1
Introduction

The National Children’s Study (NCS) is planned to be the largest long-term study of environmental and genetic effects on children’s health ever conducted in the United States. It proposes to examine the effects of environmental influences on the health and development of approximately 100,000 children across the United States, following them from before birth until age 21. It defines environment broadly by including a wide array of measures of biological, chemical, physical, genetic, social, cultural, geographical, and other factors in a child’s environment that can affect health and development. It proposes to examine many different exposures and establish—or rule out—relationships between them with many different outcomes. By archiving all of the survey, observational, medical, and other data collected, including biological and environmental specimens, it is intended to provide a valuable resource for analyses conducted many years into the future.

BACKGROUND

Origins of the NCS

The impetus for the NCS, which has been in development since 2000, has many sources. A confluence of concerns led to the establishment, in April 1997 by Executive Order 13045, of the President’s Task Force on Environmental Risks and Safety Risks to Children. The task force was charged to identify and assess the nature and extent of environmental health and safety risks to children and to recommend strategies for protecting children



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1 Introduction T he National Children’s Study (NCS) is planned to be the largest long-term study of environmental and genetic effects on children’s health ever conducted in the United States. It proposes to examine the effects of environmental influences on the health and development of approximately 100,000 children across the United States, following them from before birth until age 21. It defines environment broadly by including a wide array of measures of biological, chemical, physical, genetic, social, cultural, geographical, and other factors in a child’s environment that can affect health and development. It proposes to examine many different ex- posures and establish—or rule out—relationships between them with many different outcomes. By archiving all of the survey, observational, medical, and other data collected, including biological and environmental specimens, it is intended to provide a valuable resource for analyses conducted many years into the future. bACKgROuND Origins of the NCS The impetus for the NCS, which has been in development since 2000, has many sources. A confluence of concerns led to the establishment, in April 1997 by Executive Order 13045, of the President’s Task Force on En- vironmental Risks and Safety Risks to Children. The task force was charged to identify and assess the nature and extent of environmental health and safety risks to children and to recommend strategies for protecting children 

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN against environmental threats. It was cochaired by the secretary of the U.S. Department of Health and Human Services and the administrator of the U.S. Environmental Protection Agency. It included representatives of 16 departments and White House offices. Motivating the call for the task force was evidence that certain environ- mental exposures early in life, such as lead poisoning and alcohol exposure in utero, compromise the health of children. At the same time, there was considerable uncertainty about the relationship of other environmental fac- tors to what often appeared to be growing health problems among children, including asthma, autism, developmental disorders, obesity, and childhood cancers. A task force recommendation called for legislation to mandate a large study to identify the risks to children from environmental exposures. In response, on October 17, 2000, Congress enacted the Children’s Health Act (Public Law 106-310). Section 1004 of the act reads as follows (see http://nationalchildrensstudy.gov): SEC. 1004. LONg-TERM ChILD DEVELOPMENT STuDy. (a) PURPOSE.—It is the purpose of this section to authorize the National Institute of Child Health and Human Development to conduct a national longitudinal study of environmental influences (including physical, chemi- cal, biological, and psychosocial) on children’s health and development. (b) IN GENERAL.—The Director of the National Institute of Child Health and Human Development shall establish a consortium of representatives from appropriate Federal agencies (including the Centers for Disease Con- trol and Prevention, the Environmental Protection Agency) to— (1) plan, develop, and implement a prospective cohort study, from birth to adulthood, to evaluate the effects of both chronic and intermittent ex- posures on child health and human development; and (2) investigate basic mechanisms of developmental disorders and envi- ronmental factors, both risk and protective, that influence health and developmental processes. (c) REQUIREMENT.—The study under subsection (b) shall— (1) incorporate behavioral, emotional, educational, and contextual conse- quences to enable a complete assessment of the physical, chemical, biologi- cal, and psychosocial environmental influences on children’s well-being; (2) gather data on environmental influences and outcomes on diverse populations of children, which may include the consideration of prenatal exposures; and (3) consider health disparities among children, which may include the consideration of prenatal exposures.

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 INTRODUCTION Development of the NCS The NCS has had a long and difficult gestation since its authorization as described below. Immediately following passage of the Children’s Health Act of 2000, work began to develop the NCS in response to Section 1004 (Dr. Scheidt’s presentation to the panel on September 2, 2007). An Inter- agency Coordinating Committee was formed that has included not only the National Institute of Child Health and Human Development (NICHD), the Centers for Disease Control and Prevention (CDC), and the Environmental Protection Agency (EPA), as called for in the act, but also the National Institute of Environmental Health Sciences. By 2002, a federally chartered advisory group, the NCS Advisory Com- mittee, had been established, and, by 2003, an NCS Program Office had been organized in NICHD. A large number of working groups were set up to propose hypotheses to link environmental exposure measures to child health and development outcome measures in a broad array of domains. An expert group was also established to consider an appropriate sample design for a longitudinal prospective cohort study, as called for in the Children’s Health Act. These entities produced white papers and methods studies and held workshops.1 More than 2,500 professionals in a wide range of fields contributed to the NCS development (National Institute of Child Health and Human Development, 2007:Vol. 1, Sec. 3.2). By 2005, sufficient funding was obtained for three milestone events: (1) the development of the NCS first-stage sample, comprising 110 primary sampling units (PSUs) in 105 locations around the country by the National Center for Health Statistics of CDC; (2) a competitively bid contract to Westat to run the NCS coordinating center for data management; and (3) seven competitively bid contracts for “Vanguard Centers” to begin imple- menting the study in mid-2008 in select PSUs across the country. Teams from the Vanguard Centers will be the first to work in their communities to recruit participants, collect and process data, and pilot new research methods for incorporation into the full study. Also in 2005, work began on the NCS research plan, under the gen- eral direction of the Interagency Coordinating Committee and with input from the NCS Advisory Committee, the NCS Program Office, and the Coordinating Center. Also providing input was a Steering Committee of Vanguard Center principal investigators and federal scientists that was formed following selection of the Vanguard Centers. The plan was designed for scientific peer review and public comment, by providing background on the NCS and its goals, together with descriptions of and rationales for spe- 1 See http://nationalchildrensstudy.gov/research/methods_studies/; http://nationalchildrens study.gov/research/analytic_reports/; NICHD, 2007:Vol. 2, App. J. Not all of the early white papers and methods studies remain on the NCS website.

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN cific hypotheses, exposure measures, outcome measures, and sampling and data collection strategies. Work on the research plan was not completed, however, until June 2007 for the reason that, until early 2007, funding for the NCS was limited, and it was not clear that sufficient funds would be provided to let contracts in addition to the Vanguard Centers or that actual data collection could go forward. In 2007, funding was obtained to let 22 competitively bid contracts for centers to undertake sampling, participant enrollment, and data collection in additional PSUs beginning in mid-2009 (5 of the 7 original Vanguard Centers won contracts under this procurement for PSUs in addition to their Vanguard PSUs). NICHD recently announced that contracts for another 10- 15 centers will be competitively bid in 2008, as will contracts for repository and laboratory facilities. Following review of the research plan (National Institute of Child Health and Human Development, 2007; cited hereafter in this report as NCS Research Plan) by this panel, the NICHD Institutional Review Board will complete its review of the research plan and other materials, and work will be completed on the first NCS protocol. This protocol will specify the methods and data collection instruments in detail for the first 3 years of the NCS—from enrollment (prebirth and, for about 25 percent of cases, preconception) through 24 months of age for participating children. An ac- companying study manual will prescribe detailed procedures for sampling, enrollment, data collection, and data processing. These materials will be submitted for review and clearance by the U.S. Office of Management and Budget (OMB) as required by the Paperwork Reduction Act. The plan is to develop protocols and study manuals every 3 years for submission to OMB to cover data collection for participating children ages 3-5, 6-8, and so on through age 21. ThE PANEL’S REVIEW After a long development period and uncertain funding, the NCS is scheduled to begin implementation with enrollment of participants in the seven Vanguard Centers in 2008, followed by enrollment in additional centers beginning in 2009. Prior to the completion of the detailed imple- mentation protocols and manuals for the NCS and obtaining the requisite approvals from the NICHD Institutional Review Board and OMB, NICHD decided to request a review of the research plan. The need for a scientific review to ensure that the study is scientifically rigorous and is being carried out with the best available methods was rec- ognized from the early days of the president’s task force. Such a review was first called for by the task force cochair, Department of Health and Human Services Secretary Donna Shalala. It is required by the NICHD Institutional

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 INTRODUCTION Review Board and expected by the scientific community. It is also needed to address congressional concerns. The NCS Interagency Coordinating Committee and the NICHD Program Office have consistently affirmed that there would be peer review. However, because of the funding uncertainties that delayed completion of the research plan, coupled with the pressure to get the study under way now that funding is available, the time for all of the necessary review—and, just as important, for appropriate response by NICHD—is very compressed. The Panel Charge NICHD requested the Committee on National Statistics of the National Research Council (NRC), in collaboration with the Board on Children, Youth, and Families of the NRC and the Institute of Medicine (IOM) and the IOM Board on Population Health and Public Health Practice, to con- duct a review of the research plan for the NCS. The purpose of the review is to assess the scientific rigor of the NCS and the extent to which it is being carried out with methods, measures, and collection of data and specimens to maximize the scientific yield of the study. Topics to be addressed include proposed outcomes and hypotheses; proposed measures of environmental exposure, genetic makeup, family and community environment, and per- sonal characteristics; proposed data collection and analysis methods; and other aspects of the study’s research plan. To address this request, the NRC appointed the Panel to Review the National Children’s Study Research Plan, a group of 12 people representing a range of expertise related to the scope of the study. The Panel’s Approach The panel’s review of the NCS research plan was conducted by car- rying out one pre-meeting of a subgroup of members, two in-person ple- nary meetings lasting two days each, numerous exchanges by e-mail and telephone, and a final one-day plenary meeting prior to sending the report through the National Academies review process. The principal materials reviewed by the panel included the two-volume NCS research plan, received from the sponsor on June 19, 2007, and posted by NICHD on the NCS website (http://www.nationalchildrensstudy.gov) for public comment at the same time, and a supplement to the research plan received on September 17, 2007. The supplement contained some correc- tions, some revisions, and two additional topic areas or meta-hypotheses for the NCS (for a total of 28 meta-hypotheses, each of which comprises 2-13 specific hypotheses). The sponsor provided additional material in response to various requests by the panel. In addition, panel members and

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0 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN staff consulted as needed the large volume of documents on the NCS web- site (http://nationalchildrensstudy.gov), including the minutes of the June 26-27, 2007, meeting of the NCS Advisory Committee, which included comments by its members on the research plan. Scope and Limitations of the Panel’s Review The panel’s charge is limited to a review of the scientific rigor of the overall research plan for the NCS, as set forth in the two-volume docu- ment and supplement described above. The scope of the research plan is exceedingly broad. It presents the 28 “core” meta-hypotheses (and the specific hypotheses within each topic area) that were selected to guide the study design and data collection and analysis. It covers the wide range of exposures planned for measurement in the NCS (which include the physical environment, chemical exposures, psychosocial and biological exposures, and genetic makeup), the equally wide range of outcomes planned for mea- surement in the NCS (which include pregnancy outcomes, neurodevelop- ment and behavior, child health and development, asthma, obesity, injury, and reproductive outcomes), and the interactions among these exposures and outcomes. It also includes material on sample design and statistical analyses, ethical concerns, and management. Accordingly, all of these issues are addressed in this report. The research plan was prepared to be readable by and informative to an interested and committed reviewer. Consequently, it is long and complex in order to cover all aspects of the NCS, yet it does not include full details of the study design and measurement approaches, full questionnaires, proto- cols for collection of samples and specimens and other operational aspects, or detailed implementation procedures. As noted throughout this report, in some areas the panel found that the research plan provides adequate detail for scientific review, but in other areas the panel found that the plan lacks needed detail and is a work in progress. The organization of the research plan requires the reader to consult sev- eral sections to obtain a full picture of any single topic area. For example, material on the first listed outcome area of pregnancy outcomes is provided in the research plan in Section 1.2.1.1 (brief summary), Table 7-1, and Sec- tion 8.1 (rationale) of Volume 1, and in Appendixes A-1 and A-2/Pregnancy Outcomes of Volume 2. The reader must also consult Appendixes F-I of Volume 2 for listings of measures to be collected prepregnancy, during pregnancy, and at birth.

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 INTRODUCTION ORgANIzATION OF ThIS REPORT The panel’s report addresses the main topics in the research plan and responds to the specific questions listed below, which the sponsor asked the panel to address—or, in some instances, the panel framed. Chapters 2-6 include the panel’s assessments and our recommendations for modifications to one or more aspects of the research plan. Chapter 2 is an overview of the NCS design and comments in broad terms on the NCS goals, conceptual framework, and selection of hypoth- eses. It addresses the following questions: Does the proposed study, as reflected in the research plan, respond • adequately to the directives of the Children’s Health Act of 2000, Congress, and the 1997 task force in light of the finite resources for the study and reasonable limitations on participant burden? Does the research plan set forth an appropriate conceptual frame- • work for guiding the design of the study? Does it identify sufficient and appropriate organizing hypotheses • for guiding data collection and analysis for the study? Chapter 3 describes and comments on the concepts and measures for the children’s health and development outcomes and the environmental exposures that are proposed to be identified in the study. It addresses the following questions: Does the proposed study design include the optimal set of “prior- • ity outcomes” in terms of their public health importance as well as scientific interest to meet the aims of the study? Does it include the broad range of exposures and genetic measures • necessary to study the priority outcomes? Does it employ state-of-the-science genetic and genomic measures • and analyses to enable study of interactions among environmental and biological factors that may influence the outcomes of children’s health and development? Does it employ appropriate measurements of the outcomes, expo- • sures, and confounders as can reasonably be done given the size, cost, and participant burden of this large, wide-ranging study? Chapter 4 considers methodological issues for data collection and analysis. It addresses the following questions:

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 THE NATIONAL CHILDREN’S STUDY RESEARCH PLAN Does the proposed study use appropriate sampling, estimation, and • analysis methods to obtain the most useful data and results from the study? Does it give appropriate attention to the challenges for standard- • ized data collection from a decentralized operation in which study centers implement sampling, enrollment, and data collection? Does the research plan provide information on the NCS data col- • lection strategies to maximize initial and follow-up study response rates to ensure quality data collection? Does the research plan address appropriate analytic and data dis- • semination approaches to ensure that the study research goals are achieved? Chapter 5 addresses ethical issues for the NCS. It addresses the follow- ing questions: Does the proposed study provide adequate protections for human • research participants? Does it include plans for releasing data to the research community • in a manner that maximizes what can be learned from the data, at the same time protecting the confidentiality of NCS research participants? Chapter 6 lists the panel’s conclusions and recommendations in one place for ease of reference.