Five lessons from the first five years of the All of Us Research Program

Over the past five years, more than 675,000 Americans — including 25,000-plus from Alabama — have agreed to join a groundbreaking National Institutes of Health initiative that aims to gather health data from a million or more people living in the United States.

The All of Us Research Program, launched in May 2018, was designed to create a new kind of cohort study. That is, something like the famous Framingham Heart Study, but not restricted to one part of the body, and on a scale never seen before. All of Us intentionally oversamples communities that have often been missing from such studies. More than 50 percent of people enrolled in All of Us are from racial and ethnic minorities, and 80 percent of participants are from groups that are underrepresented in biomedical research.

“Many of the studies that have been done to date have been in people largely of European ancestry, and we have learned that what you can tell from one population does not necessarily apply to others,” said Bruce Korf, M.D., Ph.D., associate dean for Genomic Medicine for the UAB Marnix E. Heersink School of Medicine. Korf is the contact principal investigator for the All of Us Southern Network, which includes institutions in Alabama, Mississippi and Louisiana. “You have to reach people of other backgrounds, and you have to be willing to learn from those communities about what is important to them and how to work with them.”

As the All of Us Research Program marks its first five years, we asked Korf to reflect on the program’s accomplishments so far and what to look for in the years ahead.

1. Making precision medicine possible

“We have been talking about the idea of precision medicine for the past few decades — customizing prevention, diagnosis and treatment of disease,” Korf said. “The theory is clear, but it is impossible to do until you actually learn what things predict and diagnose disease in different individuals. All of Us is the key that will help to make precision medicine possible.”

Bruce Korf, M.D., Ph.D.Participants provide samples of blood and urine (or in some cases saliva) and have some basic body measurements — such as height, weight, blood pressure and heart rates — recorded. They are asked to share electronic medical records with the All of Us researchers as well. Participants’ genomes are sequenced, with the option of having some specific genetic information returned to them. The information collected is critical to ushering in the long-awaited era of precision medicine, when health decisions are not one-size-fits-all but tailored to each person’s unique characteristics.

It took several years to create the analytic tools and technology framework to securely gather deidentified information from All of Us participants and share it with accredited researchers in a secure system. But now, “there is a very rich dataset” available through the All of Us Researcher Workbench, Korf said, “and we have begun to see a flurry of research papers” based on All of Us data. Recent examples posted to the All of Us website include studies discovering 118 new genetic variants in All of Us participants, confirming the connection between high blood pressure and dementia risk, and uncovering links between a person’s birthplace and their cancer risk.

This flurry of results “will only increase to the point it becomes a deluge of information that will change how medicine is practiced,” Korf said. The research is a communitywide effort; All of Us is deliberately focused on expanding the base of researchers who are involved in biomedical studies, “particularly those historically not involved in this work due to lack of resources,” Korf said.

In fact, Korf believes that an entire generation of clinicians and scientists will point to All of Us as a watershed in medicine. He uses an intriguing metaphor to explain what he means. Up until now, he says, researchers in precision medicine have been like hunter-gatherers, picking up whatever morsels they could find on the forest floor. With All of Us and other similar large cohort studies, “we are now in the area of agriculture,” Korf said. “We’re planting fields knowing that we will be able to harvest them eventually and feed millions. There were bits and pieces you could do before when you could set up a small study. Now, with a much more deliberate and carefully designed program, we can reach the point of putting precision medicine into practice.”

2. Genomic results at unprecedented scale

One of the critical components of All of Us is the analysis of genomic data. When All of Us started, genomic data were not being collected; it took time to build the infrastructure to sequence participants’ genomes and to return important data to participants in a responsible manner, Korf says. But when this infrastructure was put into place, All of Us began offering participants the opportunity to receive health-related DNA results, starting in November 2022. “There was a lot of discussion” among study investigators around return of results, Korf says. “People are curious about what is found, and there are potentially medical implications. To do this return responsibly and well at the scale of All of Us, which is massive compared to anything else that has occurred so far, took a good bit of time and careful planning.”

For participants who opt into receiving return of genetic results, samples are tested for variations in 59 genes that are “predictive of the possibility of developing a medical problem,” Korf said. Most of these are related to inherited cancers and heart conditions. Participants also learn whether they have significant variants in seven genes that are linked to response to medications. They can also receive information about continental ancestry and a set of non-medical “traits” (such as whether they find the taste of cilantro to be objectionable). Interest has been strong; tens of thousands of participants have opted to receive DNA findings in the intervening months, and several thousand more receive results each week, out of some 150,000 participants eligible to receive results at this point.

Only a relatively small proportion of participants receive significant medical information based on this genetic testing, Korf points out. (The study estimates that 97 percent to 98 percent of participants will not have a significant finding.) “But in a study as large as All of Us, 2 percent to 3 percent still adds up to a large number,” Korf said.

Participants who do have a medically significant result receive their results from trained genetic counselors, are offered clinical testing free of charge and can be connected with the appropriate medical providers. “A lot has been learned about how to do this well and how to make it more widely available to more people,” Korf said.

LEXI COON | University Relations

3. The million-participant goal is within reach

All along, the NIH has acknowledged that its plan to enroll more than a million people in All of Us was ambitious. But even with a COVID pandemic halting or slowing work for a stretch from 2020 to 2022, “it is clear that the goal of at least 1 million participants will be reached,” Korf said. “COVID wasn’t in the plan when All of Us began. We had rapid enrollment when it started, then a plateau with COVID, and now we are back on a rapid enrollment phase once again.”

The Southern Network team was not immune from the workforce challenges that have faced many health care and research organizations during the COVID pandemic. “It has taken a while to reconstitute our staff,” Korf said. But a concentrated enrollment push in May 2023, including an enrollment event for physicians at The Kirklin Clinic, demonstrated that the team is capable of leading the way nationally. Each day, Korf and other network leaders receive a snapshot of enrollments, and in May “once again we were right at the top of the country many days,” he said.

UAB's Mobile Enrollment Unit travels across the state to bring All of Us to places that would have had little chance of taking part otherwise. Find out about upcoming stops on the All of Us site.

4. Engagement efforts are bearing fruit

All of Us was never intended to simply gather data and samples at a single point in time. Participants are regularly engaged with surveys and other ongoing research efforts.

But how can researchers ensure that people living in rural areas and other locations without reliable internet connections can stay engaged with the program? During a pandemic-era pause in new enrollments, the Southern Network helped pioneer innovative efforts to retain participants who had already enrolled.

“What you learn from one population does not necessarily apply to others,” Korf said. This is true of racial and gender differences, but also of geographic ones, he notes. Most major studies revolve around academic centers such as UAB. But the Southern Network consists of three large states. “The question was ‘how can we reach more areas?’” Korf said. With additional All of Us funding, the Southern Network outfitted a mobile unit (with another to come) that carries everything needed to enroll participants, including internet connections.

“There was a concern that places in the state without good internet, or where people don’t have devices that can connect reliably, were not going to be retained in the study,” Korf said. "With the mobile units, we are piloting an approach where staff can help participants log on to the All of Us website to take part in online surveys and other connected aspects of the study."

Although the initial mobile unit arrived during the pandemic hiatus in enrollment, it has proved to be such a success that a second mobile unit to be based at UAB is on order. “We have reached out to places that would probably have been left out in the past,” Korf said.

The Southern Network is also expanding its physical locations. In March 2023, a new enrollment location was opened in Dothan, Alabama, in collaboration with the Heersink family, whose gift named UAB’s medical school in September 2022.

“We are working with a very experienced group with good contacts in their communities,” Korf said. “We have been working to gain the trust of people and engage them in enrollment.”

ANDREA MABRY | University Relations

5. Next up: “Deep dives” and pediatric enrollment

In May 2023, UAB joined with the NIH in launching the Nutrition for Precision Health study, the first ancillary study from the All of Us Research Program. The largest precision nutrition study of its kind, it aims to enroll 10,000 participants from diverse backgrounds. All participants must enroll in All of Us or already be enrolled. Of the six clinical centers in Nutrition for Precision Health, two are in the Southern Network: UAB and LSU.

All participants in Nutrition for Precision Health will complete surveys, report their daily diets and give samples for lab tests. A subset of participants will eat diets selected by researchers at home. And a final subset will participate in “meal challenge tests,” where they will eat set meals while staying in a research center so that detailed physiological changes can be measured. UAB participants will spend three, two-week blocks of time living in cottages on the Lakeshore Foundation campus, for example.

“These ancillary studies are deep dives into particular areas that build on the core dataset that All of Us is generating,” Korf said. “There are expected to be more studies like that,” including one assessing brain function, he said.

Also in 2023, the All of Us Research Program will launch pediatric enrollment; previously, participants had to be 18 or older. Adding children to All of Us will shed new light on critical issues in children’s health and increase understanding of the developmental origins of adult disease, researchers say.

All of Us is a registered service mark of the United States Department of Health and Human Services.