Health Sciences Report Summer 2006

The Power of the Big Picture
How the National Children's Study Is Playing Out in Utah

By Susan Sample
Photos By Steve Leitch

Politics may delete "national" from the title and divert millions of dollars from the National Children's Study (NCS). But the research, like its focus, the health and development of the next generation of children, will go on. That much is clear to Edward B. Clark, M.D.

"We know we have an epidemic of obesity and diabetes. We have another epidemic of asthma," Clark told National Public Radio's All Things Considered last February. "We have an epidemic of autism, and all of these really point to the fact that the current generation of children is the first in hundreds of years to be less healthy than their parents.

"I'm not only surprised, I'm baffled," said Clark, chair of the Department of Pediatrics at the University of Utah School of Medicine and medical director of Primary Children's Medical Center, "why a study that has such broad support throughout the nation should be targeted for closure."

That's what happened when the White House sent its proposed budget for fiscal year 2007 to Congress early last spring, less than four months after the National Institutes of Health (NIH) had announced with much fanfare the selection of six "Vanguard" centers to pilot the first phases of the study, including the U of U, Primary Children's Medical Center, and Salt Lake County. The designation carried with it a $16 million contract from the National Institute of Child Health & Human Development, NIH, and other federal partners. Already, the U team is gearing up to begin enrolling study participants in January 2008.

Like his colleagues across the country, Clark was caught off guard by the budget news. But within hours, Utah's principal investigator had retrenched and strategized contingency plans to continue what he considers critical research. "We're moving full speed ahead. This is political hardball," he told his core NCS team of 15 gathered in what they presciently had dubbed "the War Room" in the U pediatrics department. Taped on the wall behind them was the 16-foot-long timeline for Utah. "No matter what happens, we're committed to carrying out an extensive study in our region."

Core Team: Edward B. Clark, M.D., center seated, heads the U of U Vanguard Center Staff for the National Children's Study. Joining him are: front row, from left: Laurie Moyer-Mileur, Ph.D., R.D., seated; and Jeremy Pero; second row: Nicole Mihalopoulos, M.D., M.P.H.; Michael Varner, M.D.; Phyllis Pettit Nassi; Sean Firth, Ph.D., M.P.H.; and Brent Brown; back row�Rodney Larson, Ph.D.; Debbie Gabaldon; Jan Johnson; and Leon Pahler, Ph.D., M.P.H. Not pictured are: Carol Sweeney, Ph.D.; Cheryl Coffin, M.D.; Jeffrey Botkin, M.D., M.P.H.; Joseph Stanford, M.D., M.P.H.; Mark Leppert, Ph.D.; Shelisa Dalton; Pamela Silberman; and Jacquie Bernard.

Not because Clark and his team, who represent seven departments in the School of Medicine, in addition to others in four colleges and 10 departments across the U campus, had worked since 2000 to dream and brainstorm, analyze, write, and rewrite the 1,500-page proposal that earned them the prestigious selection as a Vanguard site. Rather, the NCS, in whatever form it takes, has a unique power: it will change lives. It already has in Utah.

Whether they're newly recruited from New York or longtime U of U faculty, individuals on Utah's Vanguard team reflect how this historic study is powered not only by professional expertise, but by what they're each most passionate about.

"What sets the NCS apart is size. By following 100,000 children for 21 years, it has the potential to make associations we're not used to seeing in epidemiological studies," said Rodney Larson, Ph.D., director of industrial hygiene for the medical school's Rocky Mountain Center for Occupational and Environmental Health. Literally the day after Larson joined the U faculty in 2004, Clark's team recruited him to the NCS team. "This really is the culmination of so much of what I've done: dealing with pesticides, heavy metals, and hydrocarbons. It's utilizing all of my skills. It's challenging," he added, "but fun and exciting."

For 14 years, Larson worked in international industrial hygiene for Exxon Mobil. He was the third person called in response to the infamous 1989 oil spill from the Exxon Valdez in Alaska. Later, at the University of Alabama at Birmingham, he earned a doctorate in environmental toxicology and worked on a study of the potential hazards of chemotherapy agents for nurses administering them. He developed methods for measuring, analyzing, and quantifying chemicals in the air and on surfaces, which later were adopted by the National Institute for Occupational Safety and Health.

Since joining the U's Vanguard team, Larson has been asked to share his expertise on a national committee, the Environmental Team, and a subcommittee on measurements. He is helping define criteria for key aspects of the NCS, among them: the most cost-effective and efficient ways to collect environmental samples, ranging from house dust to drinking water to air to soil in the backyards of children in the study; which contaminants the samples should be tested for; and how they will be measured.

His meticulous attention to detail is shared by team member Carol Sweeney, Ph.D., associate professor in the Department of Family and Preventive Medicine. "These little things are what we spend our time on," she said, referring to conference calls in which she and other epidemiologists nationwide debate the best way to administer food survey questionnaires. Like Larson, she's also discovered that the NCS is merging divergent paths in her professional life.

For five years, Sweeney worked for the U.S. Environmental Protection Agency (EPA) in Seattle, where she did risk assessments for hazardous waste sites. Increasingly, "I saw problems coming up that we didn't have answers for." She earned a doctorate from the University of Washington and since has focused on cancer epidemiology.

"For an epidemiologist, the issue is power: statistical power. You need a large population to observe and to get significant results," she explained.

The NCS presents a rare opportunity: researchers will have enough data to determine whether there are links between physical, chemical, social, and behavioral factors in the environment and chronic childhood diseases and disorders. Specifically, they'll look at asthma, obesity, diabetes, autism, and birth defects.

"This project is of unprecedented size. It's very exciting to me. And it's bringing me back to my interest in environmental health," Sweeney added.

She is helping develop programs to hire and train study coordinators and bilingual research assistants. They will be responsible for recruiting 1,250 mothers-to-be from targeted communities in Salt Lake County to participate in the NCS. With 18,350 births recorded in 2004, Salt Lake is one of the nation's youngest counties. Births are linked to the Utah Population Database, which provides information and access to several generations. Both are key reasons Salt Lake was chosen as a Vanguard site. The county also is ethnically diverse: in 16 percent of the homes, English is not the dominant language. In addition, it's a unique urban area: surrounded by mountains and wilderness and encompassing 11 Superfund clean-up sites.

"Having the right people as coordinators is so important in studies like this," stressed Sweeney. "They have to respect that people can choose not to participate. They must be positive and persistent. An ongoing one-on-one relationship between the field staff and the families has to be built."

For more than 20 years, research assistants will maintain contact with the children's families by phone and mail, and through home visits. They'll collect information about the children's lives, as well as biologic, genetic, and environmental samples.

"Each of us has our own little angle: a little picture that's part of a huge panorama," said Jeffrey Botkin, M.D., M.P.H., who knows firsthand how multiple roles fit together. He is professor of general pediatrics, professor of medical ethics, and adjunct professor of human genetics, in addition to University associate vice president for research integrity.

Research ethics is Botkin's angle on the NCS. Not only is the project the country's largest long-term pediatric study, but it's also observational. No treatment is being offered. This raises new questions for ethicists, primary among them: how should information generated from the project be dealt with?

As a hypothetical example, researchers could decide to measure the health effects of exposure to a new pesticide. If they detected a significant amount in a child's system, what would be their obligation to inform the family? "On one hand, we may not know the health effects, but we're concerned enough to measure it," said Botkin, who co-chaired the national ethics working group in 2000 and directs research integrity for the U Vanguard site. On the other, "if we do tell them, it could impact the study. We can't measure long-term exposure, if the exposure ends."

Community exposure is an additional consideration. "If you measure for a toxic agent, what is your responsibility as a research team to get that information back to the community? What if no one does an analysis for 10 years? Then what is your obligation?

"These are some of the central ethical challenges," said Botkin. "We'll collaborate to develop guidelines and make recommendations before the study starts. Hopefully, we'll also create an extemporaneous data safety monitoring board or ethics committee to which we can present problems for help with solutions.

"We're a pilot for a lot of key elements. This Vanguard site is critical," said Botkin, speaking not only as a medical ethicist, but as a pediatrician.

Children need advocates. Without money or voices, they wield no power, especially in health care, said Nicole Mihalopoulos, M.D., M.P.H. An assistant professor in the U Department of Pediatrics, she is the sole internist and specializes in adolescent and preventive medicine, with an emphasis on obesity.

That was not her original intention. As a medical student at Tulane University in New Orleans, the Utah native and graduate of the U College of Health thought she was destined for internal medicine. She began a residency with a dual focus in preventive medicine, but found herself surprised: "During the month of adolescent medicine, I loved it! I liked talking with teens. I really liked the women's health piece, too. Like being a "myth-buster,"" she explained, referring to misconceptions, like douching is a form of birth control, she helps dispel. "It's a young enough age group that I could really make a difference."

While working at the Louisiana Department of Public Health, her interest in prevention expanded. Mihalopoulos became involved in that state's Bogalusa Heart Study, a 40-year-old research project that has tracked cardiovascular risk factors in children and has led to discoveries about early heart disease in kids. That helped prepare her for a fellowship in preventive cardiology and adolescent medicine at the University of Rochester. Then came an unexpected shift in her career.

"I was going to be a clinician, but who knows? The wind blew the other way?" she mused. "I met Ed Clark in December 2004, and he told me about the National Children's Study. It was still at ground zero. To be involved from the get-go would be phenomenal. I could create my niche in the world."

Two years earlier, Clark's recruiting had taken him to Texas, where Sean Firth, Ph.D., M.P.H., was working in Austin for PPD, a contract research organization, as an assistant project manager. Previously, he'd worked for the nation's largest prospective clinical trial, ALLHAT (an acronym, more or less, for Antihypertensive Lipid Lowering Treatment to Prevent Heart Attack Trial).

"I had a job I loved in a city I loved," said Firth, an epidemiologist who'd received his doctorate from the University of Texas School of Public Health.

"Then Ed came knocking," recalled Firth, who'd earned his bachelor's and master's degrees from the U. "He convinced me to come back."

As NCS project director, Firth is responsible for operations, supervising personnel, and handling the study's problems. Or, as he humorously describes it, "This is Ed's baby, and I'm, the babysitter. I'm the one who knows his cell phone number."

Since 2004, Firth and Jan Johnson, NCS administrator, have worked to create an infrastructure for the study by anticipating all the data to be collected: biological, sociological, environmental, psychosocial. "We made some pretty ugly spreadsheets," noted Firth, research assistant professor of pediatrics. Those calculations not only helped the U win the coveted Vanguard designation, but equally important, enabled "cross-talk between disciplines." As Firth sees it, despite the politics surrounding the NCS, "people have been brought together and are talking across departments."

He's optimistic for the study's future, though. "By the time I approach retirement, the study will be done; the science, complete. I can finish my career asking poignant questions I can't even conceive of now. That's the most exciting part."

"Auspicious confluence" is how Michael Varner, M.D., views the power of the NCS to ignite the passion that drives each professional in the U team.The phrase is from Buddhism. For nearly seven years, Varner has volunteered in Tibet with a U of U humanitarian project to decrease the high incidence of maternal and fetal deaths.

"From a personal standpoint, the possibility--the privilege--of helping set up something which will have lasting effects on the health of society is pretty awe-inspiring," he said of the NCS.

"My passion is clinical research. To me, that's the most fun part of my profession," said Varner, professor and chief of the Division of Maternal-Fetal Medicine in the Department of Obstetrics and Gynecology. He also is the University's principal investigator for the national Maternal-Fetal Medicine Units Network. Fourteen academic medical centers participate in clinical trials that are shaping the practice of modern obstetrics.

Yet, he acknowledged, "we know very little about environmental influence on pregnancy outcomes. The National Children's Study is the opportunity of several professional lifetimes. It really is the opportunity to determine whether any prenatal screening we do, or could do, will have an impact on a truly meaningful outcome." Varner is quick to define a pregnancy's outcome as more than numbers. "Outcomes can have statistical significance, but to me, it's not birth weight or other clinical measures. It's whether a child can tie his or her shoes and go to kindergarten at age five."

As a senior investigator on the U team who also is active on the national level, the obstetrician is helping determine age limits for pregnant women participating in the NCS. At issue last spring was whether 16- and 17-yearolds, who are legally minors, should be asked, as well as women who become pregnant in their late 40s, past the usual age range for childbearing.

"The NCS has the potential to answer questions we've never been able to ask," noted Varner, "and to ask a number we've never even thought to ask before."

That prospect is particularly exciting to Cheryl M. Coffin, M.D., professor and chief of the Division of Pediatric Pathology. If the study is fully funded, she foresees researchers returning for the next 100 years to data collected for the NCS. "In 20, 30, 40 years, we might have new information on obesity or asthma that would make us want to go back to the Vanguard sites and test further," she said. "That's why it's so exciting. What will we discover in the next decades?"

It's equally daunting for Coffin. As leader of the U biosample team and a member of the national biosample planning team, she is responsible for the long-term storage of biosamples, ranging from blood and urine to hair, baby teeth, fingernail clippings, and placentas.

"What will be the optimal storage requirements? Minus 80 degrees in liquid nitrogen? That probably would be optimal to test for chemical compounds found in some biologic samples," she surmised. "This study is forging into uncharted territory."

And it will be a large territory. Coffin estimates that, in the first five years of the study in Salt Lake County, coordinators will collect 85,000 samples of blood alone. Multiply that by the seven Vanguard sites across the nation, and the size of the central storage facility will have to be huge. "It will need a robotic retrieval system," she noted.

Laboratory techniques used to analyze biosamples are another major concern. "Five decades ago, we began to systematically classify and develop therapeutic protocols for different types of cancer in children," said Coffin. "In the past 20 years, we've learned how to classify tumors in new ways we think are sophisticated, using immunohistochemistry, genetic tests, and classic pathology under the microscope. But 50 years from now, what we're doing may seem primitive."

The significance of the NCS, however, remains timeless. "It taps into our hearts and minds. It's about children. It's about families. It's about everyone. For me personally," Coffin paused to look around her office, beyond the microscope on her desk, the bookshelves lining each wall, "it taps into values that are important to me, environmental policy and planning for communities; although these are different from how I've spent much of my academic career.

"My focus the past 20 years has been on surgical pathology with an emphasis on soft-tissue sarcomas. But I had an early interest in public health and in family medicine. And I've always been fascinated with the epidemiology of cancer and genetic abnormalities that are becoming increasingly important in understanding human cancer."

Laurie Moyer-Mileur, Ph.D., R.D., is fascinated by what the future of the children in the NCS will reveal: "When they get to middle age, then we really can ask questions. If they develop diabetes or cancer, we can see if there is any link to childhood exposures."

For a research associate professor in the Division of Neonatology, that may seem like an unusual perspective. Moyer-Mileur's expertise is the physical measurement of growth in newborns, specifically, body composition, fat, muscle, and bone. She is immersed in national deliberations on how to standardize tests for the NCS.

"Newborns are easy to measure. They sleep," she said. "But 6- and 12-month-olds? They don't know what you're doing, and they don't like to sit still."

As a registered dietitian, Moyer-Mileur was a member of an early national nutrition and growth working group, which discussed how to evaluate children's dietary content. Again, practical details complicate the science. "It's one thing for adults to tell you what they've eaten," she said, "but a 2-year-old will travel, drop, pick up, and eat. You don't want to miss anything, because this data is important."

Parents of children enrolled in the study will be asked to freeze portions of meals they've cooked in their homes. The samples will be collected and shipped to an EPA lab, where they'll be analyzed for food composition as well as possible environmental contamination. "So many things can be tested for. Pesticides, for example," explained Moyer-Mileur. "We don't have moist weather, so we don't worry much about cockroaches coming out in kitchens. But in many areas of the country, they do."

In addition to conducting pilot studies on measurement tools, community diet assessments, and nutrition surveys for the NCS, Moyer-Mileur is collaborating with Mark Leppert, Ph.D., co-chair of the U Department of Human Genetics and senior investigator on the U team, on an adjunct study. That's an example of another advantage to being named a Vanguard site: researchers from across the U campus can use the NCS infrastructure for studies they initiate. Leppert and Moyer-Mileur will examine skeletal growth and fracture risks.

"No one is quite sure why some kids break bones frequently and some never do. We'll look at genes already linked to lower bone mass in teens and osteoporosis in adult women," said Moyer-Mileur. "Is it a new gene not identified? Or an earlier manifestation of a known gene?"

How genetics and the environment interact to influence health is particularly meaningful to the U researcher. Knowing that their grandmother and mother had breast cancer, Moyer-Mileur and her sister thought they had "done everything" to lower their risk. Neither escaped the diagnosis. The winter before last, a year before her second granddaughter was born, Moyer-Mileur finished her final round of chemotherapy.

"From a scientist's standpoint," she said, "the best part of the NCS is what we're going to learn and how it will benefit people. Then you think about your own children and grandchildren and great-grandchildren. You just hope it will make their lives healthier."

Back in Washington, D.C., Joseph Stanford, M.D., M.S.P.H., follows each skirmish in the battle to secure funding for the NCS and reports back, via conference call, to the U team. Since August 2005, the Utah associate professor of family and preventive medicine has been on sabbatical at the NIH, where he's focusing on epidemiological research into fertility-related issues.

Before the U was officially designated as a Vanguard site, "I couldn't talk to people doing the study. We had to make sure we didn't say anything to each other in the hall, other than "Hi." It would be a conflict of interest," he recalled. Afterward, "I went to the National Press Club for the announcement. That was pretty exciting. There's something about being here, not just reading about an event in the newspaper."

A specialist in conception research, Stanford has been involved in the NCS since its preconception, serving on the national fertility and early pregnancy committee. Last year, he finished a fouryear term on the FDA reproductive health advisory committee. To him, the NCS stands out for its comprehensiveness.

"Other studies are limited by windows of time and windows of exposure. You can't put the big picture together. This is a chance to get the big picture," noted Stanford. "That aspect excites me the most, more than any specific disease."

In Stanford's mind, the size of the NCS also makes the project inevitable. "My bottom line is that this study is ultimately so compelling, it's got to happen. The question is: will we have the foresight to do it now? Or will we be behind the curve?"

He cited smaller versions of the NCS already being planned in China, England, Canada, and Scandinavia. "That's one of the reasons I say it's inevitable. Many countries are recognizing the value of this study. It would be nice if the United States could be at the table, too.

"I don't know if the NCS will happen at the full scale envisioned. If it doesn't," he said, "it will be really sad, because it will be done later, and we will have lost time."

In terms of the NCS, time is measured in the lives of American children. For the current generation, epidemics of obesity, diabetes, and autism, along with alarming increases in chronic diseases, may mean these children won't be living as long as their parents. To Ed Clark, that's a frightening future.

"As a pediatrician, I'm asked three things: "Will my child be okay?" And then: "What's caused this?" Then," he said, "I'm asked if there's any research going on and: "Can we participate?"

"We know there's an environmentalgenetic interaction in children's health and development. We just don't know how it occurs and why. This study will help us immensely. To pull the plug on it is inexcusable," said Clark. "I think it's immoral to abandon the country's children."

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