This story has been updated from a previous version to clarify information about the design of the Geisinger-led study.
NEW YORK – A team led by investigators at Geisinger has demonstrated the feasibility of using genomic screening to unearth actionable clinical variants in individuals treated through a single health system in rural Pennsylvania who participated in Geisinger's MyCode Community Health Initiative.
"In this large, genomics-informed cohort study from a single health system, 1 in 30 participants had a potentially actionable genomic finding," senior and corresponding author Christa Martin, a researcher with Geisinger, and her colleagues wrote in JAMA Network Open on Monday, noting that "nearly 90 percent were unaware of their risk prior to screening."
For their study, Geisinger presented findings for 354,957 genomic screening program participants with a median age of 54 years old who were enrolled in the MyCode biobank program starting in 2007 and who consented to receive genomic results beginning in 2013. The program, which has been done in collaboration with Regeneron Genetics Center since 2014, has generated exome sequences for more than 175,000 individuals.
From these data, the team identified pathogenic or likely pathogenic variants deemed actionable in 81 genes, based on version 3.2 secondary finding recommendations from the American College of Medical Genetics and Genomics. In 3,040 of the 5,934 affected participants, these pathogenic variants fell outside of genes classified as tier 1 with the US Centers for Disease Control and Prevention criteria.
As of July 2024, the investigators returned results regarding more than 5,100 genetic findings to 5,052 individuals, including 2,267 variants implicated in the risk of cardiovascular conditions such as inherited cardiomyopathy or arrhythmia and 2,031 variants linked to the risk of breast or ovarian cancer, Lynch syndrome, or other cancers. The remaining 821 pathogenic variants that were reported to participants involved risk for other conditions.
For 87.6 percent of participants who received genomic screening results, the exome sequencing approach unearthed apparent disease risk that had not been identified during their past interactions with the health system, though at least some of the individuals did have a personal or family history that would warrant clinical genetic testing.
"Having sequenced approximately 20 percent of Geisinger's active patient population, identified results in 1 in 30 participants (3.4 percent), and disclosed more than 5,000 results, this program could serve as a model for genomic screening at scale," the authors wrote, noting that their results suggested that "genomic screening fills important gaps missed by clinical, indication-based testing and increases identification of at-risk patients."
In an invited commentary article in JAMA Network Open, Massachusetts General Hospital's Heidi Rehm noted that such genomic screening efforts are expected to provide insights into the penetrance of some disease risk variants, since population-level data is not available for many of the ACMG genes.
Even so, she explained that additional investments in genomic infrastructure, health system interoperability, physician education, specialist referrals, and insurance reimbursement would be needed to apply genomic screening more broadly, particularly for underrepresented populations.
"Given these barriers, the Geisinger program directly financed their initiative through their own investment as well as through a partnership with Regeneron to fund genomic sequencing, allowing the data to be used for research by Regeneron," she noted.
"While these industry partnership models will continue to be necessary and important to drive biomedical research, it will also be important for all healthcare systems to directly invest in the genetically informed care of patients and the track of outcomes," Rehm added. "We must build learning health systems that continuously consume and process data to directly inform medical management instead of waiting for long cycles of manual analysis, publication, and professional guideline development."