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					     THE NATIONAL CHILDREN’S STUDY
A ONCE IN A LIFETIME OPPORTUNITY TO STUDY
          CHILD HEALTH IN DEPTH


             Nigel Paneth MD MPH
           Michigan State University

          ARNOLD EINHORN LECTURE
               DC CHILDRENS
              MARCH 23, 2011
THIS TALK CAN BE FOUND ON MY WEBSITE




   http://www.epi.msu.edu/faculty/paneth.htm
ONE OF THE MOST IMPORTANT PRINCIPLES
       THAT ARNOLD TAUGHT ME




         KEEP IT SIMPLE!
Paneth N: Apgar score and risk of cerebral palsy.
         BMJ 2010, Oct 7:341:c5175.7


        MY ORIGINAL                 BMJ EDITED VERSION
  A wise clinician once             Experience suggests that
  pointed out to me that the        simple procedures that can
  most important academic           be performed widely have
  surgeons were not those           a greater impact on health
  with the best manual              than more complex and
  dexterity. Fabulous               demanding procedures
  procedures requiring              that are less widely
  intricate skills will not carry   applied. The Apgar scoring
  very far. Simple                  system works because it
  procedures that can be            comprises just a few
  performed widely by               components that can easily
  ordinary mortals will             be memorised, and
  always have more impact           requires no equipment and
  on the health of the public.      modest training
   THE CHARGE FROM CONGRESS:
 PL 106-310. Children’s 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.
             THE RESPONSE:
     The National Children’s 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 children’s
  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.
       FUNDING FOR THE NCS

• Separate line item in congressional budget; not
  a part of NICHD’s overall budget.
• Assigned to the NIH director’s office
• Administered by NICHD, with involvement of
 CDC, EPA and NIEHS
• 2007 and 2008 – Approx $60 million via
 congressional continuing resolution, because not
 supported by White House
• 2009 – 2011 – White House supporting study
 with approximately $190 M annual allocations
WHY IS SUCH A STUDY NEEDED?


• It will be expensive – likely to cost anywhere
  from three to five billion dollars over its 25
  year lifetime
• It will require a great deal of scientific research
  effort that otherwise go into other research
  projects
• It will require a considerable commitment from
  the participating families
• So we must have some very good reasons to
  undertake this massive study
  1. BECAUSE MOST CHRONIC CHILDHOOD
        CONDITIONS ARE STABLE OR
        INCREASING IN PREVALENCE

• Chronic conditions that are decreasing
  • Neural Tube Defects (folic acid)
• Chronic conditions that are not decreasing
  • Most birth defects
  • Learning Disabilities
  • Severe Mental Retardation
• Chronic conditions that may be on the rise
  • Cerebral Palsy
  • Autism
• Chronic conditions that are definitely increasing
  • Asthma
  • Premature Birth
  • Juvenile Diabetes
 2. BECAUSE CHRONIC AND DISABLING
 CONDITIONS OF CHILDHOOD ARE VERY
              COSTLY

        ESTIMATED ANNUAL COSTS IN US
• Severe Mental Retardation $51 billion
• Autism                                 $30 billion1
• Premature birth                        $26 billion
• Juvenile Diabetes                      $14 billion
• Cerebral Palsy                         $12 billion
• Birth defects                          $8 billion2
• Vision and Hearing Loss                $4 billion

                   1. No formal estimate available
                       2. Estimate from 1992
      IN OTHER WORDS….


BECAUSE THERE IS NO DECLINE IN CHRONIC
AND DISABLING CHILDHOOD CONDITIONS,
YEAR IN AND YEAR OUT THESE CONDITIONS
PRESENT US WITH AN ECONOMIC BILL OF AT
LEAST $100 BILLION.

WHAT CAN WE DO?
         WE HAVE TO FIND OUT
       HOW TO PREVENT DISEASE

• Improvement in child health over the past 50 years
  has mainly been because of improved treatment
  (e.g. cancer chemotherapy, newborn intensive
  care). There has been very little prevention.
• The only way to reduce our massive health care
  expenditures is via disease prevention
• The only way to prevent disease is to learn what the
  causes are and figure out ways to address them.
• This means undertaking research on what happens
 before disease arises, the antecedents of disease.
        WEIGHING THE COSTS

• The NCS budget is currently about $200 M per
  year. At that pace, over 25 years, it would
  cost $5B. (actually pace of spending is likely to
  decline once enrollment is complete).
• This is less than 0.2% of the costs of the
  diseases we study.
• This $5B will be returned to our economy in
 three years, if the only result is
 • Preventing 20% of preterm birth, or
 • Preventing 5% of autism, or
 • Preventing 3% of mental retardation
    RESEARCH IS EXPENSIVE



BUT NOT DOING RESEARCH IS
  MUCH MORE EXPENSIVE
WHAT IS THE STRATEGY FOR A STUDY
THAT COULD LEAD TO PREVENTION?

1. Start with healthy people
2. Follow them until disease occurs
3. See what was different about people,
   who later got disease or didn’t get
   disease, when they were healthy.
4. This is called the longitudinal cohort
   study approach in epidemiology



    15
          LARGE PROSPECTIVE
      LONGITUDINAL STUDIES WORK!

• The best example of success using the longitudinal study
  model is the reduction in heart disease.
• 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.
• Risk factor control has been the largest contributor to the
  60% reduction in the heart disease death rate, the 42%
  reduction in the overall death rate, and an extra 9 years of
  life expectancy over the past 50 years in the US.
• Framingham had 5,000 participants because heart disease
  is common. To study the several rarer childhood chronic
  conditions, a much larger sample size is needed.
• We needs a Framingham study for children!
    Consequence of Framingham:
Incidence of Coronary Heart Disease,
    USA, 1950-2000 (age-adjusted)
THE NATIONAL CHILDREN’S STUDY




    WHAT, WHERE, WHO?
               WHAT IS BEING STUDIED?


    Priority       Examples          Priority Health         Examples
   Exposures                           Outcomes

Physical       Housing quality     Pregnancy            Preterm birth
Environment    neighborhood        Outcomes             Birth defects
               Pesticides                               Autism
Chemical
               Phthalates                               learning
Exposures                          Neurodevelopment
               metals                                   disabilities
                                   & Behavior
Biologic       Infectious agents                        behavior
Environment    diet                                     problems
               Interaction of      Injury               Head trauma
Genetics       genes and
               environment
                                   Asthma               Asthma
               Family structure
                                                        Obesity
Psychosocial   social networks,    Obesity & Physical
milieu                                                  Diabetes
               Media exposure      Development
               to violence                              altered puberty
       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?
DATA TO BE COLLECTED PRIOR TO
            BIRTH

• Study begins with a home visit prior to
  conception (in women trying to get pregnant)
  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.
• A major emphasis on collecting biological and
  environmental samples in pregnancy and at
  birth to use to study future hypotheses.
   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
   DATA TO BE COLLECTED AT BIRTH


• Maternal blood prior to delivery
• Cord blood
• Placenta and umbilical cord
• Neonatal examination and measurements
• Heel stick blood from infant
• Meconium from baby

• Breast milk
  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
     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
WHERE DOES THE NCS TAKE PLACE?


              All Births     ~4 million births
            in the Nation    in 3,141 counties


           Sample of Study   105 primary
                             sampling units
              Locations
                             (mostly counties)

           Sample of Study   Selection of
                             Neighborhoods or
             Segments
                             segments

               Study         All households within
             Households      segments

                             All eligible women in
            Study Women      the household
• 7 VANGUARD SITES FROM 2009
• 30 NEW VANGUARD SITES FROM 2011
• ANOTHER 68 SITES TO BE ACTIVATED IN
THE FUTURE
 TOTAL = 105 SITES
TIME FRAME FOR ENROLLMENT


• Primary sampling units (PSU) are usually
  counties, but in some cases are a group of very
  small counties (e.g. in Minnesota-South
  Dakota) or sub-divisions of counties (e.g. Los
  Angeles county is 4 PSU’s).
• The segments are chosen so that about 350-
  400 births per year are expected to take place.
• This should allow each PSU to recruit 250
  births a year for 4 years, or 1,000 total per
  PSU, thus producing the sample of 100,000
          DIFFERENCES ACROSS
          COUNTIES IN THE US

• Study centers (universities or consortia who submitted
  proposals for the NCS contracts) manage variable
  numbers and types of counties across the US, ranging
  from one (many) to eight counties (NY-NJ
  consortium).
• The Michigan Alliance for the National Children’s Study
  has contracts for five counties.
• In our largest county, Wayne, we must enroll 250
  births from 25,000 annual births taking place in 26
  hospitals and cared for in 150 prenatal care settings
• In our smallest county, Grand Traverse, we have a
  total of 1,000 births, all cared for in 5 prenatal care
  settings and delivering in one hospital
 INITIAL ENROLLMENT STRATEGY:
   DOOR-TO-DOOR ENROLLMENT

• 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
  at their residences.
• We attempt to enroll the woman is she is planning
 a pregnancy or is pregnant and in the first
 trimester.
• This system was used in the 7 vanguard counties,
  and had difficulty identifying pregnancies, although
  consent rates once pregnancies were identified
  were good, nearly 70%.
  NEW ENROLLMENT STRATEGIES

• Recognizing that enrollment was not as efficient
  as hoped in the Vanguard Counties, and risked
  creating a non-representative sample, a
  decision was made in 2010 to have an
  experimental phase in which enrollment would
  proceed in one of three ways:
  • 10 counties would continue household enrollment
  • 10 counties would enroll in prenatal care settings
  • 10 counties would emulate the census and mail surveys
   to a large number of women, and then select within
   that sample for more in depth study.

• All three approaches retain the fundamental
  sampling frame (i.e. households in segments)
The Michigan Alliance for
 the National Children’s
     Study (MANCS)
    THE FIVE STUDY COUNTIES IN
             MICHIGAN




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                      
                       
      THE FIVE MANCS
PARTICIPATING INSTITUTIONS


1. Henry Ford Health System (HFHS)
2. Michigan Department of Community Health
   (MDCH)
3. Michigan State University (MSU)
4. University of Michigan (UM)
5. Wayne State University (WSU); Children’s
   Hospital of Michigan (CHM)
Plus the health departments of each of the
five counties
  WORK BEFORE ENROLLMENT


• Selection of segments
• Engaging the community, including
  formation of a community advisory
  board
• Making arrangement with hospitals
  and providers
• Dealing with IRB’s
• Hiring and training staff
          A COMMON IRB

• We have managed to get agreement
 from our four partners to have the MSU
 IRB serve as the IRB of record for all
 MANCS protocols
• Our partners send representatives to
 the MSU IRB when it discusses MANCS
 protocols
• Some, but not all, hospitals in Wayne
 County accept this arrangement, and
 defer to the MSU IRB, if they think they
 are engaged in research
   PREGNANCY ASCERTAINMENT VIA
     PRENATAL CARE PROVIDERS


• We do surveillance in prenatal care to identify
  women from the study segments
• We obtain lists from clinics of upcoming prenatal
  patient appointments and then use address-
  matching software identify women eligible for
  the NCS
• We then ask providers or their staff to let women
  know about the study and ask permission for us to
  approach the women.
• We currently do this for 34 practice sites, soon to
 expand to 41, which cover some 70% of all
 prenatal care in Wayne County.
       LABOR ASCERTAINMENT BY
              HOSPITALS

• We cannot rely on study women to let us know
  they are in labor, so we work with hospitals to
  notify us if an eligible woman is admitted in
  labor.
• We make arrangements with each hospital to
  collect the required specimens
• We spend a great deal of time working to bring
  hospitals on board.
   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 is usually the first person to tell a woman about the study
• She keeps in touch with the participant reminding her of the
  protocol requirements
• The PAC will go with subjects to study visits, and to L&D with
  mother, if required
• In Wayne County, we have one PAC per 30 women per 7
  months (from first trimester visit to delivery)
   ENROLLMENT RESULTS IN THE
         FIRST MONTH

• We began working in our clinics in mid-
  February, and in the first five weeks we have:
  • Address-matched 5,621 women listed on prenatal care
   appointment lists
  • Identified 112 women who are likely to be pregnant
  • Obtained permission to contact from 47 of 51 mothers
   who were approached by providers.
  • Approached 26 of them, finding 19 eligible (the 7
   ineligible were not pregnant or trying)
  • All 19 eligibles have consented to participate.
  • Another 5 women ready to consent, awaiting Spanish
   or Arabic language consent forms, or address
   verification.
THANKS VERY MUCH FOR LISTENING




  I’M HAPPY TO ANSWER
       QUESTIONS

				
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