[Federal Register Volume 78, Number 33 (Tuesday, February 19, 2013)]
[Notices]
[Pages 11661-11666]
From the Federal Register Online via the Government Publishing 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.

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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: http://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 [email protected]. 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, [email protected], 
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
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                                             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
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                                                                 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 (http://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 (http://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]
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