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Large-Scale Sequencing Projects Navigate Grey Area Between Research, Clinical Testing

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SAN FRANCISCO (GenomeWeb) – Organizations conducting large-scale sequencing research studies are starting to figure out an issue long considered taboo — how to return clinically relevant data to the volunteers who participate in such studies.

At this week's Precision Medicine World Conference, representatives from the Geisinger Health System, Kaiser Permanente, and the US Department of Veterans Affairs' Million Veteran Program discussed their approaches toward building large cohorts of people with genetic, clinical, and phenotypic data to drive precision medicine research. The three projects have slightly different aims but are all grappling with similar challenges related to wanting to make some clinically relevant genomic data available to the research participants.

As a number of studies have already demonstrated, people want their genetic data, and so far it seems that returning that data has not had negative consequences on participants.

"The research and clinical parts can no longer be siloed," Nazneen Aziz, executive director of the Kaiser Permanente Research Bank, said during a panel discussion at the conference.

Kaiser announced two years ago that it planned to recruit 500,000 of its members to donate a blood sample to a biobank that would be available, along with clinical health and phenotypic data, for research. And although it is not yet returning any genetic results to participants, that is one of its future goals, Aziz said.

By contrast, Geisinger Health System was one of the pioneers to return genomic results to patients through its MyCode Community Health Initiative. The Pennsylvania-based integrated health system launched a biobank in 2007, but it wasn't until it partnered with Regeneron Pharmaceuticals to conduct exome sequencing that it began to return results for 76 genes it deemed important for health risks. Included in that list are the genes recommended by the American College of Medical Genetics and Genomics as being clinically actionable.

Geisinger has already enrolled more than 180,000 of its members into the program, and David Ledbetter, Geisinger's chief scientific officer, said that it recently increased its total enrollment goal to 500,000 individuals, up from 250,000.

"In 2013, we decided to break the tradition of separating research from clinical care," Ledbetter said. "Most IRB protocols don't [allow] reporting of research data," he said, but "our participants wanted us to report clinically actionable information."

Participants consent to having their exome sequenced and used for research, but can also receive information on 76 clinically actionable genes, such as mutations in the BRCA genes, genes related to hereditary cardiovascular disease, and more.

Ledbetter said that the program has gone well, particularly in its return of hereditary cancer information. In total, the program has sequenced more than 92,000 exomes, although it has not finished analyzing them all. It has returned actionable results to over 500 MyCode participants, including identifying BRCA1 and BRCA2 variants in 200, other hereditary cancer risk variants in an additional 100 individuals, and familial hypercholesterolemia in 92 individuals. Overall, he said, between 3 percent and 4 percent of participants receive an actionable result.

Ledbetter described the case of one 57-year-old woman, Barbara Barnes, who enrolled in the program and for whom sequencing revealed a pathogenic BRCA1 mutation. She didn't have a known family history of breast or ovarian cancer, which Ledbetter noted is true for around half of BRCA1-positive individuals.

When discussing the findings and potential next steps, Barnes said that because she was raising grandchildren, she wanted to ensure that she'd be around to see them grow up, so she opted for prophylactic surgery to remove both her breasts and ovaries. At the time of surgery, doctors discovered a golf ball sized tumor in her fallopian tube, Ledbetter said. They removed it and she started chemotherapy immediately after and is now doing fine. "In this case," Ledbetter said, those genomic results were "likely life saving."

In three other cases of individuals with BRCA variants, subsequent screening has identified cancer, and two individuals with RET variants were diagnosed with medullary thyroid cancer.

"We're excited about our ability to provide anticipatory medicine," Ledbetter said.

Ledbetter said that the next steps are to expand enrollment to 500,000 individuals and ultimately, to enroll all 3 million or so members of the health system and expand the list of genes returned. Eventually, he said, Geisinger would like to move the MyCode initiative "from research to clinical care and then implement it at the beginning of life for newborns."

Ledbetter acknowledged that Geisinger's success has been due at least in part to its unique situation. It's an integrated health system that serves a rural population that tends to not move around much. Often, three generations of a family will all be members of the health system. Thus, prior to implementing the sequencing component, the health system already had extensive electronic health records on its participants that often spanned decades. In addition, its members are very engaged with the system and close to 90 percent of those asked to participate consent to do so.

Despite these unique characteristics, other healthcare systems with vastly different populations are looking to implement similar protocols.

Kaiser, which launched a biobank initiative two years, serves a much more diverse and urban population. For instance, it covers the major metropolitan areas of Los Angeles and the San Francisco Bay Area in California. Of the individuals who have enrolled in the biobank so far, Aziz said, around 23 percent are from minority populations. "In genetics, understanding the differences between different populations is very important," she said.

Although Kaiser is not yet returning any results to participants, it plans to do so. From a survey of 10,000 of its members and 5,000 providers, Aziz said, it's clear that the members want that information. As part of its biobank project, Kaiser launched a translational research arm, which will focus on developing such a protocol.

"Ultimately, the Kaiser system can learn from the experience and what it takes to incorporate genomics into healthcare," she said.

So far, 340,000 participants have enrolled in the biobank and Kaiser has set up a method by which researchers can apply to access those samples and the associated de-identified clinical health data for research projects.

In addition, around 200,000 samples have been genotyped via a SNP chip, but Aziz said she anticipates that going forward, sequencing will be implemented.

Like Ledbetter, Aziz noted that being an integrated healthcare system is an advantage in building a large biobank of samples that also includes extensive clinical and phenotypic data. Kaiser serves around 12 million people across eight different states in the US, and individuals stay in the system for an average of 10 years, so there is a lot of longitudinal data on each person, she said.

Similar to Kaiser's biobank project, the Million Veteran Program, which launched in 2011, is not yet returning results to participants, but plans to do so, according to John Michael Gaziano, principal investigator of the program. Gaziano said the project's coordinators are currently in discussion with the veteran participants on "returning results to participants and providers and using that in clinical care."

Already, more than 640,000 veterans have enrolled in the study and the VA has contracts to sequence the genomes of 45,000 of those. In addition, Gaziano said, the VA is working with the company Metabolon to generate metabolomics information, is genotyping samples, has a vast wealth of electronic health and phenotypic data on the participants, and has a partnership with the Department of Energy to deploy supercomputing power for data analysis, including artificial intelligence and deep learning to derive insights from the data.

Gaziano said that the biggest challenge in moving forward is no longer generating the data. "We have 'omics of all types and computing power," he said, "but that's just beginning to scratch the surface." The next step will be to "figure out how to integrate all that data and make it useful."

Aziz agreed that making the data useful is a hurdle. "The biggest challenge will be dealing with the rapid pace of knowledge," she said.

Nonetheless, all three panelists said they plan to keep expanding their programs. "We're thinking about the second million veterans and beyond," Gaziano said. "I'd like to see this research enterprise move into clinical practice, and the bidirectionality" that this would enable, he added, including data moving from research to the clinic, as well as data from clinical experience and outcomes informing research.

Ledbetter said one of Geisinger's big visions is that when genomics becomes part of clinical practice, the data can be used to monitor care gaps and prevent disease. For instance, cardiovascular disease is a big problem among Geisinger's population, but if sequencing is done at birth, then individuals who have an elevated genetic risk for cardiovascular disorders can start preventative treatment much earlier in life.  Similarly, he said, for things like Lynch syndrome or hereditary cancers, if the genetic risk is known early, measures can be taken to prevent disease.

"We want to demonstrate that with data, we can reduce the risk of getting these diseases," he said.

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