Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization,American Journal of Human Genetics

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Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2021-11-08 , DOI: 10.1016/j.ajhg.2021.10.005
Carrie L Blout Zawatsky ₁ , Nidhi Shah ₂ , Kalotina Machini ₃ , Emma Perez ₄ , Kurt D Christensen ₅ , Hana Zouk ₃ , Marcie Steeves ₆ , Christopher Koch ₇ , Melissa Uveges ₈ , Janelle Shea ₉ , Nina Gold ₁₀ , Joel Krier ₁₁ , Natalie Boutin ₁₂ , Lisa Mahanta ₁₃ , Heidi L Rehm ₁₄ , Scott T Weiss ₁₅ , Elizabeth W Karlson ₁₆ , Jordan W Smoller ₁₄ , Matthew S Lebo ₁₇ , Robert C Green ₁₈

Affiliation

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.
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.
Harvard Medical School, Boston, MA 02115, USA; Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
Brigham and Women's Hospital, Boston, MA 02115, USA.
Harvard Medical School, Boston, MA 02115, USA; Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
Laboratory for Molecular Medicine, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
Connell School of Nursing, Boston College, Chestnut Hill, MA 02467, USA.
Division of Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, 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.
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.
Laboratory for Molecular Medicine, Cambridge, MA 02139, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA.
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.
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.
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.
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.
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.

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.

中文翻译：

在研究生物库中返回可操作的基因组结果：分析有效性、临床实施和资源利用

全球有超过 1 亿研究参与者进行了基于芯片的基因分型 (GT) 或基因组测序 (GS)，但其中只有一小部分获得了可操作基因组发现 (gRoR) 的回报。 2017 年至 2021 年间，我们分析了麻省总医院布里格姆生物库 36,417 名参与者的基因组结果，并提出确认并返回 59 个基因的致病性和可能致病性变异 (PLPV)。参与者重新接触之前的变异验证显示，GT 在 44.9% 的样本中错误地识别了 PLPV，并且 GT 未能识别在也进行测序的样本子集中检测到的 72.0% 的 PLPV。 GT 和 GS 分别在 1% 和 2.5% 的队列中检测到经过验证的 PLPV。在 256 名被提醒携带可采取行动的 PLPV 的参与者中，37.5% 主动或被动拒绝进一步披露。 76.3% 的 PLPV 携带者不知道自己携带这种变异，其中一半以上符合已公布的基因检测专业标准，但从未接受过检测。该 gRoR 协议每年在实验室测试和研究人员支持方面的成本约为 129,000 美元，相当于每位进行 DNA 分析的参与者 14 美元，或每位确认并披露 PLPV 的参与者 3,224 美元。这些数据提供了有关 gRoR 的后勤详细信息，可以帮助计划返回基因组结果的其他研究人员。

更新日期：2021-12-02

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