Nigel Paneth MD MPH

1
The National Childrens StudyScientific
Potential and Scientific Challenges

• Nigel Paneth MD MPH
• Pediatric Grand Rounds
• University of Wisconsin
• Madison, WI
• April 3, 2009

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THE CHARGE FROM CONGRESS PL 106-310. Childrens
Health Act of 2000

• The Director of NICHD shall establish a
  consortium from appropriate Federal agencies
  (including the CDC and EPA) to
• (1) plan, develop, and implement a prospective
  longitudinal 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.

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THE RESPONSEThe National Childrens Study

• The NCS is a longitudinal study of a nationally
  representative sample of 100,000 children, their
  families, and their environment from before birth
  through age 21.
• It is the largest longitudinal study of
  childrens health and development ever conducted
  in the U.S.
• It may be the largest study combining all forms
  of measurement in depth (self-report, clinical
  examinations, biological samples) ever conducted
  on any human population.

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WHY ARE PROSPECTIVE LONGITUDINAL STUDIES SO
VALUABLE?

• If we know what happens to people before disease
  develops, we can figure out what causes disease
  and how disease can be prevented.
• The Framingham Heart Study followed healthy
  adults for many years, and taught us that factors
  such as high blood pressure, diabetes, smoking
  and high cholesterol predispose to heart disease.
  
• Applying those lessons has led to a 60 reduction
  in the heart disease death rate, a 42 reduction
  in the overall death rate, and an extra 9 years
  of life over the past 50 years in the US.
• The US needs a Framingham for kids!

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Consequence of Framingham Incidence of Coronary
Heart Disease, USA, 1950-2000 (age-adjusted)
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WHAT IS BEING STUDIED?
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SOME STUDY QUESTIONS

• How is asthma incidence and severity influenced
  by the interaction of early life infection and
  air quality?
• Do assisted reproductive technologies (ART)
  increase the risk of fetal growth restriction,
  birth defects, and developmental disabilities?
• Does impaired maternal glucose metabolism during
  pregnancy cause obesity in children?
• How does high level exposure to media content in
  infancy affect development and behavior in
  children?
• Does pre-and post-natal exposure to
  endocrine-active environmental agents alter age
  at onset, duration, and completion of puberty?

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DATA TO BE COLLECTED PRIOR TO BIRTH

• Study begins with a home visit prior to
  conception (when possible) or in the first
  trimester of pregnancy
• Two additional clinic visits and three phone
  contacts during pregnancy.
• In one of the clinic visits, a third trimester
  study ultrasound is obtained.

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PRE-CONCEPTIONAL OR FIRST TRIMESTER HOME VISIT

• Questionnaires Household Composition and
  Demographics Perceived Stress Social Support
  Family Processes Health Behaviors Diet and
  Toxicant Exposure through Food Environmental
  exposures
• Biospecimens from both partners if available
  blood, hair, urine, nail, saliva. Vaginal fluid
  from woman.
• Environmental samples dust, air, water, soil
• Physical measurements height, weight, skinfolds,
  other anthropmetry, blood pressure

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DATA TO BE COLLECTED AT BIRTH
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DATA TO BE COLLECTED AFTER BIRTH

• Home visits at six and twelve months and frequent
  phone contacts.
• Further collection of biological and
  environmental specimens at home visits (breast
  milk, formula, baby urine)
• Health surveys obtained at all visits
• Abstraction of medical records
• Continued follow-up to age 21, though full
  protocol beyond age 2.5 not yet developed

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BIOLOGICAL STORAGE AND INFORMATICS

• All material collected in the study
  (environmental and biological specimens) will be
  stored in duplicate in two locations
• After aliquotting, an estimated 32 million
  specimens will be stored in the first seven years
  of the study, most in vapor phase liquid nitrogen
  at -150 or less.
• All survey and health data collected will be
  protected by the highest levels of security

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WHERE DOES THE NCS TAKE PLACE?
All Births in the Nation
4 million births in 3,141 counties
Sample of Study Locations
105 Locations
Selection of neighborhoods
Sample of Study Segments
All or a sample of households within neighborhoods
Study Households
All eligible women in the household
Study Women
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7 Vanguard sites 29 Wave 1 sites 36 Wave
2 sites 15 Wave 3 sites 18 unassigned sites
TOTAL 105 SITES
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HOW ARE PARTICIPANTS ENROLLED?

• In sampled segments of counties (specific
  neighborhoods selected to be representative of
  the counties), all women of child-bearing age are
  contacted first by mail, then phone, then in
  person.
• If the woman is at high risk of pregnancy or in
  the first trimester, consenting and enrollment
  takes place at first contact. Otherwise,
  enrollment is deferred but contact is maintained
  with the woman.
• Surveillance of prenatal care sites is used to
  detect first-trimester pregnant women from
  segments.
• Infants can be enrolled at birth if mother lives
  in segment and was not previously enrolled.

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WHEN DOES THE STUDY TAKE PLACE?

• Contracts for Wave 1 began September 2007, and
  for Waves 2 and 3 in September 2008
• Contracts issued initially assumed a 21-month
  start up period before enrollment. This has now
  been stretched to 32-38 months because of three
  consecutive 6-month delays.
• Enrollment thus begins in 2009 in Vanguards, in
  2011 2013 in the three waves.
• Queens, NY and Duplin, NC Vanguard locations
  began enrolling in January, 2009. Waukesha, 4
  others start next month.

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WORK BEFORE ENROLLMENT

• Selection of sampling segments
• Estimating N of births to obtain 250 births per
  county for each of four years
• Aiming for county representativeness
• Engaging the community
• Making arrangement with hospitals and
  providers
• Dealing with IRBs
• Hiring and training staff

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FUNDING

• Total projected cost of study is 2.7 B - 3.1 B
  over 25 y
• (Human Genome 2B, WHI - 1B, over much shorter
  periods)
• 69 M in FY 07 budget to initiate study
• 110 M in FY 08 budget to add Wave 1 study
  centers
• 192 M anticipated for FY 09 to add Wave 2 study
  centers
• less expensive later, after pregnancy, birth
  protocol is complete

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NCS AS AN INVESTMENT.CEREBAL PALSY AS AN EXAMPLE

• The prevalence of cerebral palsy has not changed
  in 40 years, even though we know it has to do
  with pregnancy and delivery problems.
• Every year at least 8,000 children are born in
  the US with CP whose lifetime medical,
  rehabilitative and educational care will cost
  about 10 billion dollars.
• If the NCS does nothing but find a way to reduce
  the prevalence of cerebral palsy by 10 it will
  have paid for itself in 3 years.

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The Michigan Alliance for the National
Childrens Study (MANCS)
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Michigans 5 NCS Study Counties
Genesee Grand Traverse Lenawee Macomb Wayne

Funded in 2008
Funded in 2007
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THE FIVE MANCS PARTICIPATING INSTITUTIONS

• Henry Ford Health System (HFHS)
• Michigan Department of Community Health (MDCH)
• Michigan State University (MSU)
• University of Michigan (UM)
• Wayne State University (WSU) Childrens Hospital
  of Michigan (CHM)
• Plus the health departments of each of the
• five counties

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CHALLENGES IN CONDUCTING THE NCS

• Population-based survey research has rarely, if
  ever, been combined with data collection in
  clinical settings. Yet from identifying
  non-pregnant women at home
• Pregnancies must be identified in the first
  trimester
• Births must be identified when they occur in any
  hospital in which a segment woman delivers
• Intense, burdensome protocol
• Many IRBs to obtain consent from
• Increasing resistance to general population
  medical research. Resistance from medical
  providers can be a problem too.

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DIFFICULTY OF ASCERTAINING PREGNANCIES IN THE NCS

• Initial recruitment is by household recruitment
• Women aged 18 40 are stratified by risk of
  pregnancy high, medium, low
• High risk women have pre-conceptional visit
• Medium and low risk women telephone contact
• 50 of US pregnancies are unplanned, and will
  thus emerge from the medium and low risk
  categories
• How will we know when a woman gets pregnant?

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PREGNANCY ASCERTAINMENT VIA PRENATAL CARE
PROVIDERS

• We cannot rely on study women contacting us to
  let us know they are pregnant
• Therefore, we plan surveillance in prenatal care
  to identify women from the study segments
• We will provide address-matching software to
  clinics and providers (or an 800 number to call)
  to identify women eligible for the NCS
• We will then need providers to alert us to the
  presence of NCS-eligible women
• We also plan to provide free pregnancy testing
  strips upon request, so that we can track women
  as they begin to consider or to recognize
  pregnancies.

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LABOR ASCERTAINMENT BY HOSPITALS

• We cannot rely on study women to let us know they
  are in labor.
• We will develop a system by which hospitals will
  notify us if an eligible woman is admitted in
  labor.
• We will also develop arrangements with each
  hospital to collect the required specimens
• We spend a great deal of time working to bring
  hospitals on board. All centers have hospital
  negotiators to do this work

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HELPING WOMEN WITH THE PROTOCOL THE PARTICIPANT
ADVOCATE COORDINATOR (PAC)

• We budgeted an additional staff member, the PAC.
  This is a woman from the community with
  experience of pregnancy and labor issues whose
  role is to assist the participant to complete the
  protocol. She does not collect data (though she
  may help with birth collections)
• She keeps in touch with the participant reminding
  her of the protocol requirements
• The PAC will go with subjects to study visits,
  and to LD with mother, if required
• In Wayne County, we have one PAC per 30 women per
  7 months (from first trimester visit to delivery)

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A MANCS IRB?

• We are trying to get a single IRB in Michigan
  to review all MANCS protocols (including any
  adjunct studies)
• All institutions and hospitals would send
  representatives to this IRB
• MSUs may set this IRB up, but we are still
  working out the kinks
• Other four institutions have agreed to this
  arrangement

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PILOT WORK WITH PREGNANT WOMEN IN GRAND RAPIDS,
MI SUMMER 2006

• Provider attitudes
• Mudd L et al MCH Journal 2008 12(6)684-91
• Attitudes of pregnant women
• Nechuta S et al Paed Perinat Epid (in press)

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PRENATAL CARE STAFF WILLINGNESS TO HELP IN NCS
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DELIVERY ROOM STAFF WILLINGNESS TO HELP IN NCS
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PRENATAL AND DELIVERY STAFF BARRIERS TO THE NCS
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PREGNANT WOMENS ACCEPTANCE OF NCS PROCEDURES
WITH AND WITHOUT COMPENSATION
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COMMUNITY ENGAGEMENT IS KEY

• We must make sure that women know about the NCS
  in our communities.
• We must make sure that people women trust (health
  care providers, religious and political leaders)
  also know about the study.
• We must make sure that women get a positive image
  of the NCS.
• We must make the value of the NCS to the
  community is clear.
• We should measure these attitudes periodically to
  see how well we are doing.