Implementing Evidence-Based Assertions of Clinical Actionability in the Context of Secondary Findings: Updates from the ClinGen Actionability Working Group

Christine M Pak; Marian J Gilmore; Joanna E Bulkley; Pranesh Chakraborty; Orit Dagan-Rosenfeld; Ann Katherine M Foreman; Michael H Gollob; Charisma L Jenkins; Alexander E Katz; Kristy Lee; Naomi Meeks; Julianne M O'Daniel; Jennifer E Posey; Shannon M Rego; Neethu Shah; Robert D Steiner; Andrew B Stergachis; Sai Lakshmi Subramanian; Tracy Trotter; Kathleen Wallace; Marc S Williams; Katrina A B Goddard; Adam H Buchanan; Kandamurugu Manickam; Bradford Powell; Jessica Ezzell Hunter; ClinGen Resource

doi:10.1016/j.gim.2024.101164

Implementing Evidence-Based Assertions of Clinical Actionability in the Context of Secondary Findings: Updates from the ClinGen Actionability Working Group

Genet Med. 2024 May 14:101164. doi: 10.1016/j.gim.2024.101164. Online ahead of print.

Authors

Christine M Pak¹, Marian J Gilmore², Joanna E Bulkley², Pranesh Chakraborty³, Orit Dagan-Rosenfeld⁴, Ann Katherine M Foreman⁵, Michael H Gollob⁶, Charisma L Jenkins², Alexander E Katz⁷, Kristy Lee⁵, Naomi Meeks⁸, Julianne M O'Daniel⁵, Jennifer E Posey⁹, Shannon M Rego¹⁰, Neethu Shah⁹, Robert D Steiner¹¹, Andrew B Stergachis¹², Sai Lakshmi Subramanian¹³, Tracy Trotter¹⁴, Kathleen Wallace⁵, Marc S Williams¹⁵, Katrina A B Goddard², Adam H Buchanan¹⁵, Kandamurugu Manickam¹⁶, Bradford Powell⁵, Jessica Ezzell Hunter¹⁷; ClinGen Resource

Affiliations

¹ Department of Translational and Applied Genomics, Kaiser Permanente Center for Health Research, Portland, Oregon. Electronic address: Christine.Pak@kpchr.org.
² Department of Translational and Applied Genomics, Kaiser Permanente Center for Health Research, Portland, Oregon.
³ Newborn Screening Ontario, Children's Hospital of Eastern Ontario, and Division of Metabolics University of Ottawa, Ottawa, Ontario.
⁴ Department of Genetics, Stanford University School of Medicine, Stanford, California.
⁵ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
⁶ Division of Cardiology, University of Toronto, Toronto, Ontario.
⁷ Division of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
⁸ Section of Genetics, Department of Pediatrics, University of Colorado, Aurora, Colorado.
⁹ Molecular and Human Genetics Department, Baylor College of Medicine, Houston, Texas.
¹⁰ Institute for Human Genetics, University of California, San Francisco, California.
¹¹ University of Wisconsin and Marshfield Clinic, Marshfield and Madison, Wisconsin.
¹² Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
¹³ Molecular and Human Genetics Department, Baylor College of Medicine, Houston, Texas, and Roche Diagnostics, Santa Clara, California.
¹⁴ Department of Pediatrics, John Muir Health, Walnut Creek, California.
¹⁵ Department of Genomic Health, Geisinger, Danville, Pennsylvania.
¹⁶ Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio.
¹⁷ Genomics, Ethics, and Translational Research Program, RTI International, Research Triangle Park, North Carolina.

PMID: 38757444
DOI: 10.1016/j.gim.2024.101164

Abstract

Purpose: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions.

Methods: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs.

Results: The resulting rubric has a four-point scale (limited, moderate, strong, definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, pre-defined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs.

Conclusion: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Keywords: Actionability assertions; Assertions rubric; Clinical actionability; Genome sequencing; Secondary findings.