Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

Abstract

Exome and genome sequencing are increasingly utilized in research studies and clinical care and can provide clinically relevant information beyond the initial intent for sequencing, including medically actionable secondary findings. Despite ongoing debate about sharing this information with patients and participants, a growing number of clinical laboratories and research programs routinely report secondary findings that increase the risk for selected diseases. Recently, there has been a push to maximize the potential benefit of this practice by implementing proactive genomic screening at the population level irrespective of medical history, but the feasibility of deploying population‐scale proactive genomic screening requires scaling key elements of the genomic data evaluation process. Herein, we describe the motivation, development, and implementation of a population‐scale variant‐first screening pipeline combining bioinformatics‐based filtering with a manual review process to screen for clinically relevant findings in research exomes generated through the DiscovEHR collaboration within Geisinger's MyCode® research project. Consistent with other studies, this pipeline yields a screen‐positive detection rate between 2.1 and 2.6% (depending on inclusion of those with prior indication‐based testing) in 130,048 adult MyCode patient‐participants screened for clinically relevant findings in 60 genes. Our variant‐first pipeline affords cost and time savings by filtering out negative cases, thereby avoiding analysis of each exome one‐by‐one, as typically employed in the diagnostic setting. While research is still needed to fully appreciate the benefits of population genomic screening, MyCode provides the first demonstration of a program at scale to help shape how population genomic screening is integrated into routine clinical care.

A RE-AIM Framework Analysis of DNA-Based Population Screening: Using Implementation Science to Translate Research Into Practice in a Healthcare System

“…We found an overall detection rate of 2.6% for P/LP variants in the 60 genes screened by MyCode from 130,048 exomes screened at that time ( Kelly et al, 2021 ). Thus far, MyCode data have reported P/LP variant detection rates in unselected individuals for familial hypercholesterolemia (FH)-related variants (1 in 222) ( Abul-Husn et al, 2016 ) and hereditary breast and ovarian cancer (HBOC)-related variants (1 in 180) ( Manickam et al, 2018 ).…”

“…When MyCode exome sequence data reveals a pathogenic or likely pathogenic (P/LP) variant in a gene returned through MyCode, a clinically collected sample retained in the MyCode CLIA-certified repository is sent for clinical confirmation and reporting of the variant in a CLIA-certified genetics laboratory. The list of genes included for DNA screening through MyCode was developed based on several resources including to the American College of Medical Genetics and Genomics (ACMG) secondary findings list, as previously described, and is regularly reviewed and updated by research and clinical stakeholders based on current evidence ( Schwartz et al, 2018 ; Kelly et al, 2021 ). The current list of genes includes those on the ACMG secondary findings v2.0 list ( Kalia et al, 2017 ) in addition to biallelic variants in the HFE gene leading to the C282Y amino acid substitution ( Kelly et al, 2021 ).…”

Primary Care Implementation of Genomic Population Health Screening Using a Large Gene Sequencing Panel

“…Research involving return of actionable genomic sequencing results to patients for clinical use ( Duow and Marjanovic, 2016 ; Linderman et al, 2016 ; Sanderson et al, 2016 ; Suckiel et al, 2016 ; Ryan et al, 2017 ; Murray et al, 2018 ; Rego et al, 2018 ; Reuter et al, 2018 ; Sapp et al, 2018 ; Schwartz et al, 2018 ; David et al, 2019 ; Nussbaum et al, 2019 ; Williams, 2019 ; Zoltick et al, 2019 ; Walton et al, 2020 ; David et al, 2021 ; Kelly et al, 2021 ; Khoury and Dotson, 2021 ; Lemke et al, 2021 ; Miller et al, 2021 ), potential harms of proactive testing, quality of next generation sequencing technology, and implementation of genomic medicine ( Weitzel et al, 2016 ; Ginsburg et al, 2019 ; Williams, 2019 ) strongly informed our design.…”

Translational aspects of novel findings in genetics of male infertility—status quo 2021

“…It is confidently established that 2–3% of subjects are carriers of clinically actionable variants in genes causing adult-onset inherited diseases that are preventable or manageable upon early detection. 43 , 44 …”