Summary
of First Meeting
June
7-8, 2004
Washington, DC
The Secretary’s Advisory Committee
on Heritable Disorders and Genetic Diseases
in Newborns and Children was convened
for its inaugural meeting at 9:05 A.M.
on June 7, 2004, and was adjourned at
3:00 P.M. on June 8, 2004 at the Ronald
Reagan Building and International Trade
Center, Washington, D.C.
In
accordance with the provisions of Public
Law 92-463, the meeting was open to the
public from 9:05 A.M., June 7, 2004 to
3:00 P.M., June 8, 2004.
Committee
members present:
Dr. Duane Alexander**
Dr. William Becker
Dr. Amy Brower
Dr. Peter Coggins
Dr. Gregory Hawkins
Dr. Joe W. Gray
Dr. Rodney Howell
Dr. Piero Rinaldo
Dr. Coleen Boyle**
Dr. Peter van Dyck**
Dr. Stephen Edwards*
Dr. Jennifer Howse*
Dr. Reed Tuckson*
*
Liaison Members
** Ex Officio
Staff
of the Secretary’s Advisory Committee
on Heritable Disorders and Genetic Diseases
in Newborns and Children attending were:
Dr. Michele Lloyd-Puryear, Executive Secretary
LTJG Gilian Engelson, Administrative Associate
Members
of the public who presented oral or written
statements were:
Ms. Wendy Berry West, Ohio Sickle Cell
and Health Association
Anthony A. McKinney, LysoPlex, LLC
Ms. Jill Fisch, Parent
Mr. Jim Kelly, Hunter’s Hope Foundation
Ms. Jana Monaco, Organic Acidemia Association
and the National Coalition for PKU &
Allied Disorders
Dr. Philip Vaughn, Pediatrix Screening
Ms. Micki Gartzke, Parent
Dr. Mendel Tuchman, Society for Inherited
Metabolic Disorders
Ms. Kathleen Rand Reed, The Rand Reed
Group
Dr. Rebecca Buckley, Immune Deficiency
Foundation
Ms. Teri Broadstreet, Parent (written
public comment sent through the Honorable
Howard Coble’s office
Welcome
and Introductions
After
Dr. R. Rodney Howell, Committee Chairperson
and Professor of Pediatrics at the University
of Miami, called the meeting to order,
Dennis Williams, Ph.D., M.A., Deputy Administrator,
Health Resources and Services Administration
(HRSA), offered greetings from HRSA Administrator
Betty Duke and thanked attendees for participating
in the first meeting of the Advisory Committee
on Heritable Disorders and Genetic Diseases
in Newborns and Children (Committee).
Dr. Williams also thanked Dr. Howell for
serving as chairperson, and Peter van
Dyck, M.D., M.P.H., M.S., Associate Administrator
of the Maternal and Child Health Bureau
(MCHB), HRSA, for serving as the HRSA
representative for this Committee.
Dr.
Williams noted that the life-threatening
or disabling impacts of many heritable
disorders can often be prevented if detected
early in an individual’s life. The
charge of this Committee is to advise
the Secretary of the Department of Health
and Human Services (DHHS) on the most
appropriate application of screenings,
health services, and counseling to identify
and treat a range of heritable disorders.
The national guidelines that the Committee
recommends to the Secretary will help
DHHS officials develop policies to encourage
advances on many crucial issues among
their partners and State and local public
health agencies. These include improving
the quality of screening programs, promoting
equal access to genetic testing by all
newborns and their families, and standardizing
treatment and follow up from State to
State.
The
Department of Health and Human Services,
Dr. Williams said, has supported the development
of newborn screening programs since the
1960s, primarily through the activities
of MCHB, and researchers at the National
Institute of Child Health and Human Development
(NICHD). The Center for Disease Control
and Prevention’s (CDC’s) Newborn
Screening Quality Assurance Program has
improved quality practices among state
laboratories, and its national Center
on Birth Defects and Developmental Disabilities
provides expertise in the areas of epidemiologic
surveillance and evaluation.
More
recently, the Agency for Healthcare Research
and Quality (AHRQ) has supported research
that helps health care professionals use
advances in genetics to improve the care
they provide. Strengthening the scientific
basis for newborn screening is one way
the federal government can support State
newborn screening programs, and HRSA has
been a leader in translating the findings
of genetic science into practice.
The
discretionary grants portion of HRSA's
Maternal and Child Health Block Grant
Program is the primary source of Federal
funding of newborn and other genetic screening,
counseling, and information projects.
In 2000, the MCHB funded American Academy
of Pediatrics Task Force report on newborn
screening and genetic testing, “Serving
the Family from Birth to the Medical Home”
was released. In 2002, a HRSA genetics
workgroup, consisting of representatives
of all of HRSA's bureaus and offices and
chaired by Dr. Sam Shekar, HRSA Associate
Administrator for Primary Care, began
to inventory all genetics-related activities
across the agency. The group was instructed
to develop a strategic plan for future
genetic activities and to strengthen partnerships
to advance genetic education and service.
The workgroup's report is expected to
be released soon.
HRSA
also trains health care and public health
professionals in genetics via the Genetics
in Primary Care project, which targets
the next generation of health care professionals
by introducing genetics to students in
health professions, and through the new
Family History project—in partnership
with the March of Dimes and the Genetic
Alliance—that allows HRSA to educate
consumers so that they understand the
benefits, risks, and limitations of genetic
testing.
Dr.
Williams concluded by cautioning that
advances in genetic testing and understanding
are leading us into a future in which
scientific gains strain against the moral
and legal boundaries that have guided
us up until now. He noted that the role
of the Committee is to help the Secretary
and the Nation understand these challenges
and the choices that await us.
Charge
to the Committee
Dr.
Howell then reviewed the charge to the
Committee, the members of which were appointed
by Secretary Thompson. Title XXVI of the
Children's Health Act of 2000 authorized
the establishment of the Committee—the
Committee has to make recommendations
to the Secretary, if they become regular
practice in the United States, will create
the opportunity of saving children's lives.
Dr.
Howell then outlined a few of the key
issues that the Committee will address.
The Committee will review and recommend
improvements in the national newborn screening
and childhood screening programs. The
Committee also will provide advice and
recommendations to the Secretary concerning
grants and projects awarded or funded
under Section 1109 of the Public Health
Service Act. This section of the Public
Health Service Act authorizes grant awards
to enhance, improve, or expand the ability
of States and local public health agencies
to provide screening, counseling, or health
care services to newborns or children
who have or who are at risk for having
heritable disorders. The Committee also
is charged with providing technical information
to the Secretary for the development of
policies and priorities for the administration
of grants under Section 1109 of the Public
Health Service Act, and to provide such
recommendations, advice, or information
as may be necessary to expand and improve
the ability of the Secretary to reduce
the mortality or morbidity related to
heritable disorders in newborns and children.
Dr.
Michele Lloyd-Puryear, Committee Executive
Secretary, then reviewed the history of
the Committee. She noted that membership
is limited to 15 members and outlined
the specific expertise required to be
represented on the panel. MCHB structured
the Committee to include both voting and
non-voting members. In addition, several
different types of members comprise the
Committee. First are representatives of
other advisory Committees—the Secretary's
Advisory Committee on Infant Mortality
and the Secretary's Advisory Committee
on Genetics, Health, and Society. The
members representing these advisory Committees
do not vote. The Committee also includes
representatives of the American Academy
of Pediatrics, and of the March of Dimes
(representing the public at large); these
members also do not vote. The remaining
members vote, including the representatives
of the four Federal agencies on the Committee—the
AHRQ, CDC, HRSA, and the National Institutes
of Health (NIH).
Delivering
Genetic Services to Children in a Clinical
Setting
Dr.
Howell began by stating that genetic services
have been an integral part of the medical
care of children for more than 40 years.
Those services have focused on visible
clinical features, such as Down's syndrome
and dysmorphology—diagnoses supported
by increasingly sophisticated chromosomal
studies and relatively simple single-gene
defects that have commonly been detected
through newborn screening, such as biochemical
or metabolic abnormalities.
Dr.
Howell reviewed the history of children’s
genetic services, beginning with the publication
of Archibald E. Garrod’s Inborn
Errors of Metabolism. Garrod's book focused
on visual data, and his visual inspections
were corroborated by relatively simple
chemistries that were available in the
early 20th Century. Dr. Howell went on
to highlight several disorders, such as
alkaptonuria, that were explained by Garrod
and later backed up by biochemical studies.
The
next phase in the evolution of clinical
genetics and biochemical genetics in children
started with the simple screening tests
that were used 35 to 40 years ago. Children
who had special conditions or abnormalities
such as mental retardation commonly received
simple urine tests to see if there was
anything in the urine that gave a clue
to the diagnosis. Around that time, Robert
Guthrie developed a simple screening test
using dried blood spots in the diagnosis
of phenylketonuria.
Dr.
Howell reviewed the criteria used at that
time for the mass screening of all newborn
infants:
The
disorder should be treatable.
The screening program should be administratively
feasible.
Methods should be simple, quick, inexpensive,
and reliable.
The program should be justified on economic
grounds.
At
the time of the development of the dried
blood spot test, treatment for a disease
was considered to be very specific, a
concept that “you could get your
hands around,” such as a diet or
medication, rather than a complex treatment.
However, tandem mass spectrometry and
other high-throughput genetic testing
have changed how we look at inborn errors
of metabolism, and the practice of newborn
screening is expanding rapidly. These
technologies have raised even more sophisticated
issues. For example, conditions have been
identified about which we have little
data regarding their natural histories
and the treatment. Another challenge for
the researchers is that relatively few
health care professionals in the United
States are available with the expertise
to follow up, diagnose, and treat patients
with some of these uncommon conditions.
In
addition to newborn screening, the Human
Genome Project (HGP) has ushered in the
era of predictive medicine and created
an enormous opportunity for prevention.
Dr. Howell briefly reviewed what we have
learned thus far from HGP. The goal of
HGP was to map and sequence the human
genome, and after the completion of the
sequence, the recent focus has been on
sequencing the genomes of model organisms.
Comparisons with other organisms, such
as the mustard weed, the fly, and the
worm, have shown that the human genome
has more genes than other organisms, but
not as many as scientists thought originally.
However, humans have considerably more
proteins than the organisms listed above,
and the way that genetic information is
used in humans is vastly more complicated,
which will pose difficulties as scientists
look at gene sequences to try to predict
health outcomes. The public availability
of the data emerging from HGP has stimulated
technology development, as well as significant
discussions of the ethical, legal, and
social issues associated with genetic
advances.
Dr.
Howell then discussed the emerging scientific/medical
fields that have resulted from genetic
advances, including transcriptomics (the
study of RNA transcripts), proteomics
(the study of all the proteins in the
cell) and metabolomics (the study of metabolomes—all
of the small molecules within the cell).
Combined, these fields will provide information
about all of our genes, proteins, and
RNA and create a complete picture of a
fully functioning assembly of the human
organism.
The
discovery of the specific genes that underlie
genetic defects are dramatically enhancing
diagnosis. One of the areas that has undergone
an enormous explosion in technology has
been cytogenetics, which permits very
sophisticated testing for small gene deletions,
and diagnose important clinical conditions
in childhood accurately. Dr. Howell used
several case studies of diseases, such
as Cornelia de Lange syndrome, Pompe’s
disease, and Krabbe’s disease, to
illustrate how recent genetic advances
are helping children who suffer from those
diseases.
Another
emerging field of genetic study is pharmacogenetics.
The problem of adverse drug reactions
is increasing in the United States; in
fact, some data has indicated that it
causes more deaths than pneumonia and
diabetes. Although much is known about
polymorphisms and how they might affect
metabolism reactions to drugs at times
remain unpredictable. Dr. Howell used
the case of a mitochondrial mutation that
causes a rare adverse reaction, ototoxicity
(deafness), in response to a drug commonly
used in the newborn nursery, particularly
in premature infants who are diagnosed
with sepsis. Dr. Howell illustrated the
theory that with a very rapid test for
that mutation, children could be screened
before that drug is used.
Another
issue that the Committee must address
is testing for adult onset disorders in
children, a problem about which the American
Academy of Pediatrics has issued a specific
comment. The Academy's recommendation
is that you do not test children unless
there is an immediate medical benefit,
or if there is a benefit to another family
member and no other recognized harm to
that minor.
How
conditions are diagnosed is changing dramatically.
In addition to making a visual diagnosis,
or measuring the patient’s features,
many more accurate diagnostic tests are
available. Scientists also are learning
that some conditions are considerably
more variable and complicated than originally
thought, because of varying expressions
of disease genes.
Dr.
Howell stated that over time, the challenges
that some of these discoveries present
will be addressed, including the education
of professionals, which will be necessary
for the public to take the best advantage
of emerging genetic discoveries.
Committee
members then discussed Dr. Howell’s
presentation, raising the issue of costs,
especially when there are 43 million Americans
who are uninsured: How do we best use
limited resources? Dr. Howell pointed
out the economics of scale when using
tandem mass spectrometry—once you
decide to use the technology to test for
one disorder, the incremental cost to
examine other disorders is modest. Some
of the treatments are inexpensive, such
as biotinidase, while others, such as
the treatment for lysosomal enzyme disorders,
although life-saving, are more expensive
to treat. These diseases, however, are
rare, which prevents the costs of treatments
from reaching crisis proportions in the
population.
Two
levels of economics must be considered
when reviewing newborn and childhood screening—both
at the population and individual family
levels. No matter how rare the disease,
it is devastating to that particular family,
and the results can be life changing and
costly, including loss of productivity
and the amount of time spent looking for
a diagnosis. In light of the economics
of the treatment and the economics of
the diagnostic costs for the individuals
and the society in terms of health care
cost increases, the Committee must consider
the issues for public health, and State
and local governments, as they try to
decide how to best use their resources.
Committee
members then spent some time clarifying
their charge—whether or not they
are to make recommendations in terms of
public health or clinical practice. They
agreed that the charge was broad, especially
since newborn screening and clinical genetics
in particular bring public health and
clinical practice together. A lot of the
issues that have been discussed fall somewhere
between appropriate clinical practice
and mandated public health screening,
and the Committee is not limited in how
it structures its recommendations.
Committee
members also discussed briefly the issues
of genetic counseling and the importance
of the public understanding of the impact
that genetics will have on their lives,
especially those families that include
members who suffer from a genetic condition.
Genetic professionals who are knowledgeable
about each disease that is screened must
be available to the general public.
State
of the States: Newborn Screening—Challenges
and Opportunities
Dr.
Marie Y. Mann then gave an overview of
state newborn screening programs. She
noted that the term "newborn screening"
could mean newborn hearing screening,
which screens for congenital hearing loss,
or the more traditional biochemical screening
for inherited and congenital conditions.
For the purpose of her presentation, newborn
screening would refer to the traditional
biochemical screening.
Newborn
screening is recognized as an essential
public health program that has been lauded
as an effective strategy for preventing
significant morbidity and mortality in
those infants with certain genetic or
congenital. It also is a complex system
that is dependent on many individuals
and organizations, including the family
members of the affected newborns, as well
as myriad program officials, laboratory
and follow-up professionals, and the primary
subspecialty care clinicians who care
for these infants. Policymakers, manufacturers,
and the general public also are involved.
Newborn
screening began in the early 1960s, when
Robert Guthrie showed that a blood sample
from the newborn could be absorbed and
dried onto a standardized filter paper
and that this sample could be analyzed
for biochemical markers of metabolic disorders,
such as phenylketonuria (PKU). However,
it took the lobbying efforts of parents
to convince health policymakers that this
method could be used to screen newborns
routinely. In 1965, the American Academy
of Pediatrics Committee on the Fetus and
Newborn recommended a newborn screening
blood test for PKU for all newborns. Within
a few years, most States had passed legislation
mandating PKU screening. By 1973, 43 States
had formal statutes.
Over
the next decade, other filter-paper tests
became available, for testing for such
diseases and conditions as congenital
hypothyroidism, congenital adrenal hyperplasia,
and sickle cell anemia. With improvement
in technological tests—such as automated
specimen preparation, testing, and data
handling systems—the program expanded
to test for other disorders, such as congenital
hypothyroidism. As the number of conditions
for screening increased, the cumulative
risk of being diagnosed with one of the
conditions also increased. And so with
congenital hypothyroidism being the condition
of higher incidence, when hypothyroidism
screening was added to the newborn screening
program, cost effectiveness improved.
This was important, because as programs
had to justify themselves, their existence,
and their spending, the State legislatures
expected the programs to be self-supporting.
Throughout
the 1980s, these programs continued to
expand, and this expansion was assisted
by computerized data management and record
keeping that accommodated the increased
testing volume, as well as the required
follow up. Toward the end of the 1980s
and into the early 1990s, the ability
to extract DNA from dried blood spots
allowed for genotypic confirmation of
sickle cell anemia. Subsequently, researchers
discovered that DNA extraction could be
used as a secondary tier for cystic fibrosis
screening. Around this time, advances
were being made in mass spectrometry technology,
so during the early 1990s, the technique
of linking two mass spectrometers in tandem
was applied to newborn screening. Tandem
mass spectrometry allows the simultaneous
detection of multiple conditions, including
organic acid, amino acid, and fatty acid
oxidation disorders. With this new technology,
public pressure to expand the programs
increased, and the conditions to be screened
increase in number.
The
expansion of many of these programs has
been the dramatic result of this work.
Meanwhile, the equipment and procedures
for screening newborns for hearing loss
also were refined. Newborn hearing screening
is now mandated in most States; however,
unfortunately because many of the newborn
hearing screening programs have been developed
independent of the blood spot screening
programs, the two often are not well linked.
There is increasing interest in linking
the two screening programs, as well as
linking these programs with related newborn
and child public health programs, such
as birth registration, and immunization.
Such linkage may be facilitated by data
linkage and integration, keeping in mind
the need to preserve and respect privacy
and confidentiality of those involved.
Programs also are examining the issue
of storage of samples, as well as the
impact of the Health Insurance Portability
and Accountability Act of 1996 (HIPAA)
on the operations of the programs.
Dr.
Mann then reviewed what a typical system
looks like. The system is complex, and
the components of this system need to
be well coordinated for the system to
function optimally. The system begins
with screening, which involves sample
collection, submission, and transportation
to the laboratory and the testing itself.
The results are then sent to the appropriate
places Such as to the pediatrician. If
the results are such additional testing
is warranted, the family is brought back,
and the child is retested. When a result
is positive, the program must ensure that
the child receives the appropriate follow
up, appropriate testing, retesting if
necessary, and referral for diagnostic
testing. This diagnosis must be confirmed,
and if it indeed is confirmed, then the
child is referred to the appropriate subspecialist,
and the family receives counseling, if
needed.
The
program would not be complete without
continuous monitoring, as well as evaluation
of the effectiveness of the program. Overlaying
this system is essential education involving
pretesting education for the families,
the parents, and the expectant families,
as well as the education of the hospital
staff and personnel, and continuing education
of the laboratory and program staff, the
clinicians responsible for the care of
the newborns, and the various policymakers
and payers. Dr. Mann urged Committee members
to remember that the system must be considered
in its entirety to remain efficient and
effective.
In
2002, at the request of Senators Dodd
and DeWine, the General Accounting Office
(GAO) was asked to examine the U.S. newborn
screening programs. Some of the findings
from the report were released in a March,
2003 report, which Dr. Mann summarized.
Fifty-one States and the District of Columbia
mandate newborn screening. Three of the
programs require consent for the testing,
and those are Maryland, WY, and the District
of Columbia. Although most programs allow
dissent, a few do not permit dissent for
any reason. Eight programs mandate two
separate screens, a screening during the
newborn period and a second screen between
2 to 4 weeks of age. Several other States
do not mandate the two screenings but
strongly suggest that a second screening
be performed.
Eight
programs do not charge a fee for the newborn
screening, but for others, the fee can
be as high as $70, excluding hospital
and administrative costs. The amount of
Medicaid reimbursements varies widely,
with about one-third of all births being
Medicaid. The storage time and protocols
for accessing and using residual blood
spots remain after testing varies widely.
Dr.
Mann then reviewed the status of newborn
screening in the country, beginning with
the most commonly screened conditions
in the United States, and the number of
States screening for them. Currently all
States and the District of Columbia screen
for PKU, congenital hypothyroidism, and
galactosemia; for other screened conditions,
such as sickle cell diseases, congenital
adrenal hyperplasia, biotinidase, maple
syrup urine diseases, homocystinuria,
medium-chain acyl-CoA dehydrogenase, but
considerable variation among States exists.
Only a few States currently mandate cystic
fibrosis screening; even fewer screen
for infectious diseases; and only the
District of Columbia mandates screening
for glucose-6-phosphate dehydrogenase,
G6PD deficiency.
In summary, one State screens only for
three disorders, and other States screen
for more than 30.
Not
only do the States vary in the number
of conditions screened, but they also
vary in other ways. One significant variation
is the entity that performs the laboratory
analyses. For example, Oregon’s
state laboratory conducts the testing
for four other States. Massachusetts is
another state lab that conducting the
testing for other States in their region.
Although most States use their own public
health laboratory to conduct the laboratory
analysis, some contract out that testing
to other state or commercial labs.
Shortly
after the HRSA funded-Council of Regional
Networks (CORN) for Genetic Services came
into existence in the 1980s, it began
collecting newborn screening information
from the State. With the dissolution of
CORN in the late 1990s, this information-gathering
activity was assumed by the National Newborn
Screening and Genetics Resource Center.
Dr. Mann summarized 10 years of data,
listing conditions in order of prevalence.
Sickle cell disease is the most prevalent
condition, according to the data that
have been recorded over the 10-year period,
and homocystinuria is the rarest.
Dr.
Mann then reviewed how decisions and regarding
newborn screening are made. She noted
that there is no Federal mandate—rather,
newborn screening is a state-mandated
public health activity, and as noted by
the GAO, every State has enacted a law
mandating screening. Sometimes, State
law defines and specifies the conditions
to be screened, as well as who is going
to be doing this testing. Policies generally
are made by the state health officers,
as well as the state boards of health,
and the state advisory Committees. All
but two States have standing advisory
Committees. Decisions about newborn screening
policies are influenced by the interests
of the various stakeholders, as well as
the costs and benefits associated with
screening, and the scientific evidence
of such screening. Local politics, economics,
and culture exert tremendous influence
on these decisions as well.
Historically,
the formal groups that periodically have
made recommendations have provided the
framework for much of the decision making
in newborn screening policy. In the 1960s
the World Health Organization (WHO) Scientific
Group for Inborn Errors of Metabolism
made recommendations, which resulted in
Wilson and Jungner's criteria for population
screening. They identified 10 criteria,
focusing on treatable disorders, affecting
a significant population, that would have
cost-effective outcomes. In 1975 the National
Academy of Sciences also reviewed genetic
screening. It made several recommendations
in establishing some fundamental principles
for genetic testing, as well as some guidelines
for newborn screenings. These guidelines,
however, differ very little from the WHO
recommendations—the recommendations
suggest that under controlled conditions,
screening is appropriate, and that the
responsibility for screening should reside
in an agency representing both the public
and health professions, and that there
should be extensive public and professional
education and involvement. They suggest
that screening should not be mandatory,
and privacy should be protected. If mandated,
they recommend that there be a formal
body to provide the structure for such
screening, and that research should be
conducted in an ethical manner to support
decisions.
In
1998, HRSA's MCHB funded the American
Academy of Pediatrics to convene a national
Task Force on newborn screening, chaired
by Drs. Edward McCabe and Thomas Tonniges.
This AAP task force was jointly sponsored
by a number of Federal agencies. The Task
Force members represented individuals
who operate programs, conduct research,
persons who functioned within that system,
and those who were affected by the system.
Task Force findings and recommendations
were published in August of 2000. These
recommendations were based on the following
fundamental principles:
- Infants
should benefit from and be protected
by newborn screening programs.
-
Public health agencies should assume
responsibility for oversight of newborn
screening systems.
-
Standards and guidelines for newborn
screening should be more consistently
applied, because greater uniformity
would benefit families, professionals,
and public health agencies.
-
Newborn screening systems should link
to a medical home.
In
conducting its work, the task force divided
up into five workgroups, which made recommendations
in several key areas, including public
health infrastructure, public and professional
involvement, surveillance and research,
as well as financing. Finally, the task
force prepared to recommend an agenda
for action that involved public health
partnering with health professionals and
consumers. The action agenda would model
regulations for newborn screening systems,
define Federal and State responsibility,
define minimum standards for newborn screening,
model guidelines and protocols for professionals,
model systems of care from infancy to
adulthood, design strategies to inform
and involve families and the general public,
and demonstration projects to evaluate
technology, quality assurance, and health
outcomes.
Subsequent to the Task Force report, various
congressional directives were made, where
a Committee urged the availability and
accessibility of newborn screening service
to apply to public health recommendations
for expansion of effective strategies.
It directed that HRSA, in collaboration
with CDC and NIH, encourage implementation
of a strategy for evaluating and expanding
newborn screening programs, and that tangible
steps be taken to protect patient privacy
and to avert discrimination based upon
information obtained via screenings. In
addition to congressional interest, Federal
agencies also have been actively engaged
in various activities that support newborn
screening.
In
2000, the March of Dimes made a recommendation
that all newborns should be screened for
nine conditions as well as for congenital
hearing loss. Since then, public interest
has remained high, and in 2002, a Senate
Committee meeting provided a forum from
which individuals had the opportunity
to make presentations.
One
educational training activity that has
been jointly supported by HRSA, CDC, the
HRSA funded-National Newborn Screening
and Genetics Resource Center, and the
Association of Public Health Laboratories
is designed to meet the needs of State
programs that were implementing tandem
mass spectrometry. The activity provided
a one-week intensive course on the basis
of tandem mass spectrometry methods interpretations
that has been conducted at Duke, as well
as at the Institute for Metabolic Disease
at Baylor University. These programs have
been designed to fill the training gaps
for the States.
With
continued funding from HRSA, the National
Newborn Screening and Genetics Resource
Center continues to send expert teams
to States that request review and consultation.
The team is made up of members who are
experts in laboratory follow up, administration,
quality assurance, and clinical care,
to address specific program needs of the
State programs. Since 1987, more than
22 States have requested such visits.
A limited external evaluation of this
activity found overwhelmingly favorable
response by the States visited. The National
Newborn Screening and Genetics Resource
Center, located at the University of Texas
Health Science Center in San Antonio,
also provides genetics and newborn screening
information online. The information includes
program links and testing summaries for
the various programs, information about
individual State newborn screening programs,
as well as State genetics plans, and a
searchable genetics education materials
database, as well as other reports of
regional and national significance.
In
summary, Dr. Mann stated that of the approximately
4.1 million babies born annually in the
United States, almost all are screened
during the newborn period for a number
of genetic and congenital conditions,
and yearly approximately 4,000 of these
newborns are found to have one of those
conditions. In recent years, increasing
differences among the States’ screening
programs have resulted in more than 1,000
newborns with detectable conditions may
go undetected, because they are not screened
for all the conditions for which tests
are currently available. There is Federal
and State interest in improving these
programs to improve the equity between
the programs, and although no national
mandate exists, there is national interest
in expanding newborn screening programs.
Some of the challenges include the issue
of financing and reimbursement for laboratory
services, as well as for referral and
follow up, and the long-term care of these
infants; the availability of expertise,
both at the laboratory level and the clinical
level; and education and communication
with all involved in the system.
Committee
members asked Dr. Mann whether clear science
is available for all currently available
tests that indicate when that they should
be performed and whether variation in
States is due to competing views of what
types of tests should be performed, or
unclear science. Where do we turn for
consensus on the best science available
and for guidelines regarding what States
should do? Dr. Mann reiterated that HRSA’s
contract with the American College of
Medical Genetics (ACMG) will address one
of those action items from the American
Academy of Pediatrics Task Force to examine
the science behind available tests and
develop a mechanism by which conditions
can be assessed based on the available
scientific and clinical evidence before
being added to screening panels. Dr. Therrell
noted that some national guidelines—not
federally mandated—were developed
over the years of conducting reviews of
State programs. The national guidelines
are interpreted differently by different
programs. Each State develops its own
guidelines, and it is usually the responsibility
of the advisory Committee to develop them.
Dr.
Therrell noted that there is a Catch-22
related to the science, because in some
cases, “if you don't do the screening,
you don't get the science,” and
we haven't done the screening because
there weren't treatments.
Committee
members also discussed whether they can
recommend a Federal mandate for conditions
to screen, and whether the States are
ready for a Federal mandate. Dr. Van Dyck
cautioned that terms such as mandates,
guidelines, and standards are different,
and each has different implications for
States.
Committee
members also recognized that there are
activities going on outside of the recommendations
of this Committee. There are commercial
companies advertising over the radio about
available tests. Questions also have been
raised about the use of the testing and
about whether patients who are covered
by public programs should have access
to the same sort of testing as patients
who are covered by private insurance.
All of these issues create a complex dilemma.
Federal
Agency and Liaison Briefings
U.S. Preventive Services (USPS) Task Force
Agency for Healthcare Research and Quality
Elizabeth
Edgarton, M.D., M.P.H., represented the
USPSTF as the new Director of Clinical
Prevention. Dr. Edgerton explained that
AHRQ has identified 10 focus areas related
to the Agency's mission and that these
areas encompass quality care, safety,
and improving health outcomes among Americans.
The prevention portfolio at AHRQ oversees
both the USPSTF, and also the dissemination
of these findings at the patient and provider
level.
Dr.
Edgerton gave Committee members an overview
of the methodology of the Task Force,
in order to help them understand how one
group approaches some of these same questions.
The USPS Task Force was modeled after
the Canadian Task Force, and was established
in 1984. Over time, it has developed recommendations
regarding around health care issues that
are relevant to primary care physicians.
Currently it has a rotating board that
participates for a term of 3 years.
The
recommendations of the USPSTF are founded
on evidence-based medicine for preventative
health services used in the primary care
setting. It looks at health outcome issues
that relate to screening tests, counseling,
and chemoprevention. Some of the relevant
topics it has addressed are congenital
hypothyroidism, Down syndrome, sickle
cell hemoglobinopathies, neural tube defects,
PKU, and newborn hearing screening.
The
USPSTF is an independent panel of experts
that includes primary care physicians,
family practitioners, internists, pediatricians,
experts in behavioral science, and experts
in methodology. It also uses evidence
practice centers in the systematic review
of the evidence, as well as Federal and
private organizations as expert partners
to review the recommendations. Its goal
is to provide impartial assessment of
the existing evidence, and although this
evidence evaluation is examined apart
from any Federal agency, it is supported
by AHRQ in the sense that it represents
the mission to enhance the quality, appropriateness,
and effectiveness of health care services.
Federal
guidelines often fall into two categories:
formal consensus or expert panels and
those that are evidence-based. The USPSTF
employs an evidence-based approach, which
can sometimes cause concern when a decision
needs to be made, and the USPSTF has concluded
that not evidence exists. Dr. Edgerton
reviewed the process used by the USPSTF,
starting with topic selection, development
of questions, a systematic review of the
literature (including an assessment of
internal and external validity, effectiveness,
benefit, and a summary of results in narrative
and table format), then recommendations
and rationale. A published methodology
regarding systematic evidence reviews
and the engagement of expert opinion to
consider the results of these reviews
has been developed. The USPSTF issues
recommendations in the form of letter
grades or insufficient evidence. A finding
of insufficient evidence often suggests
a potential research agenda. Dr. Edgerton
urged the Committee to consider what types
of outcomes will be important for them
to assess going forward with their work—whether
it is identification, improved quality
of life, or improved morbidity/mortality.
One
of the important issues that the USPSTF
as well as the Committee must address
is the issue of efficacy versus effectiveness.
The USPSTF recommendations are supposed
to consider real-world settings. Benefits
often decrease as risk increases, and
interventions are implemented in real-world
versus the trial setting. Again, requiring
effectiveness data may seem too limiting
and inconsistent with medical practice,
but Dr. Edgerton explained that this is
the methodology and the standards of the
USPSTF. Dr. Edgerton also identified the
challenge in assessing the magnitude of
the net benefit and noted that no explicit
criterion for magnitude exists. The USPSTF
uses outcome tables to illustrate tradeoffs.
Dr.
Edgerton also addressed the challenges
of pediatrics. What are the health outcomes
to mark the benefit of genetic testing?
Outcomes can be biochemical, school performance,
interaction with family and peers, and
knowledge of the child's condition by
parents, etc.
Committee
members asked whether they would be able
to obtain a list of the critical issues
considered by the USPSTF. The Committee
also suggested that certain topics be
examined by the USPSTF.
Centers
for Disease Control and Prevention
Colleen
Boyle, Ph.D., Associate Director of the
Science and Public Health Team at the
CDC, presented CDC’s activities
in newborn screening, which are distributed
across four groups at the CDC—the
National Center on Birth Defects and Developmental
Disabilities, and the Office of Genomics
and Public Health, the laboratory education
group, and the Newborn Quality Assurance
Screening Laboratory. These activities
began out of the need to improve the science
base for newborn screening. CDC’s
activities primarily encompass the areas
of surveillance, long-term follow up,
and epidemiologic studies that generally
are developed from surveillance and monitoring
programs, and laboratory quality control
and standards.
In
terms of surveillance and long-term follow
up with regard to newborn screening, the
CDC is examining the issue of clinical
utility, to try to understand the long-term
impact on children and their families.
Their mission is to ensure that every
State and Territory has a complete early
hearing detection and intervention, tracking,
and surveillance program. The reason for
developing the data system is to ensure
that children are followed through early
identification, via screening, diagnosis,
and intervention.
CDC
has funded 32 State surveillance and tracking
programs. These States provide CDC with
data to help answer a number of questions
in relationship to clinical utility, the
implications of the program for various
ethnic minority groups, or other questions
that arise. CDC also has a number of research
programs to address issues such as cost
analysis, quality of life in Utah, and
the contribution of the cytomegalovirus
to congenital hearing loss. They also
are looking at family and psychological
issues, genetic services issues in North
Carolina, long-term outcomes in Hawaii,
a family satisfaction collaborative project
in Colorado and Massachusetts, and a more
detailed etiologic genetic study that
is based in four locations in the United
States. They are interested in developing
long-term follow-up programming for blood
spot and MS/MS screening, and currently
are running pilot programs in Oregon,
Idaho, and Iowa. These programs are funded
to develop a medical records abstraction
system for long-term follow up of infants
identified through MS/MS screening, in
the hopes of developing a tracking system
that easily can be adapted by other State
programs. Another project in Colorado
is investigating integrating newborn screening
programs into one database, linking hearing,
metabolic screening, and screening for
hemoglobinopathies.
In
the area of epidemiology, the CDC has
conducted a number of different activities.
Some of them are based on data that have
been collected on State levels, and others
are evaluations of the evidence. CDC has
conducted a number of scientific evidence
reviews of quantitative evaluations, including
screening for cystic fibrosis and muscular
dystrophy, as well as maternal hypothyroidism.
CDC scientists also have published an
article in the Morbidity and Mortality
Weekly Report regarding the contribution
of select metabolic disorders to unexpected
early childhood deaths, finding that about
1 percent of children who died under the
age of three actually had an undiagnosed
fatty acid oxidation disorder, or organic
acidemia.
The Office of Genomics and Public Health
(OGPH) also is interested in the idea
of using newborn dried blood spots for
epidemiologic and other public health
purposes, and has held a series of discussions
over the last couple of years regarding
the use of stored newborn dried blood
spot specimens, including discussions
of the implications, both in terms of
their utility for newborn screening ,
assessment of new technology, and laboratory
quality-control issues. Dried blood spots
can provide a “gold mine”
in terms of public health epidemiological
research, and there are other applications
as well. A recent survey conducted in
concert with the Association of Public
Health Laboratories found that 40 percent
of responding States stored spots for
more than 12 months. More than 80 percent
favored storage of identifiable spots
at either a state or regional level. But
importantly, 20 percent of the responding
States, which represent about 2 million
annual births, would consider participating
in an anonymous multistate survey, whether
it be looking at the prevalence of specific
genetic markers or other factors representing
utility and potential, at least from a
research perspective, in trying to answer
some of the questions that the Committee
will develop.
The OGPH has also used the National Center
for Health Statistics NHANES III DNA databank
to examine the prevalence of genes of
public health significance—more
than 87 variants of 57 genes will be examined
in this study.
CDC
also has developed a Newborn Screening
Quality Assurance Program specifically
for dried blood spots that addresses more
than 35 disorders and includes close to
400 laboratories in 35 countries that
are now enrolled in newborn screening
quality assurance and proficiency testing
programs. This will help standardize testing
from both within the United States, as
well as from outside. The types of activities
or services provided by this program include
filter-paper quality control, provision
of reference materials, proficiency testing,
and consultation. The major partner for
this activity is the Association of Public
Health Laboratories. In terms of research
and development, the laboratory is examining
genotype proficiency testing for some
of the newborn screening conditions on
the horizon, including cystic fibrosis
and MCAD. CDC also has a number of projects
related to genetic markers, such as one
for Type I diabetes, and other to the
impact of early identification and treatment
in terms of long-term outcomes for children.
The laboratory and training group also
is involved in training courses for laboratory
personnel for newborn screening, such
as MS/MS, as well as quality assurance.
After
Dr. Boyle’s presentation, Committee
members discussed a number of issues,
including whether anyone at the level
of the Secretary's office is responsible
for examining integrational coordination
of the recommendations arising from various
Federal Committees, or the information,
knowledge, and the behavior related to
newborn screening activities, because
the previous presentations indicate that
they are operating independently of one
another without an overall strategic plan,
relying instead on “friendly collaboration.”
Committee
members also discussed the absence of
large population-based studies. NIH has
been planning the National Children's
Study, which will be a large population-based
study of about 100,000 pregnancies. A
family genome study from NIH has been
discussed as well. CDC is overseeing a
number of population-based studies that
include biological samples, and focus
on specific conditions like birth defects,
diabetes, cancer, or heart disease.
Committee
members discussed the issue of communication,
not just between Federal agencies, but
also among all professionals involved
in these activities. Dr. Boyle stated
that CDC is just beginning to reach out
to professional organizations, to take
advantage of collective knowledge, and
to work through those organizations to
research some of the science. A model
for this type of collaboration exists
in the National Vaccine Program Office,
which was used in the last President's
childhood immunization initiative and
included representatives from a variety
of agencies who coordinated an approach
similar to that suggested by several Committee
members. Dr. Puryear noted that the Committee
is able to add representatives from Centers
for Medicare and Medicaid Services, the
Food and Drug Administration, and others,
as non-voting consultants.
March
of Dimes
Jennifer
Howse, Ph.D., President of the March of
Dimes (MOD), then offered a summary of
the March of Dimes’ recent activities.
Dr. Howse emphasized the March of Dimes’
focus on the needs of the newborn and
the need for greater uniformity in testing.
MOD identified the irreducible minimum
of newborn screening tests that they would
recommend, called “core tests.”
Using two criteria—that the test
be reliable and that the condition identified
be treatable (meaning that early discovery
of the condition would make a demonstrable
difference in the health of the newborn
and the child)—they arrived at a
list of nine core tests, plus newborn
hearing screening. Dr. Howse said that
"we believe that a test, even for
a rare disease, as long as its early discovery
makes a difference to the child, must
be conducted for every newborn”—a
sentiment that also was published in the
August 2000 issue of Pediatrics, stimulating
national debate.
At
the time of that inventory in the year
2000, nine States performed all 10 tests.
Using advocacy to persuade other States
to adopt these tests, the March of Dimes
persuaded 25 States to perform the core
tests. MOD recommends that the Committee
propose a set of core newborn screening
tests with whatever criteria this group
deems appropriate, so that regardless
of what State a child is born in, he or
she is guaranteed a minimum set of tests.
MOD also supports when States add tests,
beyond the 10 March of Dimes recommended
core tests.
Dr.
Howse stated that it is essential to be
prepared and to have a strong foundation
on a state-by-state basis, so as this
field grows and matures, and the science
comes to bear on so many different tests
and conditions, we will be in a position
to reap the benefits of that progress
for our newborns.
Committee
members then discussed the meaning of
“genetic test” and the fact
that many people don't view newborn screening
as genetic testing, when in reality, newborn
screening is by far the most common type
of genetic testing done in this country.
Committee members also discussed the difference
between the types of technology necessary
to conduct various types of genetic analyses.
It was noted that one State screens for
toxoplasmosis as part of newborn screening,
which is not a genetic test; thus, it
may not be under the purview of this Committee.
American
Academy of Pediatrics
E.
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