Lessons from the WHI
Research within the Women’s Health Initiative, perhaps Prentice’s largest and most successful effort, also still continues unabated.
Launched by the first woman director of the NIH, Bernadette Healy, MD, the WHI was a national health study that focused on strategies for preventing heart disease, breast and colorectal cancer and osteoporosis in postmenopausal women, in part as an effort to make up for a lack of research in this area (women and minorities weren’t well represented in most clinical research until the NIH made it a requirement in 1993).
The effort, sponsored by the NIH’s National Heart, Lung and Blood Institute, included a randomized controlled clinical trial, a large observational study and a community prevention study. Ancillary studies and additional analyses continue to this day.
The multi-faceted WHI clinical trial, which enrolled nearly 70,000 postmenopausal women, included a component to rigorously assess the risks and benefits of combined hormone therapy used mainly for menopausal symptom control. This trial component was terminated early by a safety monitoring committee because the overall risks of hormone treatment were considered to outweigh the benefits.
“Our 2002 JAMA publication was a defining moment for WHI,” Prentice recalled in his Statistical Science interview. “There was an elevation of breast cancer incidence in the active hormone randomization group, in conjunction with some elevation in coronary heart disease and a noteworthy elevation in stroke.”
The response was profound — and much of it negative — particularly from the gynecologic community, which was suddenly inundated with phone calls from women asking for advice. There was also pushback from the cardiovascular community who believed hormone therapy was beneficial, Prentice said, and from the pharmaceutical companies that made the popular combined hormone therapy.
But the FDA and other regulatory agencies took the results seriously and combined hormone therapy soon started to come with health warnings. More importantly, 70% of American women using these preparations stopped taking them. As a result of this one WHI finding, breast cancer incidence has been reduced by 15,000 to 20,000 women per year in the U.S. since the data was published.
“That one trial also saved many billions of dollars in health care costs, due to the sea change in the use of menopausal hormones that these trials induced,” Prentice said.
The WHI trial also offered valuable lessons for how to dovetail good science with good communication: when a subsequent WHI trial of estrogens alone was stopped early due to stroke risk, Prentice and his team gave professional societies a heads-up before results were published so they could adequately prepare.
Prentice would like to see today’s NIH develop a similar focus on prevention — complete with large randomized controlled trials, or RCTs. Many of the diseases that plague us are preventable in a much larger way, he said, pointing to the 20 to 25% reduction in coronary heart disease that came about as a result of focused disease prevention research and trials conducted in the 1980s and 90s.
A coordinated research agenda for chronic disease prevention is much needed, he said.
“We need to have additional compelling approaches to preventing major cancers, heart disease, obesity and diabetes,” he said. “Lifestyle interventions are what you want to get to, but these need to be effective in terms of health benefits versus risks. But the NIH, as good as it is, is not highly supportive of this type of prevention research. It’s an extremely hard-sell.”
The WHI provided a great model, he said, since it “conducted research that had outcomes across the entire spectrum of chronic disease.” It also helped researchers from a variety of fields connect and collaborate, learning from each other along the way.
“Some of my most valued colleagues work in cardiovascular disease, endocrinology, bone disease or diabetes, all through WHI,” he said. “These collaborations give one insights as to what might contribute to overall health benefit versus risk for our U.S. population.”
Mentoring and collaborating
Collaboration has long been a hallmark of Prentice’s career and was the inspiration behind the Ross L. Prentice Endowed Professorship of Biostatistical Collaboration, one of the many honors bestowed on the scientist.
“At every turn, Ross fostered a collaborative spirit between the Hutch and UW,” Thomas R. Fleming, PhD, a UW professor of biostatistics and former department chair, said in a recent UW news story. “And in recognition of his achievements, of his dedication and of his leadership, the UW and Fred Hutch jointly established the Ross Prentice Endowed Professorship of Biostatistical Collaboration in 2005.”
Mentorship has also been a significant part of Prentice’s career.
Fred Hutch biostatistician Li Hsu, PhD, who first started working with him as a student at the UW, said she found him to be kind, patient and thoughtful.
“Ross was my PhD advisor and when I did my dissertation with him, he gave me a lot of space,” she said. “Whatever ideas I brought to him, he always listened carefully and showed interest.”
Hsu said in hindsight, many of her ideas and thoughts were probably “naïve or wrong” but Prentice never once discouraged or disparaged her.
“He would instead discuss and explore these ideas with me and guide me into the right direction without me even realizing it at that time,” she said.
Understandably, Prentice’s many contributions to science have garnered him dozens of awards and honors. He holds an honorary doctorate in mathematics from the University of Waterloo, where he received his Bachelor of Science degree; the Nathan Mantel Lifetime Acheivement Award from the American Statistical Association; the Mortimer Spiegelman Award from the American Public Health Association; the Committee of Presidents of Statistical Societies Presidents’ Award; the Marvin Zelen Leadership Award in Statistical Science from Harvard University; the American Association of Cancer Research/American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention; and the American Association for Cancer Research Team Science Award. In 1990, he was elected to the Institute of Medicine/National Academy of Medicine. Even part of the Public Health Sciences building is named for him — the Ross L. Prentice Atrium.
Despite this “celebrity scientist” status, Prentice is very approachable, said Ruth Etzioni, PhD, who was selected as a Prentice professor in 2018.
Although it took a while for her to discover this.
“I watched Ross from a distance for the bulk of my years at Fred Hutch, but was always starstruck,” she said. “He wasn’t just a giant in statistics and methodology, but a giant in epidemiology, as well. He literally wrote the book on survival analysis.”
Etzioni, holder of the Rosalie and Harold Rea Brown Endowed Chair, said she worried about presenting a worthy enough lecture all during the year in which she held the Prentice professorship before finally working up the courage to ask Prentice to lunch to discuss her chosen topic.
“It was like all of these walls I’d envisioned between him and me vanished,” she said. “I discovered that he’s mischievous and funny and spiritual and humble while at the same time confident, which he should be. He’s just a genuinely kind person.”
Many others agree, including colleague Charles Kooperberg, PhD, who’s worked with Prentice since the early days of the WHI.
“Ross is a great leader and colleague,” he said. “I’ve learned a lot from him over the years. We all have. He has accomplished so much and positively influenced so many in his lifetime.”
