How NIH's massive research program could shape the delivery of medicine

When Dr. Jeffrey Whittle graduated from medical school in 1984, colleagues told him he’d soon be using patients’ genetic information to manage their care. By studying a patient’s genome, or entire set of DNA, in conjunction with other factors such as lifestyle or environment, clinicians would be able to determine which medication is best suited to treat their cholesterol, diabetes or hypertension.

“I’ve been a doctor for almost 40 years now, and I am still not using genetic information in my everyday practice,” said Whittle, a primary care doctor and inpatient hospitalist at Clement J. Zablocki Veterans’ Administration Medical Center and a professor of medicine at the Medical College of Wisconsin, both in Milwaukee.

Although physicians use genetic data to help inform treatment in some specialties, such as oncology, the practice is not yet routine in general medicine. Whittle serves as one of the Medical College of Wisconsin’s principal investigators for the National Institutes of Health’s All of Us Research Program, which works to bring the scenario his colleagues described closer to reality. The precision medicine initiative aims to build a large-scale database for researchers by performing whole-genome sequencing on a diverse cohort of participants and conducting longitudinal follow-ups via surveys. One of its eventual goals is to enable clinicians to better tailor healthcare to each patient’s needs.

More than 60 healthcare organizations and academic institutions are enrolling participants, sharing electronic health records and collecting biosamples for the All of Us initiative. As the program nears its five-year mark, researchers are beginning to use the data to publish studies with potential clinical implications. But stakeholders say All of Us needs the long-term commitment of participants, partner organizations and researchers to reach its full potential.

An ambitious target

All of Us, which opened to participants nationwide in 2018, aims to enroll 1 million or more people by 2028. Its goal is to develop a cohort where 75% of participants are from historically underrepresented groups in medical research, as defined by the NIH with input from the National Institute on Minority Health and Health Disparities and other stakeholders. Although the program said it does not have specific targets for enrollment numbers within demographics, representatives said it’s seeking participants from socioeconomically disadvantaged populations, rural areas and the LGBTQ community. It also strives for half of its enrollment to comprise members of racial or ethnic minority groups.

“Many research studies have focused mainly on Caucasian and European descent individuals, and we really wanted to make sure that we were actually going to be coming up with discoveries and potential cures for everyone, and not just a one-size-fits-all based on research that was done on just one tiny bit of the population,” said Sheri Schully, deputy chief medical and scientific officer for All of Us.

More than 420,000 people have agreed to share electronic health records, provided blood or urine samples, given physical measurements like hip-waist ratio and completed three initial surveys. The program is seeking to draw people into the cohort from the upper Midwest, particularly rural areas.

The NIH also aims to allow researchers to consider non-clinical factors. In addition to the core surveys inquiring about basic demographics, lifestyle and overall health, all participants are periodically offered the chance to complete other questionnaires, geared toward creating a more holistic understanding of wellness.

Joyce Bell Winkler, a retired registered nurse and the former principal investigator for All of Us at Eau Claire Cooperative Health Center in Columbia, South Carolina, helped prepare a survey launched in November 2021 that asked participants about various social and environmental concerns. She said the goal was to show how access to housing, transportation and jobs drives health outcomes.

“So much of what people think about their health is in one dimension,” Winkler said.

Why partner?

The 21st Century Cures Act, passed in 2016, approved $1.5 billion for the program over 10 years. Much of the money goes toward healthcare institutions, which annually receive a few million dollars in grant funding to assist with enrollment initiatives and compensate faculty and staff. Principal investigators at organizations are responsible for overseeing the research projects and grant awards.

In addition to the financial incentives, organization representatives said having more complete data on those they serve will yield better patient care.

The Medical College of Wisconsin, in partnership with Froedtert Health, has enrolled more than 7,300 participants. Social determinants of health influencing communities of color in Milwaukee differ from those driving outcomes for people in other parts of the country, Whittle said.

Whittle also noted health outcomes across the state can vary as a result of different external factors. For instance, exposure to mining and agricultural chemicals may affect those living in the northern part of the state, whereas segregation may drive different health outcomes for those in its cities, he said.

“One advantage of being one of the [All of Us] sites is we can study not just the Hispanic population, but we could study the Hispanic population [who] lives here in Milwaukee,” Whittle said.

He emphasized the program’s broad-scale usefulness. Although All of Us does offer participants individualized information about their health, such as whether they carry the BRCA gene mutation that indicates a risk for breast cancer, Whittle said he wouldn’t make any treatment decisions as a doctor based on the initial results. Participants can repeat tests in a clinical lab, but health insurers may opt out of covering them.

Informing participants they can’t use seemingly important medical information for care is “one of the struggles that the All of Us Research Program faces,” Whittle said, although it does make genetic counselors available through a partnership to participants seeking more information. The partnership can also help connect some participants with a free clinical test.

The Medical College of Wisconsin encourages individuals to get involved to advance population health.

“We recruit people because they’re thinking, ‘I want to help my children,’” Whittle said.

Cherokee Health Systems, a Knoxville, Tennessee-based federally qualified health center that operates 21 clinics, has recruited more than 1,800 participants through events, system newsletters and new patient registration packets.

Federally qualified health centers don’t typically have the funds to conduct research like regional medical centers do. The partnership could help the center expand its research capabilities over the next several years, said Eboni Winford, Cherokee Health Systems’ director of research and health equity and the site’s principal investigator for All of Us.

In the shorter term, she said partnering has boosted the federally qualified health center’s reputation and helped it when applying for grants to enhance clinical services.

“As an institution, I think [the partnership] sets us apart,” Winford said.

In Winford’s view, the research program’s use of healthcare organizations—and the relationships they’ve built with patients—for recruitment helps foster a culture of trust, especially among those historically overlooked or harmed by research. She and the health system’s team wanted to participate in part so their mostly low-income, uninsured or underinsured patients had the opportunity to ask questions about how their data would be used and provide informed consent in a familiar environment.

“Even though we couldn’t clearly, at the beginning, see the direct return of benefits for individuals, we wanted to provide a safe space where if they wanted to participate … they could,” she said.

Involvement in the program hasn’t always been easy. Organizations have had to overcome obstacles related to enrolling and retaining participants, using technology and learning to use the research platform.

For instance, when All of Us began, it required email addresses to participate. Winford and others at Cherokee Health Systems had to help many interested patients create their own. After considering feedback from clinics, All of Us now asks for phone numbers instead.

Cherokee Health Systems also used digital equity funding it received from the Health Resources and Services Administration to install computers in its waiting rooms for enrollment purposes.

“We had to build in the technology that I think the program assumed most people would have,” Winford said.

Data in, research out

Researchers approved through a credentialing process to access the data are pursuing more than 4,000 projects, although fewer than 150 have been published to date. The early studies include examinations of hypertension among underrepresented groups and the associations between thyroid eye disease and glaucoma. Schully said the program aims to double the number of published papers by the end of the year.

The research generated from the initiative will promote a better understanding of the intersections of genomics, social determinants of health and various risk factors, said Dr. Raj Shah, a principal investigator for the program at Rush University Medical Center in Chicago, which has recruited 2,800 people. The information can then help physicians like himself unlock the most effective treatment for each individual, he said.

Genetic analysis “has to be, like any tool, put into the right position with other information,” said Shah, a geriatrician and professor in the department of family and preventive medicine at Rush Medical College.

The published papers also include so-called demonstration projects, meant to evaluate the quality of the data and guide adjustments to the program. Rush University Medical Center and about a dozen other institutions teamed up for one such research article published in PLOS One in September, which investigated cancer prevalence among the All of Us study population compared with data reported by the National Cancer Institute’s Surveillance, Epidemiology and End Results program. It found that medically underrepresented groups were not self-reporting cancers on All of Us surveys as frequently, potentially affecting future research. The initiative’s leadership team changed the survey timeline to address some of the potential limitations.

Although All of Us was initially funded as a 10-year project, its stakeholders are seeking a longer-term strategy through collaboration.

“Our goal is to have relationships with our participants for decades ... [and] we seek future partnerships with health provider organizations as well as various folks on the outside so that everyone really feels invested in making this program a success for decades to come,” Schully said.

Considering the progress of other large-scale biomedical databases and research hubs, it will take several years for the number of All of Us research papers to grow, said Christine Cole Johnson, chair of the department of public health sciences and a principal investigator for the program at Detroit-based Henry Ford Health, which has recruited more than 12,300 participants and is running three demonstration projects. But Johnson said she anticipates momentum increasing quickly from there.

With the extensive information generated, Johnson said she expects doctors to gain a greater understanding of the metabolic variations that cause people to process drugs differently. She said she thinks it will soon become the norm for people to have their genomes sequenced.

“I think the promise is amazing. I think we’re not going to recognize how we do medicine in 10 or 15 years,” Johnson said. 

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This story has been corrected to reflect the All of Us program’s goals for enrollment and to note the program makes free clinical tests available to some participants through a partnership.