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The National Children's Study Participates in Largest Proposed Study of Childhood Cancer
Could low folic acid intake during pregnancy play a role in the development of childhood cancer?
Do infections or other exposures lead to chromosomal changes in utero found to be associated with childhood leukemia?
 An international alliance of organizations conducting child health cohort studies—including the National Children's Study—may be able to answer these and other questions about rare childhood diseases, particularly about the etiology of childhood leukemia, the most common form of childhood cancer.
Still in the planning stages, the International Childhood Cancer Cohort Consortium, or I4C, would pool information from 11 environmental health studies representing approximately 700,000 children, in hopes that together the data will shed light on how childhood cancer is associated with exposures such as birth weight, maternal folic acid intake, chemical exposures, and infections.
"The I4C is significant because it will allow scientists to look at very rare outcomes that have never been studied before. It has the potential to open new doors of research whose questions have never been answered," said Terry Dwyer, AO, MD, MPH, Director of the Murdoch Children's Research Institute in Melbourne, Australia. Dr. Dwyer was among the first involved in organizing the I4C while serving as a consultant at the National Children's Study Program Office in 2004.
The I4C would allow investigators to uncover associations between certain environmental influences and childhood cancer because of its longitudinal design and large sample size, which is required for these associations to be considered statistically meaningful.
Carol Kasten, MD, is Medical Officer and Geneticist at the National Cancer Institute's Division of Cancer Control and Population Sciences and a member of the I4C Steering Committee. "We know that chromosomal abnormalities associated with some childhood leukemias, called leukemogenic chromosomal translocations, are present at birth. We also know that childhood leukemia from these translocations may not develop for years," she said. "With its large sample size, the consortium can help answer questions like, ‘What environmental events ultimately contribute to the development of these leukemias? How prevalent are these abnormalities in newborns in China? What about in developing countries?'"
Due to the rarity of childhood cancers, researchers generally have had to rely on case control retrospective studies in which data are obtained after an illness has developed. "Retrospective studies yield data that are considered less reliable, because parents may remember the child's early years differently than they would have if their child had remained healthy. The longitudinal design of the I4C will allow researchers to observe children as they develop, rather than depending on parental recall," Dr. Dwyer explained.
Participating Studies
Independently, each cohort study examines the influences of environmental exposures on child health and development, beginning before or at birth. Some cohorts, such as the National Children's Study, are also designed to provide data before conception. Representing nations across four continents, the 11 participating I4C cohorts include:
- The Avon Longitudinal Study of Parents and Children (United Kingdom)
- Bradford Babies: Growing up in Bradford (United Kingdom)
- China Family and Children Cohort Study
- China-U.S. Collaborative Project on Birth Defects and Disabilities Prevention
- Danish National Birth Cohort Study
- French Study on Environment and Children's Health (Étude française sur l'environnement et la santé de l'enfant)
- Environment and Childhood (Infancia y Medioambiente ) (Spain)
- Jerusalem Perinatal Study
- National Children's Study (United States)
- Norwegian Mother and Child Cohort Study
- Tasmanian Infant Health Survey (Australia)
A combined investigation of this size and scope requires sophisticated coordination and communication across cohorts, as well as systems to support the collection, management, and analysis of large and complex data. "Each individual cohort has its own measurements for collecting data but we've already found some to be the same across studies. Consortium members are currently analyzing other common measures, and exploring the best ways to organize all the data," explained Dr. Dwyer.
Consortium Leadership
The I4C coalesced after researchers from the various cohorts met to discuss the feasibility of cross-cultural collaboration at a September 2005 workshop sponsored by the National Children’s Study, the National Cancer Institute (NCI), and the U.S. Environmental Protection Agency (EPA). The I4C is led by a Steering Committee of principal investigators from the National Children's Study, the Danish National Birth Cohort, the China Family and Children Cohort Study, and the Tasmanian Infant Health Survey, as well as representatives from the National Institute for Child Health and Human Development (NICHD), the NCI, and the EPA.
The I4C works in tandem with the National Children's Study International Interest Group (IIG), established in 2002 to encourage the international exchange of information about how the environment affects children. Co-led by the NICHD and the World Health Organization, the IIG is working to determine the feasibility of longitudinal cancer studies in developing nations and to create core protocols for international long-term cancer studies. Protocols are guidelines for a study's sampling, recruitment, and data collection activities.
Consortium Activities
I4C planners are currently developing their own protocols to test the concept and feasibility of the consortium and to analyze childhood cancer data for two hypotheses—how low maternal folic acid intake at conception is related to the development of childhood leukemia and whether infections or other exposures lead to the presence of chromosomal changes in utero found to be associated with childhood leukemia.
Once protocols are completed, biological samples and other information obtained from the active cohort studies—those studies whose data collection is under way or complete—will be evaluated. Consortium members will meet to discuss these analyses about the first two hypotheses at their next meeting in 2007.
"There is a great deal of excitement and enthusiasm for this collaboration across the cohorts. Working together, we can explore research areas that could never have been investigated in our individual studies alone," said Dr. Dwyer.
Questions or comments about the I4C can be sent to NCS@mail.nih.gov.
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Update on National Children's Study Activities and Funding
The National Children's Study continues to move forward with planned activities that set the stage for full Study implementation. These activities include, but are not limited to, refinement of the Study protocol; further development of the information management system; creation of an electronic informed consent tool; and development of a focused recruitment and retention plan that includes activities for community outreach and engagement. Study stakeholders are providing essential input in the development of each of these tasks. For instance, recruitment and retention efforts are led by a working team of representatives from each of the seven Vanguard Centers and the Program Office, with input from the National Children's Study Federal Advisory Committee members and the Interagency Coordinating Committee.
The timeline for these activities, and the Study's progression into the recruitment phase, depends on the outcome of budget negotiations in Congress this summer and fall. If Congress approves adequate FY 2007 funding for the Study, planning activities will continue and the seven operating Vanguard Centers will begin preparing for recruitment to occur in about a year. Other implementation activities—the release of a Request For Proposals for further Study Centers, implementation of the information management system, and the development of a repository for stored samples—would soon follow.
If the National Children's Study does not receive the $69 million needed for continued operation in FY 2007, the Study would not continue on its current course and would cease operation. Currently, both the Senate and House Appropriations Committees are preparing to bring their budgets to the floor for consideration.
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Barbara Entwisle, PhD
"The social and environmental context of people's lives is really important for health, health behavior, and related outcomes," said Dr. Barbara Entwisle, Director of the Carolina Population Center (CPC) at the University of North Carolina (UNC) at Chapel Hill and Principal Investigator of the National Children's Study Vanguard Center for Duplin County, North Carolina.
The Duplin County Vanguard Center is one of seven centers across the country that are setting up systems to support enrollment and data collection for the National Children's Study.
"With the National Children's Study, we have the opportunity to understand the biological mechanisms that translate contextual influences into health outcomes for children," said Dr. Entwisle, one of a large group of social scientists who, along with health and medical scientists, are interested in the Study. "This is the frontier of science. It's at the cutting edge." Of particular appeal is the Study's representative nature. Social as well as biomedical aspects are important to children's health, and the Study design allows both to be pursued with scientific rigor.
Duplin County is one of the 105 locations selected throughout the United States for the Study. Though rural and sparsely settled, it is home to one of the fastest-growing Hispanic populations in the country, many of whom are attracted by jobs in agriculture and in the hog and poultry processing industries. Duplin County is located in a part of North Carolina that is, and has been, in economic decline. It has higher-than-average poverty (almost 23% of Duplin County children were living in poverty in 2000).
These characteristics raise important health issues for children. "The Study provides a way to link health outcomes with social inequality, one of my longstanding interests," said Dr. Entwisle. Death rates for infants and children living in Duplin County are above the average for the state and the nation. Results from the Study might lead to effective ways to reduce these death rates, as well as to shed light on the health concerns of Hispanic families in Duplin.
After receiving her doctorate in sociology from Brown University, Dr. Entwisle held faculty positions at the University of Michigan and Dartmouth College. She is a social demographer with primary interests in social and biophysical contexts and their consequences for families and children. She has particular expertise in the measurement of community and neighborhood characteristics, including the biophysical environment. She has extensive survey experience, contributing to the design and implementation of longitudinal population-based surveys collecting social and health data in the U.S. and around the world. Her central role in the field of demography was recently recognized when she was elected President of the Population Association of America.
One of the questions she hopes the National Children's Study will answer is how neighborhoods matter for children—that is, ways in which neighborhoods that are integrated, cohesive, and willing to intervene on behalf of children make a difference for children's health and well-being. In social science, this concept is called neighborhood collective efficacy. If collective efficacy is beneficial to children, according to Dr. Entwisle, results of the Study might suggest policies and approaches that would help improve collective efficacy, and consequently, benefit children.
The National Children's Study Program Office and Coordinating Center are currently defining the segments within the seven active locations nationally where women will be recruited for the Study, pending funding availability. In Duplin County the process is aided by the staff at the CPC and Duplin County's Vanguard Center's partners at Duke University, Battelle Memorial Institute, and Mount Sinai School of Medicine. Getting these neighborhood boundaries right, with the help of county residents, is vital if questions about collective efficacy and other social science constructs are to be understood.
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Folic Acid: Beyond Prevention
Two randomized, controlled clinical trials in the early 1990s showed that the B vitamin folic acid can prevent a large proportion of neural tube defects (NTDs). 1, 2These defects result when the neural tube—a groove in the embryo that gives rise to the brain and spinal cord—fails to close completely or correctly early in pregnancy. One such defect, spina bifida, is an incomplete closure of the spinal column; in its severest form, a portion of the spinal cord may protrude through the back. Another defect, encephalocele, results when one or more plates that make up the skull fail to seal.
Today, women with the possibility of becoming pregnant are advised to take 400 micrograms of folic acid every day. To further reduce the incidence of NTDs, the U.S. Food and Drug Administration authorized optional, followed by mandatory, folic acid fortification of the country's flour and grain supply.
A new study in Pediatrics shows that folic acid may not only prevent NTDs but also reduce the severity of NTDs when they occur. 3For the National Birth Defects Prevention Network, researchers studied two cohorts of infants born between 1995 and 2001: 2,841 infants born with spina bifida and 638 infants born with encephalocele. The researchers estimated first-year survival rates across three folic acid fortification periods: pre-fortification, optional fortification, and mandatory fortification. Mandatory folic acid fortification coincided with improved first-year survival rates for infants with spina bifida (92.1 percent vs. 90.3 percent) and encephalocele (79.1 percent vs. 75.7 percent).
The International Childhood Cancer Cohort Consortium, of which the National Children's Study is a part, plans to examine the role of maternal folic acid intake through diet and supplementation, along with the role of variations or mutations in genes that affect how the body uses folic acid, in the development of childhood leukemia. This investigation can build on our understanding of folic acid by measuring actual folic acid intake among women as opposed to exposure to folic acid fortification, and it will look at health outcomes beyond infancy.
1. Czeizel, A.E., & Dudas, I. (1992). Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. TheNew England Journal of Medicine, 327, 1832–1835.
2. Medical Research Council Vitamin Study Research Group. (1991). Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet, 338, 131–137.
3. Bol, K.A., Collins, J.S., & Kirby, R.S. for the National Birth Defects Prevention Network. (2006). Survival of infants with neural tube defects in the presence of folic acid fortification. Pediatrics, 117, 803–813.
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