The Third Meeting of the National Children’s Study Advisory Committee (NCSAC)
September 12-13, 2002
U.S. Environmental Protection Agency (EPA
Crystal City, Virginia

Meeting Minutes

The National Children’s Study (NCS) is led by a consortium of federal agency partners: the U.S. Department of Health and Human Services (including the National Institute of Child Health and Human Development [NICHD] and the National Institute of Environmental Health Sciences [NIEHS], two parts of the National Institutes of Health, and the Centers for Disease Control and Prevention [CDC]) and the  U.S. Environmental Protection Agency (EPA).

The NCSAC convened for its third meeting on Thursday, September 12, 2002. Donald R. Mattison, M.D., a consultant to the Division of Epidemiology, Statistics, and Prevention Research at the NICHD, chaired the meeting. This meeting included some representatives of the NCS Interagency Coordinating Committee (ICC), NCS Working Group chairs, and members of the public.

Appendix A provides a list of those present at this NCSAC meeting.

June 13, 2002
Call to Order and Introductions
Dr. Mattison, NCSAC chair, called the meeting to order at 8:16 a.m., and proceeded with the official NCSAC agenda.

Dr. Mattison thanked Lynne Goldman, M.D., and Robert Michael, Ph.D., for developing the agenda items. He also thanked the EPA for providing the meeting facilities. Events Since the Last NCSAC Meeting Dr. Mattison asked Peter Scheidt, M.D., M.P.H., to update the participants on progress made since the last NCSAC meeting. Dr. Scheidt stated that major activities since the last meeting included:

• Preparation of Working Group hypothesis proposals
• Conduct of a pilot study on sampling strategies and preparation for an October 11, 2002, presentation on the pilot study’s progress by the authors
• Initiation of a pilot study on the feasibility of using primary care facilities as data gathering sites
• Staff recruitment at the NICHD program office
• Presentations on the NCS to various agencies and organizations
• Meeting with the Office of Management and Budget (OMB) to ensure the study complies with the Paperwork Reduction Act
• Planning the next NCS Assembly Meeting, scheduled for December 17-18, 2002, in Baltimore, Maryland

Dr. Mattison indicated that Judith Graham, Ph.D., has served as chair of an ad hoc Working Group involving representatives of both the NCSAC and the NCS ICC. The primary goal of the Working Group was to define a path for moving forward. According to Dr. Graham, the first step was to conduct a cursory review of the hypotheses proposals and to consolidate proposals whenever possible. The second step was to assign a rating to each proposal using the following system:

• Group 1: ¿Strong evidence, most likely will be a core hypothesis
• Group 2: Needs more clarification, detail, power calculations, etc; determine core status later
• Group 3: Proposals not likely to be considered further, or may be integrated later

Dr. Graham then indicated that the next step would be to create interdisciplinary hypothesis Working Groups to refine proposals. Existing Working Groups would stay together as centers of expertise. No objections to this approach were noted, and Dr. Mattison indicated that the NCSAC would proceed in this manner. Dr. Mattison then invited the participants to introduce themselves. Report from Community Outreach and Communications Working Group Dr. Mattison asked the Community Outreach and Communications Working Group to review its hypotheses and get the community perspective. Edith Parker, Dr.P.H., and Diane Dennis-Flagler, M.P.H., co-chairs of the Working Group, participated by telephone. Dr. Parker gave a brief overview of issues related to community engagement. The following issues were presented:

• One of the primary concerns was that the study would involve populations that had not been actively involved in research before. Many populations in past research projects have been wary of research activities and hesitant to participate.
• Community involvement was in the best interest of the study. It was critically important to engage communities early on.
• The study offered benefits to communities, and they must be aware of these benefits.
• Study recruitment and retention strategies offered the potential to improve the quality of the science.
• Cultural contexts will vary from suburban areas, to inner cities, to Native American reservations.
• Community input could help facilitate implementation of the NCS, help develop acceptable solutions to ethical issues, and help assist in the design and dissemination of information about the study and study results.
• No community input had been solicited to date.
• Research questions and data collection methods required standardization, but at the same time, it was critical to customize products and data collection methods for different communities.
• The Working Group planned to convene a panel discussion in October 2002, and had developed a general guidance document.
• The Working Group was open to suggestions regarding its future role.

The following comments by NCSAC members were noted:

• One member asked for more information about the diversity of the Working Group membership.
• The issue was raised regarding the conflict between hypothesis research and intervention research.
• It was echoed that communities need to be involved before hypotheses were determined. At the same time, hypotheses were needed to inform sampling strategies. It was difficult to engage communities before they had been identified.
• Participants were reminded that there had been some discussions in previous meetings about having communities represented on the NCSAC. If that was not possible, then he suggested establishing a community advisory panel that included both, ethnic groups and cause-oriented groups.

Report from the Study Design Working Group Dr. Mattison introduced Peter Gergen, M.D., M.P.H., federal co-chair of the Study Design Working Group. Nigel Paneth, M.D., M.P.H., non-federal co-chair of the Working Group joined the meeting by telephone. The co-chairs presented the findings of their preliminary review of a subset of hypotheses. Dr. Mattison noted that the Working Group’s report contained three sections: first, an analysis of the hypotheses; second, a review of pilot study proposals most relevant to study design issues; and third, a grouping of the hypotheses. Dr. Gergen presented the Working Group’s operational definition of a core hypothesis. He also summarized the screening and evaluation instruments developed by the Working Group and stated that the instruments have worked well thus far. He indicated that the Study Design Working Group had discussed the need to develop a matrix of hypotheses to identify major content gaps (e.g., neurodevelopment issues, childhood cancer, etc.). The following NCSAC member comments were noted:

• It was proposed that the NCSAC endorse the Working Group’s definition of a core hypothesis.
• One member stated that other potential gaps included adverse pregnancy outcomes, mental health outcomes, basic growth and development issues, and some other issues, which may not require sophisticated measurements.
• It was proposed to look at data collection from the standpoint of what kinds of data would be useful to investigators in 2060.
• It was stated that some hypotheses may put limitations on the study design (e.g., if oversampling of certain populations was required).
• Some of the NCSAC members asked about the sample size of 100,000 and who had ultimate authority to determine the NCS sample size. Dr. Scheidt indicated that the NCSAC may recommend a sample size based on the findings of the Working Groups. Final authority rested with the NICHD director. It was proposed to develop a subcommittee to explore this issue in more detail.
• One member indicated that it would be necessary to have statisticians involved in calculating the power necessary to implement a hypothesis. It was added that calculations could not be completed for many of the proposals in their present form.
• Another member noted that the timing of measurements also affected the power calculations. He proposed that the study employ a full-time statistician.

Hypothesis Review Dr. Mattison stated that most of the remaining time for the NCSAC meeting would be devoted to commenting on the hypotheses proposals submitted by each NCS Working Group. Each hypothesis was assigned a primary reviewer and a secondary reviewer. Upon presentation of the primary and secondary reviewers, the other NCSAC members would be given an opportunity to share their comments. Fertility and Early Pregnancy Hypothesis Proposal Number 1-Children whose conceptions were aided by infertility treatments such as assisted reproductive technologies (ART) are at increased risk for fetal growth restriction and birth defects when compared to children whose conceptions were unassisted by such treatments. Comments by Primary Reviewer: Donald Dudley, M.D.

• This proposal, while of great interest and importance in the field of reproductive disorders, did not have great relevance to environmental impacts on the health of children.
• The issue was limited in scope and unlikely to yield data of significant importance. The problem was topical, and there were limited data available upon which to base recommendations for patients undergoing infertility treatments.
• This proposal was unlikely to benefit a large number of individuals and offered limited value to the NCS. However, this study may be folded into other key hypotheses as a secondary outcome variable (e.g., Pregnancy and the Infant Hypothesis Proposal Number 2, Birth Defects).
• The cost of this study would be relatively small.
• Given the importance of this problem and the paucity of data, this hypothesis might be better suited for the NICHD’s Reproductive Medicine Network.

Comments by Secondary Reviewer: Dr. Michael

• If ART was either an environmental condition or discretionary circumstances such as ART were deemed relevant, then the hypothesis had substantial value.
• This research could influence future use of ART.
• The hypothesis may require preconception sampling and may be cost-prohibitive unless other hypotheses also require preconception sampling.
• There was no mention of the socioeconomic co-factors that may influence outcomes observed among ART children, if any.

NCSAC Member Comments about Fertility and Early Pregnancy Hypothesis Proposal Number 1:

• One member noted that ART was a major concern linked to preterm birth, negative neonatal outcomes, and negative neurologic outcomes. ART methods were not uniform. ART was a therapeutic exposure that would not go away. However, the NCS most likely was not the appropriate study to examine this issue.
• Another member suggested that it may be valuable to reserve the proposal for a nested, case-control study using the NCS cohort.

NCSAC Rating for this Hypothesis Proposal: Group 3 Fertility and Early Pregnancy Hypothesis Proposal Number 2-Pre- and peri-conceptional exposure to endocrine active compounds, specifically phthalates, and certain pesticides, are associated with increased risk for selected congenital anomalies, including hypospadias, cryptorchidism, transposition of the great arteries, and limb reduction defects. Comments by Primary Reviewer: Dr. Graham

• This hypothesis required a prospective study. Longitudinal epidemiological studies were essential to test the hypothesis.
• The hypothesis was important because the incidences of these male congenital anomalities were increasing, and the morbidity was significant, with impacts on the quality of life.
• The hypothesis was reasonable founded in the animal toxicology literature. Because many of these compounds were ubiquitous, it was even more important to test the hypothesis in an epidemiological study to determine if adverse risk existed.
• The proposal provided insufficient information to assess costs. However, it was expected that the costs would be high because it would be necessary to assess chemical exposures prior to conception (as well as later).
• This proposal was similar to the Fertility and Early Pregnancy Hypothesis Proposal Number 5 (subpart 3) and to the Fertility and Early Pregnancy Hypothesis Proposal Number 6.
• The Working Group needed to collaborate with the Exposures to Chemical Agents Working Group.
• The proposal needed to ensure that the measures were inclusive. As noted in the proposal, there were more agents of interest than just phthalates. The pesticides of interest were not specified. Phytoestrogens (e.g., genistein) should be included given their prevalent use.

Comments by Secondary Reviewer: M.A. Spence, Ph.D.

• The proposal raised concerns about sampling and costs.
• The proposal raised ethical issues (e.g., if a high rate of exposure was detected in a pregnant woman).

NCSAC Member Comments about Fertility and Early Pregnancy Hypothesis Proposal Number 2:

• It was noted that several hypotheses appear to require preconceptional measurement of exposures.
• Assessment of preconceptional exposures would add expense to the study. It was suggested that an analysis be conducted to identify the added value of preconceptional measurement.
• One member noted three issues that had been raised thus far: 1) how to measure exposure (e.g., terms such as "close to exposure" are too ambiguous); 2) overlap of hypotheses; and 3) ethical issues related to detection of exposures, even if it was unknown that an exposure was harmful.
• Another member noted that, while it was necessary to discuss scientific merit of various proposals, it also was important to consider community outreach strategies, especially when the issue was not a high priority at the community level.
• It was stated that additional experts may be required to refine the list of chemical exposures.

NCSAC Rating for this Hypothesis Proposal: Group 1 or Group 2 Fertility and Early Pregnancy Hypothesis Proposal Number 3-Pre- and post-natal environmental factors can alter age at onset, duration, and completion of puberty. Comments by Primary Reviewer: Ken Sexton, Sc.D.

Dr. Sexton’s comments were not submitted for the record.

Comments by Secondary Reviewer: Willa Doswell, R.N., Ph.D.

• This hypothesis was relevant to the NCS because of the need to assess the psychosocial and biochemical environmental influences for their specific roles in the occurrence of earlier pubertal development and potential adverse health consequences in older school-age children and adolescents.
• The proposal provided empirical support for including this study in the NCS and cited outcomes that may extend into adult years. It also made a case for examining gender effects.
• Specific subhypotheses required additional detail.
• The proposal identified innovative instruments that may aid in the study of male pubertal development.
• The cost impact was not provided or discussed.
• Native Americans were not mentioned in the proposal.

NCSAC Member Comments about Fertility and Early Pregnancy Hypothesis Proposal Number 3:

• A member noted that the proposal was general in nature.It could not be rejected, but additional specificity was required. Dr. Mattison responded that the NCSAC may request another draft of the proposal that identified specific exposures and outcomes and relevant literature supporting the biological plausibility.
• It was noted that inclusion of the hypothesis would require coordination with other hypotheses and subhypotheses.
• It was stated that the onset and completion of puberty was a critical outcome that must be tracked and measured. However, the NCS was not a "fishing expedition." The proposal must be linked to environmental exposures that lay the foundation for a specific hypothesis.
• It was indicated that it would be necessary to identify an appropriate list of chemicals to measure, and additional work would be needed to specify the timing for exposure measurement. In addition, the hypothesis should be linked with related hypotheses.
• It was stated that there may be a lack of epidemiological evidence on the topic and there were still many unanswered questions about pubertal development. This research presented an opportunity to answer those questions (e.g., are sperm counts going down, and why).
• It was noted that it would be helpful to have more guidance regarding early measurements that may be collected via blood or urine, how those samples can be stored, and what opportunities would exist to study those samples at a later date. It was added that collecting data from the house or workplace would involve cost to the study.
• It was suggested that this proposal was an example of a hypothesis that may be driven more by what had been publicized in the lay press, rather than by scientific evidence. The real hypothesis was that these outcomes were important, and that additional research was needed to identify related exposures.
• It was noted that some proposals were built on arguable assumptions. It was then asked what entity would be responsible for accepting or deleting such assumptions. Dr. Mattison responded that such responsibility may rest with the NICHD program office in collaboration with the Working Groups.
• It was reiterated that the social impact of early pubertal development was an enormous public health issue. It was known that African Americans disproportionately experienced early pubertal development, and that this research presented an opportunity to identify other populations that may be affected.

NCSAC Rating: Not determined; proposal required more specificity Fertility and Early Pregnancy Hypothesis Proposal Number 4-Environmental exposures during pre- and post-natal development affect adult reproductive health and function. Comments by Primary Reviewer: Lucina Suarez, Ph.D. (not in attendance, but comments submitted for the record)

• The hypothesis that endocrine-active compounds affect reproductive health functions seemed relevant to the NCS. However, the compounds for study were not specified.
• The proposal was more relevant to young adults and would require tracking of teenage pregnancy incidence and outcome, assessment of sperm viability in males age 18 and older, and assessment of ovulatory cycling in females of age.
• While the hypothesis was contemporary in nature, it was based mainly on animal studies, circumstantial human evidence, and some speculation.
• No specific analytical approach was described. The exposures were not determined, and the reproductive outcomes were somewhat vague.
• It was not possible to assess cost implications as sampling needs were not described.

Comments by Secondary Reviewer: Dr. Goldman

• The proposal was vague and may overlap with Fertility and Early Pregnancy Hypothesis Proposals Numbers 5 and 6.
• The hypothesis was relevant to the NCS, and it was contemporary in nature.
• Chemical exposures were not identified, and costs were not determined.
• The proposal stated that additional measures must be developed to test the hypothesis.
• The proposal required more detail, but had the potential to be a core hypothesis in the NCS.

NCSAC Member Comments about Fertility and Early Pregnancy Hypothesis Proposal Number 4:

• It was stated that the proposal raised several questions regarding assent by the parents and future consent by the subject. Another member noted that it may be possible to obtain necessary consents by educating families up front. However, it was necessary to be more specific about the outcome (e.g., sperm count versus fertility), and it was possible that the question could not be answered until the subject is 18 or 21 years old. As a result, it may be necessary for another study to use NCS data as a starting point to answer the question.
• It was suggested that the hypothesis may be tested via a nested, case-controlled study.
• It was stated that this issue was pertinent to child health.
• A member noted that fertility was a characteristic of a couple, not an individual. That being the case, it would be necessary to obtain consent from both members of the couple.

NCSAC Rating for this Hypothesis Proposal: Not determined; proposal required more specificity Fertility and Early Pregnancy Hypothesis Proposal Number 5-Environmental impact on reproductive tissue development, puberty, and endocrine-based diseases. Comments by Primary Reviewer: Stephen Spielberg, M.D., Ph.D.

• The proposal identified several important outcomes, many of which could not be assessed at age 21.
• The proposal did not mention disparities in testicular cancer (higher rates among whites than African Americans).
• Early endocrine outcomes and late endocrine outcomes were more complicated than what was suggested in the proposal.
• There was no discussion of measures or how often the measures should be assessed.
• There was no examination of pregnancies that were expected during the course of the study.

Comments by Secondary Reviewer: Jonathan Samet, M.D. This reviewer was not in attendance, and his comments were not submitted for the record. NCSAC Member Comments about Fertility and Early Pregnancy Hypothesis Proposal Number:

• One member suggested that a sample size of 100,000 may not be enough to merit study of testicular cancer. It was added that, while breast cancer was a huge public health challenge, it was not observable by age 21.
• It was noted that the proposal did not distinguish between precocious puberty and early puberty.
• Another member underscored that the proposed samples for collection during the NCS may be of tremendous value to scientists seeking to conduct spin-off studies after conclusion of the NCS.

NCSAC Rating for this Hypothesis Proposal: Not determined; the proposal may merit further consideration Fertility and Early Pregnancy Hypothesis Proposal Number 6-Exposure to phthalates during critical periods of prenatal and childhood development results in long-lasting effects on male reproductive function (four subhypotheses). Comments by Primary Reviewer: Philip Landrigan, M.D. The proposal did not include anything that was not covered in Hypotheses 2 through 5 on this topic. Comments by Secondary Reviewer: Alan Fleischman, M.D. The proposal was in line with the goals of the NCS. However, the hypothesis was extremely complex and represented a daunting challenge for study design. NCSAC Member Comments about Fertility and Early Pregnancy Hypothesis Proposal Number 6:

• One member proposed looking at all of the Fertility and Early Pregnancy Hypothesis Proposals as a group. The hypotheses needed more specificity and required additional collaboration with other Working Groups.
• Another member suggested that it may be helpful to have a core hypothesis that focused on endocrine disrupters, with subhypotheses that incorporated all of the outcomes mentioned in the Fertility and Early Pregnancy Hypothesis Proposals. Additional guidance was needed regarding how the hypotheses would be assessed, which measures would be required, the degree of follow-up, and the feasibility of individual measures. Specific chemicals would have to be identified.
• It was stated that the proposals presented an opportunity for integrative thinking among the relevant Working Groups. The Working Groups should be challenged to "think big" and capitalize on this opportunity to examine a wide, yet specific, range of exposures and outcomes.
• A member proposed that most of the hypotheses related to fertility and early pregnancy be outcome-oriented, with specific attention paid to which exposures may influence those outcomes and the possible interaction with the gene environment.
• It was noted that pharmaceuticals used during pregnancy, as well as alcohol use, were important co-factors that were not adequately discussed in the proposals.
• A member proposed that the frequency of measurements and other concerns underscored the challenges the NCS will experience in maintaining the cohort.
• It was proposed that the hypotheses be considered as a group core hypothesis. However, the proposals would require more specificity, detailed outcomes and exposures, examination of co-factors, and significant Working Group collaboration.
• It was stated that the Working Groups would be asked to identify possible intermediate markers.
• One member suggested that the Working Groups be sked to explain why pre-conceptional enrollment was critical. Another member proposed that the Study Design Working Group be involved in this analysis.

NCSAC Rating for this Hypothesis Proposal: No rating was established Pregnancy and the Infant Hypothesis Proposal Number 1-Excessive maternal psychosocial stress during pregnancy, in conjunction with maternal and fetal genetic susceptibilities, is reflected in specific measures of biological function and results in an altered trajectory of fetal growth and development. These consequences predispose to adverse outcomes, such as pre-term birth, fetal/infant demise, cognitive/neurobehavioral dysfunction, and adult onset of cardiovascular disease. Comments by Primary Reviewer: Dr. Fleischman

• The proposal was relevant to the NCS.
• Some of the outcomes (e.g., pre-term birth) were critical public health issues.
• The proposal raised questions regarding the standardization of neurobehavioral assessments. It would take a great deal of work.
• The proposal presents some usable measurements.
• The Social Environment Working Group should also be thinking about this issue.
• Some of the samples (e.g., umbilical samples) were not easy samples to maintain.
• The cardiorespiratory or overnight sleep monitoring measures may not be as valuable as stated in the proposal.
• This was a reasonable hypothesis that can be linked to other hypotheses in the study.

Comments by Secondary Reviewer: Shiriki Kumanyika, Ph.D., M.P.H.

• The proposal represented an interesting area of exploratory study-perhaps too exploratory to merit inclusion as a core hypothesis.
• Measuring an exposure as ambiguous as stress would be an enormous challenge and required a definition of stress. It was difficult to measure how stress was managed among people of different cultures.
• The hypothesis held significant implications for populations (e.g., African Americans) that disproportionately experienced certain negative outcomes (e.g., low birthweight).
• The hypothesis was very relevant to a range of issues that have many unanswered questions.

NCSAC Member Comments about Pregnancy and the Infant Hypothesis Proposal Number 1:

• A member stated that pre-term birth was a major public health problem in the United States that may be related to problems affecting the mother or the fetus, and that may be related to stress. The proposal was relevant to the NCS, but how stress was measured and what measures would be used were critical factors. Since stress was mentioned in other hypotheses on asthma and neurodevelopment, it was proposed that a workshop of experts be conducted to define stress. The proposal may not constitute a core hypothesis, but it appeared to be an important issue for the NCS to examine, especially because it may be related to the early origins of adult disease and long-term outcomes (e.g., hypertension).
• Another member noted that there were many ongoing studies examining the issue of stress. It was added that it would be helpful to know what aspects would be addressed by this research that were not being examined in other studies.
• The value of convening a workshop to define stress was echoed. It was added that other topics for the workshop could include stress measures, the validation of those measures, the ways that stress was managed across cultures, and how questions could be framed in culturally appropriate ways.

NCSAC Rating for this Hypothesis Proposal: Not determined; however, given the general interest in the issue of stress and how stress was defined and measured, the Working Group would be encouraged to collaborate with other Working Groups (e.g., the Early Origins of Adult Health Working Group). Pregnancy and the Infant Hypothesis Proposal Number 2-Intrauterine infection/inflammation increases the risk of adverse pregnancy and neonatal outcomes, as well as long-term sequelae (including cerebral palsy, autism, schizophrenia, and adult onset of cardiovascular and endocrineologic diseases). Comments by Primary Reviewer: Dr. Dudley

• The proposal was relevant to the scope of the NCS.
• The proposal provided minimal detail regarding the samples to be collected.
• The hypothesis represented a good starting point for other hypotheses looking at the issue of infection.
• The costs associated with this hypothesis would most likely be high.

Comments by Secondary Reviewer: Dr. Spence

• Identifying the relative risk of this prenatal exposure to the development of subsequent disease could be a critical step in reducing the exposure and/or its effect.
• Cerebral palsy was the most common neuromotor disability of childhood, yet little was understood about its etiology.
• Many specimens would need to be collected and stored because the disease of interest may not manifest until some years after delivery.
• It would not be easy to collect data for this hypothesis, and results would be generated slowly.
• The potential benefit of this proposal was great. The potentially long delay in determining the risk made this proposal less attractive, although still the type of study that the NCS should address.
• Some of the outcomes discussed in the proposal were rare.
• Additional information was needed about the sample size and cost required to study this hypothesis.

NCSAC Member Comments about Pregnancy and the Infant Hypothesis Proposal Number 2:

• One member noted that this was an exposure-based hypothesis. Little was known about the factors that contribute to outcomes such as cerebral palsy. This proposal would constitute a heavy burden on subjects; however, if it was included, it would lay the foundation for examining a broad range of hypotheses. The member proposed that the Working Group provide more information on how to measure infection in pregnancy, and more detail on how cerebral palsy could be studied.
• Several members suggested that the Development and Behavior Working Group be involved in refining this hypothesis.

NCSAC Rating for this Hypothesis Proposal: Merited further consideration; Dr. Mattison will ask the Working Group to characterize the range of exposures to infectious agents during pregnancy. Birth Defects Hypothesis Proposal Number 1-Specific alleles for genes involved in folate metabolism predispose women who are pregnant and who have had low folate intake over the six months preceding conception to have a fetus at increase risk for birth defects. Comments by Primary Reviewer: Dr. Spence

• The proposal did not include much information.
• The hypothesis proposed to examine genotyping of women; however, genes were not predictable.
• The proposal merited consideration, but additional detail was needed to justify the cost, the preconceptional approach, the collection of DNA from extended family members, and the overall complicated approach described in the hypothesis.

Comments by Secondary Reviewer: Dr. Suarez

• The outcome was broadly defined as "birth defects" in the proposal.
• The proposal was not yet developed enough to evaluate the analytic approach, the potential benefits, and the associated costs.

NCSAC Member Comments about Birth Defects Hypothesis Proposal Number 1: NCSAC Rating for this Hypothesis Proposal: Not determined. The proposal needed additional detail. Birth Defects Hypothesis Proposal Number 3-The impact of prenatal alcohol exposure on birth defects, neurodevelopment, intelligence quotient (IQ), and antisocial behavior in children is poorly understood and is likely to vary by dose and timing of exposure and by maternal and infant metabolizing enzymes. Comments by Primary Reviewer: David Bellinger, Ph.D.

• Alcohol may be the most common reproductive toxin. The importance of the problem and its inclusion in the NCS was increased by the fact that prenatal alcohol exposure was entirely preventable.
• The hypothesis was not novel per se. However, the NCS presented an opportunity to answer questions in a more definitive way.
• Details of the dose-response/dose-effect relationships were still somewhat uncertain.
• The large sample size would permit the study of suspected gene-environment interactions for different metabolizing enzymes.
• Ideally, women and couples would have to be recruited prior to conception in order to collect the best quality exposure data on a prospective, rather than retrospective basis.
• Certain ethnic groups in which prenatal alcohol exposure was known to be a major challenge could be oversampled (e.g., Native Americans and whites).
• Additional information was needed on the metabolizing enzymes/genes of interest, on the optimal timing of questionnaire administration, and on biologic samples for biomarker measurement.
• Alcohol exposure would have to be measured as part of the study, regardless of whether the hypothesis was core.

Comments by Secondary Reviewer: Dr. Goldman

• The NCS would have to measure alcohol, but hewas not convinced about the need for preconceptional measurement or the frequency suggested in the proposal.
• The proposal raised ethical questions as to whether or not women who drink alcohol during pregnancy will be encouraged to stop.

NCSAC Member Comments about Birth Defects Hypothesis Proposal Number 3:

• One member stated that the NCS could target this hypothesis to Native Americans and whites in the sample.
• It was noted that the data collection planners would have to think about the ways people will react when you ask them about alcohol use during pregnancy.
• A member indicated that the Health Services Working Group had proposed an approach that was relevant to the ethical issues related to this proposal.
• A member noted that many subjects would not want interviewers to know about their alcohol use. In addition, the study would not be able to reach potential subjects without going through key community gatekeepers and packaging information properly.
• It was pointed out that the NCS presented an important health education opportunity that may be valuable in recruiting and retaining participants.
• It was noted that this hypothesis could provide a history of alcohol consumption, the means to identify a biomarker, and a way to study the response. In addition, this was the type of study that could be addressed more intensively in one or two study sites.

NCSAC Rating for this Hypothesis Proposal: Group 1 Birth Defects Hypothesis Proposal Number 2-Impaired glucose metabolism during organogenesis is associated with an increased risk for major structural congenital malfunctions. Maternal and fetal genetic susceptibilities and maternal environmental exposures and lifestyle factors modulate the impact of impaired maternal glucose metabolism on the developing fetus. Comments by Primary Reviewer: Dr. Dudley

• The overall number of defects identified in this proposal appeared to be small and was less than the scope of the NCS. The power calculations included in the proposal suggested that the fundamental questions could be determined using a smaller sample size than prescribed in the NCS.
• The proposal, as outlined, would address key issues in the contribution of altered glucose metabolism, and in the contribution of this condition to birth defects. The overall outline of the research was primarily epidemiologic in nature, and little data on mechanism would be provided.
• The work proposed in this hypothesis could be the cornerstone of a diabetes hypothesis. Given the extent of diabetes in the population, having these data for all pregnancies that might follow diabetes in the offspring could prove to be of great value.
• This proposal and Working Group could interact with several other Working Groups in developing an integrated hypothesis.
• The cost of this hypothesis appeared to be moderate.
• The work appeared to be of too limited a scope for consideration as a core hypothesis. However, it could be integrated with other diabetes-related proposals.

Comments by Secondary Reviewer: Dr. Spielberg

• The major challenge with this proposal was preconception and post-conception screening. It would be necessary to recruit a very large cohort up front.
• Some of the ethical issues associated with this proposal would jeopardize the observational nature of the NCS.
• The design, as presented, was not feasible.

NCSAC Member Comments about Birth Defects Hypothesis Proposal Number 2: A member indicated that the NCS would have to collect glucose data. However, this proposal did not constitute a core hypothesis. NCSAC Rating for this Hypothesis Proposal: Group 3 Infection, Immunity, and Vaccines Hypothesis Proposal Number 1-Exposure to infectious agents during pregnancy and in the perinatal period (less than one month of age) is associated with the development of sensorineural hearing loss (SNHL). Comments by Primary Reviewer: Dr. Fleischman

There were several issues that must be addressed to study this hypothesis:

• Will CMV be the only pathogen measured, or will tests be performed to assess exposure to other infectious agents?
• How will exposure to infectious agents be identified?
• All neonates will need hearing tests. Although advocated by many, this test was not done routinely throughout the country. Thus, the quality and reliability of such testing was variable and could result in false positive tests and a need for further investigation.
• Additional hearing screening during childhood was required to detect late onset hearing loss, yet these tests may not be part of routine primary care.
• This proposal could be recommended as a core hypothesis if these issues were clarified in more detail.

Comments by Secondary Reviewer: Grace LeMasters, Ph.D.

• Little was known about how viral teratogens may induce SNHL, and no population-based studies had been performed to determine the contributions of intrauterine infections with uncommon pathogens. New information would be gleaned by this study, but the power may be too low to address this issue successfully.
• The primary benefit of including the hypothesis was a better understanding of the precise etiology of SNHL and the predictive value of potential therapies.
• Cost issues were not addressed in the proposal.
• An alternative hypothesis that the NCSAC might consider was acquired hearing loss related to chronic ear infections. The incidence was high, and a very large number of children suffered from chronic ear infections.

NCSAC Member Comments about Infection, Immunity, and Vaccines Hypothesis Proposal Number 1:

• A member stated that SNHL was an outcome that should be examined in the NCS.
• The hypothesis should incorporate additional exposures beyond those identified in the proposal.

NCSAC Rating for this Hypothesis Proposal: Group 2 Infection, Immunity, and Vaccines Hypothesis Proposal Number 2-Several hypotheses related to selected IgA deficiency. Comments by Primary Reviewer: Dr. Spence

• The hypothesis could contribute to a basic understanding of the role of this set of genes.
• The proposal may relate to other hypotheses.

Comments by Secondary Reviewer: Dr. Kumanyika

• The cost of doing IgA typing, if low enough, on the entire sample could generate useful information.
• The proposal made a good case for examining autoimmune deficiency.

NCSAC Member Comments about Infection, Immunity, and Vaccines Hypothesis Proposal Number 2:

• It was suggested that the proposal was more peripheral in nature, rather than core. In addition, IgA deficiency could be acquired; it was not necessarily genetic.
• A member expressed that the public health burden of IgA deficiency was unclear.

NCSAC Rating for this Hypothesis Proposal: Not determined, but recommended that IgA be measured.

Infection, Immunity, and Vaccines Hypothesis Proposal Number 3-Perinatal exposure to immunotoxic environmental chemicals, therapeutic agents, physical agents, or other immune modulating agents prior to, or during ontogeny of the immune system results in increased incidence of postnatal disease. Such diseases include, but are not limited to, increased infection, increased or exacerbated hypersensitivity or autoimmune disorders, and increased incidence of neoplastic disorders.

Comments by Primary Reviewer: Dr. Samet This reviewer was not in attendance, and his comments were not submitted for the record. Comments by Secondary Reviewer: Dr. Spence

• The hypothesis was broad and far-reaching. It lacked sufficient specificity to provide useful guidance for study planning.
• Outcome and exposure variables were not sufficiently specified.
• This proposal required coordination with other hypotheses that attempted to tackle the same issues, and more clarification of how to achieve the desired goal.
• The Working Group stated that it needed to collaborate with other Working Groups (e.g., Asthma Working Group).

NCSAC Member Comments about Infection, Immunity, and Vaccines Hypothesis Proposal Number 3:

• A member suggested that the Working Group be asked to identify more specific questions, as there may be some interesting questions (e.g., impacts on the immune system) embedded within the hypothesis. Another member noted that the immune system idea was covered in other proposals.
• It was noted that the proposal lacked specificity in terms of outcomes.
• A member stated that, in the end of the NCS, there would be a number of measures that would piggyback, but the measurements may involve substantial cost.

NCSAC Rating for this Hypothesis Proposal: Group 3

Infection, Immunity, and Vaccines Hypothesis Proposal Number 4-Human herpes virus 6 (HHV6) acquired congenitally results in neurodevelopmental deficits, which may not be apparent at birth, but rather progressively, similar to the closely related herpes virus CMV. The risk of developing neurodevelopmental deficits, including SNHL, is partly dependent on the timing of HHV6 transmission during pregnancy, and virologic factors. Such factors include the HHV6 variant (or strain), the state of replication of the virus in the blood cord, the subsequent persistence in the infant, the sites of persistence, and the frequency of reactivation.

Comments by Primary Reviewer: Dr. Spence

• This hypothesis becomes more relevant in that the NCSAC stated that intrauterine transmission had recently been confirmed.
• No studies of the importance, prevalence, and possible consequences of HHV6 infection were available at this date, making this a candidate for study in the NCS.
• The hypothesis was reasonable. What was not understood at this time wasthe effects if contracted during pregnancy.
• The proposal, as described, would require auditory testing of infants, which could be expensive. However, many states were already doing such testing, and more were proposing to do so.
• The virus was detectable in cord blood, which probably will be collected for other hypotheses. It was also testable in saliva.
• The hypothesis was not core in nature, but could be examined as part of other hypotheses.

Comments by Secondary Reviewer: Dr. Bellinger

• There was no existing evidence to support the hypothesis. It could be examined, but not as part of the NCS.
• This was another candidate for a nested, case-controlled study.

NCSAC Member Comments about Infection, Immunity, and Vaccines Hypothesis Proposal Number 4:

• One member suggested that this hypothesis be incorporated within a neurodevelopmental hypothesis.
• Another member stated that the hypothesis could be evaluated later, but was not a core hypothesis. However, the measure could still be included.

NCSAC Rating for this Hypothesis Proposal: Group 3 Exposures to Chemical Agents Hypothesis Proposal Number 1-After adjusting for potential confounders, exposure to non-persistent insecticides such as carbamates, organophosphates, and pyrethoids is negatively associated with performance on neurobehavioral (e.g., IQ) and neuromuscular (e.g., posture balance) measures. Comments by Primary Reviewer: Dr. Bellinger

• There was an absence of good data on dose-response/dose-effect relationships in the proposal.
• A national study of this hypothesis would be a good idea, but it required a targeted subsample, not the NCS.
• Costs and methods for characterizing the exposure were not detailed.

Comments by Secondary Reviewer: Dr. Graham

• The proposal was well developed on the exposure side. However, the hypothesis may fit more appropriately as part of a neurodevelopmental hypothesis.
• It may be wise for the Working Group to interact with neurodevelopment experts.
• The proposal may require a large sample size.

NCSAC Member Comments about Exposures to Chemical Agents Hypothesis Proposal Number 1:

• A member noted that there were many questions about nonpersistent pesticides, and that a great deal of animal data seemed to indicate that it was difficult to interpret the modification of gene expressions and neurons. The challenge was measuring these exposures at the right time periods and methods development.
• It was stated that three cohort studies were currently piloting methods to address this issue. Given the wide use of these chemicals in homes and agriculture known to be neurotoxic, these exposures must be included in the NCS.
• A member suggested that the Working Group engage experts working in the field and gather information on what had been or was being pilot tested.
• It was suggested that the Working Group focus on biomarkers.

NCSAC Rating for this Hypothesis Proposal: Group 2. The Working Group would be encouraged to focus attention on analytic methods. Exposures to Chemical Agents Hypothesis Proposal Number 2-Children’s risk of cancer is associated with cumulative exposure to environmental carcinogens and with gene-environment interactions during specific periods of their growth and development (five subhypotheses). Comments by Primary Reviewer: Dr. Goldman

• Whether or not children were exposed to carcinogens was an interesting question, especially because childhood exposure could be particularly harmful.
• It was important to note that childhood cancer was not a disease. It was collection of diseases. This proposal did not reflect this complexity.
• It was not certain if the NCS could really examine the issue of childhood cancer, but the NCS could certainly collect information on the critical biomarkers.
• The costs associated with this proposal could be very expensive. However, some of the proposed carcinogen exposures may already be measured for other hypotheses.
• The proposal lacked clarity.
• The proposal seemed to have merit as a core hypothesis, but it needed more detail.

Comments by Secondary Reviewer: Roderick Little, Ph.D.

• The issue of childhood cancer clearly was relevant and important.
• It was possible that some elements of the proposal could be examined on a case-controlled basis.
• The proposal may not be feasible, as presently constructed.
• Some of the measures may be useful in other areas of study.
• The proposal did not discuss other types of confounding factors (e.g., genetics).

NCSAC Member Comments about Exposures to Chemical Agents Hypothesis Proposal Number 2:

• One member questioned whether the cohort would be large enough to make sense of the data collected. Another member agreed that a cohort of 100,000 would not capture enough children to yield meaningful data. However, because most studies of childhood cancer were retrospective, it was added that the NCS presented an opportunity to add to the body of knowledge on this issue.
• A member inquired to what extent retrospective exposure assessments correlated with prospective exposure assessments. It was suggested that this research validate or invalidate the issue. It was added that many were intrigued by the idea of combining the evidence gleaned from this work with the children’s cancer registry.
• It was cautioned that the NICHD could be criticized if childhood cancer was not included in the NCS. Perhaps the National Cancer Institute would contribute to funding a hypothesis on childhood cancer.

NCSAC Rating for this Hypothesis Proposal: Group 2 for the first three subhypotheses. The fourth and fifth subhypotheses were assigned to Group 3. Development and Behavior Hypothesis Proposal Number 1-Three subhypotheses related to the impact of parental actions related to chemical agents, the physical environment, and social circumstances.
Comments by Primary Reviewer: Dr. Suarez
Dr. Suarez did not attend but her comments were submitted for the record.

• Exposure risks and health outcomes were broadly defined.
• It was not clear whether the hypothesis was to be tested within the framework of the observational cohort, or whether parental interventions were intended.
• It was not certain that a large, longitudinal cohort was required to test this hypothesis.
• The costs associated with this hypothesis appeared to be minimal, as it would only require additional interview questions.

Comments by Secondary Reviewer: Dr. Goldman

• The proposal was almost identical to Development and Behavior Hypothesis Proposal Number 6.
• The proposal presented little rationale, no evidence, and it was unclear as to what was meant by "parental action" or how it would be measured.
• Some of the endpoints had evidence to suggest that the social environment was important.
• The proposal was not core in nature.

NCSAC Rating for this Hypothesis Proposal:

Development and Behavior Hypothesis Proposal Number 2-Differences across ethnic groups in genetics, parenting beliefs, parents "experiences, and parents" economic and social opportunities shape the structure and quality of children’s home and childcare experiences (e.g., engagements with parents and other primary caregivers, time spent in childcare). These experiences in childhood, in turn, affect children’s developmental trajectories in various developmental domains (physical and health, cognitive, social-emotional, and mental health).

Comments by Primary Reviewer: Dr. Doswell

• It would appear that the hypotheses should be focused on three to four exposures to clearly determine other factors that would make these hypotheses more successful (e.g., measurement issues, cost, sampling, etc.).
• The fact that the potential for examining parental actions at reducing risk of exposure across varied ethnic/racial groups was an advantage of the NCS, though the overlap between race and income should also be explored, so as not to falsely attribute one to the other.
• The proposal lacked detail, especially in terms of exposures to be measured.
• If the hypothesis could be more focused on a limited number of harmful exposures, to examine parental actions, then this hypothesis could be beneficial to the study.

Comments by Secondary Reviewer: Dr. Fleischman

• A robust, significant measurement of ethnicity in this study would take major work. But the proposal did not specific how to address this challenge.
• The Working Group should collaborate with others to identify meaningful outcomes.

NCSAC Member Comments about Development and Behavior Hypothesis Proposal Number 2:

• A member noted that, in terms of religion, there was often a gap between what people did and what they reported. Another member added that the way people parented and organized their homes may be a more reliable measure of ethnicity and culture, than what individuals reported. In addition, the term "quality" implied that there were some cultural practices that were better than others. The study must avoid cultural bias.
• It was proposed that a workshop be convened to determined how to deconstruct race for the purpose of research.

NCSAC Rating for this Hypothesis Proposal: Group 2, with collaboration required with other Working Groups.

Development and Behavior Hypothesis Proposal Number 3-Differences in family formation and living arrangements shape the structure and quality of children’s home, childcare, school experiences, and economic opportunities. These experiences, in turn, affect children’s developmental trajectories.

Comments by Primary Reviewer: Dr. Bellinger

• The hypothesis was relevant to the NCS, and there were considerable data on differences in child health associated with various family structures. However, the mechanisms underlying these differences remained obscure.
• The hypothesis was politically relevant.
• The proposal was somewhat fragmented and unclear.
• The hypothesis was related to other hypotheses that dealt with similar issues.

Comments by Secondary Reviewer: Dr. Landrigan

• The proposal would require evaluation of children’s families at more than one point in time. It may also be necessary to oversample certain populations (e.g. adopted children).
• The hypothesis would benefit from the contribution of people with expertise in social science.

NCSAC Member Comments about Development and Behavior Hypothesis Proposal Number 3:

• A member inquired as to whether a focus on one-parent families might be misconstrued.
• Another member stated that the proposal had serious implications for study design.

NCSAC Rating for this Hypothesis Proposal: Group 2

Development and Behavior Hypothesis Proposal Number 4-Children’s risk of developing cognitive, behavioral, and emotional problems are associated with familial psychopathology (e.g., genetics, history of psychopathology) and gene-environment interactions, including those between characteristics of the social environment (e.g., peers, family, community, neighborhood) and exposure to toxins.

Comments by Primary Reviewer: Dr. Michael

• The proposal was relevant to the NCS.
• The hypothesis was balanced and informed.
• The proposal offered benefits to the study, and the associated costs were probably low.
• The proposal needed more specificity.

Comments by Secondary Reviewer: Dr. Sexton

This reviewer was not in attendance, and his comments were not submitted for the record.

NCSAC Member Comments about Development and Behavior Hypothesis Proposal Number 4:

• A member stated that the proposal would require genotyping of every subject in the study. As a result, part of the hypothesis was not feasible unless the study intended to collect DNA from all individuals and store it. Another member, however, added, that this proposal may be more feasible in the future, as technology continued to evolve.
• It was noted that the hypothesis was loaded with ethical issues.
• It was suggested that a subcommittee of the Gene-Environment Interactions Working Group review this proposal and share thoughts on how the topic could be examined.

NCSAC Rating for this Hypothesis Proposal: Group 1 or Group 2, with more interaction with other Working Groups.

Development and Behavior Hypothesis Proposal Number 5-Chronic sleep restriction and sleep disorders present during critical phases of development have adverse effects on neurocognitive performance, social and emotional health, risks for unintentional injury, and overall adult health status, after adjusting for potential confounders (several subhypotheses).

Comments by Primary Reviewer: Dr. Spielberg

The proposal did not present enough background information (e.g., current diseases concurrent with sleep disorders). As a result, it could not be evaluated.

Comments by Secondary Reviewer: Dr. Little

The proposal may overlap with the stress hypothesis.

NCSAC Member Comments about Development and Behavior Hypothesis Proposal Number 5:

• A member suggested that the proposal may be a placeholder for something more substantive. It was suggested that members recommend individuals who could assist in further developing the proposal.
• Another member noted that a longitudinal study may not present the right opportunity to test this hypothesis.

NCSAC Rating for this Hypothesis Proposal: Not determined; the hypothesis would be referred to the Social Environment Working Group.

Development and Behavior Hypothesis Proposal Number 6-Three subhypotheses related to parental efforts to facilitate competence and the exposure to chemical agents, the physical environment, and social circumstances.

Comments by Primary Reviewer: Daniel Swartz

• The proposal had many of the same deficiencies as Development and Behavior Hypothesis Proposal 1.
• The proposal duplicated hypotheses submitted by the Social Environment Working Group.

Comments by Secondary Reviewer: Dr. Graham

• Competence was a critical endpoint. However, only parents were identified-not other sources of influence.

NCSAC Member Comments about Development and Behavior Hypothesis Proposal Number 6:

• It was noted that some parents had more influence than others.
• It was indicated that the Injury in Childhood and Adolescence Working Group had some similar, outcome-related hypotheses.
• A member stated that the ideas presented in the proposal should be integrated into other parts of the study.
• It was suggested that intervening behavior should be included in the research.
• A member stated that some of these measures still could be integrated into the NCS. However, it was unclear how child/parent interaction could be included. It was suggested that the issues were complex, but not impossible to measure. It would require the contribution of individuals who know the state-of-the-art on how to measure such issues.

NCSAC Rating for this Hypothesis Proposal: Group 2; the authors should collaborate with the Social Environment Working Group.

Adjournment Of Day 1

Dr. Mattison adjourned the first day of the NCSAC meeting at 5:31 p.m.

September 13, 2002

Appendix A provides a list of those present on this day of the NCSAC meeting.

Call to Order of Day Two
Dr. Mattison reconvened the second day of the NCSAC meeting. He stated that the first order of business was to continue the hypothesis review.

Hypothesis Review Continued

The NCSAC continued its review of hypotheses proposals. In contrast to the first day of the meeting, NCSAC members commented at the conclusion of each group of hypotheses.

Asthma Working Group

Asthma Hypothesis Proposal Number 1-Asthma and wheezing in childhood illness the role of environment and genetics in determining risk.

Primary Reviewer: Dr. LeMasters

• The primary hypothesis and three subhypotheses were extremely relevant to the NCS because asthma was a common and chronic childhood disease.
• Asthma likely represented at least three conditions (i.e., early onset transient airway obstruction, early onset persistent asthma, and late onset asthma) that only a prospective cohort study could address.
  • There were several potential environmental causes. The relationship between timing of exposures and disease onset wais critical, and a prospective study was needed to identify critical windows of exposure during prenatal and early/late childhood.
  • Asthma also had a strong genetic component, and potential genes related to allergy and asthma were currently under investigation. A prospective study with a large cohort offered the optimum method to identify these gene-environment interactions related to asthma onset and progression.

Secondary Reviewer: Dr. Samet

Dr. Samet’s comments were not submitted for the record.

Asthma Hypothesis Proposal Number 2-Infant exposure to certain bacterial/viral/protozoan infections or bacterial components (e.g., endotoxin) may be protective against the subsequent development of asthma and allergy in childhood. The proposal’s main goal is to test whether the hygiene hypothesis explains geographic and ethnic/racial differences in the relationship between socioeconomic disadvantage and the development of allergy and asthma.

Primary Reviewer: Dr. Spielberg

• Asthma was a very important childhood disease. A recent study published in the Journal of the American Medical Association, which employed a protocol similar to that proposed by the Working Group, yielded statistically significant results. However, the study was based on middle-class, Health Maintenance Organization-served populations under the care of a single provider, and faced serious challenges in terms of retention. As a result, a similar study conducted among culturally diverse populations would probably face even greater retention issues.
• The analytical approaches recommended in the proposal were questionable; there were also ethical issues. While the hypothesis would add additional data, it would be costly, involve multiple blood tests and skin testing, and may result in therapeutic misadventures.
• The hypothesis was appealing, but there were methodological and safety issues associated with the proposal.

Secondary Reviewer: Dr. Sexton

Dr. Sexton’s comments were not submitted for the record.

Asthma Hypothesis Proposal Number 3-Asthma frequency and asthma morbidity are elevated among urban socioeconomically disadvantaged populations in the United States, compared to urban populations that are more socioeconomically advantaged. Asthma rates are not elevated in all nonurban socioeconomically disadvantaged U.S. populations.

Primary Reviewer: Mr. Swartz

• The summary of the proposal was misleading. The study proposed to examine the effects of exposure to one element of diesel exhaust at one time frame, from conception to 24 months of age. However, it was not clear how or when the exposure would be assessed.
• While the hypothesis stated that socioeconomically disadvantaged populations were at risk, the proposal did not explain how. Yet, because exposures from diesel were highly localized, the hypothesis presented an interesting candidate for explaining existing disparities.
• The proposed measurements were very complicated and the potential costs could be enormous, especially because an effective traffic monitoring system wais not in place. Meanwhile, the potential benefits of the research appeared to be limited.
• The proposal needed to be revised to include more elements of diesel exhaust and additional outcomes.

Secondary Reviewer: Dr. Landrigan

• Diesel was a critical exposure to include in the NCS because the National Institute of Occupational Safety and Health had declared diesel a carcinogen. The study must incorporate diesel exposures into the design.
• However, the proposal lacked sufficient detail.

Asthma Hypothesis Proposal Number 4-We propose to determine the role of prenatal maternal stress exposure in predicting the risk of childhood asthma, with consideration of effect modifiers of the association between maternal psychosocial stress and development of asthma, by concurrent assessment of genetic and environmental factors thought to influence immune development and lung growth/airway inflammation in early life. We will also determine the comparative role of maternal genetic background versus the child-s genetic background in modifying the effect of prenatal environmental exposures in predicting asthma.

Primary Reviewer: Dr. Little

There was increasing interest in the three-way interaction of maternal prenatal stress, genetics, and biotransformation in childhood asthma. There were several questions about the costs associated with the proposal. It was likely that measures of stress and asthma would be included in the study, however a clear definition of stress was needed.

Secondary Reviewer: Dr. Spielberg

The hypothesis had potential, but lacked specifics; it may be difficult to analyze the contribution of other interactions.

Asthma Hypothesis Proposal Number 5-After adjusting for potential confounders, the incidence of asthma in children is positively associated with chronic exposures to air pollutants (particulate matter, ozone, polycyclic aromatic hydrocarbons, volatile organic compounds, etc.), allergens, (endotoxins, dust mites, cockroaches, etc.), and outdoor aeroallergens (pollen, fungi, etc.). Includes several subhypotheses.

Primary Reviewer: Dr. Goldman

• There was a great deal of literature about asthma exacerbation successfully done on small cohorts, but little was really known about the topic. As a result, this was an important issue to examine in the study.
• The proposal identified three core hypotheses and seven subhypotheses. Measures will have to be validated to assess exposures, and additional work will be needed prior to the study, to ensure a common toolkit for use during the study.
• The proposal was not very specific and did not reflect what was already known in existing literature. This proposal should be integrated with Hypothesis Proposal Number 3. Some of the proposed measures (e.g., skin testing) may be too burdensome for participants, and too costly to the study. Yet, the proposal represented an important area of study for the NCS.

Secondary Reviewer: Dr. Doswell

Dr. Doswell agreed with Dr. Goldman’s comments and recommended the hypothesis for inclusion in the NCS.

Asthma Hypothesis Proposal Number 6-Exposures to respiratory viral agents and/or gastrointestinal agents, such as Paramixo viruses, Pneumo viruses, Retroviruses, Caliciviruses, EAD, etc., as well as environmental factors, including chemicals such as heavy metals during the first year of life, predisposes to reactive airway diseases such as asthma and other respiratory diseases, which may be accompanied by a decrease in pulmonary function. In contrast, exposure to some infectious agents of bacterial enteritis, depending on the period of life, may yield some protection or sensitize subsequently to reactive airway disease.

Primary Reviewer: Dr. Samet

Dr. Samet’s comments were not submitted for the record.

Secondary Reviewer: Dr. Graham

A mega-hypothesis on lung disease was needed. The proposal as presented, however, could drive the study. There was a need to measure infections in the study, but the proposal should be integrated with other hypotheses.

Asthma Hypothesis Proposal Number 7-Disparities in the prevalence, severity, and effective management of asthma by race and socioeconomic status are explained, in part, by social environmental factors and processes that influence exposure to physical environmental risk factors, psychosocial stress, and health-related behaviors.

Primary Reviewer: Dr. Suarez

The proposal may not be costly and would only require additional interview questions. The proposal should be considered.

Secondary Reviewer: Dr. Dudley

The proposal was relevant to the NCS but did not include any power calculations. The proposal may not constitute a core hypothesis.

NCSAC Member Comments about the Asthma Working Group Hypothesis Proposals:

• Measuring at day care centers presented a challenge because there were both formal day care centers and informal day care centers in homes. Measuring at informal day care in homes presented logistical challenges for the NCS. Urban and rural exposures were frequently mentioned in the asthma proposals, but not suburban exposures.
• Perhaps the Exposures to Chemical Agents Working Group should be tasked with developing a list of exposures to measure that may be related to asthma.
• The relationship between asthma and the immune system was not adequately discussed in any of the asthma proposals.
• There were concerns about the level of DNA sampling proposed in the first asthma hypothesis. It may be necessary to identify specific genes as part of the study design.
• The expertise of an asthma immunologist would be helpful in refining the asthma hypotheses. A better definition of asthma was needed.
• Going into people’s homes would inevitably result in the observance of behavior (e.g., abuse) that will require some level of intervention.
• The participants discussed the possibility of using technology, such as personal monitors, to capture the environment wherever a subject goes, which would eliminate the need to obtain consent from multiple sources. It was noted, however, that such technology did not read all exposures, and some questioned the potential for error.
• There was a need to place limitations on various proposals that were not feasible.
• There were ethical obligations associated with the NCS (e.g., when abuse was observed, the degree of intervention, providing information to families, linking the study to health care services, etc.).
• Asthma was an outcome that must be included in the core hypotheses. The various groups that developed asthma proposals should work together. It was suggested thatAsthma Hypothesis Proposal Number 1 be offered to the Working Groups as a model, provided that clinical assessment issues were addressed and more information was included.
• The Asthma Working Group should be asked to define what caused asthma, and to explain how a cohort of 100,000 children could be used effectively to examine these hypotheses.
• The question was asked as to whether hypotheses should be limited to asthma, or if there needed to be a stronger emphasis on the broader issue of pulmonary disease. A proposal could be developed on the survival of premature infants and the long-term impact on their health.

Dr. Mattison stated that the Asthma Working Group would be given responsibility for integrating the proposals and for collaborating with other Working Groups to develop integrated hypotheses.

NCSAC Rating for this Hypothesis Proposal:

Injury in Childhood and Adolescence Working Group

Injury Hypothesis Proposal Number 1-The physical environment of the child has significant risk and protective factors for the occurrence of injury. This risk is modified by family- and community-based factors, in interaction with the child-s age and developmental level.

Primary Reviewer: Dr. Landrigan

The proposal provided a starting point for consideration, but lacked specifics. The hypothesis proposed to examine the precursors to injury. These data most likely will be collected in the NCS. However, the proposal did discuss potential chemical exposures that predisposed children to injury.

Secondary Reviewer: Dr. Michael

Potential precursors to injury should be measured in the NCS.

Injury Hypothesis Proposal Number 2-Components of the psychosocial environment are significant risk and protective factors for risk taking and injury occurrence.

Primary Reviewer: Dr. Doswell

• The outcomes identified in the proposal would be best studied in a longitudinal design such as the NCS. The hypotheses focused on children aged birth to 10 years, but the proposal did not mention violence-related injury (e.g., guns in homes).
• Specific measurements were not discussed in the proposal, therefore the feasibility of the proposal could not be evaluated. However, the idea behind the proposal would contribute to the body of literature on the subject.

Secondary Reviewer: Mr. Swartz

The proposal, as currently presented, was too ambitious and was not feasible.

Injury Hypothesis Proposal Number 3-The functional outcome following an injury is affected by the antecedent psychosocial factors, as well as psychosocial factors consequent to the injury.

Primary Reviewer: Dr. Sexton

Dr. Sexton was not in attendance, and his comments were not submitted for the record.

Secondary Reviewer: Dr. Spielberg

The proposal sought to increase understanding of the functional outcome of injury. However, the proposal was not novel. In addition, it was unclear how the hypothesis would contribute to the body of knowledge on the subject; specific instruments were also not discussed.

Injury Hypothesis Proposal Number 4-Proposes three hypotheses related to Chronic Physical Aggression.

Primary Reviewer: Mr. Swartz

• The hypothesis dealt more with aggressive behavior than injury; yet violence, aggression, and specific markers were not defined.
• The hypothesis needed to be re-categorized with behavioral outcomes and linked with other hypotheses. The proposal was relevant to the NCS and may be appropriate for a large cohort. However, the proposal was vague about the exposures to measure.
• The analytical approach was not specific; the proposal, in general, needed to be more developed. In addition, while it was impossible to estimate the costs associated with the proposal, some of the information may be collected as part of other hypotheses. Implementing the proposal may be burdensome to families.

Secondary Reviewer: Dr. Little

The proposal was relevant to the NCS, but the analytical approach was not discussed. The proposal needed substantially more detail.

Injury Hypothesis Proposal Number 5-There is a cumulative effect of repeat traumatic brain injuries over time on subsequent neurocognitive development.

Primary Reviewer: Dr. LeMasters

Dr. LeMasters was not in attendance, but her comments were submitted for the record. She suggested that the proposal be included as a subhypothesis.

Secondary Reviewer: Dr. Bellinger

• It would most likely be easy to incorporate this proposal within the study design. A large prospective cohort study such as the NCS would offer the advantage of baseline information and preinjury cognitive assessments that have never been possible before. The hypothesis would allow an opportunity to conduct rigorous assessments of cumulative injuries.
• It was unclear how many study subjects in the sample would have recurring brain injuries. The research was worth doing because the NCS presented the only opportunity to study this issue. In addition, the study would impose a limited burden on subjects.

NCSAC Member Comments about the Injury in Childhood and Adolescence Working Group Hypothesis Proposals

• The fourth hypothesis mentioned studies of internalized racism, and how it may relate to aggression. The idea resonated with the observation of increased incidence of hypertension among black men and the potential relationship with internalized anger. Working Group members may want to examine this issue as a risk factor for hypertension. It may also be possible to examine the music and movies to which children are exposed.
• Traumatic Brain Injury was an important issue. However, brain scans posed a risk to subjects, especially younger ones. The proposal could provide an opportunity for research based on controlled data starting early in life.
• If injury constituted a core hypothesis, then the NCSAC should advise the Working Group which hypothesis should be the focus of their efforts.
• The Working Group was encouraged to determine what could be learned via the NCS; rather than focusing on areas about which so much was known. More injury incidence and prevalence data would be helpful in identifying areas of study for the NCS.
• One member was intrigued by the Injury Hypothesis Proposal Number 1 and the potential predictive value of injury in predicting high-risk behaviors.
• Violence was almost routine in some communities, and there was concern that the NCS may ultimately pathologize certain communities.
• The pediatric community was concerned about the relationship between aggression and certain comorbid disorders (e.g., Attention Deficit/Hyperactivity Disorder).

NCSAC Rating for these Hypothesis Proposals: Dr. Mattison would ask the Injury in Childhood and Adolescence Working Group to develop a more concrete and more specific integrated proposal. In particular, a core hypothesis should address a broad range of endpoints, including motor vehicle crashes, falls, fires, sports, drownings, and other outcomes. There was evidence to suggest that some individuals possessed genotypes that recover better from brain injury, so the NCS may want to explore that issue in more detail. The Injury in Childhood and Adolescence Working Group will need to collaborate with other Working Groups to refine the proposal.

Early Origins of Adult Health Working Group

Obesity/Diabetes Hypothesis Proposal Number 1-What are the genetic determinants of obesity in childhood, specifically which factors influence adipocyte proliferation and growth in children, and how are they modified by environmental factors such as quality and quantity of nutrition and physical activity? (These ideas can be extended to include mechanisms for insulin resistance, lipid metabolism, and cardiovascular disease risk.)

Primary Reviewer: Dr. Kumanyika

The proposal may have some potential, as genetics and obesity was an important area of study. However, the proposal was not well developed and was not recommended as a core hypothesis.

Secondary Reviewer: Mr. Swartz

Mr. Swartz concurred with Dr. Kumanyika’s review. However, he noted, a proposal to examine the genetic and environmental determinants for physical activity would be an interesting area of study.

Obesity/Diabetes Hypothesis Proposal Number 3-The development of beta cell and other autoantibodies, which subsequently increases risk for type 1 diabetes and other autoimmune disorders, occurs early during childhood, and is due to one or more environmental exposures among children who are genetically susceptible.

Primary Reviewer: Dr. Graham

Some studies had explored the risks for developing type 1 diabetes, and there may be an opportunity to augment these studies by examining the progression of exposures over time. The proposal needed to be refined.

Secondary Reviewer: Dr. Samet

The proposal, as currently presented, did not provide sufficient detail about environmental exposures and the potential benefits of this proposal.

Obesity/Diabetes Hypothesis Proposal Number 4-Impaired glucose tolerance (IGT) and/or gestational diabetes (GDM) causes in childhood: increased adiposity and increased risk of IGT/Type 2 Diabetes Mellitus (presents a life-course approach to prevention of obesity and type 2 diabetes in adolescence).

Primary Reviewer: Dr. Doswell

The hypothesis was a critical area to study in the NCS. Some of the subhypotheses could be examined via questionnaires. However, the analytic approach was not described, and costs could not be assessed.

Secondary Reviewer: Dr. Sexton.

Dr. Sexton was not in attendance, and his comments were not submitted for the record.

Obesity/Diabetes#5-Economic, cultural, social, and policy characteristics of the social environment, along with characteristics of the physical environment, influence the development of obesity from conception to adulthood. These factors operate largely through influences on family and social network resources and processes that affect behaviors related to energy balance (diet, activity, and inactivity).

Primary Reviewer: Dr. Little

• The proposal was of high relevance to the NCS. However, the hypothesis was generic in nature, and the analytic approach lacked specificity. In addition, the power model was basic and lacked detail; measurements were also not discussed.
• While there needed to be a core hypothesis in the NCS that focused on obesity, this proposal needed additional detail.

Secondary Reviewer: Dr. Spence

• The hypothesis was broad and complex, and the authors stated that retrospective data were inadequate. The proposal would require teams of investigators who were sensitive to the needs of culturally diverse populations. The proposal contained numerous gaps.
• How data would be collected was not specified in the proposal. However, given the fact that obesity was a paramount public health concern, this proposal may fit into an overarching hypothesis on obesity.

NCSAC Member Comments on the Early Origins of Adult Health Working group Hypothesis Proposals

• Obesity was a significant public health problem; yet the existing proposals were underdeveloped.
• Type 2 diabetes was more common than type 1 diabetes, and while it was once uncommon to see type 2 diabetes in adolescents, high rates of obesity among children were a disease condition waiting to happen as obese children reached adulthood. Type 2 diabetes among adolescents could represent a focal point of the study.
• There could be some interesting and specific hypotheses for examining genotypes of children who developed diabetes, as well as of those who did not. The existing hypothesis on gene interaction, however, was underdeveloped.
• Obesity research was evolving, and there was an enormous need for data. The NCS could track major environmental influences that cut across hypotheses, but there was a great deal of work that needed to be done before the NCS was implemented.
• Like the injury-related hypotheses, additional thought should be given to what might be learned about obesity and diabetes via the NCS. The NCS presented an opportunity to collect data and measurements before specific outcomes appeared.

NCSAC Rating on these Hypothesis Proposals: Dr. Mattison proposed that, because the Early Origins of Adult Health Working Group had looked at this issue from a staged approach, it should work with this and other Working Groups to create a single hypothesis driven by specific endpoints (e.g., type 1 and type 2 diabetes) and the opportunities to collect prediagnostic data.

Obesity/Diabetes Hypothesis Proposal Number 2-Altered timing of early childhood immunizations will lead to no increased rate or severity of disease later in life (focus on diabetes).

Primary Reviewer: Dr. Spielberg

The Infectious, Immunity, and Vaccines, Hypothesis Proposal Number 1 was designed to test the theory of an association between immunizations and autism. That group’s Hypothesis Proposal Number 2 focused on immunizations and diabetes. Both proposals hoped to examine the sequelae of vaccines. There was growing concern surrounding immunizations and possible relationships to certain adverse outcomes. It would be important for the NCS to look critically at outcomes associated with immunizations.

NCSAC Member Comments on Early Origins of Adult Health Working Group Hypothesis Proposal Number 2

• The prospective and longitudinal design of the NCS afforded an opportunity to examine the issue of immunization in a way that had never been done before (e.g., participants in vaccine trials tend to be racially and geographically homogenous).
• The NCS would provide an opportunity to answer questions about vaccine safety, and to offer these findings to policymakers in hopes of informing future public policy. Children in the cohort who did not get vaccinated would also constitute an opportunity for research. However, families who did not vaccinate their children most likely will not participate in the NCS.
• Vaccines were a mixture of many types of substances. As a result, it would be critical to know the actual