December 2002 Study Assembly Meeting Summary Minutes

December 17, 2002
Baltimore Marriott Waterfront
Baltimore, MD

Plenary Session

This meeting was held in conjunction with the National Children’s Study, which is led by a consortium of federal agency partners: the U.S. Department of Health and Human Services (including the National Institute of Child Health and Human Development [NICHD] and the National Institute of Environmental Health Sciences [NIEHS] , two parts of the National Institutes of Health , and the Centers for Disease Control and Prevention [CDC] ) and the  U.S. Environmental Protection Agency (EPA) .

Welcome

Peter C. Scheidt, M.D., M.P.H., NICHD, NIH

Dr. Scheidt opened the Plenary Session. He welcomed and thanked everyone for participating in the National Children’s Study Assembly Meeting. Dr. Scheidt briefly summarized the goals of the Study. He also outlined objectives for this Study Assembly Meeting:

1. Communicate priority focus areas and hypotheses to Study Assembly members and provide an opportunity for them to react to this information
2. Update progress on Study design
3. Get input from Assembly participants on Study hypotheses
4. Identify specific Study measures
5. Determine when those measures will occur.

Dr. Scheidt reiterated that the Study is a large, complex, and challenging effort. The planning process has involved many individuals. Much work still lies ahead. Therefore, a key part of the Assembly is the cross-working group planning sessions—interaction among diverse participants is critical to the success of the Study.

Dr. Scheidt also encouraged Assembly participants to write down questions for the panel to respond to at the end of the Plenary. He then introduced Dr. Alexander.

Duane F. Alexander, M.D., NICHD, NIH

Dr. Alexander also thanked Study Assembly participants and all who have been involved in any way in helping plan the Study. He emphasized that he was very pleased with progress of the Study to date. He noted that the hard work and input from literally hundreds of members of the Working Groups and the Advisory Committee (NCSAC) have assured this substantial progress. Dr. Alexander explained that the organizational structure of the Study is multi-tiered, with fairly rigid lines of formal communication. He pointed out that this structure is mandated by the Federal Advisory Committee Act (FACA), and is necessary if the Study is to utilize the necessary expertise of non-federal professionals. The NCSAC provides direction to the Working Groups and reviews findings from each Working Group. Dr. Alexander also noted that while this inclusive process may seem slow and cumbersome, its benefits far outweigh its inefficiencies.

Dr. Alexander reviewed progress to date:

• Core hypotheses: Much work has been accomplished so far. More than 50 hypotheses have been proposed by the Working Groups and others. The proposed hypotheses have been reviewed by the Study Design Working Group and by the NCSAC. The Interagency Coordinating Committee (ICC) has compiled five primary topic areas or themes under which the hypotheses fall. Dr. Alexander encouraged Assembly participants to comment on these hypotheses, noting that they will need to be refined. He also noted that while there is still considerable time to develop the hypotheses, the process cannot be delayed. The current draft is a starting place—there will be extensive discussion and work to add hypotheses and make modifications.
  
• Pilot studies: Several studies have been completed regarding state-of-the-art measures, while others are ongoing or are in the planning stage. Four workshops were held on Monday, December 16. These sessions have added information to the process. The posters provide information on pilot studies. Moreover, new program staff are being added. They will work on pilot studies; other pilot studies will be conducted through contracts.

Dr. Alexander emphasized that it is critical to move ahead in finalizing Study design and sampling scheme. He noted that this issue would be addressed extensively during the Study Assembly Meeting. Dr. Alexander also explained that it will be essential to get informed consent from Study participants so that future studies can be conducted using data collected. A new federal committee will begin meeting in January regarding human subject protection laws. This committee will look at longitudinal studies and consent issues.

Dr. Alexander explained that the more-than-50 hypotheses have led to formulation of five broad themes:

• Environmental factors that influence pregnancy outcome
• Environmental exposures that influence neurobehavioral development
• Environmental exposures altering injury
• Environmental exposures altering asthma
• Environmental exposures influencing metabolic, nutritional, and endocrine health (obesity and altered physical development).

Dr. Alexander also reminded participants that funding for the full Study is not yet assured. Although the Study has current funding for planning, to date, Congress has not finalized a budget for fiscal year 2003. The Institute hopes for augmented funding in fiscal year 2004 to be able to move toward launching the Study and completing pilot work.

Dr. Klebanoff provided background on development of Study hypotheses and discussed practical constraints such as funding and participant burden. He noted that specification of required measurements is the first step in estimating the burden and refining costs. Dr. Klebanoff explained that the NICHD Director is responsible for making final decisions about Study hypotheses. Dr. Alexander receives input from the ICC, Working Groups, and the NCSAC. Dr. Klebanoff also mentioned that the Study Design Working Group, ICC, and NCSAC have reviewed hypotheses currently under consideration. Assembly members now need to begin to organize these hypotheses into major themes, refining these hypotheses and beginning a dialogue about specific measurements.

The purpose of the core hypotheses is to establish a framework for the Study design in order to create the Study protocol (details regarding sampling strategies, frequency of followup, and collection of data). The framework also helps in prioritizing recommended pilot studies, providing a public identity for the Study, and helping funders understand the Study. In addition, identification of the core hypotheses will help the Working Groups define their tasks and develop specifications for data collection and for requisite pilot studies.

A number of sources provided input in the formulation of the hypotheses. The NCSAC reviewed each hypothesis, using evaluation guidelines developed by the Study Design Working Group and approved by the NCSAC. Briefly, these guidelines stipulated that a hypothesis should have a definable and measurable exposure and outcome. Also, it should be possible to calculate the sample size needed. Other guidelines were:

• What is the significance to public health and human development?
• Can the hypothesis justify a large, prospective study, and is the required sample size appropriate?
• Will the sample size allow for evaluation of interactions of different exposures?
• Does the hypothesis allow for studying mechanisms of associations with respect to disparities, health care, etc.?
• Does the hypothesis require a large, prospective study?
• What is the scientific merit of the hypothesis?
• Is there potential for innovative research?

Dr. Klebanoff explained that while individual core hypotheses did not have to meet each criterion, the final set of priority outcomes and core hypotheses combined must do so. Additionally, the package of core hypotheses should return important results at multiple points in the lifecycle (pregnancy, infancy, preschool age, childhood, and adolescence).

Dr. Klebanoff noted that the December 2000 Consultation, an early meeting in the development of the Study, concluded that a hybrid approach should be used, selecting a few general themes under which more specific hypotheses could be generated. This group looked at ways to construct Study themes, which could be defined based on exposures leading to outcomes, or based on outcomes associated with exposures. The group concluded that the most cohesive approach would be to frame the core hypotheses in terms of outcomes. The group assumed that social and genetic factors are part of the priority outcomes and that data will be collected to enable the evaluation of health disparities.

Dr. Klebanoff reviewed the five themes—priority outcomes—that the ICC has proposed for the core hypotheses to fall under and also gave examples of each:

1. Pregnancy outcome : For example, impaired glucose metabolism is a risk factor for birth defects, and intrauterine exposure to inflammatory mediators is a risk factor for preterm birth.
2. Altered neurobehavioral development, developmental disabilities, psychiatric outcomes : For example, pesticide exposure (prenatally or postnatally) increases risk of poor performance on neurobehavioral and cognitive tests, and prenatal exposure to infection and inflammatory mediators increases the risk of certain disabilities.
3. Injury : For example, early neurotoxic exposure is associated with an increased risk of injury; attributes of child care and relationship with caregivers influence risk of injury; repeated head trauma has cumulative adverse effects on neurocognitive development.
4. Asthma : For example, exposure to indoor and outdoor air pollution, respiratory viral infections early in life, and maternal stress during pregnancy are associated with increased risk of asthma; antioxidants in the diet and early exposure to bacterial and microbial products decrease risk; access to health care and management of asthma are strongly related to asthma hospitalization and morbidity.
5. Obesity and altered physical development : For example, impaired maternal glucose metabolism during pregnancy, intrauterine growth restriction, breastfeeding, and other factors are related to risk of obesity and insulin resistance in the child; dietary predictors of obesity and insulin resistance include reduced intake of fiber and whole grains and high glycemic index foods; environmental factors that support exercise are associated with the risk of obesity and insulin resistance; and exposure to environmental agents that affect the endocrine system can alter the age of puberty.

Dr. Klebanoff noted that many other possible hypotheses can be tested as well using data collected for the core hypotheses. He also cautioned that this is not a perfect list, but it is a great start. He emphasized that the importance of the Assembly Meeting as an opportunity to move along the planning phase of the Study by talking in more specific terms about Study components. Groups convened at the Study Assembly were to provide more specific data for these hypotheses, and the ICC would be able to consider comments received in revising the Study design.

Adolfo Correa, M.D., Ph.D., M.P.H., CDC

Dr. Kimmel provided background and described pilot studies conducted to date. She explained that initial studies addressed general questions about exposures and outcome measures. A number of workshops have been planned for fiscal year 2002–03. Future studies will address more specific issues related to core hypotheses and Study design.

Dr. Kimmel provided poster numbers for the poster session so that participants could easily find results of studies of interest to them. The pilot studies include exposure studies, cross-cutting studies, health-related studies, and study design issues research.

Dr. Correa discussed the workshops that have been held and summarized their outcome, primarily reports and white papers. Workshops include:

• Communications Outreach and Communications Workshop (December 3, 2002)
• Fetal and Neonatal Growth and Development Workshop (December 16, 2002)
• Drug (Prescription and Over-The-Counter) and Dietary Supplement Exposures Workshop (December 16, 2002)
• Ethics Workshop (scheduled late February 2003, which will address “lessons learned”).

Dr. Correa also mentioned the International Consultation (December 16, 2002). This meeting facilitated information exchange and interaction. He noted that a listserv and portal e-room will be set up, and data will be collected for inventory.

Ideas for future pilot studies generated by the Working Groups will be reviewed by the NCSAC during the Study Assembly Meeting. The full protocol will eventually be piloted at vanguard centers.

Amy Branum, M.S.P.H., NCHS, CDC

Ms. Branum reviewed the schedule of events for the rest of the Assembly Meeting. She also reiterated desired outcomes, including completion of worksheets by the various inter-working groups and one-page action plans to be submitted by each Working Group by the end of the Assembly Meeting.

The Q&A Panel:

Carole Kimmel, Ph.D., EPA

Mark Klebanoff, M.D., M.P.H., NICHD, NIH

Matthew P. Longnecker, M.D., Sc.D., NIEHS, NIH

Pauline Mendola, Ph.D., EPA

Peter Scheidt, M.D., M.P.H., NICHD, NIH

Kenneth C. Schoendorf, M.D., M.P.H., CDC

Will the inter-working groups continue to meet after today?

For the purposes of this meeting, the inter-working groups are one-time ad hoc groups in compliance with the Federal Advisory Committee Act. In an effort to avoid making the planning organizational structure for the Study even more complex, the products of the inter-working group meetings are to go to the Working Groups to take further.

How will the Study address pre-conception issues, especially hypothyroidism—TSH levels before a woman becomes pregnant?

We are considering pre-pregnancy enrollment; the NCSAC will consider this issue today, and a white paper will be prepared.

What happens if government funding is unavailable or inadequate?

We hope that won’t be an issue. But, realistically, we have already made progress with pilot studies and unprecedented collaboration between federal agencies and non-federal agencies. If inadequate funds are available, we would have to prioritize components of the Study, might have to cut out more expensive measurements, reduce the frequency of measurements, etc. Since a major strength of the Study is that it will look at multiple exposures and outcomes at the same time, we hope to preserve this. If funding becomes a problem, perhaps the component agencies would try to continue some aspects of the Study.

What is being done to ensure accurate representation of different ethnic and linguistic groups in the sample?

We want the Study to be representative of all children in the U.S. so we may have to oversample certain groups. The Study Design Working Group is considering these issues.

Which of the three recruitment strategies is being favored?

None yet, options are still being considered; this is also on the agenda today for the NCSAC.

When will the Working Groups be dissolved?

This will vary depending on when the Working Groups complete their tasks. Some will end earlier; others may continue for years. The Working Groups come under the NCSAC and the NCSAC will decide on this as needed.

What will be the mechanism for funding future pilot studies?

To the extent possible, we will use an open, competitive process. We probably won’t use a traditional grants program because of the short timeframe. (We need some answers quickly.) We do anticipate that we will use a variety of mechanisms.

In selecting outcomes to frame the core hypotheses, why did the ICC focus only on negative outcomes? Is the Study not interested in identifying pathways to health promotion as well as disease prevention?

We are very interested in finding out what is helpful and harmless as well as things that are harmful in children’s environmental health. We considered many frameworks for how to describe the major themes and these key public health outcomes/exposures were the best workable framework we came up with. But we are happy to consider other ideas and are looking for what will fill in the core hypotheses.

Are other hypotheses that were submitted by Working Groups still under consideration?

Yes, the hypotheses are still open for discussion. If you think a topic should be revisited, frame your ideas and pass them to the ICC so that we can understand why the issue should be reconsidered. We tried to develop a framework for a comprehensive assessment of children’s health and tried to think about optimizing proposed hypotheses.

What is the timeframe for the initial enrollment?

The Study will begin enrollment in 2005. We plan on completing enrollment over a three-year period, depending on funding availability each year.

If a convenience sample is applied to the Study, how can we be assured that an appropriate sub-sample representing minorities, ethnicities, and language diversity (reflecting the U.S. population) will be recruited?

Having a convenience sample could allow us to recruit specialized centers that represent certain exposure groups or ethnic groups. There is a concept known as quota sampling. This can be dealt with either by using a convenience sample or a representative sample.

How will risk behaviors and health outcomes during adolescence and transition to adulthood be addressed?

We are very interested in people’s input relative to certain measures. Please contribute suggestions in inter-working group meetings.

Will the presentations given today be widely available on the portal? (e.g., Study core hypotheses and overview of pilot studies)?

They will be, as soon as possible.

How will genetic variation be used for early identification of individuals at risk? Will any intervention be offered for individuals at risk?

We recognize the importance of this issue and are working with the Ethics Working Group to address it; clearly the Study will communicate findings of clinical significance and refer affected individuals to appropriate sources of care.

How will participants in the Study be informed of findings, either on a personal level or general findings?

Here is another issue where we expect to make use of the expertise in the Ethics and Community Participation Working Groups. There are multiple options for keeping the participants informed of the Study—quarterly newsletters, community outreach workshops, etc. We will need to ask people around the country how much information they want, how they would like to receive information, and identify how much information is too much.

Why and how were 100,000 pregnancies chosen as the sample size?

We wanted the sample size to be large enough to capture rare events but also be manageable and feasible. The sample size may depend on budget, so it is not as settled as it may seem. We needed to start somewhere.

What about the Heisenberg principle? How will you account for the impact of such significant observation on the subjects on outcomes? Will the Study be observational only?

Maybe not—we want to improve children’s health, so there may be some benefits of the Study as it goes along and it may include some interventions.

Is there a plan to obtain specimens to be stored? That is, samples that will remain “on file” because invariably some of the information at the time a study is planned becomes irrelevant. Specimens allow testing of new hypotheses as time moves forward. If so, the ethical and consent issues related to the process must be carefully considered.

A Repository Working Group is considering sample storage issues (e.g., how many samples to collect, where to store them, how long to keep them, and associated costs). We need to look at ethical issues such as subject ID and confidentiality. Decisions will come as the Study focus and design are finalized. We will need to prioritize what to sample and save as storage could be expensive—there will be biological samples, 3D ultrasound data, etc., that will be stored for future use.

Regarding neurodevelopmental hypotheses—why were pesticides chosen and not other chemicals?

The neurodevelopment hypotheses are based primarily on materials that were submitted in late summer/early fall, the same time the Development and Behavior Working Group began meeting. We haven’t received our best results from this Working Group as to what hypotheses there should be.

Regarding injury hypotheses—how is injury defined?

The Injury Working Group is expected to create definitions during this Study Assembly Meeting. There is a pilot study underway to help define injuries.

What family will agree to such a vast array of invasive measurements? Shouldn’t the Study be more carefully focused?

The law directs that we make this Study comprehensive. Funding constraints are probably not going to be as important to the final structure of the Study as participant burden is. Participant burden is one of the biggest Study constraints. We will use incentives and other retention strategies to keep subjects in the Study. At some point, we need to prioritize the measures, which may be based on ease or cost. The inter-working group sessions will help consider these issues.

Did yesterday’s workshop reach a conclusion about the use of placentas and cord blood?

No. The group didn’t address this issue (and wasn’t charged with doing so); they were asked to address fetal growth and development. The answer will come as Working Groups decide what and minimum data/samples are to be collected.

Plenary Session Panel and Presenters

Duane Alexander, M.D.

Director

National Institute of Child Health and Human Development

National Institutes of Health

Amy Branum, M.S.P.H.

Health Statistician, Infant and Child Health Studies

National Center for Health Statistics

Centers for Disease Control and Prevention

Adolfo Correa, M.D., Ph.D., M.P.H.

Epidemiologist, Division of Birth Defects and Developmental Disabilities

National Center on Birth Defects and Developmental Delays

Centers for Disease Control and Prevention

Carole Kimmel, Ph.D.

Senior Scientist, National Center for Environmental Assessment

Office of Research and Development

U.S. Environmental Protection Agency

Mark Klebanoff, M.D., M.P.H.

Director, Division of Epidemiology, Statistics, and Prevention Research

National Institute of Child Health and Human Development

National Institutes of Health

Matthew P. Longnecker, M.D., Sc.D.

Senior Investigator, Epidemiology Branch

Division of Intramural Research

National Institute of Environmental Health Sciences

National Institutes of Health

Pauline Mendola, Ph.D.

Epidemiologist, Epidemiology and Biomarkers Branch

U.S. Environmental Protection Agency

Peter Scheidt, M.D., M.P.H.

Director, National Children’s Study Program Office

Division of Epidemiology, Statistics, and Prevention Research

National Institute of Child Health and Human Development

National Institutes of Health

Kenneth C. Schoendorf, M.D., M.P.H.

Chief, Office of Analysis, Epidemiology, and Health Promotion

National Center for Health Statistics

Centers for Disease Control and Prevention