ROCHESTER, Minnesota (GenomeWeb) – Ahead of an anticipated full launch for the All of Us Research Program next year, around 4,000 beta testers are currently helping the NIH and its collaborators refine the project's protocols for giving consent, sharing electronic health records, and donating biological samples.
In coming years, "we anticipate the platform evolving quite a bit," said Stephanie Devaney, deputy director of the All of Us program, at Mayo Clinic's Individualizing Medicine conference today. The goal of the All of Us Research Program is to collect in a longitudinal fashion a variety of data, including genomic, medical, and environmental, and use that to fuel research and advance precision medicine.
The program entered beta testing over the summer. Early users' experience engaging with the study protocol via the newly launched JoinAllofUs.org has already revealed some areas that need refinement.
"The beta [phase] is intended to see where things are working well and where we can make it work better, as we continue to develop new things," said Josh Denny, professor of biomedical informatics at Vanderbilt University, in a recent interview. Vanderbilt is setting up the data and research center where all the data sets collected from participants will be stored and organized for research.
For example, beta testing has shown that the digital interface that participants encounter within JoinAllofUs.org after registering an account needs to more clearly delineate what the participants are being asked to do. "There's sort of a linear progression of how you work your way through the protocol," Joni Rutter, director of scientific programs for All of Us, said in a recent interview. "Within that participant portal, we're working on making it more clear how you transition from one section of the protocol to another."
While there are around 4,000 registered participants, around 3,000 are currently fully enrolled in the beta testing phase after providing primary consent agreeing to join the project and agreeing to be contacted in the future, authorizing the use of their electronic health records, and filling out three surveys on demographics, lifestyle, and overall health status.
Pilot sites around the country will test out the capabilities within the program to grab participants' EHR information for donation to All of Us. Collecting this information also enables NIH and collaborators to test out the processes for reporting data back to participants. Testing out this ability is particularly important, since the All of Us Project has promised to return collected data and certain study results back to participants.
However, there is some concern among beta testers about sharing their EHR data with the program. "We think there might be a better way to relay the information to them that might not be as scary," Rutter said.
Moreover, because the base consent process that informs the participants about the project and the things they need to do to enroll takes 30 minutes or longer, "some people drop out at that point," said Mark Begale, director of strategic partnerships at Vibrent Health, which is developing the technology platform through which people can digitally enroll in All of Us. Begale acknowledged at the meeting that even in this early stage, it's not easy getting people to sign into the site, do the things they need to do, and stay in the project.
Participants will also have to provide physical measurements and donate blood and urine samples. The bulk of the biospecimens will be stored at Mayo Clinic's biorepository in Rochester. The program will collect 35 aliquots per participant, which means that for 1 million study volunteers, Mayo's biorepository will store 35 million samples.
The recruiting facilities — 10 regional medical centers, six federally qualified health centers, and the US Department of Veterans Affairs Medical Centers — will also use the beta testing phase to refine their enrollment process.
In order to meet the NIH's 1 million participant recruitment goal, regional medical centers are expected to recruit 150,000 participants — 10,000 in the first year, and 35,000 participants in the subsequent four years. Akinlolu Ojo, associate VP for clinical research at the University of Health Sciences, noted at the meeting that this translates to enrolling 50 people each day into All of Us in the first year, and 170 people a day in the following years.
The university, along with Arizona-based non-profit health system Banner Health, received an NIH grant to recruit underserved communities, such as Indian/Alaska Native and Hispanic populations, into All of Us. According to Ojo, the regional medical center has a goal to recruit 50 percent of the 150,000 participants from these communities. To ensure that the recruitment center can keep up the pace of enrollment, the regional medical center is partnering with state government agencies, advocacy organizations, and community groups, and will have a social media presence "to inform the public" and "present the program in a good light," Ojo said, so that when individuals are approached about enrollment they'll already have a sense of what it's about.
In early November the program will enter an expanded beta phase in which around 10,000 participants will continue to further stress test the project's capabilities. Following this expanded beta phase, the program is slated to launch officially in the spring of 2018
Advancing a genomics strategy
All of Us was a pet project of President Barack Obama, whose administration was very involved in the initial phases of the project. The Trump Administration has not shown much public enthusiasm for the project, though Devaney assured there is support.
According to Devaney, who formerly led the coordination of the project from the Office of the Chief of Staff at the White House during the Obama Administration, All of Us leaders have discussed the program at the "highest levels" of the Trump Administration but didn't elaborate. She highlighted, however, that there is bipartisan support for All of Us in Congress.
With the passage of the 21st Century Cures Act last year, Congress granted $1.45 billion in additional funding to All of Us over 10 years and flexible funding mechanisms. "We intend to keep [legislators'] trust and we intend to show value early on so they continue to support us," Devaney said.
When the All of Us program initially launched, many in the genomics field hyped the project as a vehicle for sequencing a million people. However, the program organizers have determined that the state of the science, the cost of sequencing technologies, and the difficult ethical issues around returning results require further consideration before introducing genomics into such a large-scale project.
"Because of our core value of returning information to participants, we wanted to make sure we understood the ramifications of doing so," Rutter said. "Given the scope and scale of the program, we wanted to be very careful about that. … We'd rather do it right than do it quickly."
The NIH earlier this year held a workshop to discuss which results to return, how to minimize reporting false positives, and how to provide counseling to help participants navigate the sometimes uncertain and evolving evidence on genetic information. During that meeting, Robert Green, director of the Genome2People Research Program within Brigham and Women's Hospital and Harvard Medical School, cautioned about the impact of false positives in such a large study.
At the Mayo Clinic meeting, he reiterated a rough, back-of-the-envelope calculation that sequencing a million people for rare, genetically dominant conditions could yield around 8,000 true positive results and 49,500 false positive results.
In the studies that Green has done within the Genome2People Research Program, privacy and discrimination concerns are a hindrance to participation. Devaney noted at the meeting that some of these concerns might be mitigated by the fact that All of Us is covered by a certificate of confidentiality, which means that investigators cannot be compelled to divulge participant data in any civil, criminal, administrative, legislative, or other proceeding.
In August, All of Us formed its genomics working group, which in the coming months will outline a plan for collecting genomics data from participants and return of results. The All of Us program will likely pilot the working group's suggestions ahead of broader implementation.
"We're looking at options around doing an array-based approach initially, until we can convince ourselves that the cost is really worth doing a whole-genome sequencing approach," Rutter said. "We do anticipate that's going to happen … but we want to make sure the computational approaches for doing that type of analysis on the scope and scale we're talking about are well in hand and understood before we dive into those plans more completely."
"I am a geneticist, and I do like the genomics aspect of it," Rutter continued. "But that's not the only thing we want to talk about," she said, noting that the project aims to fuel research projects based on a variety of datasets donated by participants, including medical, lifestyle, behavioral, and environmental information. Adding genomic and other molecular data on top of that other information will only bolster researchers' ability to pinpoint the underlying causes of diseases and advance precision medicine approaches, Rutter added.
Ultimately, the success of the project will depend on how successful healthcare provider organizations are in bringing participants in and keeping them engaged. Remaining committed to All of Us may prove to be a tough balance for organizations that have already launched local precision medicine programs.
Geisinger Health System, which has enrolled more than 160,000 participants and sequenced more than 92,000 exomes within its precision health project called MyCode, recently decided to drop out of All of Us. "We found it was too difficult to continue our MyCode partnership with Regeneron [Pharmaceuticals], and to be a good active participant [in All of Us]," David Ledbetter said at the Mayo Clinic meeting.
Despite the fact that Geisinger is now engaging with All of Us only in an advisory capacity, Vanderbilt's Denny maintained that that the commitment level remains high among the many other industry and academic collaborators.
Vanderbilt operates a biobank with more than 225,000 DNA samples as of late last year, and although this repository has spurred numerous research efforts, "it's a limited audience and smaller in size" compared to All of Us, Denny said. "There are certain questions we'll never be able to answer with it. We'll be able to answer more of those kinds of questions with All of Us ... [and] we are eagerly supporting both."