1. Briefing for the National Vaccine Advisory Committee October 6, 2004 Peter Scheidt U.S. Department of Health and Human Services NICHD, CDC, NIEHS U.S. Environmental Protection Agency

2. àCompared to adults, children are especially vulnerable to environmental exposures – metabolism, behavior àExposures to some agents demonstrate potential for serious developmental effects – lead, prenatal alcohol àCurrent known exposures of high frequency – pesticides, violence, media àNumerous high burden conditions with suspected environmental contribution – learning disabilities, autism, diabetes, asthma, birth defects, premature birth àExisting research too limited in size and scope to answer the questions àLife-course (longitudinal) design needed to correctly link with multiple exposures and multiple outcomes From The President’s Task Force on Environmental Health and Safety Risks to Children, 2000* Rationale for the National Children’s Study * Reappointed 2001 and 2003

3. Children’s Health Act of 2000 (a) Authorize NICHD to conduct a national longitudinal study of environmental influences (including physical, chemical, biological, and psychosocial) on children's health and development. (b) Established 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.

4. Study Concepts àLongitudinal study of children, their families and their environment àNational in scope àHypothesis driven àEnvironment defined broadly (chemical, physical, behavioral, social, cultural) àStudy common range of “environmental” exposures and less common outcomes (n~100,000)

5. Study Concepts (con’t) àExposure period begins in pregnancy àEnvironment & genetic expression àState-of-the-art technology – tracking, measurement, data management àConsortium of multiple agencies àExtensive public-private partnerships àNational resource for future studies

6. Study Population - Issues àGeneralizability to U.S. population àAdditional study populations, e.g. àSpecific high-risk populations àAgricultural àIndustrial àEconomically disadvantaged àWomen of child-bearing age - possible effects on fertility & pregnancy

7. Population Size for Selected Outcomes OutcomesRate 1.5 1.75 2 Injuries-Hosp. (<18) 37.4/10K42K 20K13K Fractures 10/10K157K 77K 47K Head injuries 5/10K313K153K 94K Autism Spectrum Disorders* 20/10K78K 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) 1.54/10K1019K498K 306K ALL (Acute Lymphoblastic Leukemia) 0.27/10K 5813K2842K1744K CNS tumors 0.29/10K5413K2646K1623K Hypospadias (males) 20/10K78K 38K 23K Spina Bifida 5/10K313K153K 94K Relative Risk *prevalence

8. Sample for the NCS àNational probability sample àCenter based structure – up to 50 centers, 100+ clusters àFor measures and observation requiring expertise and facilities àIncorporate expertise and productivity of Academic Centers àMultiple dense clusters àProvide information about communities – chemical, physical, social àLogistical and economical feasibility àSelection àOf clusters – probability or quota by characteristics àOf participants in cluster – probability or 100% àFeasibility/pilot study essential

9. Priority Environmental Exposures àPhysical environment: housing, neighborhoods and communities, climate, radiation… àChemical exposures: air, water, soil, food, dust, industrial products, pharmaceuticals… complex ubiquitous low-level exposures unique exposures (special sub-studies) àBiological environment: intrauterine, infection, nutrition; inflammatory and metabolic response… àGenetics: genetic components of disease; effects of environmental exposures on gene expression… àPsychosocial milieu: influence of family, socio- economics, community, stress…

10. Priority Outcomes àPregnancy outcome: preterm birth, birth defects, fetal influences on adult health. EARLY results! àNeurodevelopment and Behavior: cognitive development (IQ), autism, learning disabilities, schizophrenia, depression, adjustment, normal variation, resilience… àInjury: intentional and unintentional; violence… àAsthma: envir/genetic/infectious/immune factors.. àObesity and Physical Development: diabetes,pubertal/reproductive development, growth, obesity ‘epidemic’…

11. Hypotheses necessary for framing the study àNo single hypothesis àAssure answers to “big issue” questions àHypothesis required for costly elements àImportant for child health & development (prevalence, severity, morbidity, mortality, disability, cost, public health significance) àReasonable scientific rationale àRequire the large sample size (~100,000) àMeasurable with study of this size àRequires longitudinal follow-up

12. Example Hypotheses à low-level exposure to non-persistent pesticides in utero (or postnatally) increases risk of poor performance on neurobehavioral and cognitive examinations during infancy and later in childhood, among those with genetically decreased paraoxonase activity àAsthma incidence and severity is associated with early life experience with infections àInfection and mediators of inflammation during pregnancy and the perinatal period are associated with increased risk of schizophrenia

13. Proposed vaccine related hypotheses* àAltered timing of early childhood immunizations will lead to no increased rate or severity of disease later in life àThe receipt of childhood routine vaccination is not linked to Autism or other developmental disabilities identified during childhood and adolescence * Infections, immunity and vaccines working group

14. Associations and Interactions Asthma Birth Defects Development & Behavior Growth Fertility & Pregnancy Social Environ Physical Environ Chemical Exposure Medicine & Pharm Health Care Gene Expression Infection

15. How will Study size produce results not otherwise available? àExposures for “big issue” low frequency outcomes àAutism àDiabetes àStill birth àBirth defects, etc. àSub-groups and multi-factor interactions àObesity àAsthma àBehavior, etc

16. Measures Anticipated: Exposures àEnvironmental samples: air, water, dust àBio-markers for chemicals: blood, breast milk, hair, tissue, etc. àInterview and history àSerology and medical data àHousing & living characteristics àFamily and social experiences àNeighborhood and community characteristics

17. Measures Anticipated: Outcomes àFetal growth and outcome of pregnancy àBirth defects and newborn exam àGrowth, nutrition, and physical development àMedical condition and history: illness (e.g. asthma, obesity), conditions, & injuries àCognitive and emotional development àMental, developmental and behavioral conditions

18. Use of Data to Maximize Output àResults available beginning ~2010 àTargeted hypotheses-testing analyses àSuccessive public-use data sets with support àSuccessive funding for investigator initiated research and analyses àExpected translation of results into related prevention initiatives

19. Projected Time Line 2000-2005Pilot study/methods development work Periodically:Meetings, peer reviews, consultations Mid 2004Finalize specific hypotheses, develop study design Late 2005Select initial centers or alternatives and pilot test core protocol Late 2006Begin full study with initial centers 2006-2007Enroll additional centers 2009-2010First preliminary results available from pregnancy 2007-2030 Analyze data as collection continues, publish results throughout: hypothesis specific, public use datasets, RFA’s

20. Contact information Check the Web site: http://NationalChildrensStudy.gov http://NationalChildrensStudy.gov Join the listserv for news and communication Contact us at ncs@mail.nih.gov