2
NCS Goals, Conceptual Framework, and Core Hypotheses

The National Children’s Study (NCS) was designed to respond to the requirements of the Children’s Health Act of 2000. Design choices were made in accordance with the overarching goals and conceptual framework developed for the study and to reflect the data needs for analysis of 28 core or meta-hypotheses (comprising over 100 specific hypotheses) that link environmental exposures to child health and developmental outcomes.

This chapter provides an overview of the NCS design to orient the reader and convey a sense of the large scale and scope of the effort; it then presents and comments in broad terms on the NCS goals, conceptual framework, and selection of core hypotheses as outlined in the research plan (NCS Research Plan, Vol. 1, Précis, Chs. 1, 2, 4). The chapter ends with a recommendation for lengthening the time between activities of the Vanguard Centers and the corresponding activities of the other study centers. The purpose of this recommendation is to provide adequate time, not only for the NCS to learn from the experience of the Vanguard Centers with regard to study operations, but also to adequately develop key constructs and hypotheses.

As a prefatory note to our critique of various aspects of the NCS in this and subsequent chapters, we acknowledge and appreciate the enormous effort that has gone into its development. Its designers, in an environment of uncertain funding and with the need to involve many different agencies and research communities, have exhibited professionalism and strength of purpose throughout. They have often confronted difficult choices, given that no study, no matter how complex, could cover every possible exposure and



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2 NCS Goals, Conceptual Framework, and Core Hypotheses T he National Children’s Study (NCS) was designed to respond to the requirements of the Children’s Health Act of 2000. Design choices were made in accordance with the overarching goals and conceptual framework developed for the study and to reflect the data needs for analy- sis of 28 core or meta-hypotheses (comprising over 100 specific hypoth- eses) that link environmental exposures to child health and developmental outcomes. This chapter provides an overview of the NCS design to orient the reader and convey a sense of the large scale and scope of the effort; it then presents and comments in broad terms on the NCS goals, conceptual framework, and selection of core hypotheses as outlined in the research plan (NCS Research Plan, Vol. 1, Précis, Chs. 1, 2, 4). The chapter ends with a recommendation for lengthening the time between activities of the Vanguard Centers and the corresponding activities of the other study cen- ters. The purpose of this recommendation is to provide adequate time, not only for the NCS to learn from the experience of the Vanguard Centers with regard to study operations, but also to adequately develop key constructs and hypotheses. As a prefatory note to our critique of various aspects of the NCS in this and subsequent chapters, we acknowledge and appreciate the enormous ef- fort that has gone into its development. Its designers, in an environment of uncertain funding and with the need to involve many different agencies and research communities, have exhibited professionalism and strength of pur- pose throughout. They have often confronted difficult choices, given that no study, no matter how complex, could cover every possible exposure and 

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN outcome of interest in the same depth. Funding would never be sufficient to do that, nor would the burden on study participants be acceptable. We detail instances in which we think the particular choices made for the NCS merit reconsideration or refinement—indeed, earlier work by NCS working groups and advisers often included options that we think should be on the table but did not appear in the final research plan. Nonetheless, we remain cognizant throughout of the resource limitations for the study, as well as the design constraints imposed by some of the decisions needed to bring the NCS to its current state. At the same time, we note—as does the NCS research plan itself—the opportunity afforded by the study’s length to alter course in one manner or another as appropriate, not only to take account of our comments, but also to take advantage of relevant new measurement techniques and research insights. DESIgN IN bRIEF The NCS is designed to be a long-running, observational panel study of a nationally representative probability sample of 100,000 births to be followed from before birth to age 21. Data will be collected on multiple exposures and multiple outcomes with repeated measures over time. Sample Design The sample design (see NCS Research Plan, Vol. 1, Secs. 6.1-6.4) is multistage and based primarily on households (discussed further in Chapter 4). Omitting some details, the first stage (already completed) was to draw a sample of 110 primary sampling units (PSUs) in 105 locations; the PSUs are counties or groups of counties (or parts of counties in Cook County, Illinois; Harris County, Texas; and Los Angeles County, California), each of which is expected to experience a minimum of 2,000 births during a 4-year enrollment period for the study. The second stage (implemented to date in the PSUs covered by the seven Vanguard Centers) will be to draw a sample of segments in each sampled PSU; the segments are census blocks, groups of blocks or similar subdivisions (some PSUs may be other subunits, such as school catchment areas). A third stage, implemented only in very large segments of sampled PSUs, will be to draw a clustered sample of house- hold addresses. These stages of sampling use stratification on geographic and other variables to ensure representation of population groups (such as minorities) and areas; there is no planned oversampling or undersampling by population groups or areas. Finally, all of the household addresses in the sampled segments (or clusters) will be visited to identify women who are eligible to participate; such women include those ages 18-44 who are not pregnant as well as all

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES women in the first trimester of pregnancy, regardless of age. Women who are not pregnant will be recontacted several times to determine whether they have become pregnant and hence are eligible to continue in the study, with the intensity of follow-up varying depending on whether a woman is deemed to have a high or a low-to-moderate probability of becoming pregnant. It is hoped that at least 25 percent of all births in the study will be to women who were not pregnant at the time of enrollment, in which case preconception measures would be available, and that 90 percent of all births in the study will be to women who were enrolled before the end of the first trimester of pregnancy (NCS Research Plan, Vol. 1, Sec. 6.1). The final-stage sampling, enrollment of participants, and initiation of data collection will be spread over several waves, beginning in mid-2008 for PSUs covered by the Vanguard Centers, followed by another set of PSUs in mid-2009, a third set in mid-2011, and the final set in mid-2012. During the preparation and initial sampling phases, the 35 to 40 study centers that will ultimately be part of the NCS operation will engage in outreach activi- ties to inform local communities of the study and encourage participation (see NCS Research Plan, Vol. 1, Sec. 6.5, and Chapter 5 of this report). To identify eligible women who moved into the selected segments after the initial screening, providers of prenatal care, birthing centers, and hospitals will be visited in those segments. In each of the 110 PSUs, the enrollment period will extend over 4 years, with the goal of enrolling about 1,000 newly born children by the end of the period. Data Collection The data collection plan (see NCS Research Plan, Vol. 1, Sec. 6.6) is complex and uses multiple collection modes. Details of items to be col- lected, from whom, when, and by which method have been specified in any detail only for ages prior to birth through 24 months. A provisional schedule of contacts with study participants has been outlined for ages 3- 21, but this schedule is subject to change, as are the specific items and data collection methods. The research plan argues that maximum flexibility is needed to enable the NCS to take advantage of new data collection and measurement technologies. Table 2-1 provides summaries of the planned data collection from pre- birth through age 24 months. Locations and modes of collection include personal home visits, telephone calls to homes, and clinic and hospital visits. The mother (or primary caregiver if the biological mother leaves the child after birth) is the main respondent; the biological father or partner may also participate, although relatively little data will be obtained for that person; and, presumably, the child will be interviewed later in the study be- ginning at an appropriate age. Types of data collected at one or more points

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 TAbLE 2-1 Planned NCS Data Collection from Prebirth Through 24 Months After Birth Type and Time of Biologic Clinical/Developmental Environmental Contact Questionnaire and Diary Samples Examination Samples Prepregnancy Maternal contact only (unless otherwise noted) Home visit–interview Demographics Blood Anthropometrics Indoor air Household composition Urine Blood pressure House dust Medication use Saliva Health behaviors Vaginal swabs Housing characteristics Hair Chemical exposures Product use Occupational exposures Diet Phone follow-up Diet ---- ---- ---- Chemical exposures

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During pregnancy First trimester home visit Demographics (also P)* Blood (also P) Anthropometrics (also P) Indoor air Household composition (also P)* Urine (also P) Blood pressure (also P) House dust Medication use* Saliva Fetal ultrasound (from medical Drinking water Health behaviors* Vaginal swabs report or clinic visit) Soil Housing characteristics* Hair (also P) Chemical exposures* Product use* Occupational exposures* Diet* Medical history (also P) Stress and social support Depression Tobacco use (P) Cognition (P) Second trimester phone Major life events ---- ---- ---- follow-up Mental health update Medical update Chemical exposures update Housing update continued 

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TAbLE 2-1 Continued  Type and Time of Biologic Clinical/Developmental Environmental Contact Questionnaire and Diary Samples Examination Samples Third trimester clinic Updates on: Blood Anthropometrics Indoor air visit Demographics Urine Blood pressure House dust Household composition Saliva Fetal ultrasound (self-collected Medication use Vaginal swabs and mailed in) Health behaviors Hair Housing characteristics Chemical exposures Product use Occupational exposures Diet Medical history Stress and social support Prenatal life events Depression From birth on Maternal (M)/child (C)/ paternal (P) contact Birth: At delivery, Health behaviors (M) Blood (M) Anthropometrics (C) hospital Diet (M) Urine (M) Dysmorphology and neurologic ---- Chemical exposures (M) Cord blood exam (C) Plans for infant feeding, sleeping, Placenta and cord Digital photographs of face and etc. samples anomalies (C) Heel stick (C) Chart abstraction (M, C)

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3-month phone call Child care Breast milk (mailed in at Medical update (C) 4-6 weeks) ---- ---- 6-month home visit Stress and social support Urine (C) Anthropometrics (C) Indoor air Family process and parenting Hair (C) Dysmorphology exam and photos House dust practices (also P) Saliva (M, P) (C) Drinking water Health behaviors (M) Breast milk Dermatologic exam (C) Soil Depression and Social development observation Visual assessment cognition (M) (M, C) of house and Diet (C) neighborhood Medical update (C) Medication use (C) Media exposure (C) Child care Chemical exposures Temperament (C) Tobacco use (P) Cognition(P) 9-month phone call Child care Medical update (C) ---- ---- ---- Housing update Chemical and occupational exposures (M, C) continued 

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TAbLE 2-1 Continued 0 Type and Time of Biologic Clinical/Developmental Environmental Contact Questionnaire and Diary Samples Examination Samples 12-month home visit Household composition update Blood (C) Anthropometrics Indoor air Family process and parenting Urine (C) Blood pressure House dust practices (also P) Hair (C) Dermatologic exam Drinking water Health behaviors (M) Saliva (C) Cognitive exam Soil Diet (C) Breast milk Motor and language assessments Visual assessment Medical update (C) Social development of house and Medication use (C) observation (child and neighborhood Media exposure (C) father, if available) Noise survey Child care Housing update Chemical and occupational exposures (M, C) Language acquisition and social interaction (C) Tobacco use Cognition (if not assessed at first trimester meeting) 18-month phone call Child care Medical update (C) ---- ---- ---- Diet (C) Housing update Chemical and occupational exposures (M, C)

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24-month phone call Child care Indoor air Medical update (C) ---- ---- House dust Housing update (self-collected Chemical and occupational and mailed in) exposures (M, C) Life events (M) NOTE: P = paternal, M = maternal, C = child. *Updates if in prepregnancy cohort. SOURCE: NCS Research Plan, Vol. 1, Tables 6-2 through 6-4. 

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN in time include biological specimens (blood, urine, hair, saliva, breast milk), results of physical examinations (for example, anthropometrics, blood pres- sure), residential environmental samples (air, dust, drinking water, soil), medical records, responses to personal and telephone interview questions, mailed-back questionnaires, diaries or logs of several types, and interviewer observations. Topics covered in interviews at one or more points in time in- clude household composition; housing characteristics; maternal (or primary caregiver) characteristics (demographics, medication use, health behaviors, chemical exposures, product use, diet, medical history, stress and social support, depression and cognition, occupational exposures, child care); paternal (or partner) characteristics (demographics, tobacco use, medical history, cognition, mental health, parenting practice); and child character- istics (medical history, diet, medication use, media exposure, temperament, chemical and occupational exposures). There is also the potential to ob- tain measures of neighborhood characteristics from auxiliary data sources linked to a participant’s census block group. Following data collection at age 24 months by telephone call to the mother, a clinic visit is planned for age 3 years. Another in-home or clinic visit is planned for age 5 years and every few years subsequently—provi- sionally, for ages 7, 9, 12, 16, and 20 (with telephone calls presumably at more frequent intervals), although the location and timing of such visits beginning with the visit for age 5 years are not yet decided (NCS Research Plan, Vol. 1, Table 6-1). Substudies Substudies, outside additions to the core research, and adjunct studies (see NCS Research Plan, Vol. 1, Ch. 16) are included in the research plan to enable the NCS to serve as a platform for additional scientific research. Substudies are defined to include research that is planned in a similar man- ner as the planning for the core research and is supported with NCS funds but applies to only a part of the study cohort. Examples are not given but could presumably include studies of particular population groups with some added data collection. The NCS will also entertain proposals from other agencies, to be funded by the proposing body, for additions to the NCS core research plan. Both substudies and outside additions to the core research must go through the appropriate reviewing process, and approved studies will be included in the workload of all NCS study centers. Adjunct studies are defined as studies proposed by other agencies, with outside funding, to be conducted at only one or a subset of study centers on a portion of the cohort. Adjunct studies will largely be supported with outside funding, though to a limited extent NCS funds may support some

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES adjunct studies. Adjunct studies are implemented only with the concurrence of the involved study centers, so they are optional for the centers. STuDy gOALS Description The overarching goal of the NCS, as stated in the NCS research plan (Vol. 1, Précis, pp. xv-xvi), is: to provide information that will ultimately lead to improvements in the health, development, and well-being of children. The primary aim of the NCS is to investigate the separate and combined effects of environmental exposures (chemical, biological, physical, and psychosocial), as well as gene-environment interactions, on pregnancy outcomes, child health and development, and precursors of adult disease. In addition to this broad purpose, the Study has several more specific goals: (1) Determine the presence or absence of effects, both harmful and help- ful, related to the timing, frequency, magnitude, and duration of specific chemical, physical, biological, and psychosocial exposures in children’s environments from preconception to adulthood. (2) Determine possible environmental contributions to, or causes of, spe- cific diseases and conditions of children, including, but not limited to, prematurity and other outcomes of pregnancy, neurological and devel- opmental disorders, psychiatric and behavioral disorders, altered physi- cal development and sexual maturation, obesity and insulin resistance, asthma, and injuries. (3) Determine how genotypic variation and mechanisms, and the interac- tion of genes with environmental factors, influence disease risk and devel- opmental trajectories in children. (4) Serve as a national resource for future studies of child health and de- velopment by providing a rich database and repository of environmental and biological samples and information that can be used to address future questions and hypotheses. Overall Assessment We draw one overarching conclusion about the responsiveness of the NCS goals and design, in broad terms, to the requirements of the Children’s Health Act of 2000. Conclusion 2-1: The stated overall and specific goals for the NCS—and the design of the NCS to achieve those goals—largely reflect the stipu-

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN specific alterations of function. In this regard, the NCS is currently best de- signed to study relationships involving factors operative during pregnancy and the perinatal period because of the intensity and frequency of observa- tion during this phase of child development (see Table 2-1). Although we recognize the budgetary costs of both more frequent in- home visits and the abstraction and coding of medical and other administra- tive records, we urge the NCS to reconsider both decisions. Children grow and change very rapidly, and it seems imperative to have more frequent personal visits. If this is not feasible for the full study, then more frequent visits should be implemented for a sufficient subsample (ideally randomly selected) to test the effects on data quality and retention of participants and make it possible to use appropriate statistical methods to adjust the data for other participants. With regard to medical records, we urge the NCS, at a minimum, to make arrangements with providers to permit the NCS to obtain relevant records to keep in a repository to be abstracted when bud- getary resources allow. We also urge the NCS to investigate the feasibility of obtaining relevant records from schools and social service agencies. Recommendation 2-2: The NCS should seek resources and develop methods to obtain more frequent in-person measures and medical and other administrative records data on study participants. CONCEPTuAL FRAMEWORK Description Chapter 2 in the NCS research plan (NCS Research Plan, Vol. 1) is labeled “Conceptual Design and Framework”; it states broad design cri- teria, such as assessments of multiple exposures and outcomes, repeated measures, following children through to adulthood, and generalizability to the U.S. population, on which we comment in the previous section. It also provides a very simple conceptual model, in which environmental exposures in various domains are linked to outcomes in various domains with gene expression and health care as mediating factors (NCS Research Plan, Vol. 1, Sec. 2.1, Figure 2-1). We found Chapter 1 in the NCS research plan, which is labeled “Back- ground,” to be more informative about the conceptual thinking that un- derlies the study design. It provides a succinct statement of the principles underlying the study. Vol. 1, p. 1-1 states: The National Children’s Study design rests on the principle that both health and susceptibility to disease are determined by dynamic processes that occur throughout life. Perturbations (“insults”) that impact health

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES states may occur any time from preconception through adult life. These insults can affect viability, differentiation of major organ systems, somatic growth, and the development of functional processes including maturation of metabolic systems. A range of determinants acting either in concert or synergistically may impact growth and development. These include the built and natural environments with their chemical and physical factors, the social environment, individual behaviors, and biological factors includ- ing genetics. Of particular importance are the earliest stages of human development, pregnancy and early childhood, when cell division, differen- tiation, and maturation are most rapid. These health determinants may influence development in many ways. For those with high potency when acting at critical periods of develop- ment, such as thalidomide or Accutane, severe birth defects will result in most exposed offspring. Most environmental factors, however, are not so potent. More often, factors operating at critical or sensitive periods of development will interact with other factors over the life course to raise or lower the risk of adverse health outcomes. These factors may be genetic or non-genetic. For example, accelerated weight gain during childhood is associated with increased risks of diabetes and cardiovascular outcomes later in life; this phenomenon is accentuated among children born with restricted fetal growth. . . . Only with this appreciation of the complexity of interactions among genetic and environmental factors will we be able to inform the next generation of caregivers about effective prevention and treatment to lower the burden of common chronic conditions of childhood and later-onset diseases that arise from early developmental results. Assessment We appreciate the acknowledgment in the NCS research plan of the complexity of child development and the complex ways in which myriad factors may interact to affect that development. However, we find the con- ceptual framework for the NCS to be less well developed than we would have expected for this stage of the project. While invoking a dynamic, mul- tifactorial, life-course model, the research plan does not specify any particu- lar model or models to guide decisions on which conditions and potential causal factors are chosen for study, the timing of data collection points, the types of data to be collected, and the overall analytical approach. There is also little attempt to capitalize on the interconnections among the condi- tions chosen for study. Relatedly, we find that the research plan fails to define key constructs. While noting that the Children’s Health Act mandated a study on the many environmental influences affecting the health and development of children, the plan does not provide clear definitions of “health” and “development.”

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN There are a number of existing approaches to the conceptualization and modeling of health and development that could be used as a framework against which the data collection and analysis for the NSC could be as- sessed. For example, a life-course approach has been defined (Ben-Shlomo and Kuh, 2002:285) as: the study of long-term effects on chronic disease risk of physical and social exposures during gestation, childhood, adolescence, young adulthood, and later adult life. It includes studies of the biological, behavioral and psycho- social pathways that operate across an individual’s life course, as well as across generations, to influence the development of chronic diseases. While Ben-Shlomo and Kuh (2002) focus their discussion on chronic illness, they argue that such an approach would also apply to wider notions of health and well-being. The Institute of Medicine report (2006), Genes, Behavior, and the Social Environment: Moving Beyond the Nature/Nurture Debate, discusses the kinds of life-course models that are needed to un- derstand the interactions of genetic, behavioral, and social factors as they affect human health. A life-course model would include the identification of critical or sen- sitive periods when a specific exposure might cause specific alterations of function, as well as the identification of risk factors or effect modifiers later in life. These additional risk and protective factors could be further charac- terized as acting independently or in correlated clusters or additive “chains of risk.” In addition, a life-course model could incorporate different levels of influence from the individual to the family and could include neighbor- hood and broader societal influences. The analytic strategy for investigating such a chain of events would be broader than a focus on logistic regression and confounders and would require multilevel modeling as well. Moreover, consideration of multiple influences on outcomes could serve to link some of the outcomes selected. A broader conception of health and a dynamic framework for assess- ing health and development trajectories over time can be found in a recent report by the Board on Children, Youth, and Families (National Research Council and Institute of Medicine, 2004); see Box 2-1. This approach emphasizes optimality and functionality rather than disease and deficit and in that sense is more consistent with the World Health Organization definition of health as “positive, physical, mental and social well-being and not just absence of disease” (World Health Organization, 1946; see also Drotar, 1998; Eiser and Morse, 2001). Such an approach would lead to more of a focus than is evident in the NCS research plan on factors that protect against adverse outcomes or that mitigate the effects of risk factors; on multiple factors affecting outcomes; and on the interplay of chronic ill- ness and development for such specific conditions as asthma (see Hayes,

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES BOX 2-1 A New Definition of Children’s Health The report of the Committee on Evaluation of Children’s Health, Children’s Health, The Nation’s Wealth (National Research Council and Institute of Medicine, 2004), defines children’s health as follows (p. 33): Children’s health is the extent to which individual children or groups of children are able or enabled to (a) develop and realize their potential, (b) satisfy their needs, and (c) develop the capacities that allow them to interact successfully with their biological, physical, and social environments. This definition draws upon an explanation from the World Health Organization that health is a state of complete physical, mental, and social well-being, not merely the absence of disease or infirmity; a collaborative effort of the European Union Health Monitoring Programme to develop the Child Health Indicators of Life and Development (CHILD) model; the positive health principles embraced by the Ot- tawa Charter for Health Promotion (1986); and the research literature cited in the report. Key features of the new definition of children’s health include three distinct but related domains (pp. 34-35): • health conditions, “a domain that deals with disorders or illnesses”; • unctioning, “which focuses on the manifestations of individual health in daily life”; f and • ealth potential, “which captures the development of health assets that indicate h positive aspects—competence, capacity, and developmental potential.” The report describes these domains in detail and also describes ways to measure not only aspects of each domain, but also the influences on children’s health, which are defined to include (p. 46): • Children’s biology • Children’s behavior • Physical environment o Prenatal exposures o Childhood exposures o Home, school, and work settings o Child injury and the provision of safe environments o The built environment • Social environment o Family o Community o Culture o Discrimination • Services • Policy

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN 1997; Hobbs, Perrin, and Ireys, 1985; Stein et al., 1993; Thompson and Gustafson, 1999). Likewise there are models of psychological development that might guide the NCS. Although the research plan cites the seminal National Research Council publication on child development, From Neurons to Neighborhoods: The Science of Early Childhood Development (National Research Council and Institute of Medicine, 2000), it does not reflect the conceptualization of child development and the factors affecting develop- ment that are discussed in that report. In the area of physical development, the research plan, as presented, does not incorporate the notion of physical development as a normal developmental process. Finally, the research plan does not discuss the interplay of physical growth and aspects of psychologi- cal and behavioral development (French, Story, and Perry, 1995; Molinari et al., 2002). We are not necessarily recommending that the NSC operationalize any of these constructs of health and development completely, but such frame- works could serve as benchmarks against which the study could map what is feasible for the NSC. For example, some constructs might prove too time- consuming or expensive to measure because they require laboratory-based assessments. Others might require more frequent assessments than are pos- sible with the resources of the overall study. In any event, the rationale for what is being done would be clear, and the gaps evident. Such gaps might very well be useful guides to what substudies or adjunct studies individual sites might conduct. Employing explicit frameworks would not necessarily mean going back to the beginning. However, it would involve a review of the relevant theoretical and epidemiologic approaches, selection of the most appropri- ate with an explicit rationale for the choice, a mapping of the currently proposed conditions and measures to be collected against the framework with a description of the potential choices to be made, taking account of feasibility, costs, and response burden, and an assessment of the implica- tions for analysis capitalizing on the power and longitudinality of the NSC. In choosing specific measures to include on the basis of the chosen framework, the NCS should consider—in addition to, or in place of, those already proposed—such indicators of child well-being and mental health as secure attachment relationships, social competence, cognitive development and achievement, optimism, and empathy. One can add to this list assess- ments of positive emotionality, healthy attributional style, ego-resilency, and many more. Some of this work may already have been done and be contained in background white papers, but such thinking is not evident in the research plan. We recognize the pressures on the NCS to get the study under way, but we caution against stinting on conceptual development. We think there is

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES time to consider more fully the appropriate conceptual framework to guide the selection of measures and analytical methods for subsequent stages of the project, given that the data collection plan is being developed in 3-year stages, as described above, and only the first stage has been fully specified thus far. Furthermore, if the NCS adopts our recommendation (see last section below) to allow more time than is currently planned between the completion of an operation by the Vanguard Centers and the implemen- tation of that operation by other centers, then there will also be time to consider more fully the appropriate conceptual framework for the study from the earliest stage. We understand that it is not possible—and should not be attempted—to foresee every research question of interest or to develop fully specified, complete models for every possible analysis at the outset of a long study. Indeed, an advantage of such a lengthy data collection period is that the NCS should be able to support important research that has not yet been conceived. Yet without an appropriately rich conceptual framework and well-developed key constructs, there is no assurance that the most ap- propriate measurements will be obtained for even those conditions that are identified for study at the outset. The NCS may want to consider the use of expert consultants to assist in the assessment and specification of appropriate frameworks, constructs, and measures to guide decisions on measures and the timing of assessments to be obtained in the study, with the Vanguard Centers used for pilot testing as recommended below. Recommendation 2-3: The NCS should clearly define the key con- structs of child health and development and more fully develop a conceptual framework for understanding child health and develop- ment over the life course of infancy, childhood, and adolescence. CORE hyPOThESES Description As indicated in the research plan (NCS Research Plan, Vol. 1, Sec. 4.2), the framing of hypotheses was considered essential to guide study planning and to ensure that important questions would be addressed. In planning the study, a standard was established that a supporting hypothesis must be developed for inclusion of measures or design elements in the NCS. To guide the selection and prioritization of outcome and exposure measures, 28 topic areas for hypotheses, referred to as core or meta-hypotheses, were developed to fulfill the study’s aim of ascertaining the effect of environmen- tal factors on the health and development of children; see Box 2-2. The specific hypotheses in each of the topic areas identify relevant

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN BOX 2-2 Hypotheses Topics (Meta-Hypotheses) of the National Children’s Study • Birth defects from impaired glucose metabolism • Increased risk of preterm birth from intrauterine exposure to mediators of inflammation • Increased risk of fetal growth restriction, preterm birth, birth defects, and developmental disabilities in children born through assisted reproductive technologies • Maternal subclinical hypothyroidism and neurodevelopmental disabilities/ adverse pregnancy outcomes • Nonpersistent pesticides and poor neurobehavioral and cognitive skills • Prenatal infection and neurodevelopmental disabilities • Gene-environment interactions and behavior • Prenatal and perinatal infection and schizophrenia • Family influences on child health and development • Impact of neighborhood and communities on child health • Impact of media exposure on child health and development • Social institutions and child health and development • Influences on healthy development • The role of prenatal maternal stress and genetics in childhood asthma • Exposure to indoor and outdoor air pollution, aeroallergens, and asthma risk • Dietary antioxidants and asthma risk • Social environmental influences on asthma disparities • Early exposure to structural components and products of microorganisms decreases the risk of asthma • Environmental exposures interact with genes to increase the risk of asthma and wheezing in children • Obesity and insulin resistance from impaired maternal glucose metabolism • Obesity and insulin resistance from intrauterine growth restriction • Breastfeeding associated with lower rates of obesity and lower risk of insulin resistance • Fiber, whole grains, high glycemic index, and obesity and insulin resistance • Genetics, environmental exposures, and type 1 diabetes • Repeated mild traumatic brain injury and neurocognitive development • Behavioral exposures, genetics, and childhood or adolescence onset aggression • Antecedents and resiliency to traumatic life events in childhood • Hormonally active environmental agents and reproductive development SOURCE: National Institute of Child Health and Human Development (2007, Vol. 1, Sec. 4.2, Table 4-1; specific hypotheses in each of these areas are provided in Vol. 2, App. A-2).

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES environmental exposures, including physical, chemical, biological, and psychosocial factors, that affect the identified priority outcomes, includ- ing pregnancy outcomes, neurodevelopment and behavior, injury, asthma, obesity and growth, child health and development, and reproductive de- velopment. Many hypotheses also take into consideration the impact of gene-environment interactions. The criteria outlined in the research plan for the meta-hypotheses and specific hypotheses are: • they are scientifically compelling, • they have important public health implications, • they are feasible to test, and • they clearly justify the need for a prospective birth cohort study of 100,000. Assessment Although the panel recognizes that the framing of hypotheses is es- sential to guide study planning, we also think that many of the most in- teresting studies that are ultimately carried out with the data are likely to involve concepts and relationships that could not clearly be envisioned at the outset of the study. In our view, the NCS design, as represented in the research plan, allows for the genesis of new research ideas and hypotheses in a number of ways, including the length and breadth of the data-gathering platform, the nationally representative, equal probability sampling design, the provision for substudies and adjunct studies, and the storage of biologi- cal and environmental specimens for later analysis. Nonetheless, the set of initial hypotheses that are developed to guide the study should be carefully selected and well framed to enable the study to collect the most appropriate outcome and exposure measures. The core hypotheses need to be well based in theory and prior research; reflect ap- propriate conceptual models of plausible pathways that relate exposures, mediating factors, and outcomes; and relate clearly to public health policy issues. We are in broad agreement with the NCS’s selection of the seven prior- ity outcome areas—they represent important topics for research to inform public health policy for children. Turning to the specific hypotheses in each area, however, we think that some of them are more compelling and more fully specified than others. Some hypotheses are very broad and lack clear specification and justification, and other hypotheses are very nar- row and limited in usefulness. By outcome area (see Chapter 3 for fuller discussion):

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0 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN The NCS pregnancy outcome hypotheses are well justified, with • the exception of subclinical maternal hypothyroidism as a factor in adverse pregnancy outcomes, for which a compelling case is not offered either on public health or scientific grounds. The neurodevelopment and behavior hypotheses are not well justi- • fied in terms of why some outcomes were selected and not others— for example, it is proposed to study schizophrenia, which often does not become manifest until after the period of study (after age 21), while other behaviors that manifest themselves in adolescence, such as bipolar disorder, eating disorders, substance abuse, and others, are overlooked. The child health and development hypotheses are very broad: they • do not articulate pathways by which such factors as the family and community environments affect or mediate developmental trajectories, and they do not clearly define the range of normal development. The hypotheses regarding environmental risk factors for the inci- • dence of asthma are well developed; they represent an important and original contribution of the NCS to the field of child public health. The obesity hypotheses focus on maternal intrauterine environ- • ments and childhood diets as factors in obesity, to the exclusion of such domains as parental support, physical activity, food avail- ability, schools, and TV watching. The injury hypotheses are problematic in several respects (for ex- • ample, it will be very difficult to accurately measure repeated mild traumatic brain injury) and do not address important public health concerns related to the environmental causes of childhood injuries or the effects of clinical treatment or nontreatment. The reproductive development hypotheses are potentially an im- • portant and original contribution of the NCS, although the specific outcomes (for example, polycystic ovary syndrome) need to be more clearly specified. Hypotheses are nearly missing altogether in the area of racial and eth- nic disparities, as we noted above. The study will undoubtedly contribute to a better understanding of the sources of racial and ethnic, language, so- cioeconomic, and geographic differences in child health, but it has formed almost no hypotheses about these differences that could have informed the study design and made it more useful in this regard. Such hypotheses could have included attention to perceptions of discrimination or stigma that may affect parents’ mental health and their inclination to use social services and medical facilities. Based on the research plan, this subject area appears to

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 GOALS, CONCEPTUAL FRAMEWORK, AND CORE HYPOTHESES be largely left to the future: “The NCS will be able to address many major health disparities that currently exist in the United States, and to collect sufficient data to address others not yet recognized” (NCS Research Plan, Vol. 1, Sec. 2.2.2). Finally, we note that no matter how well specified a hypothesis may be, considerable thought and imagination will be required to test it adequately on NCS data (see further discussion in Chapter 4). The difficulties of test- ing hypotheses on observational data are well recognized in the social and health sciences. Such data are rife with selection biases that can produce distorted outcomes unless great care is taken in both design and analysis. For example, what appear to be neighborhood effects should often be at- tributed to the characteristics (sometimes unmeasured) of individuals who live in an area. As the NCS moves from data gathering to analysis, more attention will need to be given to methodological issues in the use of ob- servational data than is evident in the research plan. uSINg ThE VANguARD CENTERS AS PILOTS An important shortcoming of the NCS, as currently planned, is the absence of a pilot phase for thorough testing, evaluation, and refinement of study concepts, measures, instruments, and procedures. The study design is complex in every aspect, from developing appropriate constructs, hypoth- eses, and measures of outcomes and exposures, to identifying and enrolling participants, maintaining a high response rate over the life of the study, administering the very large number of survey, clinical, and environmental sampling instruments, and managing very large databases to which many study centers have contributed. Moreover, in this and other chapters, we raise many questions about concepts, measures, frequencies and types of data collection, and other aspects of the study. For the study to achieve its full potential, we think that more time is needed at the outset for refinement of key constructs and measures and for full testing, evaluation, and modification, as appropriate, of study proce- dures. At present, it appears that little, if any, formal experimentation will be included in the work of the Vanguard Centers. Moreover, while the Vanguard Centers will begin enrollment and data collection a year in ad- vance of other study centers, a year does not seem long enough to allow for thorough analysis of how well procedures worked in the Vanguard Centers and for improvements to be effected prior to when operations begin in the other centers. We urge the NCS to consider lengthening the time between the start of Vanguard Center operations and the start of operations in other study centers. Although we do not think that we can make a specific recom- mendation about the duration of the pilot, we do think that an additional

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN 6 months to a year between the Vanguard sites data collection and the collection of data by all the sites would be beneficial. The increase in time should be implemented not only for the first phase of enrollment through age 24 months, but also for the introduction of each new set of operations and instruments for subsequent 3-year periods throughout the life of the study. In addition, we encourage the NCS to build in experimentation with instruments and study procedures into the Vanguard operations when the extant literature is not sufficiently clear about the preferred approaches. Recommendation 2-4: We strongly urge the NCS to delay enroll- ment at new sites to make effective use of initial findings from participant enrollment and data collection in the Vanguard Center sites to improve study procedures, as appropriate, and to refine key concepts, hypotheses, and measures of outcomes and exposures. Throughout the life of the study, the NCS should use the Vanguard Centers to pilot test and experiment with data collection methods and instrumentation.