Pragmatic Trial Suggests It May Take A Village To Tap Full Potential Of Genomics

By Deborah Borfitz

April 25, 2022 | In a pragmatic clinical trial at a pair of health systems in New York City, researchers at the Mount Sinai Health System have determined that the full potential of genomics to improve clinical patient management may well depend on engaging community-based racial and ethnic minority groups in the effort. Buoyed by results of the community-based approach in the Genetic Testing to Understand and Address Renal Disease Disparities (GUARDD) study, the National Institutes of Health is now funding a larger and more comprehensive nationwide study (GUARDD-US) through the Implementing Genomics in Practice (IGNITE) network aimed both at changing health behaviors and making pharmacogenomics-based treatment recommendations, according to Girish N. Nadkarni, M.D., MPH, the Irene and Dr. Arthur Fishberg Professor of Medicine at Mount Sinai’s Icahn School of Medicine.

The subjects in the original GUARDD study were 2,050 patients of African ancestry with hypertension without chronic kidney disease who, along with their physician, were given results of genetic testing for the apolipoprotein L1 (APOL1) gene variant that would put those individuals at risk of gradually losing kidney function. As recently reported in JAMA Network Open (DOI: 10.1001/jamanetworkopen.2022.1048), disclosure was associated with a greater reduction in blood pressure, kidney disease screening, and self-reported behavior changes in those with high-risk APOL1 genotypes.

Enrolled subjects were all patients of the two health systems, most of whom were identified by electronic health records (EHRs) as potentially meeting the study’s inclusion criteria, Nadkarni says. Coordinators in the community had mailed them a recruitment letter, with telephone follow-up to screen them and schedule their enrollment. Some hard-to-reach patients were also personally intercepted during a routine clinic visit.

Subjects were randomly assigned to immediate (intervention) or delayed (waiting list control group) APOL1 testing. For those in the intervention group, results were received from trained staff either by telephone if they tested negative or in person if they tested positive. Meanwhile, test results were also automatically sent to the patients’ primary care physician through the clinical decision support engine in the EHR, says Nadkarni.

In the intervention group, systolic blood pressure readings were significantly higher among patients with the high-risk versus low-risk APOL1 genotypes. At three months, improvement in the blood pressure level of the high-risk group also notably improved relative to their low-risk counterparts. At 12 months, those in the high-risk group also saw the biggest increase (12%) in urine kidney disease testing compared to the low-risk intervention and control groups (6% and 7%, respectively).

Finally, testing prompted patients with high-risk APOL1 genotypes to make lifestyle changes, including better dietary and exercise habits, more often than those in the low-risk group (59% versus 37%). They also twice as often reported increased blood pressure medication use (10% versus 5%). And nearly all of them (97%) indicated they would get tested again.

All around, survey results suggest participants had a positive experience in the study, says Nadkarni. About 95% of patients felt that they had enough information about the genetic testing and the information was easy to understand.

For patients, participation required no additional visits beyond the frequency they would normally see their primary care provider because the study was completely integrated into clinical care, Nadkarni continues. But heavy involvement of familiar and trusted leaders from various community and faith organizations was the real linchpin motivating the positive, health-benefitting changes witnessed in the study.

Individuals from the community were engaged as paid coordinators to not only enroll patients, but also administer genomic testing and deliver the results—and most had no special clinical training, he says. They were people who “spoke the language of the patients,” and were trained and supervised by a senior genetic counselor to ensure patients received standardized information in a timely manner.

Sounding Boards

Much of the hard work of engaging people in nearby neighborhoods had already been done by Mount Sinai Health System before the GUARDD study launched in 2014, Nadkarni says, including creation of a Community Advisory Board by Carol Horowitz, M.D., MPH, principal investigator of the study. The 30-member group is comprised of healthcare providers and consumers and intended to help hospital administrators better understand challenges facing the East Harlem community. “We had a pretty strong baseline and structure to build on.”

A Genomics Stakeholder Board—a group that included local patients, clinicians, advocates, and health system leaders—was a sounding board for the community-based study approach, continues Nadkarni. Board members responded enthusiastically to the idea because they were all too aware that African Americans were disproportionately impacted by hypertension and its negative side effects.

Chronic kidney disease is commonly associated with high blood pressure. But Blacks with hypertension are five times more likely than Whites to experience end-stage renal disease, a more severe form of kidney disease, he notes. The high-risk APOL1 variants are also almost exclusively found in people of sub-Saharan African descent.

Members of the Genomics Stakeholder Board were especially attuned to the reality that genetic testing can be a touchy issue among their family and friends because scientists have sometimes conflated race (a social construct) and genetics (biology), thereby perpetuating racism, says Nadkarni. The 12-year journey from concept to study publication thus began with a series of meetings between Mount Sinai researchers and members of the Genomics Stakeholder Board to have those difficult but necessary conversations to ensure messaging about the initiative was properly crafted and culturally sensitive.

A rapid electronic system for delivering genetic test results to primary care physicians also had to be developed, as did the team of layperson volunteers who would be serving as study coordinators, he says. Subjects were enrolled over a two-year period, followed by two years of statistical analysis of the collected data with the Community Advisory Board right before the COVID-19 pandemic hit.

APOL1 testing was done with a validated assay in a lab accredited by the Clinical Laboratory Improvement Amendments and College of American Pathologists. The EHR system at Mount Sinai enabled privacy-protected data flow and real-time communication with the genetic testing laboratory and study team, says Nadkarni.

Scaling The Study

When the GUARDD study was being written, scientists had only just discovered that APOL1 variants put people at higher-than-average risk for experiencing chronic kidney disease, says Nadkarni. The clinical utility of APOL1 genotyping for people who already had kidney disease wasn’t even up for discussion, although it is now thought that timely and accurate information about the biological underpinnings of the disease could influence patient outcomes and the treatments they’re prescribed. 

The GUARDD-US study underway at nine sites across the country seeks to enroll more than 5,000 African Americans diagnosed with hypertension, both those with and without chronic kidney disease, he notes. As with the initial, two-center study, researchers will be monitoring changes in blood pressure and kidney disease screening, and actively engage communities of color to serve as coordinators.  

This will be the largest study looking at the impact of APOL1 testing results on the behavior of patients and their primary care physicians, including their appropriate diagnosis, Nadkarni says. Additionally, “some [APOL1-negative] patients will be tested for genes that affect the medication they are taking for hypertension and [current] recommendations based on pharmacogenomics.”

GUARDD-US will leverage the EHR capabilities of each partnering institution, which will need to establish clinical decision support software to send appropriate alerts with test results to primary care providers. Those findings will all be centralized at Duke University, where Christina Wyatt, M.D., is serving as principal investigator of the coordinating center, Nadkarni says.