Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization

Carrie L Blout Zawatsky; Nidhi Shah; Kalotina Machini; Emma Perez; Kurt D Christensen; Hana Zouk; Marcie Steeves; Christopher Koch; Melissa Uveges; Janelle Shea; Nina Gold; Joel Krier; Natalie Boutin; Lisa Mahanta; Heidi L Rehm; Scott T Weiss; Elizabeth W Karlson; Jordan W Smoller; Matthew S Lebo; Robert C Green

doi:10.1016/j.ajhg.2021.10.005

Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization

Am J Hum Genet. 2021 Dec 2;108(12):2224-2237. doi: 10.1016/j.ajhg.2021.10.005. Epub 2021 Nov 8.

Authors

Carrie L Blout Zawatsky¹, Nidhi Shah², Kalotina Machini³, Emma Perez⁴, Kurt D Christensen⁵, Hana Zouk³, Marcie Steeves⁶, Christopher Koch⁷, Melissa Uveges⁸, Janelle Shea⁹, Nina Gold¹⁰, Joel Krier¹¹, Natalie Boutin¹², Lisa Mahanta¹³, Heidi L Rehm¹⁴, Scott T Weiss¹⁵, Elizabeth W Karlson¹⁶, Jordan W Smoller¹⁴, Matthew S Lebo¹⁷, Robert C Green¹⁸

Affiliations

¹ Brigham and Women's Hospital, Boston, MA 02115, USA; Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Ariadne Labs, Boston, MA 02215, USA; The MGH Institute of Health Professions, Boston, MA 02129, USA.
² Brigham and Women's Hospital, Boston, MA 02115, USA; Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
³ Harvard Medical School, Boston, MA 02115, USA; Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
⁴ Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ Harvard Medical School, Boston, MA 02115, USA; Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
⁶ Laboratory for Molecular Medicine, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
⁸ Connell School of Nursing, Boston College, Chestnut Hill, MA 02467, USA.
⁹ Division of Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Harvard Medical School, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹¹ Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
¹² Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹³ Laboratory for Molecular Medicine, Cambridge, MA 02139, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹⁴ Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹⁵ Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Laboratory for Molecular Medicine, Cambridge, MA 02139, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹⁶ Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹⁷ Brigham and Women's Hospital, Boston, MA 02115, USA; Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Laboratory for Molecular Medicine, Cambridge, MA 02139, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
¹⁸ Brigham and Women's Hospital, Boston, MA 02115, USA; Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Ariadne Labs, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA. Electronic address: rcgreen@bwh.harvard.edu.

Abstract

Over 100 million research participants around the world have had research array-based genotyping (GT) or genome 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 participant 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.

Keywords: biobank; genetic; genomic; research.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Biological Specimen Banks*
Cohort Studies
DNA
Disclosure
Disease / genetics*
Duty to Recontact
Female
Genetic Research
Genetic Testing
Genetic Variation*
Genome, Human*
Genomics* / economics
Genomics* / standards
Genomics* / trends
Humans
Informed Consent
Male
Middle Aged
Reproducibility of Results

Substances

DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding