Returning Actionable Genomic Results in a Research Biobank: Analytic Validity, Clinical Implementation and Resource Utilization

Abstract

Over 100 million research participants around the world have had research array-based genotyping (GT) or sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to patient recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.

Algorithmic identification of atypical diabetes in electronic health record (EHR) systems

“…In brief, genotyping for approximately 36,000 individuals in the MGB Biobank had been completed at the time of our analysis. Genotyping was performed using three single nucleotide polymorphism (SNP) arrays offered by Illumina (Multi-Ethnic Genotyping Array, the Expanded Multi-Ethnic Genotyping Array, and the Multi-Ethnic Global BeadChip), as has previously been described [ 10 ]. Individual SNPs were quality controlled by excluding those with high missing call rate, deviation from Hardy-Weinberg equilibrium, differences in proportions of missingness between cases and controls, or low minor allele frequency.…”