A Longitudinal Study of Environmental Effects on Child Health and Development http://NationalChildrensStudy.gov Donald

1. A Longitudinal Study of Environmental Effects on Child Health and Development http://NationalChildrensStudy.gov Donald R Mattison, MD, NICHD, NIH, HHS U.S. Department of Health and Human Services NICHD, CDC, NIEHS U.S. Environmental Protection Agency

2. Rationale for the National Children’s Study • Children may be especially vulnerable to environmental exposures – size, body composition, metabolism, behavior • Potential for serious developmental effects with long term consequences – lead, prenatal alcohol • Current known exposures of high frequency – pesticides, violence, media • Numerous high burden conditions with suspected environmental contribution – learning disabilities, autism, diabetes, asthma, birth defects, premature birth • Existing research too limited in size & scope to answer the questions • Life-course (longitudinal) design needed to correctly link with multiple exposures and multiple outcomes

3. Known exposures of concern, and examples • Diet & Drugs • Food additives • Pharmaceuticals • Chemical • Heavy metals • Pesticides • Biological • Infection in early life • Metabolic • Physical • Built environment • Radiation • Psychosocial • Abuse and neglect • Family structure

4. Birth Defects Prematurity Autism Cerebral Palsy Type I diabetes Mental retardation Obesity Cancer Asthma Injuries Schizophrenia Learning disabilities Important childhood conditions with suspected environmental components

5. President’s Task Force on Environmental Health Risks and Safety Risks to Children • Charged to develop strategies to reduce risk of environmental exposures to children • Co-chairs – Secretary HHS, Administrator USEPA • Conclusions • Risks to children are poorly characterized • Need for longitudinal study of environmental effects • New money would be required to carry out the study

6. Rationale • Converging factors • Increased vulnerability to environmental exposures • Exposures may cause long term effects – lead, alcohol • Known exposures of high frequency – • Existing research to limited in size & scope to answer the questions • Study needed to identify what is harmful, harmless and helpful to child development • Life-course design to correctly link with multiple exposures and multiple outcomes

7. PL 106-310 Children’s Health Act of 2000 (a) PURPOSE- . . . to authorize NICHD to conduct a national longitudinal study of environmental influences (including physical, chemical, biological, and psychosocial) on children's health and development. (b) IN GENERAL- The Director of NICHD shall establish a consortium of representatives from appropriate Federal agencies (including the CDC and EPA) to-- (1) plan, develop, and implement a prospective cohort study, from birth to adulthood, to evaluate the effects of both chronic and intermittent exposures on child health and human development; and (2) investigate basic mechanisms of developmental disorders and environmental factors, both risk and protective, that influence health and developmental processes. . . .

8. Study Concepts • Longitudinal study of children, their families and their environment • National in scope • Environment defined broadly (chemical, physical, behavioral, social, cultural) • Study of sufficient size to identify causal factors for important but less common outcomes (approx. 100,000 participants)

9. Study Concepts (con’t) • State-of-the-art technology – tracking, measurement, data management • Consortium of multiple agencies • Extensive public-private partnerships • Hypothesis driven • National resource for future studies

10. Longitudinal Cohorts StudiesAdvantages/strengths* • Can infer causality • Clear temporal sequences between life stages • Multiple outcomes can be studied • Mediating pathways between exposure and disease can be studied • Recall bias in relation to exposure is minimized * Nigel Paneth, NCS Consultation II, Dec 2000

11. Longitudinal Cohort StudiesDisadvantages/weaknesses* • Can become outdated as cohort ages • Require advance knowledge of important exposures • Consumes large resources • No matter how large, will not be large enough • Too many measurements at great cost • Will torture the data until it confesses to something * Nigel Paneth, NCS Consultation II, Dec 2000

12. Study Population - Issues • Generalizability to U.S. population • Additional study populations, e.g. • Specific high-risk populations • Agricultural • Industrial • Economically disadvantaged • Women of child-bearing age - possible effects on fertility & pregnancy

13. Population Size for Selected Outcomes Relative Risk Outcomes Rate 1.5 1.75 2 Injuries-Hosp. (<18)37.4/10K 42K 20K 13K Fractures 10/10K 157K 77K 47K Head injuries 5/10K 313K 153K 94K Autism Spectrum Disorders* 20/10K 78K 38K 23K ADHD (school age) 800/10K 1.8K 0.9K 0.5K Asthma (<18) 690/10K 2K 1K 0.6K Hospitalizations (<15) 27.7/10K 56K 28K 17K Cancer incidence (<20) 1.54/10K 1019K 498K 306K ALL (Acute Lymphoblastic Leukemia) 0.27/10K 5813K 2842K 1744K CNS tumors 0.29/10K5413K 2646K 1623K Hypospadias (males) 20/10K 78K 38K 23K Spina Bifida 5/10K 313K 153K 94K

14. What Kind of Sample? National probability Disbursed cluster Concentrated cluster Center-based convenience

15. NCSIssues for Sample Designs • Representativeness • Pre-pregnancy vs. early in pregnancy • Sub-populations for over sampling • Measure community/neighborhood environment & characteristics • Stability of exposure • Complexity of observation – center based vs. home • Sampling units, segments, design effect

16. Criteria for Core Hypotheses • No single hypothesis • Hypothesis required for costly elements • Important for child health & development (prevalence, severity, morbidity, mortality, disability, cost, public health significance) • Reasonable scientific rationale • Require the large sample size (~100,000) • Measurable with study of this size • Requires longitudinal follow-up

17. Priority Outcome Areas (and example hypotheses) • Undesirable outcomes of pregnancy (Infection and mediators of inflammation during pregnancy are major causal factors associated with pre-term birth) • Neurobehavioral development (Low level pesticide exposure in utero is associated with impaired neurobehavioral and cognitive performance) • Injury (Repeated head trauma w/o anatomic damage is a causal factor for cumulative adverse effects on neurocognitive development)

18. Priority Outcome Areas (and example hypotheses) • Asthma (maternal stress during pregnancy is associated with the prevalence and severity of asthma in offspring) • Obesity and physical development (Obesity and insulin resistance is associated with impaired glucose metabolism in pregnancy, intrauterine growth restriction, and interacting factors in the physical and social environment)

19. Proposed Hypotheses Related to Development and Behavior • Persistent pesticides and risk of impaired neurobehavioral and cognitive performance • Prenatal infection/inflammation and risk for neurodevelopmental disabilities, e.g., CP, Autism • Infection/inflammatory mediators associated with risk of schizophrenia • Parenting and parental actions associated environmental exposures that affect child development

20. Proposed Hypotheses Related to Development and Behavior (cont.) • Family formation, structure, and living arrangements associated with child development • The risk of cognitive (ADHD), emotional (schizophrenia) and developmental (autism) is associated with interacting environmental and genetic factors • Genotype and environmental exposures interact to affect and determine the trajectory of positive development in children. • Ethnicity interacts with genetic factors to affect child development

21. Core Hypotheses – A first step • Work in progress • Doubtless more consideration and discussion will ensue • Not all of them will stay, and others will probably be included • Data and specimens collected will allow many additional hypotheses to be addressed • Use them to frame study

22. Associations and Interactions in the National Children’s Study Chemical Expos. Asthma Infection Birth Defects Gene expression Social Environ Development & Behavior Physical Environ Health Care Growth Medicine & Pharm Fertility & Pregnancy

23. Measures Anticipated - Exposures • Environmental Samples: air, water, dust • Bio-markers for chemicals: blood, breast milk, hair, tissue, etc. • Interview and history • Serology and medical data • Housing & living characteristics • Family and social experiences • Neighborhood and community characteristics

24. Measures Anticipated –Outcomes • Fertility, time to pregnancy, early loss • Fetal growth and outcome of pregnancy • Birth defects and newborn exam • Growth, nutrition and physical development • Medical condition and history: illness (e.g. asthma), conditions, & injuries • Cognitive and emotional development • Mental, developmental and behavioral conditions

25. Use of Data to Maximize Output • Results available beginning ~2010 • Targeted hypotheses-testing analyses • Successive public-use data sets with support • Successive funding for investigator initiated research and analyses • Expected translation of results into related prevention initiatives

26. National Children’s Study Organization of Planning Phase -Extensive multi-agency collaboration -Broad scientific and advocacy input • Interagency leadership and funding – HHS (NICHD, NIEHS, CDC) & EPA • Dedicated staff at NICHD for operations • Federal Consortium of all HHS agencies + 12 other Departments and independent agencies • Chartered Federal Advisory Committee for advice and peer review • Working Groups (20) with approx. 250scientists and experts for consultation and guidance re: hypotheses, design, measures • Network of all interested parties, 2,000+

27. Projected Time Line 2000-2004 Planning, pilot studies, gather input 2001-2002 Form advisory committee and working groups 2004-5 Finalize central hypotheses, draft study design 2005-6 Select NCS study sites across the U.S. 2005-6 Begin participant enrollment ~2010 First research results available 2010-2030+Results continue; Translate into etiology and disease prevention strategies

28. Expected Benefits of the NCS for Prevention of Diseases

29. The NCS will provide • The answer to concerns about known exposures during childhood to potential toxicants • The power todetermine absence of effects or benefit of exposures to various products important for our economy • Causal factors for a number of diseases and conditions of children with suspected environmental causes • How multiple causes interact to result in multiple outcomes • Large sample size required to apply knowledge of the human genome to understand multifactoral genetic conditions • Identification of early life factors that contribute to many adult conditions • A national resource to answer future questions by using stored biological and environmental samples and the extensive data

30. Contact information • Web site: http://NationalChildrensStudy.gov • E mail: ncs@mail.nih.gov