3
Priority Outcome and Exposure Measures

As stated in the previous chapter, the core hypotheses of the National Children’s Study (NCS) were intended to serve as guidelines for the selection of outcome and exposure measures. The elaborate NCS planning process (described in Chapter 1) led to seven priority outcome areas:

  1. pregnancy outcomes,

  2. neurodevelopment and behavior outcomes,

  3. child health and development outcomes,

  4. asthma,

  5. obesity and growth,

  6. injury, and

  7. reproductive development outcomes.

Environmental exposure factors include the natural and built environment and the psychosocial environment. They comprise a wide range of biological, physical, chemical, genetic, social, cultural, and geographical factors. The NCS will attempt to examine many different exposures and link them in dose-response relationships with multiple outcomes. The study’s geographical dispersion and the varied socioeconomic and demographic characteristics of the study population have important implications for the collection of exposure measures.

This chapter first discusses each priority outcome area, which necessarily includes some discussion of the kinds of exposures that are proposed



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3 Priority Outcome and Exposure Measures A s stated in the previous chapter, the core hypotheses of the National Children’s Study (NCS) were intended to serve as guidelines for the selection of outcome and exposure measures. The elaborate NCS planning process (described in Chapter 1) led to seven priority outcome areas: 1. pregnancy outcomes, 2. neurodevelopment and behavior outcomes, 3. child health and development outcomes, 4. asthma, 5. obesity and growth, 6. injury, and 7. reproductive development outcomes. Environmental exposure factors include the natural and built environment and the psychosocial environment. They comprise a wide range of bio- logical, physical, chemical, genetic, social, cultural, and geographical fac- tors. The NCS will attempt to examine many different exposures and link them in dose-response relationships with multiple outcomes. The study’s geographical dispersion and the varied socioeconomic and demographic characteristics of the study population have important implications for the collection of exposure measures. This chapter first discusses each priority outcome area, which neces- sarily includes some discussion of the kinds of exposures that are proposed 

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN to be associated with one or more outcomes. The chapter then reviews categories of exposure measures in more detail. PRIORITy OuTCOMES For each priority outcome area, the discussion summarily describes the proposed hypotheses regarding specific outcomes and associated en- vironmental factors as presented in the NCS research plan. It then offers the panel’s assessment in terms of public health significance and sound- ness of concepts and methodology. Each area ends with one or more recommendations. Pregnancy Outcomes (1) Description The specific pregnancy outcomes identified in the NCS research plan are birth defects, prematurity, outcomes of artificial reproductive technol- ogy (ART), and outcomes of pregnancy when the woman has subclinical hypothyroidism (NCS Research Plan, Vol. 2, App. A-2, Pregnancy Out- comes). The NCS proposes to focus on altered maternal glucose metabolism and folate and vitamin supplementation as risk (or protective) factors for birth defects; the role of inflammation in the pathogenesis of prematurity; the association of ART with fetal growth restriction, prematurity, and de- velopmental disabilities; and the relationship between maternal subclinical hypothyroidism and developmental disabilities. Assessment: Public health Significance The outcomes of pregnancy clearly represent an important area for research to which the NCS could make significant contributions. If the outcomes proposed for the NCS, birth defects, prematurity, and the out- comes of ART (and subfecundity generally) are certainly of public health significance. Taken together, they account for up to 15 percent of all preg- nancies. Moreover, prematurity and birth defects have proven difficult to predict and prevent (Centers for Disease Control and Prevention, 2007; Institute of Medicine, 2006). Although ART is responsible for a relatively small percentage of births (1-5 percent), it nevertheless contributes signifi- cantly to poorer birth outcomes in the United States. Thus, a strength of this section of the NCS research plan is its focus on significant public health problems. The public health significance of maternal subclinical hypothyroidism is less clear. Limited studies suggest that unrecognized hypothyroidism during

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 PRIORITY OUTCOME AND EXPOSURE MEASURES pregnancy may lead to poorer cognitive function in the child. Most cases of hypothyroidism represent autoimmune disorders, but the NCS investigators hypothesize that environmental exposures may act to disrupt the endocrine system and produce hypothyroidism, although this has not been demon- strated outside the laboratory or wildlife. The reference cited (Landrigan, Garg, and Droller, 2003) does not list the candidate exposures, and it is not clear what these would be. Another factor potentially contributing to subclinical hypothyroid- ism is maternal depression with alteration of the hypothalamic-pituitary- adrenal (HPA) axis. Although maternal distress can result in alterations of hormonal function and is associated with adverse pregnancy outcomes, it is unclear that the operational pathway is through subclinical hypothyroid- ism. Maternal depression is certainly associated with poorer cognitive and especially behavioral outcomes in the child, but, again, the operational pathway seems more likely to be through poorer maternal-child interactions than subclinical hypothyroidism. While clinical hypothyroidism is associ- ated with such complications of pregnancy as preeclampsia, no evidence is presented that subclinical hypothyroidism poses such a threat. In addition, because the NCS data collection sites have been selected using equal probability sampling, the distribution of exposures to environ- mental agents that might result in subclinical hypothyroidism is unclear. There may not be sufficient variability, especially of high and low levels of specific agents, to permit detection of their effect. In sum, the question ad- dressed by the posited relationship of subclinical hypothyroidism and child development outcomes represents a highly speculative chain of logic, and the importance of the problem is not entirely clear, especially since it is said to affect only 2 percent of births. With regard to other hypotheses that could be worth evaluating in the NCS—perhaps in place of the proposed research on subclinical hypo- thyroidism—we make three suggestions. First, the NCS could expand the proposed study of maternal depression as a factor in adverse pregnancy outcomes: The research plan limits evaluation of its role to its effects on subclinical hypothyroidism. Second, the NCS could reconsider its decision not to obtain dental records to establish maternal periodontal disease (NCS Research Plan, Vol. 2, App. A-2, p. A2-16), or at least mount a substudy (see Chapter 2) to collect the information needed to examine the effects of maternal periodontal disease on prematurity and other adverse pregnancy outcomes. Finally, in regard to public health significance, the current list of hy- potheses does not directly address one of the most critical and enduring re- productive public health issues in the United States: the causes of racial and ethnic disparities in birth outcomes, especially the elevated rates of poor birth outcomes among African American women. The current hypotheses

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN address a relatively narrow set of clinical concerns, although this extensive study of 100,000 births has the potential to help focus the country’s intel- lectual attention on addressing its most fundamental issues with respect to reproductive outcomes. Assessment: Methodological Concerns Pregnancies without a live birth One concern about the treatment of preg- nancy outcomes is that the research plan provides insufficient detail to un- derstand how pregnancies that do not end in a live birth are to be handled. The NCS preconception and early pregnancy sampling design means that it has the potential to be one of the most important sources of scientific information on fetal loss, a critical pregnancy outcome. Many pregnancies may end in very early miscarriages, even before pregnancy testing, which could affect the ability to detect an association of early termination with inflammatory factors. In addition, prenatal diagnosis may lead to termina- tion of pregnancies in which the fetus is assessed to be severely affected or nonviable. The research plan suggests that information on such outcomes will be sought. It will be important to employ sensitivity in data-gathering so that accurate information is obtained on these matters. The extent to which autopsy and other diagnostic materials will be obtained to ensure accurate descriptions of outcomes is unclear. Appropriateness of the NCS design Clearly, a 20-year, longitudinal cohort study with an equal probability sample is not required to study pregnancy outcomes themselves. Most, if not all, of the pregnancy outcomes under investigation will be evident within a year or two of birth or perhaps by early school age, so that a 21-year time frame is not required to study them. Nevertheless, following up children into the later years of childhood will help track whether the impact of the reproductive outcomes persists beyond early childhood and what risk factors determine persistence and severity. Prepregnancy exposure measures Many of the important questions about the effects of various exposures on pregnancy outcomes may require obtain- ing assays before pregnancy. For the hypotheses considered under birth out- comes and others in the research plan that involve birth defects, the period of concern is the first few weeks of pregnancy, when much of organogenesis occurs. In terms of the hypotheses about maternal glucose metabolism, it would seem that a more efficient design for that specific investigation would be a case-control study of women with established diabetes who are intend- ing to become pregnant with careful attention to the periconception period alterations in glucose metabolism. One specific hypothesis involves the role of folate and multivitamin

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 PRIORITY OUTCOME AND EXPOSURE MEASURES supplementation in the prevention of birth defects. While the literature cited indicates that such supplementation may reduce the risk of a number of birth defects, it is not clear that it will affect specific defects due to impaired glucose metabolism. In addition, for many of these defects, supplementation must begin before pregnancy, which again raises the question of the size of the prepregnancy sample. Relationships among outcomes The research plan does not explicitly con- sider the connections, or “crosswalks” among the outcomes selected. For example, preterm infants have twice the risk of birth defects as full-term infants, but these two outcomes are not well connected in the plan. Prema- turity is considered as an outcome for ART, but ART is not considered an exposure for prematurity. It is not clear how causality will be attributed when outcomes may be associated. Statistical power The statistical power to address some of the proposed research topics is not clear. For example, the plan indicates that 1 percent of couples are exposed to ART, which would yield about 1,000 pregnan- cies (1 percent). As shown in the power tables (NCS Research Plan, Vol. 1, Sec. 10.2.3, Tables 10-1 and 10-2), this is a lower figure than required for many estimates. Clearly, there will be insufficient power to examine the effect of specific types of ART on the many different types of birth defects. The situation may be even more problematic with the restriction to single- ton pregnancies, as the hypotheses propose. No estimate of the number of singleton ART pregnancies is given in the research plan. The proposed data collection effort does not appear to include the number of embryos implanted. This is an unfortunate omission, because a singleton pregnancy may have different implications if it results from the implantation of a single embryo rather than from the implantation of two or more embryos with spontaneous intrauterine demise or selective reduction. The question of statistical power also affects the hypotheses regarding altered maternal glucose metabolism and birth defects. The research plan argues the importance of this question from the rise in obesity and type 2 diabetes. Even if the prevalence doubles from the plan’s estimates, only about 10 percent of women with altered glucose metabolism will have a child with a birth defect. The power calculations are based on all birth de- fects and all heart defects, yet “birth defects” is not a homogeneous group of conditions. Even such categories as “heart defects” comprise a large number of derangements of organogenesis. The ability to detect specific defects of a single organ, the heart, is considerably less than that suggested by the calculations for all defects. Thus, it is not clear that the study is ad- equately powered to explore the hypotheses under question.

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN Ascertaining birth defects Physical exams and digital photographs with specific attention to dysmorphology are planned for birth and 6 months to identify birth defects; however, these methods will not pick up birth defects that are not associated with external stigmata. For example, the diagnosis of heart lesions not associated with other external physical signs might be missed without such specific examinations as EKGs and echocardiograms. Presumably, significant birth defects will be reported by the mother dur- ing subsequent interviews, but this is not clear. The accuracy of maternal reports in characterizing birth defects needs to be determined. Medical records would provide more accurate diagnoses, but the NCS only plans to abstract medical records at the time of delivery and neonatal examination for both mother and infant. Subsequent to the birth, medical and clinical event data will be collected by a personal health record only with the parent as the primary respondent (see Chapter 2). The research plan proposes ultrasound examinations in the second and third trimesters; however, the second trimester ultrasound will be obtained only if the mother has not already had an early ultrasound for gestational age dating (NCS Research Plan, Vol. 1, Sec. 6.6, Table 6-1). Such early ul- trasounds may vary considerably in the quality of the reading. In addition, such limited periodicity would not be sufficient to detect many instances of fetal growth restriction. As noted above, the teratogenicity of an exposure is often dependent on the timing of the exposure during pregnancy. Experience of a teratogen in the first few weeks of pregnancy, when major organ development is oc- curring, is more likely to cause greater disruption than later in pregnancy. This argument would suggest that if, for example, impaired glucose me- tabolism serves as a teratogen, then it would be especially important to assess exposure in the first few weeks of pregnancy, when major organs are developing. In this regard, the proposed use of hemoglobin A1C as a measure will reflect the average blood glucose over weeks and not any fluc- tuations around the period of conception and organogenesis. Blood glucose measurements at various visits will reflect glucose metabolism at that visit and may not capture variations that occur as the woman’s metabolism adjusts to pregnancy. Interventions The degree to which the study would ascertain ART interven- tions other than in vitro fertilization is not clear. Superovulating agents are not only more common, but also are frequently used by practitioners who do not specialize in the treatment of infertility. However, some of the diary and hormonal information collected by ART centers will be unavailable with these techniques. Moreover, ART is but one of many interventional reproductive health service technologies that could be a focus of this large perinatal study. For

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 PRIORITY OUTCOME AND EXPOSURE MEASURES example, there is critical debate and a serious lack of information about the sequelae of Caesarian births and the use of analgesics. Similarly, significant variations in outcomes among hospitals with neonatal intensive care units have been documented (Vohr et al., 2004). Attribution of developmental outcomes to ART or to any other prenatal intervention or exposure needs to account for this variation. Recommendations We have identified a number of issues and concerns with the NCS re- search plan proposals for assessing environmental influences on pregnancy outcomes. We offer two recommendations for steps that we judge to be of high priority for the NCS: one on the set of hypotheses that merit study and the other on the need for more specificity of the proposed research on pregnancy outcomes, which will be among the very first for which data are to be collected. Recommendation 3-1: The NCS should consider replacing research on subclinical maternal hypothyroidism as a factor in adverse preg- nancy outcomes with research on the effects of a broader set of maternal physical and mental health conditions, such as maternal depression, maternal perceived stress, and maternal periodontal disease. Recommendation 3-2: The NCS should develop refined, detailed protocols for investigating all pregnancy outcomes, specifically a detailed protocol for obtaining information on various types of pregnancy loss, before beginning data collection at the Vanguard Centers, given that pregnancy outcomes are among the first out- comes to be examined; many outcomes lack clarity in measure- ment; and there are important questions regarding the adequacy of statistical power and the planned data collection (for example, the need for prepregnancy measurements of some exposures). Although development of a detailed protocol will not help the statisti- cal power issues for some outcomes as now specified, detailed protocols with more specific calculations on anticipated numbers of various expo- sures and subjects would certainly clarify what outcomes could be realisti- cally studied, and whether changes to the research plan might be needed (e.g., not restricting assessment of the effects of ART to singleton births). Such protocols might also indicate subgroups for which more intensive study might be warranted, such as mothers with preexisting problems with glucose control. In addition, such protocols might lead to more focused

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0 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN outcomes (e.g., specific definitions with prevalence) and identify additional data collection required to ascertain these outcomes (e.g., echocardiogram data on congenital heart defects). Neurodevelopment and behavior (2) and Child health and Development (3) The Children’s Health Act mandate to “investigate basic mechanisms of developmental disorders” and “incorporate behavioral, emotional, [and] educational . . . consequences” of environmental influences encompasses an exceedingly broad range of developmental outcomes. Moreover, while developmental disorders are a clear study priority, environmental influences can also affect the much broader spectrum of age-normative developmental functioning. Given resource and burden limitations, the NCS faces difficult choices regarding the type and nature of its measurements of disorders and normative developmental outcomes. To organize discussion of the issues and because the two domains are intertwined conceptually and in NCS planning, this section first dis- cusses the specific plans for each domain and then provides a combined assessment. Description: Neurodevelopment and behavior Outcomes The NCS proposes to focus on identifying specific developmental, behavioral, or mental health disorders, including sensory, motor, and learn- ing disabilities, autism spectrum disorders, attention deficit–hyperactivity disorder (ADHD), anxiety disorders, depression, and schizophrenia and relating them to specific environmental exposures. The NCS will examine four broad hypothesized relationships (meta-hypotheses, NCS Research Plan, Vol. 2, App. A-1, p. A1-2; see App. A-2, Neuro/Behavior, for specific hypotheses within each meta-hypothesis): Repeated, low-level exposure to nonpersistent pesticides . . . in utero or postnatally increases risk of poor performance on neurobehavioral and cognitive examinations during infancy and later in childhood. . . . Prenatal infection and mediators are risk factors for neurodevelopmental disabilities such as cerebral palsy and autism. . . . Exposures to adverse psychological, chemical, and physical environments and other stressors during vulnerable periods of pregnancy and early child- hood can interact with genotype to cause or modulate behavioral problems in childhood. . . .

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 PRIORITY OUTCOME AND EXPOSURE MEASURES Prenatal infection and mediators of inflammation during pregnancy and the perinatal period are associated with increased risk of schizophrenia. According to the research plan (Vol. 1, Ch. 8, pp. 8.5-8.11), the NCS will rely on a combination of screening instruments and diagnostic infor- mation to identify developmental and mental health disorders. However, as stated earlier, the National Institute of Child Health and Human Develop- ment (NICHD) study staff have indicated that resources are not available at this time to abstract medical records except at birth (see Chapter 2). Sensory, motor, and learning disabilities Some sensory and motor difficul- ties are evident very early in the child’s life. Learning disabilities, however, are often not identified until children enter school. Routine infant hearing screening is recorded in the hospital chart at birth, which will be abstracted by the NCS. Screening for sensory and motor disabilities will begin before the neonate has been discharged from the hospital by using the Network Neurobehavioral Scale to assess the infant’s neurological status. The NCS plans to track children’s developmental status during infancy with regard to cognitive, motor, and language delays using multiple assess- ment strategies. At 12 months, the NCS will administer three of the Bayley III Scales of Development: Cognitive, Motor, and Language to all enrolled children to assess the achievement of developmental milestones in these do- mains. Actual diagnosis of learning, sensory, and motor disabilities will be confirmed whenever possible through the child’s medical records, including the diagnoses and treatment plans of their medical providers. The child’s health care visits will be reviewed at every contact with the parents, includ- ing both in-person contacts at 6 and 12 months and phone contacts at 3, 9, 18, and 24 months, and they will continue to be assessed regularly after that. Throughout childhood and adolescence, the child’s developmental sta- tus with regard to cognitive, language, and motor functioning will continue to be assessed periodically through direct testing by the NCS and diagnoses confirmed whenever possible through health care providers. Autism spectrum disorders These disorders are not generally diagnosed un- til the child’s second year or later. The NCS will begin screening for autism spectrum disorders when the child is 18 months old and continue to screen for symptoms periodically through the toddler and preschool period by us- ing the Modified Checklist for Autism in Toddlers (M-CHAT), a parental report instrument presumably provided over the telephone. The M-CHAT, however, is a screen for risk of autism; it does not yield a diagnosis of au- tism spectrum disorders. For diagnostic information, the NCS proposes to use diagnostic assessments conducted by the children’s health care providers and abstracted from medical records whenever possible.

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN Behavioral, attention, and mood disorders These disorders are rarely di- agnosed in infants. At 12 months the parent will be asked to complete the Brief Infant-Toddler Social and Emotional Assessment (BITSEA), a screen- ing instrument that assesses risk for mood problems, behavior problems, and self-regulatory deficits. The BITSEA, or an age-appropriate modifica- tion of the BITSEA, will be repeated through the toddler and preschool period to track any problems over time. As the children become older, other similar screening instruments will be used, such as the widely used Strengths and Difficulties Questionnaire, which assesses conduct problems, emotional problems, hyperactivity and inattention problems, and relation- ship problems, and can be completed by parents, teachers, and in the teen years by the adolescents themselves. Early diagnoses of disorders will be confirmed whenever possible through the children’s health care providers’ records. Later in childhood, measures and diagnostic interviews, such as the Preschool Age Psychiatric Assessments (PAPA) interview or the National Institute of Mental Health Diagnostic Interview Schedule for Children (NIMH-DISC-IV), may be used to supplement diagnostic information from children’s health care providers and ensure diagnostic information on children who do not visit health care providers regularly. Schizophrenia This psychotic disorder, believed to have both genetic and environmental etiology, will also be studied in the NCS. Schizophrenia, however, is rarely diagnosed before late adolescence or early adulthood. The research plan identifies no specific screening or diagnostic tools, stat- ing that screening and diagnostic procedures for schizophrenia are likely to continue to evolve before the NCS children reach the life stage when schizophrenia is usually diagnosed. Description: Child health and Development Outcomes Normative child health and development is concerned not with disor- der or symptoms of disorder, but with individual differences in trajectories of normal, healthy adaptation over time. The NCS proposes to examine cognitive and language development and also social and emotional devel- opment. The research plan spells out five broad meta-hypotheses (NCS Re- search Plan, Vol. 2, App. A-1, p. A1-3; see App. A-2, Health/Development, for specific hypotheses within each meta-hypothesis). The first meta-hypothesis links family resources and processes to the structure and quality of children’s home, child care, school experiences, and economic opportunities, which, in turn, affect developmental and health trajectories. The second hypothesis links geographic area of residence to

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 PRIORITY OUTCOME AND EXPOSURE MEASURES exposure to social, physical, psychological, and environmental factors that adversely affect the risk of health problems and decrease access to protec- tive resources. The third hypothesis links media use and content (TV, video, electronic games, Internet, mobile devices) to developmental trajectories from prosocial to antisocial behavior. The fourth hypothesis links interac- tions between children and families and the formal child care, school, and religious institutions in their communities to cognitive, social, and emo- tional development. Cognitive and language development will be tracked throughout child- hood using the procedures and instruments outlined for sensory, motor, and language disabilities above. The intent in this instance will be to identify normal development. Under the rubric of social and emotional development, the NCS pro- poses to cover several domains of child functioning, both intrapersonal and interpersonal, including temperament, mother-child interaction, and relationship skills. The research plan posits that assessing temperament early in development is important, as temperamental qualities not only exert direct influence on children’s adjustment, but also influence parental reactions to the infant’s signals and needs and thus affect subsequent de- velopment indirectly. When the infant is 6 months old, the NCS proposes to collect mater- nal reports of child temperament using three subscales of the Rothbart Infant Behavior Questionnaire-Revised (IBQ-R), including activity level, fearfulness, and positive anticipation of and approach to novelty. Also at 6 months, the NCS will conduct its first videotaped observation of mother- child interaction. At 12 months, the child’s social and emotional develop- ment will be assessed using parental reports on the BITSEA. During the toddler and preschool years, the same constructs will be assessed again, using the same procedures when appropriate, or using assessments that are age-appropriate measures of these constructs, such as the Strengths and Difficulties Questionnaire, which assesses prosocial behavior and relation- ship skills. As the child ages and begins to spend time in the broader social contexts of school and community, assessments of developmental trajecto- ries in social and emotional competence will be tailored to include these experiential changes. Assessment: Public health Significance and Conceptual Concerns Both the domain of neurodevelopment and behavior disorders and that of normal child health and development are clearly important areas to which the NCS could make significant contributions. However, the re- search plan has serious conceptual limitations in each domain that warrant concern.

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0 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN biological Exposure Measures The NCS investigators plan to obtain measures of biological exposures at several points in time. The measures fall into six main categories: al- lergens, markers of infection/inflammation, maternal glucose metabolism, endocrine markers, parental medical history, and other health behaviors. Most are to be obtained through a combination of questionnaire and direct measurement. The panel of allergens includes those related to cats, dogs, mice, rats, cockroaches, and mites, as well as a panel of molds and pollen to be ob- tained from regional ambient monitoring. Infections are generally to be obtained by a medical history provided by the parent with ascertainment of a variety of inflammatory markers. Maternal glucose metabolism during pregnancy is to be obtained from studies done as part of clinical care and obtaining a hemoglobin A1c, a measure of the average glucose for several weeks. The endocrine markers of interest include maternal thyroid function and cortisol as a measure of stress. Cortisol measures will be obtained from the mother and child on several occasions, and exposure to stress will also be ascertained by questionnaire. Parental history will include attention to the presence of chronic illness, diet, physical activity, use of tobacco and alcohol, use of illicit drugs, and use of medications and supplements. Other health habits to be ascertained include dental health (by questionnaire), maternal sleep patterns, and maternal douching. This list of potential markers of biological exposure is comprehensive. Several, such as diet, allergens, and maternal physical activity, are to be obtained by well-standardized methods. The use of standard and well-tested approaches to obtaining data on these biological exposures is a strength of the study. Methodological Concerns Less clear is whether plans to obtain other exposure measures are as state of the art. Information on child infections is to be obtained primarily by maternal history. The recall period for this information (6 months in the first year) is greater than that generally considered desirable to produce accurate data on relatively brief illnesses. Moreover, it is unclear that moth- ers will be able to report accurately about the type of infecting organism, information that could prove vital to analysis of subsequent growth and development. The timing of the measurement of inflammation relative to the infection that may have caused it is also not clear, raising questions about what types of infection/inflammation may be missed. Interest in maternal glucose metabolism in pregnancy is driven pri- marily by its potential effect on birth defects and child obesity. However,

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 PRIORITY OUTCOME AND EXPOSURE MEASURES the planned measure of glucose metabolism during pregnancy will be an average measure over some weeks that is not obtained close to the onset of pregnancy, when organogenesis is occurring. The research plan indicates that the study did not think more active measures of glucose metabolism could be obtained given that the first data collection point during pregnancy is a home visit, but it does not speculate on the effect that decision might have on the testing of core hypotheses. Likewise, the research plan notes that the only endocrine measures of interest are maternal thyroid function during pregnancy and cortisol levels in the mother and infant at various times. With regard to the former, it should be noted that child hypothyroidism may be a mechanism for the linkage between hormonally active agents and reproductive outcomes, so it is not clear why only maternal thyroid function is of interest. It would have been helpful in the discussion of cortisol levels to have some sense of the time over which cortisol will represent an accurate marker of stress in order to assess whether the frequency of data collection will be adequate. The parental medical history seems quite comprehensive. In conjunc- tion with measures of maternal physical activity, there are plans to estimate infant physical activity at 6 and 12 months through developmental observa- tions and questions about usual activities. It is not clear what significance infant physical activity at this age has, whether developmental observa- tions can actually characterize infant activity, or whether questions about usual activities provide information that is comparable to concerns about parental activity. Other health behaviors are to be elicited by questionnaire. Ascertaining intensity and frequency of intake of alcohol, and even more so of illegal drugs, from interviews with pregnant women is potentially problematic. In particular, exposures are likely to be underestimated. It is troubling to see little if any discussion of how this potential threat will be addressed. Sim- ply promising anonymity may not suffice. One plan that seems particularly problematic is ascertaining dental health through questionnaire and not examination. With the poor coverage of dental health care in the United States, it is likely that many dental problems will go unrecognized by the parent. To the extent that dental disease, such as peridontitis, is a risk fac- tor for prematurity and other child outcomes, inaccurate data will make it more difficult to establish the link. A serious concern is that there does not appear to be a conceptual framework guiding the selection of the various biological markers of ex- posure. In particular, it is not clear that all aspects of parental health that might be relevant to people’s ability to be effective parents will be ascertained.

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN Recommendation Most important among the concerns we have raised about biological exposures is the timing of data collection. Recommendation 3-14: The NCS should review some of the pro- posed measures of biological exposures, such as maternal glucose metabolism and child cortisol levels, to ensure that the proposed times for data collection are appropriate for capturing the underly- ing exposure. genetic Measures Each project outlined in the NCS research plan includes investigation of how genetic variation contributes to variation in risk of the study’s key outcomes, ranging from childhood obesity to neurobehavioral traits. With advances in high-throughput genotyping technologies, it is now possible to directly measure hundreds of differences in particular genes and millions of mutations in the whole genome of large numbers of individuals to elucidate the genetic contributions to a human trait or disease. In general, human variability in any trait arises from a complex interaction among genetic variations and environmental variations. The association studies proposed by the NCS are currently the most efficient strategy to explore the puta- tive contribution of genetic variations or gene-environment interactions to variations in disease risk. The basic design and analysis principles of genetic association studies have been well established for decades, albeit with continual evolution in such areas as study designs (e.g., family-based association studies, case- only designs); genotyping (e.g., multiplexing assays, array-based genotyp- ing); dealing with underlying genetic confounders, such as variations in population groups studied (Haines and Pericak-Vance, 1998); and reduc- ing the probability of false positive results (e.g., Benjamini and Hochberg, 1995). All of these issues appear to be adequately addressed in the research plan. There are, however, several major weaknesses in the plan proposal that should be addressed before the genetic component of the project is actualized. Changing Science and Scientific Standards The field of genetics and genomics is changing rapidly. Just within the past year, dozens of genome-wide association studies have identified new genes and variations that are involved in such complex traits as blood glu- cose levels, obesity, height, and variation in common disease risk (English

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 PRIORITY OUTCOME AND EXPOSURE MEASURES and Butte, 2007; Fox et al., 2007; Hayes et al., 2007; Peeters et al., 2007). In many of the NCS proposed analyses, in contrast, the old approach of studying “established” candidate genes (i.e., genes that are thought to be involved in a disease or trait because of the knowledge of underlying bio- logical pathways) is put forward and is a major weakness of the proposed genetic studies. The NCS research plan does discuss in several places the use of new technologies, namely, gene expression profiling and epigenetic profiling. These new methods may be of some use in unraveling the potential molecu- lar mechanisms underlying genetic associations. However, in the NCS, these biological signatures will be measured on tissues—namely, components of blood—that may not be relevant to the trait or disease being investigated. For example, neurodevelopmental outcomes are not likely to be associ- ated with transcriptomic variation in lymphocytes, which will be the only biological tissue available for study. Great care must be exercised in mak- ing inferences from these transcriptomic and epigenomic types of studies because they are, in many cases, studies of convenience rather than studies designed for their scientific rigor. Although it may be convenient to measure gene expression or epigenetic changes in blood samples, there is very little evidence that the gene expression profiles in this tissue are biologically relevant to the neurobehavioral outcomes or other outcomes investigated in the NCS. The scientific standards for genetic association studies are also quickly changing, as scientists come to grips with the limited success of the past two decades of genetics research, which has failed to identify the key genetic factors with reproducible or replicable effects on common human diseases or traits. The previous lack of high scientific standards for publication has resulted in the dissemination of false information (including false positive results from genome-wide association studies), the waste of millions of tax- payer dollars, and an increase in genetic deterministic thinking among the public. Three systematic studies of the genetic association literature have documented the extent of the problem (Hirschhorn et al., 1999; Ioannidis et al., 2001; Lohmueller et al., 2003), in which the odds of a published genetic association being replicated when 3-4 other studies were conducted were approximately 1 in 30. Moreover, Lohmueller et al. (2003) found that less than half of what are considered established susceptibility genetic markers pass the standards of a rigorous statistical meta-analysis. Cited reasons for the lack of reproducibility include genetic and environmental differences across the populations being studied, low statistical power, and misclas- sification of disease outcomes (e.g., Cardon and Bell, 2001; Colhoun et al., 2003; Freedman, Reich, Penney, et al., 2004). In the current NCS research plan, the strategy for investigating genetic associations appears to lack an appreciation of the more rigorous standards

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN now being imposed by the scientific community. There are multiple reasons for adopting a high standard in the NCS by which genetic association stud- ies must be internally and, optimally, externally validated before any type of publication or media release. First, the field of genetics research is finally imposing its own higher standards. Second, given the powerful implications of genetic information (for example, stigmatization and discrimination) for children if a genetic marker of a trait, say ADHD, is identified in the NCS, there must be a mechanism in place for validation at both the population and molecular levels to avoid the reporting of false results, many of which have already flooded the literature and mass media from other sources. gene-Environment Interactions A major strength of the NCS research plan is its emphasis on gene- environment interactions. However, the implications of this emphasis for the measurement of exposures are not fully appreciated. The lack of ad- equate measures of psychosocial and behavioral variables is particularly important, for it severely limits the ability to examine gene-environment interactions that are likely to affect obesity, neurobehavioral phenotypes, asthma, and pregnancy outcomes (Institute of Medicine, 2006). The genetic measures proposed in most analyses are quite limited. For each of the major outcome areas, genetic associations are proposed based on previous candidate gene association studies, many of which would not pass more modern standards of evidence. Furthermore, the variation within these genes is not well represented or discussed in the research plan. Most of the genetic variations targeted for study are not considered causative, have no known biological function, and are simply markers of the effect of a currently unknown genetic variation. Thus, more variations within each gene need to be considered if the true goal is to understand the genes responsible for modifying the effects of environmental exposures. Another weakness in the research plan is the lack of detail on how genetic variation will be measured. There are considerable cost consid- erations, which are not dealt with adequately. For example, it can be as expensive to genotype 20 single nucleotide polymorphisms (one at a time) as it is to genotype thousands (or millions) of them with array-based ge- notyping platforms. Given the size and scope of the NCS, there is also the need to consider gene-environment correlations in analyses, in addition to gene-environment interactions. Data Collection Concerns Because the DNA sequence variation proposed to be investigated in the NCS genetic association studies does not change over time, the one-

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 PRIORITY OUTCOME AND EXPOSURE MEASURES time collection of a blood sample for genetic analysis (summarized in NCS Research Plan, Vol. 2, App. G) will be adequate for the genetic analyses proposed. However, unlike DNA variation, gene expression and epigenetic variation will dynamically shift over the life course of the mother, father, and child. They are also tissue-specific. Currently, there is no proposed col- lection of blood samples for studies of gene expression profiling of parents. In addition, only a single cord blood sample from the child is being set aside for transcriptomic and epigenomic studies. This is a major oversight and an inconsistency between the neurodevelopment analysis plan (NCS Research Plan, Vol. 2, App. A-2) and the biospecimen collection plan (App. G). Although this oversight can be easily remedied by collecting and storing additional blood samples for gene expression studies at other time periods, it must be actively addressed or this opportunity will be missed. As we cau- tioned above, the NCS must be aware that examining gene expression and epigenetic patterns in blood may not be relevant or appropriate to study with such outcomes as the neurodevelopment outcomes. Great care must be taken, since false positives are much more likely than true positives in these domains. Appropriateness of the NCS for genetics Research The greatest potential benefit of the NCS to the field of genetics is its linkage between prospective environmental exposure data and high-quality, high-density genetics data. The field of gene-environment interaction has very few examples in which prospective environmental exposure data are linked to genetic susceptibility data. Virtually all genetic association study designs are either family-based or case-control designs, because DNA se- quence is static and can be measured at any time. The most difficult aspect of a genetics study is finding probands and conducting sound phenotyping. Since it is assumed that genotype precedes phenotype, genetic studies nearly always focus on phenotyping first and genotyping second. The value of the NCS is that it can solve both problems—that is, some genetic studies can be conducted prospectively in this NCS cohort, and environmental studies on the same disease will have good unbiased, expo- sure data. This is a unique opportunity for high-quality gene-environment interaction research. After 22 years, there will be sufficient cases for several diseases (autism, ADHD, asthma) to conduct nested case-control GXE interaction studies with prospective environmental data. This is of critical value. The concept of critical developmental windows indicates that the timing of exposure matters a great deal. In either case-control or family- based association designs, sampling is dependent on case designation. With either design, environmental exposure is nearly always either measured cross-sectionally or retrospectively. Exposures during developmental win-

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN dows cannot be reconstructed retrospectively. Case-control designs for gene-environment interaction ignore what is known about gene expression changes in development. Genes are not always active throughout each life stage or may be more or less active during different life stages (e.g., hormones and adolescence). Logically, a chemical or other environmental exposure that modifies a genetic variant may only do so when the exposure corresponds with a developmental stage. Unless the exposure dose and the timing of exposure are matched to the genetic variant, critically important gene-environment interactions may be missed. This is the greatest value of the NCS: Not only will it provide measures of environmental exposures of interest, but it will also provide their timing and relationship to genetic variation. This is not well articulated in the research plan, yet it is the study’s greatest strength in this field. Recommendations Recommendation 3-15: The NCS should adopt a clear mechanism by which genetic association studies are internally and, optimally, externally validated before any results are published or released to the media. The NCS should also revise its proposed “established” candidate gene approach to take advantage of the new informa- tion emanating from the current wave of genome-wide association studies, with appropriate replication. Recommendation 3-16: The NCS should consider consolidating its genetic studies in order to reduce costs and to coordinate the best science at the least cost to the project. One approach would be to simply collect the biological samples and properly store them for later genetic analysis when a better selection of polymorphisms and cost-effective genotyping across studies are possible. Missing Exposures Access to and Quality of Services Clearly, even such a large study as the NCS is limited in the data that can be collected. A discussion of what exposures were considered and rejected and why would have been useful for the panel in its review. In particular, a notable omission is information on access to services, especially health services, both as potential mediators of outcomes and as factors in the accuracy of information obtained through maternal report. A substantial amount of information—such as diagnoses of child health problems—is to be ascertained through interviews with the mother, but

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 PRIORITY OUTCOME AND EXPOSURE MEASURES children and mothers do not have equal access to health care providers, teachers, or day care workers who may be capable of making the correct diagnoses. Furthermore, a mother may not be able to report reasonably accurately what she has been told. Unequal access to services or access to lower quality services will lead to biased ascertainment of outcomes. For example, in the 1980s, Newacheck, Budetti, and McManus (1984; Newa- check, Budetti, and Halfon, 1986) examined the doubling since 1960 of the proportion of children reported to have chronic conditions on the National Health Interview Survey. They concluded that much of this doubling did not reflect major shifts in the population, such as deinstitutionalization. Rather, it reflected changes in attitudes and perhaps diagnostic practices among clinicians, and it may have included better ascertainment resulting from better access to medical care for disenfranchised populations through programs like Medicaid. Similarly, diagnoses of learning difficulties may differ depending on the availability of services in the school, teacher de- mand, and because of changes in the conditions for which special education services may be received. Furthermore, much of the observed increase in diagnoses of autism reflects changes in the special education categories and more awareness of the spectrum (Croen, Grether, Hoogstrate, and Selvin, 2002). In addition, access to and the quality of services may actually affect outcomes. Interinstitutional variation in the quality of medical and day care and its effect on outcomes are now well established. For example, the NICHD Study of Child Care and Youth Development documented differ- ences in outcomes with higher or lower quality of day care, while Vohr et al. (2004) documented an almost fivefold difference in the rates of cerebral palsy and mental retardation among infants born at 1,000 grams across 12 neonatal intensive care units. The NCS research plan proposes to pay some attention to child care, schools, and religious institutions in the revised section on child health and development, but it is not clear that attention to such issues will also inform other outcomes (e.g., schools as a source of environmental exposures for asthma and as a factor in diets leading to obe- sity). Clearly, access to early intervention services might alter developmental trajectories, but such services do not seem to be listed for investigation. Only for asthma does there appear to be a concern about studying the effect of access to medical care. Yet there are many conditions for which variations in developmental screening and other procedures will lead to differential diagnoses and referral for services. For some conditions, like autism, earlier intervention has clearly led to improved outcomes. The NCS does not propose to investigate such factors, despite the well-documented substantial variation that occurs in the services children receive (Mangione- Smith et al., 2007).

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN Recommendation Recommendation 3-17: The NCS should add measures of access to and quality of services, including medical care, education, child care, and services, as potential mediators of health and develop- ment outcomes and to improve the assessment of information obtained through maternal reports. Policy Environment The NCS research plan pays little attention to the implications of policy analysis for the study design. A strong analytic design for policy analysis is the use of “natural experiments,” which take advantage of variations in policies across states or communities and across time. An example is the Currie and Gruber (1996a, 1996b) analysis of the impacts of the state expansions of the Medicaid program on use of medical care and birth outcomes. Because states expanded their Medicaid programs in different ways and at different times, the analysis was able to compare outcomes before and after the expansions in each state and control for time effects with the variation in the timing of state implementation. Since interesting policy variation will arise in states, counties, cities, and even neighbor- hoods, analysts conducting these kinds of policy analyses will need to be able to match detailed information on policies to the geographic location of respondents. Additional Exposures That Could be Studied Through Data Linkage A major potential benefit of the NCS household-based sample design is that a wide range of exposure measures can be obtained by matching existing and future sources of environmental information to respondents’ residential addresses. For example, neighborhood demographic and socio- economic data drawn from the decennial census and often aggregated to the level of the census tract have long been linked in research studies to individuals and households. With the advent of the American Community Survey, which replaces the decennial census long-form sample, demographic and socioeconomic neighborhood information can be linked to individual data more frequently than once a decade (National Research Council, 2007). Crime data from the FBI’s Uniform Crime Reporting system can be used to characterize community crime. Environmental data from the Environmental Protection Agency monitoring stations can provide a range of useful measures of environmental pollutants. Data on the policy environ- ment for safety net programs can be derived, for example, from state- or county-specific rules for such programs as Temporary Assistance to Needy

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 PRIORITY OUTCOME AND EXPOSURE MEASURES Families. Data on weather conditions, commercial activity, and access to public transportation may all prove useful in characterizing maternal and child exposures. An enormous advantage of these kinds of measures of neighborhood exposures is that they can be added to the NCS database without increasing respondent burden, provided they can be linked to sample members’ residential addresses and, for some exposures, dates of interview. While the research plan acknowledges these kinds of linkages, it does not provide a thoughtful discussion of the steps that need to be taken to optimize NCS linkages to other sources of environmental information. A first priority is to geocode (that is, characterize with standardized measure- ments of location, such as census block, census tract, city, county, state) all of the residential addresses in which sample children reside over the course of the study. Then a wealth of information stored in other geocoded databases will potentially be available to link to the NCS data. How much residentially linked information the study intends to gather itself and under what conditions geocoded data will be available to analysts to perform their own linkages are not clear. Given the fundamental importance of a full array of exposure data for testing many of the key study hypotheses and for testing new hypotheses that arise over the course of the study, it is vital that researchers—both in- side and outside the designated study centers—be able to access information about all respondents’ geographic locations. Such access raises important confidentiality concerns, but these concerns have been met in other national studies, such as the National Longitudinal Survey of Adolescent Health and even Census Bureau data sets, through a variety of mechanisms. One of the most promising for the NCS would appear to be the network of Census Re- search Data Centers that have been established for researcher use of various census and other governmental sources of information (see Chapter 5). Turning from the matching tasks to the environmental data themselves, it is important to realize that sources of exposure information are a vital public good for the NCS. The study should encourage researchers, with some combination of internal and adjunct study funding, to compile local exposure data that can be matched to the residential locations of all NCS respondents and to make these data available to all analysts. Westat’s data repository would appear to be the logical place in which these geographic data and their documentation would be stored. Recommendation 3-18: To facilitate linkages of NCS data with environmental exposures from other databases, such as measures of demographics, crime, government programs, and pollution, the NCS should develop a plan for geocoding the residential addresses from prebirth through adulthood of all participating children to

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00 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN standard census geographic units. In addition, the study should develop arrangements by which researchers, both inside and out- side the NCS study centers, can access geocodes for respondent addresses and are encouraged to perform linkages and make their environmental information available to the NCS analysis com- munity. Such arrangements must safeguard the confidentiality of NCS respondents.