communication will depend on the coordination of communication strategies among various groups, targeting of appropriate audiences with messages that result in health promotion and disease prevention, and provision of messages that are accurate and technically and culturally appropriate. Communication strategies to increase awareness build on the public health assessment of PI diseases and an improved understanding of the uses of new genetic tests, recognition of PI diseases with valid clinical tools, and the impact of early recognition on outcomes. Speakers from organizations and agencies that have developed educational and outreach efforts targeted to patients, providers, and the public discussed their activities; reviewed strategies and successes; identified lessons learned; and proposed recommendations for future education and communication efforts, including how to develop and evaluate activities to enhance early identification and awareness of PI diseases. Summary of Recommendations for Future Public Health Research and Activities Public Health Assessment Recommendations include the collection of good epidemiologic data on incidence, prevalence, and the natural history of single-gene disorders, such as PI diseases; the relationship between genotype and phenotype; and the impact of early recognition and effective therapies on morbidity and mortality. Certain PI diseases were targeted as priorities for public health assessment which included profound T-cell defects, antibody deficiencies, and chronic granulomatous disease (CGD). Pilot activities to collect, use, and improve epidemiologic and surveillance data should be considered and included convening a working group to provide guidance on accurate case definitions and for registry and surveillance activities; developing collaborative efforts between public and private groups to expand current PI disease registries in terms of data collection, completeness, and analysis; examining existing population-based databases; and developing collaborative surveillance activities at the state level for genetic diseases, including PI diseases. In addition, the group promoted the development of a network of model centers, and encouraged the use of these centers for epidemiologic data collection and specimen repository. Laboratory Issues Recommendations included ensuring that referral centers and laboratory testing are accessible for the diagnosis of persons with rare genetic diseases, such as suspected PI diseases. Data should be collected on the analytic and clinical validity of molecular tests used for diagnosis of PI diseases or any proposed screening programs. Public Health
Interventions
- Recommendations for practical and effective public health interventions to
reduce morbidity and mortality from genetic diseases such as PI diseases focused
on two areas: early clinical recognition and newborn screening.
SCID or profound T-cell deficiency were considered as potential candidates for pilot studies of population-based newborn screening. Partnerships among investigators and CDC laboratory personnel should be encouraged to develop and validate methods to measure T-cell lymphocytes from dried blood spots (DBS). Validation could include blinded comparisons of T-cell counts using an assay from DBS, with manual differential count from cord blood samples as the gold standard. Once an assay is developed and validated, pilot testing of the screening assay should be conducted in collaboration with states, CDC, Health Resources and Services Administration (HRSA), National Institutes of Health (NIH), and other partners. Communication and Information Dissemination The goal of a comprehensive communication strategy
must consider and integrate the principles of effective communication within every phase of the
PI campaign process from research to education and outreach. The first step should include convening a working group of PI experts to
develop consensus regarding the case definition and clinician recommendations
that will form the basis of the communication messages. The second step would be
to convene a working group of health communication specialists and other
appropriate PI partners to establish a comprehensive communication strategy that
accomplishes the formative research, process, and outcome evaluation based on
the findings from the first working group. The third step includes conducting
the formative evaluation research to test pre-existing knowledge, determine
target audiences, and define concepts to include in the communication messages, in
addition to considering these aspects of materials already developed and
disseminated. Another component is to establish and encourage partnerships
with health care provider organizations, public and private advocacy groups, and
academic centers. The next
component includes developing or revising existing educational materials, using
messages consistent with formative research findings; pre-test messages with
target audiences and revise messages based on outcomes of
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