Clinical Studies By Design

 Biostatistics Division Helps Researchers Analyze And Focus Investigations

 By Barbara Rodriguez

 Medical maxims, such as ‘Exercise can reduce heart attack risk,’ often help physicians direct their healing efforts. Such guidelines result from well-designed clinical trials that are integral to research institutions such as the School of Medicine.

But developing studies to add to the breadth of medical knowledge is difficult. It requires dedicated physicians, cooperative patients and scrutiny of myriad issues that can cast doubt on study findings.

The medical school’s division of biostatistics, which guides clinical study design, data collection and data analysis, helps investigators tackle the challenges posed by clinical trials. Division members offer advice on diverse issues, such as the number and type of patients to enlist to ensure confidence in a drug study’s results, how to measure the effects of a lifestyle change, or provide statistical know-how to make the most of study data. The division also collaborates with the recently established Center for Clinical Studies when protocols need to be designed or data is to be analyzed for industry-sponsored studies.

The ultimate goal is to use the information we gain for the benefit of average Americans," says Dabeeru C. Rao, PhD, director of the division and professor of biostatistics.

A leader in the field of genetic epidemiology, Rao joined the medical school faculty in 1980 to direct the division at a time when biostatistics was rapidly developing. Until the mid-1960s, says Rao, clinical trials often suffered from lack of focus. The medical school’s biostatistics division, begun in 1966, established a network of support services that Rao says has resulted in a higher caliber of clinical studies.

Quality Control

Clinical study specialists, such as J. Philip Miller, AB, professor of biostatistics, and Ken Schechtman, PhD, associate professor of biostatistics and research associate professor of medicine, help ensure the quality of studies at the medical school.

"There are many ways that problems can creep into a study," Schechtman says. "Biostaticians tend to be more sensitive to these issues than the people in the trenches gathering data from real patients.Schechtman guides several studies on the physiological benefits of exercise in the elderly. In one study, staff at the medical school’s Claude D. Pepper Older American Independence Center are evaluating 300 elderly men and women undergoing nine months of exercise training. Schechtman worked with researchers to select tests to measure physical strength, aerobic fitness and other fitness attributes before and after the training period.

Schechtman and his colleagues in the division also investigate ways to ensure the success of clinical studies. For example, Schechtman has found that researchers benefit from meeting with potential volunteers before a study begins to see if they make their appointments and are comfortable performing the required regimens. This process weeds out those who may be unable or unwilling to follow study guidelines, he says.

Schechtman and Miller also assist in setting standards for cancer studies as part of the Medical Center’s efforts to become a National Cancer Institute-designated Cancer Center. Miller, who directs the Cancer Center’s Biostatistics and Clinical Trial Core, spends much of his time collaborating with investigators planning new cancer studies.

He also oversees biostatistical efforts for collaborations here that focus on aging and other health issues. Currently, Miller is co-director of the coordinating center for studies on ocular hypertension and glaucoma. In another study — a landmark investigation on Duchenne’s muscular dystrophy begun in 1978 — Miller convinced Washington University researchers and others to use standardized tests to gauge disease status and patient responses to potential therapies, an uncommon procedure at the time. The approach allowed the investigators to pool results and provided convincing support for treating Duchenne patients with cortico-steroid hormone drugs that slow the muscle-weakening disease. As director of the division’s Washington University Biostatistics (wubios) Computing Resource Center, Miller creates web sites for information about clinical studies, provides e-mail discussion lines, and encourages use of advanced computer programs that provide combined access to patient information and research data.

Along with Miller and Schechtman, Michael Province, PhD, associate professor of biostatistics, conducts workshops on clinical study design to assist junior faculty and others in soliciting grant funding. In addition, he provides expertise on study management and related areas that ensure data integrity and quality and is one of several senior faculty who conduct seminars and short courses on biostatistics.

Managing Multicenter Studies

In addition to assisting researchers here, the biostatistics division involves itself in a number of large, multicenter studies outside of the Medical Center.

Rao coordinates the most comprehensive family study of its kind to examine factors that may alter the risk of some sedentary people for diabetes or cardiovascular disease with regular exercise. The HERITAGE Family Study began in 1992 after previous studies suggested that some people who exercise only lose weight, while others also improve their heart rates and gain additional benefits that reduce disease risk.

"We want to nail down the genetic and environmental factors underlying these differences and determine how they interact," Rao says.

To do that, clinicians put sedentary members of 103 African- American families and 98 Caucasian families on a 20-week exercise program at field centers at the University of Indiana, Texas A&M University, the University of Minnesota, and Laval University in Quebec, Canada. Rao and Province managed the complex study that involved performing tests for cardiovascular fitness and diabetes risk before and after the exercise program.

In phase two of the study, Rao, Province, Treva Rice, PhD, research assistant professor of biostatistics, and Ingrid Borecki, PhD, research associate professor of biostatistics, will work with Laval University researchers to combine health data with genetic data gathered from blood samples of each volunteer.

The analyses are expected to reveal dozens of lifestyle and hereditary factors that may be relevant. For the past two decades, Rao has directed funding toward development of biostatistical models to help tease out elements that warrant further study. Province has used his background in mathematics to develop a model called SEGPATH to provide more powerful ways to look for disease genes.

Province also is principal investigator for the Family Heart Study begun in 1992 to define factors that influence development of heart disease. In phase one of the multicenter study, he helped select a battery of tests to be used at four research sites in evaluating 1,200 families — 600 that were suspected of being at risk for heart disease and 600 of unknown risk. The Herculean task of hunting for specific heart disease genes in these families is now underway, using markers that function like flags along the DNA to indicate gene locations.

"If there are any fairly big genetic players in heart disease, this study should find them," Province says of the investigation, which is taking place here and at Boston University, the University of Utah, the University of North Carolina at Chapel Hill and the University of Minnesota.

Biostatisticians Rice and Borecki, who help develop and manage large epidemiology studies such as the Family Heart Study, also participate in their own collaborations with other universities. For example, both work with Claude Bouchard, PhD, at Laval University, who began searching two decades ago for genetic factors associated with obesity.

Their work suggests that a relatively rare gene is associated with extreme obesity. The unidentified gene appears to influence how much fat a person carries and an individual’s body mass index, a measure of weight and height that helps indicate disease risk. Another more prevalent gene also appears to influence obesity. "There’s a good list of candidate genes we can take a closer look at to find those specifically involved," Borecki says. 

The division’s success with clinical trials has paved the way for larger endeavors that could provide a model for medical research in the 21st century. With Province’s assistance, Rao directs a multicenter hypertension study called HyperGEN that is part of the largest research effort funded by the National Heart, Lung, and Blood Institute (NHLBI).

HyperGEN researchers at five field centers will evaluate more than 1,200 brothers and sisters who share a risk for high blood pressure. Rao and his collaborators will combine results from this network with those of three other similar networks the NHLBI has funded.

"The entire National Institutes of Health system is watching closely," says Rao. "I am certain the division will continue providing crucial support for key genetic studies such as this and for active clinical efforts at the School of Medicine."