A Model for Genome-First Care: Returning Secondary Genomic Findings to Participants and Their Healthcare Providers in a Large Research Cohort

Abstract

BackgroundResearch cohorts with linked genomic data exist, or are being developed, at many research centers. Within any such “sequenced cohort” of more than 100 participants, it is likely that there are participants with previously undisclosed risk for life-threatening monogenic diseases that could be identified with targeted analysis of their existing data. Identification of such disease-associated findings are not usually primary to the enrollment research goals. At Geisinger Health System, MyCode® Community Health Initiative (MyCode) participants represent one such large sequenced cohort. Since 2013, MyCode participants in discovery research have been consented for secondary analysis of their existing research genomic sequences to allow delivery of medically actionable findings to them and their healthcare providers. This return of genomic results program was developed to manage an anticipated 3.5% of MyCode participants who will receive clinically confirmed genomic variants from an approved gene list out of more than 150,000 total participants. Risk-associated DNA sequences alone without any clinical parameter, prompt “genome-first” follow-up encounters.MethodsThis article describes our process for generating clinical grade results from research-based genomic sequencing data, delivering results to patients and their providers, facilitating targeted clinical evaluations of patients and promoting cascade testing of at-risk relatives. We also summarize our early data about the results generated during this process and our ability to contact patients and their providers to disclose the information.ResultsThis process has been used to generate 343 results on 339 patients. 93% of patients with a result have been successfully contacted about their results as evidenced by direct interaction about their result with the research team or a healthcare provider. 222 healthcare providers have been notified of a result on one or more patient through this result delivery process.ConclusionsHere we describe the existing GHS model to deliver genomic data into the electronic medical record and the clinical interactions that are prompted and supported. Elements of this genome-first care model can be applied in other healthcare settings and in national efforts, such as “All of Us”, that wish to establish programs for returning genomic results to research participants.

Personalized Medicine and the Power of Electronic Health Records

“…Furthermore, protected health information can be challenging to strip completely from EHRs when synthesizing data for research purposes, particularly from free text and images, requiring special regulation models that may restrict some access (Boyd et al, 2007). Increasingly, biobanks are being built with recontact in mind for future research or for the return of genomic results to participants (Schwartz et al, 2018), and some newer biobanks operate under a model of continuous engagement and partnership with participants (Collins and Varmus, 2015). A cornerstone of genomic research using EHRs is the ability to replicate findings across different health systems, populations, and clinical contexts.…”

“…The DiscovEHR collaboration between GHS and the RGC was established in 2014 to combine exome sequence data with de-identified, longitudinal EHR data from MyCode participants. These data are being used to fuel genomic research and genome-guided drug discovery efforts (Abul-Husn et al, 2018;Dewey et al, 2016b), as well as the GHS Genome-FIRST Medicine program, which returns genomic results to MyCode participants (Schwartz et al, 2018). The first 50,000 individuals sequenced through the DiscovEHR collaboration have been screened for genomic variants associated with HBOC (Manickam et al, 2018) and familial hypercholesterolemia (FH, another CDC tier 1 genomic application) (Abul-Husn et al, 2016), among other conditions.…”

“…To date, there are not clear guidelines or procedures in the United States on reporting medically actionable genomic results to research participants, and biobank policies vary on how they address the return of genomic results (Jarvik et al, 2014;Wolf et al, 2012). In the GenomeFIRST Medicine Program, exome sequence data are analyzed for variants in 80 genes for return of results to MyCode participants (Schwartz et al, 2018). These include 59 genes that the American College of Medical Genetics (ACMG) has recommended for return to patients having undergone clinical exome or genome sequencing, even when unrelated to the primary indication for testing (Kalia et al, 2017).…”

Clinical and Molecular Prevalence of Lipodystrophy in an Unascertained Large Clinical Care Cohort

“…While lipodystrophy is not a condition currently covered by the ACMG SF v2.0 gene list (29), LMNA is one of the genes screened for clinically actionable secondary findings in genomic sequencing studies due to its association with dilated cardiomyopathy characterized by cardiac dilation and reduced systolic function (29,30). It is possible that as more genomic sequencing efforts start looking for pathogenic variants in this gene, additional cases of molecularly undiagnosed lipodystrophy patients will become evident (31), further informing the prevalence and contribution of LMNA pathogenic variation to partial lipodystrophy and metabolic disease in unascertained patients.…”

The Clinical Autopsy and Genomic Testing

“…4 Several medical institutions have recently initiated investigative programs that screen the genomes of living patients to link genetic variants with diseases and conditions, ultimately to enable the prediction of future disease and allow preventive interventions in individual patients. 5,6 Because the essence of the autopsy is a full description of the final physical state of the patient's body, accompanied by a close review of the accumulated, lifelong clinical history, the ability to make such correlations would only be enhanced by using autopsies for this purpose rather than by relying exclusively on testing of living patients.…”