Request for Information: Main Study Design for the National Children's Study, 11661-11666 [2013-03716]
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Federal Register / Vol. 78, No. 33 / Tuesday, February 19, 2013 / Notices
hereby given of a meeting of the Board
of Scientific Counselors of the NIH
Clinical Center.
The meeting will be closed to the
public as indicated below in accordance
with the provisions set forth in section
552b(c)(6), Title 5 U.S.C., as amended
for the review, discussion, and
evaluation of individual intramural
programs and projects conducted by the
CLINICAL CENTER, including
consideration of personnel
qualifications and performance, and the
competence of individual investigators,
the disclosure of which would
constitute a clearly unwarranted
invasion of personal privacy.
Name of Committee: Board of Scientific
Counselors of the NIH Clinical Center.
Date: March 4–5, 2013.
Time: 8:00 a.m. to 12:00 p.m.
Agenda: To review and evaluate the
Department of Laboratory Medicine.
Place: National Institutes of Health,
Building 10, 10 Center Drive, Room 4–2551,
Bethesda, MD 20892.
Contact Person: David K. Henderson, MD,
Deputy Director for Clinical Care, Office of
the Director, Clinical Center, National
Institutes of Health, Building 10, Room 6–
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Dated: February 12, 2013.
Michelle Trout,
Program Analyst, Office of Federal Advisory
Committee Policy.
[FR Doc. 2013–03643 Filed 2–15–13; 8:45 am]
BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Request for Information: Main Study
Design for the National Children’s
Study
AGENCY:
National Institutes of Health,
HHS.
ACTION:
Notice.
The Eunice Kennedy Shriver
National Institute for Child Health and
Human Development (NICHD), National
Institutes of Health (NIH), is issuing a
Request for Information (RFI) as part of
the National Children’s Study’s (NCS)
effort to engage communities and
receive public input on specific design
questions for incorporation into the
Main Study Design of the NCS. The
information obtained from RFI
responses will be used to guide the
construction of decision points or
parameters for the Main Study design
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SUMMARY:
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over the next 12–18 months. This RFI
was preceded by a workshop with the
National Academy of Sciences which
posed similar questions. For background
information on this workshop, please
visit: https://www.nationalchildrens
study.gov/research/workshops/Pages/
nationalacademyofsciences
workshop.aspx.
RFI Release Date is February 11,
2013. Response Close Date is February
25, 2013.
ADDRESSES: To respond by February 25,
2013, please submit comments via email
to NCS_RFI@mail.nih.gov. Please
include citations for any references or
reports that can be used as source
material.
DATES:
FOR FURTHER INFORMATION CONTACT:
Questions about this request for
information may be directed to Kate
Winseck, MSW, The National Children’s
Study, Eunice Kennedy Shriver National
Institute of Child Health and Human
Development, National Institutes of
Health, 6100 Executive Blvd., Rm. 5C01,
Bethesda, MD 20891,
NCS_RFI@mail.nih.gov, 301–594–9147.
SUPPLEMENTARY INFORMATION: The
National Children’s Study is a
congressionally mandated longitudinal
birth cohort study intended to examine
the effects of environmental exposures
on the growth, development, and wellbeing of children. The NCS was
mandated by the Children’s Health Act
of 2000 (Pub. L. 106–310). The Study
consists of several components,
including: a pilot or Vanguard Study, a
Main Study focused on exposureresponse relationships, substudies
embedded in the Vanguard Study or the
Main Study, and formative research
projects. Data collection for the
Vanguard Study began in January 2009.
The design was changed in 2010 from
a door-to-door household recruitment
model to include an Alternate
Recruitment Study (ARS). The ARS
tested three different recruitment
strategies that differed as to initial point
of contact with potential participants—
direct outreach, household-based
through an NCS contractor, and
provider-based through a licensed
health care practitioner. Currently the
NCS is testing, through Provider-Based
Sampling Substudy, a further
refinement of the provider-based
sampling and recruitment using
hospitals and birthing centers in
addition to clinics and health care
provider offices that are sampled.
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Between the summer of 2011 and the
fall of 2012, the NCS held a series of
meetings with federal and non-federal
statistical sampling experts and others
to discuss the most effective sampling
approach and design for the Main
Study. The NCS had multiple separate
discussions and consultations with
additional individuals and
organizations. Based on these extensive
discussions and consultations, the NCS
is proposing the use of a multi-stage
probability sample for the Main Study.
The NCS plans to enroll women through
multiple entry points into the Main
Study, such as perinatally at hospitals
and birthing centers, and prenatally
through prenatal care providers.
Additionally, women whose children
are already enrolled will be followed as
a preconception sample of subsequent
births. Lastly, about 10% of the total
number of participants to be recruited
would be set aside for recruitment of a
convenience sample for populations
with characteristics or exposures of
particular scientific interest that would
likely be underrepresented in the other
strata.
The questions solicited in this RFI
focus on how much the NCS should
emphasize prenatal data collection, and
what the NCS could anticipate gaining
through the prospective data collection
compared to retroactive data acquisition
and the use of extant sources such as
medical records, other databases and
modeling. The issue is not whether to
have a prenatal stratum, but what
proportion of NCS resources should be
devoted to the effort.
Responses to this RFI will be used to
inform the Main Study design.
Proposed Main Study Design
1. Goals and Outcomes
The primary objective of the NCS is
to examine relationships among
exposures and outcomes that affect
children’s health and development.
These factors include environmental
exposures (with a broad definition of
environment) and biological/genetic
context. The NCS is not a study in a
conventional sense. It will primarily
function as a high quality data
collection platform for researchers to
explore hypotheses, access
biospecimens and environmental
samples, and analyze data. The Study’s
objectives stated in the Children’s
Health Act of 2000 are presented, along
with the respective design
considerations, in Table 1.
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TABLE 1—THE MAIN STUDY OBJECTIVES AS STATED IN THE CHILDREN’S HEALTH ACT OF 2000 WITH DESIGN
IMPLICATIONS
Study objectives
Sample and study design implications
Evaluate the effects of both chronic and intermittent exposures on child
health and human development.
Visit schedule with an emphasis on documenting early exposures and
events High retention of children is important to gather chronic and
intermittent exposures.
Broad scope of data collection to determine the association and influence of exposures on outcomes supplemented and informed by
formative research program.
Broad scope of exposure and outcome data collection supplemented
by personal health records.
Need to recruit diverse population groups and capture prenatal exposures.
Ensure sampling of disadvantaged population groups (in terms of exposures, education, socioeconomic status, etc.).
Investigate basic mechanisms of developmental disorders and environmental factors.
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Perform complete assessments of environmental influences on children’s well-being.
Gather data from diverse populations of children including prenatal exposures.
Consider health disparities among children .............................................
Exposures and Outcomes
A non-exhaustive list of examples of
exposures of potential interest includes:
• Natural products and industrial
chemicals and byproducts in the air,
water, soil, and commercial products;
• Pharmaceuticals used for therapy and
in the environment;
• Ionizing and non-ionizing radiation
• Proximity to manufacturing,
transportation, and processing
facilities
• Living with animals, insects, plants,
media and electronic device exposure,
• Noise
• Access to routine and specialty health
care
• Structured and unstructured learning
opportunities
• Diet and exercise
• Family and social network dynamics
in a cultural and geographic context
A non-exhaustive list of examples of
outcomes of potential interest includes:
• Premature birth
• Birth defects
• Growth and development
• Interpersonal relationships and
bonding
• Inflammatory processes including
allergies, asthma, and infections
• Epigenetic status
• Epilepsy and other neurologic
disorders
• Cardiovascular function
• Cancer
• Multidisciplinary, multidimensional
aspects of sensory input
• Autism and other
neurodevelopmental disorders
• Learning and behavior
• Precursors and early signs of chronic
diseases such as obesity, asthma,
hypertension, and diabetes
Both public health impact (based on
severity, as well as prevalence) on the
overall population of children and
scientific opportunity will inform the
prioritization of mechanisms to be
investigated. Examples of conditions of
potential interest are shown in Table 2.
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TABLE 2—THE PREVALENCE ESTIMATES PER 100,000 FOR SELECTED
CHILDHOOD ILLNESSES*
Estimated
prevalence per
100,000
Condition
Obese ...................................
Overweight ............................
Premature Birth ....................
Learning Disorders ...............
Asthma ..................................
Birth Defects (aggregate) .....
Autism Spectrum Disorders
(aggregate) ........................
Schizophrenia .......................
Congenital Heart Disease ....
Epilepsy ................................
Childhood Cancers ...............
Down Syndrome ...................
Fragile X Syndrome ..............
17,000
30,000
12,500
5,000
5,000
3,000
1,000–3,000
1,100
800
470
320
125
50
* Note that the legal federal threshold for a
rare disease is a prevalence of about 64 per
100,000.
The prevalence of many of the
conditions in Table 2 is possibly
underestimated due to disparities in
health and access to health care,
limiting diagnosis. In addition, the
prevalence presented represents only
the level of each disease spectrum
where formal evaluation and
intervention are required. Children with
less severe symptoms or with restricted
access to health care may have health
impacts from these conditions but not
rise to a level captured by formal health
care records.
Use of Exemplar or Illustrative
Hypotheses
Because there is no universal and
unambiguous definition of health, the
NCS plans to employ investigation of a
select number of exposure outcome
illustrative hypotheses. Illustrative
hypotheses will be prioritized with
consideration for the public health
importance of the outcome, availability
of study visit measurement assessments,
and sampling considerations such as
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sample matrix, specificity and stability
of analytes, informative value, and
options for other study visit
measurement assessments to collect the
same kind of information. Each
exposure will be assigned to each
outcome in a matrix table to generate
illustrative hypotheses as a reference
point to test many other hypotheses,
including those that may not be
envisioned at this time. For example,
the appearance of a chronic
inflammatory condition may result from
an interaction between host
characteristics that include genotype
and exposures that may include diet,
microbiome, and infection. Another
example may be that exposure to nuts
may have a beneficial effect in some
people and may provoke a life
threatening allergic response in others.
In this illustrative hypothesis
paradigm, select exposures proposed as
surrogates for additional exposures are:
analysis of
• Heavy metals
• Pesticide residues
• Semi-volatile organic compounds,
and
• High frequency sound in samples of
• Household dust
• Blood
• Urine, and
• Questionnaires on exposures
including social environment.
The select outcomes proposed as
surrogates for additional outcomes are:
• Linear growth rate and body mass
index as a surrogate for general health
• Metabolic screen of serum total
protein, blood urea nitrogen,
cholesterol, iron, and calcium for
nutrition and dietary assessment
• Frequency and duration of health
system encounters for respiratory illness
for pulmonary health, and
• Timing of standard
neurodevelopmental landmarks and any
deviation from adjusted trajectory for
cognitive and social development.
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Future research questions for the NCS
are likely to be complex and involve
multiple ‘‘exposures’’ from behavioral,
environmental, and sociologic domains
along with phenotypic information in
relation to an outcome. The hypotheses
that will be pertinent to the field 15 to
20 years from now are impossible to
predict and therefore model. We
propose this matrix as an exemplar, and
will focus our Study design on the
construction of a robust platform of data
from a national probability sample.
2. Proposed Study Design
Target Population
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A birth cohort of children born to
mothers residing in the United States
will be the primary target population. In
addition, populations that might
otherwise be underrepresented in the
cohort on the basis of exposures,
demographics, or other factors will be
supplemented through targeted
recruitment.
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Study Sample Size
The proposed sample size will be
about 100,000 live births.
Sampling and Recruitment Strategy
The NCS is proposing a multi-stage
probability design for the Main Study.
The rationale for using the proposed
approach is the perception of
differences among the characteristics of
each recruited population that have
analytic, logistical, or cost implications
and the difficulty of identifying and
enrolling a single generalizable sample
of women, spanning from preconception
to birth, in a practical manner. The
design will be based on a national
probability sample recruited through
health care providers as the major
component of the overall Study sample,
with about a 10 percent of the total
sample size set aside for targeted
populations for addressing additional
questions of scientific interest. A health
care provider can be a hospital, birthing
center, community based practitioner,
or clinic.
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The target population is children born
to mothers in the United States during
a predefined recruitment period. In
order to sample this population we
propose taking a probability sample
(with probability proportionate to the
number of deliveries) from a national
listing of hospitals and birthing centers.
From these sampled hospitals and
birthing centers a second stage of the
sampling design will be a listing of
prenatal care providers that ‘‘feed’’
patients for delivery at the hospital.
From these ‘‘feeder’’ providers, we will
attempt to recruit women during their
prenatal period. These women would be
considered a prenatal stratum of the
design (Figure 1).
Some women may not be enrolled
prenatally. This may be because they
did not seek prenatal care, or because
they sought care from a provider not
selected by the steps above. These
women could be enrolled at the hospital
at delivery, and would be considered a
part of the birth stratum of the design.
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composition and bias of any prenatal
sample of women.
Regardless of the point of entry into
the Study, women enrolled in the Study
would be followed and any subsequent
births of siblings could also be enrolled
in the Study. These subsequent births,
or higher birth order siblings, would be
considered a preconception stratum of
the design as there would be
environmental assessments prior to the
conception of the sibling as a result of
already being enrolled in the Study.
What is important to note is that
women recruited from health care
providers will have different timing for
their entry into the Study, and therefore,
different amounts of information
collected. Women recruited prenatally
from their prenatal care provider will
have the opportunity for prospective
environmental assessments during the
prenatal period. Women recruited
through hospitals will have data
collected at the birth visit that may be
representative of a portion of the
prenatal period (such as the collection
of a vacuum cleaner bag of dust and
questionnaire data), however this would
be collected retrospectively and the
inference period of the samples will
vary. Study visits and assessments from
the birth visit onward will be uniform
across strata (Table 3).
Table 3. Summary of the data
collection opportunities from the strata
in the Main Study probability sample.
The x’s are a representation of the
quantitative measure of the amount of
information that can be gathered from
the stratum at a particular point in the
pre- or perinatal period, with xxx
referring to the greatest amount of
information.
OPPORTUNITIES TO OBTAIN PROSPECTIVE BIOLOGICAL SPECIMENS AND ENVIRONMENTAL SAMPLES
Birth
Point of Entry Into Study:
Birth ...........................................................
Prenatal .....................................................
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3rd Trimester
2nd Trimester
1st Timester
Preconception
XXX
XXX
............................
XXX
............................
XX
............................
X
............................
............................
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The most cost effective and simplest
approach is to enroll women
perinatally. About 98 percent of
pregnant women in the United States
deliver at hospitals or birthing centers,
so the recruitment opportunity is
greatest at birth. The proportion of the
entire sample that can be enrolled
prenatally and perinatally can be
adjusted by the number of prenatal
providers engaged, the number and
duration of opportunities the design
uses to enroll participants, and the
logistics and efficiency of each location.
NCS field experience to date is mixed
with regard to the cost, ease, accuracy,
and cooperation of engaging community
providers. One consideration is that
women seek prenatal care at various
times along the continuum of pregnancy
with factors such as access,
affordability, complex medical
conditions, etc. influencing the
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OPPORTUNITIES TO OBTAIN PROSPECTIVE BIOLOGICAL SPECIMENS AND ENVIRONMENTAL SAMPLES—Continued
Birth
The supplemental, or targeted studies,
could be outside the cooperating
institutions and would target
populations that are underrepresented
for any reason of scientific interest. An
example of one of these cohorts would
be a small sample of pregnant women
residing in a community where pressure
extraction for natural gas by hydraulic
fracturing, or fracking, is taking place,
and thus, the scientific interest lies in
the environmental exposure. However,
the area or number of births may be so
small that the probability of selection
into larger probability samples is low.
These cohorts could be part of ancillary
studies that would leverage the
resources of the NCS. These targeted
cohorts are not expected to be part of
the larger probability samples described
above, although probability-based
approaches may be used. These cohorts
are intended to be analyzed
independently. We propose a scientific
review process to screen proposals for
targeted cohorts for alignment with the
Study goals and prioritization with
available resources.
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a. Retention Strategy
The primary recruitment mechanism
will be through health care providers,
with the birth stratum recruited through
hospitals and birthing centers, and the
pregnancy stratum recruited through
prenatal care providers who feed into
the hospitals and birthing centers
participating in the birth sample.
A key goal for the NCS Main Study is
to obtain information on the health and
developmental outcomes of participants
as they move through childhood,
adolescence, and early adulthood. To
answer many of the potential scientific
questions, it will be essential to retain
a sample of sufficient size throughout
the course of the Main Study to obtain
robust longitudinal data. Determining
expected rates of retention of
participants through pregnancy to birth
and beyond is a key part of the analytic
plan for the Vanguard (Pilot) Study.
Retention of participants from visit to
visit will be carefully monitored.
Specifically, the NCS will use the
following data from the Vanguard Study
to monitor and plan retention strategies
for the Main Study:
• The proportion of consented
women who participate in at least one
data collection Study visit,
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2nd Trimester
1st Timester
Preconception
XXX
Sibling .......................................................
3rd Trimester
XXX
XXX
XXX
XXX
• The proportion of women enrolled
during pregnancy and participating in
all data collection visits through the
birth of a child who is enrolled into the
Study,
• The proportion of women who
receive a pre-birth data collection visit
who also receive a successful birth visit,
and
• The proportion of women enrolled
during pregnancy and participating in
all data collection visits of an enrolled
child.
Retention challenges and solutions
will likely vary by the nature of the
visit, the length of time between visits,
and the participant’s stage in the Study
cycle. Information collected from field
data collectors represents a critical
source of data from which to evaluate
the feasibility and acceptability of the
NCS Vanguard Study. Our ability to
utilize these data to inform subsequent
decisions requires coordination of
several operational efforts, including
hiring, training, and monitoring of field
staff and the development of
instruments, Study procedures, and case
management documentation. For
example, unit nonresponse—both initial
and due to attrition—will be assessed
systematically through the
administration of a Nonrespondent
Questionnaire. Additionally, our
understanding of participant reactions
to introducing the collection of
biospecimens from infants will be
informed by these multiple sources.
b. Study Visit Schedule
Both the Vanguard Study and the
Main Study emphasize data collection
early in pregnancy and early in child
development because the largest
knowledge gaps, and perhaps the most
critical events, occur during those time
periods. Consequently, pregnancy data
collections are scheduled twice, if
possible, prior to approximately 20
weeks gestation and once later in
pregnancy. Data collections for children
are scheduled at birth and every 3
months for the first year and every 6
months until 5 years old, for a total of
13 opportunities for data collection.
Seven of the opportunities will be faceto-face encounters and may include
biospecimen and environmental sample
collection (https://
www.nationalchildrensstudy.gov/
research/workshops/Pages/NCSproposed-example-outcome-exposure-
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table.pdf). The other six are remote data
collections, typically by telephone
interview. Subsequent data collections
have not been scheduled, but will be on
average about every other year until 21
years old, for a total of 8 additional data
collection opportunities. In sum, 21 data
collection opportunities per child are
planned, but that may change based
upon experience from the Vanguard
phase, scientific opportunity, logistical
factors, and resources available.
Scheduling the majority of data
collection within the first five years of
life will address both the critical
knowledge gaps, as well as maximize
data collection while retention of
participants is highest.
c. Study Visit Structure
Multiple modalities for data
collection are under evaluation, with
the current plan based on a core
questionnaire model administered at
every childhood visit plus supplemental
modules to be administered to specific
participants or subpopulations based on
events and conditions such as age,
developmental stage, and other triggers
such as specific exposures or
hospitalizations. While the core
questionnaire is intended for all
participants, supplemental modules
may be administered on a missing by
design basis, to leverage the large Study
population and extend resources. In
addition, the visit schedule is flexible,
in that children will not have
assessments administered precisely at a
given age, but instead, within a window
of several weeks around a particular age
to improve compliance and to capture
data across a range of specific ages. The
module-based visit strategy should
provide an opportunity to collect
information about very specific
exposures or outcomes while decreasing
burden on respondents as all the
modules will not be offered to all
participants.
Information Requested
This RFI invites the scientific
community, health professionals, and
the general public to provide comments
and suggestions on the following topics:
1. What should be the criteria for the
stratum allocation decision between
perinatal and prenatal enrollment and
what evidence is available to support an
assessment of each criterion? Examples
include:
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a. Recruitment costs, which include
the costs of constructing the frame and
the relative costs and efficiency of
enrolling a participant;
b. Generalizability. What population
is being represented?
c. Extent of exposures and other
information that can be gathered. By
definition, women who enter the study
at the birth visit will have more limited
data on prenatal exposures than
participants enrolled during the
prenatal period; while prenatal
participants will have less information
on prenatal exposures (and much less
information on preconception
exposures) than the subsequent births to
already enrolled mothers or a separate
preconception sample.
2. What should be the allocation of
sample cases among the various strata?
Assume that 10% of the sample is
reserved for preconception and special
studies; then, the allocation involves the
remaining 90,000.
a. One option is the current proposal
which is about a 50–50 split or 45,000
participants in each.
b. Another option is something like an
80–20 split allocated between birth and
pregnancy, with the pregnancy sample
used to form the basis for imputing
prenatal exposures (after using medical
records for the mothers to get as much
prenatal information as possible).
c. Yet another option is like an 80–20
split allocated between pregnancy and
birth, with the birth sample used to
form the basis for providing
generalizability to the data analysis.
d. One extreme could be the entire
initial enrollment allocated to the birth
stratum, with studies of prenatal and
preconception exposures using
primarily the subsequent births to
originally enrolled mothers.
e. At the other extreme, most of the
sample could be allocated to the
prenatal stratum with a small birth
sample consisting of women who did
not receive any prenatal care and are
enrolled at the hospital.
3. Given the challenge as stated in the
Children’s Health Act of 2000 to
‘‘perform complete assessments of
environmental influences on children’s
well-being,’’ does the proposed visit
schedule and environmental sample
collection (https://
www.nationalchildrensstudy.gov/
research/workshops/Pages/potentialenvironmental-exposures-ofinterest.pdf) balance the complex
requirements? Specifically comment on
the proportion of different types of data
collection—primary environmental
sample collection, use of biological
specimens for biomarkers of exposure,
and use of secondary sources including
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retrospective analysis for environmental
exposures. Considerations may include:
a. Are the proposed measures
(biomarkers, questionnaires, physical
measures) the most appropriate to assess
exposures of interest? If not, what
measures should be taken?
b. On what decision points should the
NCS prioritize exposure assessments?
Some examples of factors to consider
are:
1. Potential public health impact of
the outcome
2. Technical feasibility including
timing of data collection with regard to
potential developmental vulnerability
3. Scientific opportunity to address
knowledge gaps and illuminate
developmental pathways
This RFI is for planning purposes
only and should not be construed as a
solicitation for applications or proposals
and/or as an obligation in any way on
the part of the United States Federal
government. The Federal government
will not pay for the preparation of any
information submitted, and/or for the
government’s use of that information.
Additionally, the government cannot
guarantee the confidentiality of the
information provided.
Dated: February 7, 2013.
Alan E. Guttmacher,
Director, Eunice Kennedy Shriver National
Institute of Child Health and Human
Development, NIH.
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A wide range of client and program
information is captured through SAIS
for approximately 600 grantees.
Substance abuse treatment facilities
submit their data on a monthly and even
a weekly basis to ensure that SAIS is an
accurate, up-to-date reflection on the
scope of services delivered and
characteristics of the treatment
population. Over 30 reports on grantee
performance are readily available on the
SAIS Web site. The reports inform staff
on the grantees’ ability to serve their
target populations and meet their client
and budget targets. SAIS data allow
grantees information that can guide
modifications to their service array.
Continued approval of this information
collection will allow SAMHSA to
continue to meet Government
Performance and Results Act of 1993
(GPRA) reporting requirements that
quantify the effects and
accomplishments of its discretionary
grant programs which are consistent
with OMB guidance.
Note that there are no changes to the
instrument or the burden hours from the
previous OMB submission.
Based on current funding and
planned fiscal year 2010 notice of
funding announcements (NOFA), the
CSAT programs that will use these
measures in fiscal years 2013 through
2014 include: the Access to Recovery 2
(ATR2), ATR3, Addictions Treatment
for Homeless; Adult Criminal Justice
Treatment; Assertive Adolescent Family
Treatment; HIV/AIDS Outreach; Office
of Juvenile Justice and Delinquency
Prevention—Brief Intervention and
Referral to Treatment (OJJDP–BIRT);
OJJDP-Juvenile Drug Court (OJJDP–JDC);
Offender Re-entry Program; Pregnant
and Postpartum Women; Recovery
Community Services Program—
Services; Recovery Oriented Systems of
Care; Screening and Brief Intervention
and Referral to Treatment (SBIRT),
Targeted Capacity Expansion (TCE);
TCE/HIV; Treatment Drug Court; and
the Youth Offender Reentry Program.
SAMHSA uses the performance
measures to report on the performance
of its discretionary services grant
programs. The performance measures
information is used by individuals at
three different levels: the SAMHSA
administrator and staff, the Center
administrators and government project
officers, and grantees
SAMHSA and its Centers will use the
data for annual reporting required by
GPRA and for NOMs comparing
baseline with discharge and follow-up
data. GPRA requires that SAMHSA’s
report for each fiscal year include actual
E:\FR\FM\19FEN1.SGM
19FEN1
Agencies
[Federal Register Volume 78, Number 33 (Tuesday, February 19, 2013)]
[Notices]
[Pages 11661-11666]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-03716]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Request for Information: Main Study Design for the National
Children's Study
AGENCY: National Institutes of Health, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Eunice Kennedy Shriver National Institute for Child Health
and Human Development (NICHD), National Institutes of Health (NIH), is
issuing a Request for Information (RFI) as part of the National
Children's Study's (NCS) effort to engage communities and receive
public input on specific design questions for incorporation into the
Main Study Design of the NCS. The information obtained from RFI
responses will be used to guide the construction of decision points or
parameters for the Main Study design over the next 12-18 months. This
RFI was preceded by a workshop with the National Academy of Sciences
which posed similar questions. For background information on this
workshop, please visit: https://www.nationalchildrensstudy.gov/research/workshops/Pages/nationalacademyofsciencesworkshop.aspx.
DATES: RFI Release Date is February 11, 2013. Response Close Date is
February 25, 2013.
ADDRESSES: To respond by February 25, 2013, please submit comments via
email to NCS_RFI@mail.nih.gov. Please include citations for any
references or reports that can be used as source material.
FOR FURTHER INFORMATION CONTACT: Questions about this request for
information may be directed to Kate Winseck, MSW, The National
Children's Study, Eunice Kennedy Shriver National Institute of Child
Health and Human Development, National Institutes of Health, 6100
Executive Blvd., Rm. 5C01, Bethesda, MD 20891, NCS_RFI@mail.nih.gov,
301-594-9147.
SUPPLEMENTARY INFORMATION: The National Children's Study is a
congressionally mandated longitudinal birth cohort study intended to
examine the effects of environmental exposures on the growth,
development, and well-being of children. The NCS was mandated by the
Children's Health Act of 2000 (Pub. L. 106-310). The Study consists of
several components, including: a pilot or Vanguard Study, a Main Study
focused on exposure-response relationships, substudies embedded in the
Vanguard Study or the Main Study, and formative research projects. Data
collection for the Vanguard Study began in January 2009. The design was
changed in 2010 from a door-to-door household recruitment model to
include an Alternate Recruitment Study (ARS). The ARS tested three
different recruitment strategies that differed as to initial point of
contact with potential participants--direct outreach, household-based
through an NCS contractor, and provider-based through a licensed health
care practitioner. Currently the NCS is testing, through Provider-Based
Sampling Substudy, a further refinement of the provider-based sampling
and recruitment using hospitals and birthing centers in addition to
clinics and health care provider offices that are sampled.
Between the summer of 2011 and the fall of 2012, the NCS held a
series of meetings with federal and non-federal statistical sampling
experts and others to discuss the most effective sampling approach and
design for the Main Study. The NCS had multiple separate discussions
and consultations with additional individuals and organizations. Based
on these extensive discussions and consultations, the NCS is proposing
the use of a multi-stage probability sample for the Main Study. The NCS
plans to enroll women through multiple entry points into the Main
Study, such as perinatally at hospitals and birthing centers, and
prenatally through prenatal care providers. Additionally, women whose
children are already enrolled will be followed as a preconception
sample of subsequent births. Lastly, about 10% of the total number of
participants to be recruited would be set aside for recruitment of a
convenience sample for populations with characteristics or exposures of
particular scientific interest that would likely be underrepresented in
the other strata.
The questions solicited in this RFI focus on how much the NCS
should emphasize prenatal data collection, and what the NCS could
anticipate gaining through the prospective data collection compared to
retroactive data acquisition and the use of extant sources such as
medical records, other databases and modeling. The issue is not whether
to have a prenatal stratum, but what proportion of NCS resources should
be devoted to the effort.
Responses to this RFI will be used to inform the Main Study design.
Proposed Main Study Design
1. Goals and Outcomes
The primary objective of the NCS is to examine relationships among
exposures and outcomes that affect children's health and development.
These factors include environmental exposures (with a broad definition
of environment) and biological/genetic context. The NCS is not a study
in a conventional sense. It will primarily function as a high quality
data collection platform for researchers to explore hypotheses, access
biospecimens and environmental samples, and analyze data. The Study's
objectives stated in the Children's Health Act of 2000 are presented,
along with the respective design considerations, in Table 1.
[[Page 11662]]
Table 1--The Main Study Objectives as Stated in the Children's Health
Act of 2000 With Design Implications
------------------------------------------------------------------------
Sample and study design
Study objectives implications
------------------------------------------------------------------------
Evaluate the effects of both chronic Visit schedule with an emphasis
and intermittent exposures on child on documenting early exposures
health and human development. and events High retention of
children is important to
gather chronic and
intermittent exposures.
Investigate basic mechanisms of Broad scope of data collection
developmental disorders and to determine the association
environmental factors. and influence of exposures on
outcomes supplemented and
informed by formative research
program.
Perform complete assessments of Broad scope of exposure and
environmental influences on children's outcome data collection
well-being. supplemented by personal
health records.
Gather data from diverse populations of Need to recruit diverse
children including prenatal exposures. population groups and capture
prenatal exposures.
Consider health disparities among Ensure sampling of
children. disadvantaged population
groups (in terms of exposures,
education, socioeconomic
status, etc.).
------------------------------------------------------------------------
Exposures and Outcomes
A non-exhaustive list of examples of exposures of potential
interest includes:
Natural products and industrial chemicals and byproducts in
the air, water, soil, and commercial products;
Pharmaceuticals used for therapy and in the environment;
Ionizing and non-ionizing radiation
Proximity to manufacturing, transportation, and processing
facilities
Living with animals, insects, plants, media and electronic
device exposure,
Noise
Access to routine and specialty health care
Structured and unstructured learning opportunities
Diet and exercise
Family and social network dynamics in a cultural and
geographic context
A non-exhaustive list of examples of outcomes of potential interest
includes:
Premature birth
Birth defects
Growth and development
Interpersonal relationships and bonding
Inflammatory processes including allergies, asthma, and
infections
Epigenetic status
Epilepsy and other neurologic disorders
Cardiovascular function
Cancer
Multidisciplinary, multidimensional aspects of sensory input
Autism and other neurodevelopmental disorders
Learning and behavior
Precursors and early signs of chronic diseases such as
obesity, asthma, hypertension, and diabetes
Both public health impact (based on severity, as well as
prevalence) on the overall population of children and scientific
opportunity will inform the prioritization of mechanisms to be
investigated. Examples of conditions of potential interest are shown in
Table 2.
Table 2--The Prevalence Estimates per 100,000 for Selected Childhood
Illnesses*
------------------------------------------------------------------------
Estimated
Condition prevalence per
100,000
------------------------------------------------------------------------
Obese................................................... 17,000
Overweight.............................................. 30,000
Premature Birth......................................... 12,500
Learning Disorders...................................... 5,000
Asthma.................................................. 5,000
Birth Defects (aggregate)............................... 3,000
Autism Spectrum Disorders (aggregate)................... 1,000-3,000
Schizophrenia........................................... 1,100
Congenital Heart Disease................................ 800
Epilepsy................................................ 470
Childhood Cancers....................................... 320
Down Syndrome........................................... 125
Fragile X Syndrome...................................... 50
------------------------------------------------------------------------
* Note that the legal federal threshold for a rare disease is a
prevalence of about 64 per 100,000.
The prevalence of many of the conditions in Table 2 is possibly
underestimated due to disparities in health and access to health care,
limiting diagnosis. In addition, the prevalence presented represents
only the level of each disease spectrum where formal evaluation and
intervention are required. Children with less severe symptoms or with
restricted access to health care may have health impacts from these
conditions but not rise to a level captured by formal health care
records.
Use of Exemplar or Illustrative Hypotheses
Because there is no universal and unambiguous definition of health,
the NCS plans to employ investigation of a select number of exposure
outcome illustrative hypotheses. Illustrative hypotheses will be
prioritized with consideration for the public health importance of the
outcome, availability of study visit measurement assessments, and
sampling considerations such as sample matrix, specificity and
stability of analytes, informative value, and options for other study
visit measurement assessments to collect the same kind of information.
Each exposure will be assigned to each outcome in a matrix table to
generate illustrative hypotheses as a reference point to test many
other hypotheses, including those that may not be envisioned at this
time. For example, the appearance of a chronic inflammatory condition
may result from an interaction between host characteristics that
include genotype and exposures that may include diet, microbiome, and
infection. Another example may be that exposure to nuts may have a
beneficial effect in some people and may provoke a life threatening
allergic response in others.
In this illustrative hypothesis paradigm, select exposures proposed
as surrogates for additional exposures are: analysis of
Heavy metals
Pesticide residues
Semi-volatile organic compounds, and
High frequency sound in samples of
Household dust
Blood
Urine, and
Questionnaires on exposures including social environment.
The select outcomes proposed as surrogates for additional outcomes
are:
Linear growth rate and body mass index as a surrogate for
general health
Metabolic screen of serum total protein, blood urea
nitrogen, cholesterol, iron, and calcium for nutrition and dietary
assessment
Frequency and duration of health system encounters for
respiratory illness for pulmonary health, and
Timing of standard neurodevelopmental landmarks and any
deviation from adjusted trajectory for cognitive and social
development.
[[Page 11663]]
Future research questions for the NCS are likely to be complex and
involve multiple ``exposures'' from behavioral, environmental, and
sociologic domains along with phenotypic information in relation to an
outcome. The hypotheses that will be pertinent to the field 15 to 20
years from now are impossible to predict and therefore model. We
propose this matrix as an exemplar, and will focus our Study design on
the construction of a robust platform of data from a national
probability sample.
2. Proposed Study Design
Target Population
A birth cohort of children born to mothers residing in the United
States will be the primary target population. In addition, populations
that might otherwise be underrepresented in the cohort on the basis of
exposures, demographics, or other factors will be supplemented through
targeted recruitment.
Study Sample Size
The proposed sample size will be about 100,000 live births.
Sampling and Recruitment Strategy
The NCS is proposing a multi-stage probability design for the Main
Study. The rationale for using the proposed approach is the perception
of differences among the characteristics of each recruited population
that have analytic, logistical, or cost implications and the difficulty
of identifying and enrolling a single generalizable sample of women,
spanning from preconception to birth, in a practical manner. The design
will be based on a national probability sample recruited through health
care providers as the major component of the overall Study sample, with
about a 10 percent of the total sample size set aside for targeted
populations for addressing additional questions of scientific interest.
A health care provider can be a hospital, birthing center, community
based practitioner, or clinic.
The target population is children born to mothers in the United
States during a predefined recruitment period. In order to sample this
population we propose taking a probability sample (with probability
proportionate to the number of deliveries) from a national listing of
hospitals and birthing centers. From these sampled hospitals and
birthing centers a second stage of the sampling design will be a
listing of prenatal care providers that ``feed'' patients for delivery
at the hospital. From these ``feeder'' providers, we will attempt to
recruit women during their prenatal period. These women would be
considered a prenatal stratum of the design (Figure 1).
Some women may not be enrolled prenatally. This may be because they
did not seek prenatal care, or because they sought care from a provider
not selected by the steps above. These women could be enrolled at the
hospital at delivery, and would be considered a part of the birth
stratum of the design.
[[Page 11664]]
[GRAPHIC] [TIFF OMITTED] TN19FE13.000
The most cost effective and simplest approach is to enroll women
perinatally. About 98 percent of pregnant women in the United States
deliver at hospitals or birthing centers, so the recruitment
opportunity is greatest at birth. The proportion of the entire sample
that can be enrolled prenatally and perinatally can be adjusted by the
number of prenatal providers engaged, the number and duration of
opportunities the design uses to enroll participants, and the logistics
and efficiency of each location.
NCS field experience to date is mixed with regard to the cost,
ease, accuracy, and cooperation of engaging community providers. One
consideration is that women seek prenatal care at various times along
the continuum of pregnancy with factors such as access, affordability,
complex medical conditions, etc. influencing the composition and bias
of any prenatal sample of women.
Regardless of the point of entry into the Study, women enrolled in
the Study would be followed and any subsequent births of siblings could
also be enrolled in the Study. These subsequent births, or higher birth
order siblings, would be considered a preconception stratum of the
design as there would be environmental assessments prior to the
conception of the sibling as a result of already being enrolled in the
Study.
What is important to note is that women recruited from health care
providers will have different timing for their entry into the Study,
and therefore, different amounts of information collected. Women
recruited prenatally from their prenatal care provider will have the
opportunity for prospective environmental assessments during the
prenatal period. Women recruited through hospitals will have data
collected at the birth visit that may be representative of a portion of
the prenatal period (such as the collection of a vacuum cleaner bag of
dust and questionnaire data), however this would be collected
retrospectively and the inference period of the samples will vary.
Study visits and assessments from the birth visit onward will be
uniform across strata (Table 3).
Table 3. Summary of the data collection opportunities from the
strata in the Main Study probability sample. The x's are a
representation of the quantitative measure of the amount of information
that can be gathered from the stratum at a particular point in the pre-
or perinatal period, with xxx referring to the greatest amount of
information.
Opportunities To Obtain Prospective Biological Specimens and Environmental Samples
--------------------------------------------------------------------------------------------------------------------------------------------------------
Birth 3rd Trimester 2nd Trimester 1st Timester Preconception
--------------------------------------------------------------------------------------------------------------------------------------------------------
Point of Entry Into Study:
Birth................................................ XXX ................. ................. ................. .................
Prenatal............................................. XXX XXX XX X .................
[[Page 11665]]
Sibling.............................................. XXX XXX XXX XXX XXX
--------------------------------------------------------------------------------------------------------------------------------------------------------
The supplemental, or targeted studies, could be outside the
cooperating institutions and would target populations that are
underrepresented for any reason of scientific interest. An example of
one of these cohorts would be a small sample of pregnant women residing
in a community where pressure extraction for natural gas by hydraulic
fracturing, or fracking, is taking place, and thus, the scientific
interest lies in the environmental exposure. However, the area or
number of births may be so small that the probability of selection into
larger probability samples is low. These cohorts could be part of
ancillary studies that would leverage the resources of the NCS. These
targeted cohorts are not expected to be part of the larger probability
samples described above, although probability-based approaches may be
used. These cohorts are intended to be analyzed independently. We
propose a scientific review process to screen proposals for targeted
cohorts for alignment with the Study goals and prioritization with
available resources.
a. Retention Strategy
The primary recruitment mechanism will be through health care
providers, with the birth stratum recruited through hospitals and
birthing centers, and the pregnancy stratum recruited through prenatal
care providers who feed into the hospitals and birthing centers
participating in the birth sample.
A key goal for the NCS Main Study is to obtain information on the
health and developmental outcomes of participants as they move through
childhood, adolescence, and early adulthood. To answer many of the
potential scientific questions, it will be essential to retain a sample
of sufficient size throughout the course of the Main Study to obtain
robust longitudinal data. Determining expected rates of retention of
participants through pregnancy to birth and beyond is a key part of the
analytic plan for the Vanguard (Pilot) Study. Retention of participants
from visit to visit will be carefully monitored.
Specifically, the NCS will use the following data from the Vanguard
Study to monitor and plan retention strategies for the Main Study:
The proportion of consented women who participate in at
least one data collection Study visit,
The proportion of women enrolled during pregnancy and
participating in all data collection visits through the birth of a
child who is enrolled into the Study,
The proportion of women who receive a pre-birth data
collection visit who also receive a successful birth visit, and
The proportion of women enrolled during pregnancy and
participating in all data collection visits of an enrolled child.
Retention challenges and solutions will likely vary by the nature
of the visit, the length of time between visits, and the participant's
stage in the Study cycle. Information collected from field data
collectors represents a critical source of data from which to evaluate
the feasibility and acceptability of the NCS Vanguard Study. Our
ability to utilize these data to inform subsequent decisions requires
coordination of several operational efforts, including hiring,
training, and monitoring of field staff and the development of
instruments, Study procedures, and case management documentation. For
example, unit nonresponse--both initial and due to attrition--will be
assessed systematically through the administration of a Nonrespondent
Questionnaire. Additionally, our understanding of participant reactions
to introducing the collection of biospecimens from infants will be
informed by these multiple sources.
b. Study Visit Schedule
Both the Vanguard Study and the Main Study emphasize data
collection early in pregnancy and early in child development because
the largest knowledge gaps, and perhaps the most critical events, occur
during those time periods. Consequently, pregnancy data collections are
scheduled twice, if possible, prior to approximately 20 weeks gestation
and once later in pregnancy. Data collections for children are
scheduled at birth and every 3 months for the first year and every 6
months until 5 years old, for a total of 13 opportunities for data
collection. Seven of the opportunities will be face-to-face encounters
and may include biospecimen and environmental sample collection (https://www.nationalchildrensstudy.gov/research/workshops/Pages/NCS-proposed-example-outcome-exposure-table.pdf). The other six are remote data
collections, typically by telephone interview. Subsequent data
collections have not been scheduled, but will be on average about every
other year until 21 years old, for a total of 8 additional data
collection opportunities. In sum, 21 data collection opportunities per
child are planned, but that may change based upon experience from the
Vanguard phase, scientific opportunity, logistical factors, and
resources available. Scheduling the majority of data collection within
the first five years of life will address both the critical knowledge
gaps, as well as maximize data collection while retention of
participants is highest.
c. Study Visit Structure
Multiple modalities for data collection are under evaluation, with
the current plan based on a core questionnaire model administered at
every childhood visit plus supplemental modules to be administered to
specific participants or subpopulations based on events and conditions
such as age, developmental stage, and other triggers such as specific
exposures or hospitalizations. While the core questionnaire is intended
for all participants, supplemental modules may be administered on a
missing by design basis, to leverage the large Study population and
extend resources. In addition, the visit schedule is flexible, in that
children will not have assessments administered precisely at a given
age, but instead, within a window of several weeks around a particular
age to improve compliance and to capture data across a range of
specific ages. The module-based visit strategy should provide an
opportunity to collect information about very specific exposures or
outcomes while decreasing burden on respondents as all the modules will
not be offered to all participants.
Information Requested
This RFI invites the scientific community, health professionals,
and the general public to provide comments and suggestions on the
following topics:
1. What should be the criteria for the stratum allocation decision
between perinatal and prenatal enrollment and what evidence is
available to support an assessment of each criterion? Examples include:
[[Page 11666]]
a. Recruitment costs, which include the costs of constructing the
frame and the relative costs and efficiency of enrolling a participant;
b. Generalizability. What population is being represented?
c. Extent of exposures and other information that can be gathered.
By definition, women who enter the study at the birth visit will have
more limited data on prenatal exposures than participants enrolled
during the prenatal period; while prenatal participants will have less
information on prenatal exposures (and much less information on
preconception exposures) than the subsequent births to already enrolled
mothers or a separate preconception sample.
2. What should be the allocation of sample cases among the various
strata? Assume that 10% of the sample is reserved for preconception and
special studies; then, the allocation involves the remaining 90,000.
a. One option is the current proposal which is about a 50-50 split
or 45,000 participants in each.
b. Another option is something like an 80-20 split allocated
between birth and pregnancy, with the pregnancy sample used to form the
basis for imputing prenatal exposures (after using medical records for
the mothers to get as much prenatal information as possible).
c. Yet another option is like an 80-20 split allocated between
pregnancy and birth, with the birth sample used to form the basis for
providing generalizability to the data analysis.
d. One extreme could be the entire initial enrollment allocated to
the birth stratum, with studies of prenatal and preconception exposures
using primarily the subsequent births to originally enrolled mothers.
e. At the other extreme, most of the sample could be allocated to
the prenatal stratum with a small birth sample consisting of women who
did not receive any prenatal care and are enrolled at the hospital.
3. Given the challenge as stated in the Children's Health Act of
2000 to ``perform complete assessments of environmental influences on
children's well-being,'' does the proposed visit schedule and
environmental sample collection (https://www.nationalchildrensstudy.gov/research/workshops/Pages/potential-environmental-exposures-of-interest.pdf) balance the complex requirements? Specifically comment on
the proportion of different types of data collection--primary
environmental sample collection, use of biological specimens for
biomarkers of exposure, and use of secondary sources including
retrospective analysis for environmental exposures. Considerations may
include:
a. Are the proposed measures (biomarkers, questionnaires, physical
measures) the most appropriate to assess exposures of interest? If not,
what measures should be taken?
b. On what decision points should the NCS prioritize exposure
assessments?
Some examples of factors to consider are:
1. Potential public health impact of the outcome
2. Technical feasibility including timing of data collection with
regard to potential developmental vulnerability
3. Scientific opportunity to address knowledge gaps and illuminate
developmental pathways
This RFI is for planning purposes only and should not be construed
as a solicitation for applications or proposals and/or as an obligation
in any way on the part of the United States Federal government. The
Federal government will not pay for the preparation of any information
submitted, and/or for the government's use of that information.
Additionally, the government cannot guarantee the confidentiality of
the information provided.
Dated: February 7, 2013.
Alan E. Guttmacher,
Director, Eunice Kennedy Shriver National Institute of Child Health and
Human Development, NIH.
[FR Doc. 2013-03716 Filed 2-15-13; 8:45 am]
BILLING CODE 4140-01-P