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CDC
Meeting Synopsis:
Applying
Genetic and Public Health Strategies to Primary Immunodeficiency Diseases
November
8-9, 2001
Full
Meeting Summary
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Overview
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) diseases. During the 2-day meeting, participants outlined
a public health framework for PI diseases that represents a blueprint for a
public health approach to single-gene disorders. This framework assesses
the impact of these diseases and identifies public health interventions to
prevent morbidity, disability, and mortality and to improve health outcomes.
Meeting discussions centered on priority public health research questions and
recommendations for future action. A meeting summary will be available in early
2002. A complete report of recommendations for public health action will
appear in a future issue of MMWR Reports and Recommendations.
Background
PI diseases comprise a diverse
group of more than 95 diseases, many of which result from single-gene defects.1
The genetic defects may affect one or more components of the immune
system, including T cells, B cells, phagocytic cells, natural killer cells, and
complement proteins. PI diseases are characterized most notably by
increased susceptibility to infection. Defects in one or more components of the
immune system also cause increased susceptibility for autoimmune diseases and an
increased risk of cancer. Advances in molecular biology and genetics over the
last decade have led to the identification of the molecular defects associated
with approximately three-quarters of the 95 diseases. This new knowledge has, in
turn, prompted researchers to develop new diagnostic tools and new therapies,
including gene therapy.2
Advances
in human genetics and the evolution of the Human Genome Project will play a
central role in the practice of medicine and public health in the 21st century.
As part of a strategic planning process for genetics and public health, CDC has
developed a public health framework to assess the role of genetics in specific
diseases, including single-gene disorders. This framework outlines how essential
public health functions can prevent disease, disability, and death and promote
and improve health outcomes among persons who inherit specific genotypes.3 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.4
Meeting Synopsis
Meeting participants applied this public
health framework to PI diseases. 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.
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.
The incidence and prevalence of PI diseases are
largely unknown, however, estimates are available. The severity and
estimated incidence of each PI disease vary widely. For example, severe
combined immune deficiency (SCID) has an estimated incidence of 1 per 100,000;
presents early in the first 6 months of life; and, without treatment, leads to
death in the first year. In contrast, selective IgA deficiency is much more
common, with an estimated incidence of 1 per 500 in blood donors, but may cause
few clinical effects. Overall, the estimated combined incidence of PI diseases
is 1 per 10,000.
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 (hyper IgM, X-linked agammaglobulinemia, common variable
immunodeficiency, Wiskott-Aldrich syndrome, SCID, leukocyte adhesion deficiency,
and DiGeorge syndrome) 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
agammaglobulenemia. Additional mutation databases have also been developed.
Presentations
highlighted the potential for using existing population-based data (e.g.,
national mortality data, hospital-discharge data, state-based data, 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.
Laboratory
Issues/Evaluation of Genetic Testing
The Secretary’s
Advisory Committee on Genetic Testing (SACGT) provides recommendations to the
Department of Health and Human Services to enhance the oversight of genetic
testing.5 Criteria to assess the benefits and risks of genetic tests
include analytical validity, clinical validity, clinical utility, and social
consequences. Post-marketing assessment was identified as a measure that needs
to be collected after a genetic test is accepted into clinical practice.
Meeting participants emphasized the importance
of the continually developing and maintaining tests for rare genetic diseases
and establishing a comprehensive system to collect data on rare diseases.
Because the diagnosis of rare diseases is often delayed due to lack of
information, physicians who encounter patients with symptoms and signs of rare
genetic diseases should have access to information that will help them include
such diseases in their differential diagnoses, obtain diagnostic assistance, and
locate laboratories that test for rare diseases.
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 population-based screening; and
reviewed the role of genetic tests in clinical practice (diagnosis, screening,
management) and the availability and accessibility of genetic tests.
Developing,
Implementing, and Evaluating Population Interventions
About one in 20
live-born infants is expected to have a single-gene disorder or a condition with
an important genetic component by age 25 years. These infants will account
for a disproportionate fraction of premature deaths, pediatric hospitalizations,
and health care costs. Many of these conditions and their complications
can be reduced by timely and effective intervention and prevention strategies.
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.
Strategies to increase
early clinical recognition
Enhanced clinical recognition not
only requires information about disease prevalence, severity of late-stage
complications, efficacy of treatment, and the analytic validity and clinical
validity of early clinical signs and symptoms but also guidance on how to use
and interpret initial diagnostic laboratory testing. Meeting participants
discussed the development and assessment of early recognition systems and
initial laboratory tests; considered which PI diseases could benefit from and
should be targeted for early recognition strategies; and discussed the essential
components of early clinical recognition instruments, including their
practicality and usefulness to primary care providers and the evaluation of any
proposed screening instruments.
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. The purpose of the screening is to
identify people who are at sufficient risk for a specified disorder and who
might benefit from action. Both population-based screening and clinical
algorithms select high-risk persons for diagnostic testing and prompt
intervention. Participants discussed the potential role of
population-based newborn screening in enhanced early identification, using SCID
as an example. Their deliberations centered on issues pertaining to the
condition, characteristics of possible screening tests, interventions,
infrastructure, and research needs.
Communication
and Information Dissemination
Effective
communication is key to the success of public health programs involving results
from genetic research. Effectiveness 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.
Agenda
List
of Participants
References
- IUIS Scientific Group. Primary immunodeficiency diseases. Clin Exp Immunol
1999;118:1-34.
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Fischer A. Primary immunodeficiency diseases: an experimental model for
molecular medicine. Lancet 2001;357:1863-9.
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Centers for Disease Control and Prevention. Translating advances in human
genetics into public health action: a strategic plan. 1997.
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Khoury MJ, Burke W, Thomson EJ. Genetics and public health: a framework for the
integration of human genetics into public health practice. In: Khoury MJ,
Burke W, Thomson EJ, editors. Genetics and public health in the 21st century.
Oxford University press 2000.
-
Secretary’s Advisory Committee on Genetic Testing, NIH. Enhancing the
oversight of genetic tests: recommendations of the SACGT.
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