SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns

Tara L Wenger; Abbey Scott; Lukas Kruidenier; Megan Sikes; Alexandra Keefe; Kati J Buckingham; Colby T Marvin; Kathryn M Shively; Tamara Bacus; Olivia M Sommerland; Kailyn Anderson; Heidi Gildersleeve; Chayna J Davis; Jamie Love-Nichols; Katherine E MacDuffie; Danny E Miller; Joon-Ho Yu; Amy Snook; Britt Johnson; David L Veenstra; Julia Parish-Morris; Kirsty McWalter; Kyle Retterer; Deborah Copenheaver; Bethany Friedman; Jane Juusola; Erin Ryan; Renee Varga; Daniel A Doherty; Katrina Dipple; Jessica X Chong; Paul Kruszka; Michael J Bamshad

doi:10.1016/j.ajhg.2025.02.003

SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns

Am J Hum Genet. 2025 Mar 6;112(3):508-522. doi: 10.1016/j.ajhg.2025.02.003. Epub 2025 Feb 24.

Authors

Tara L Wenger¹, Abbey Scott², Lukas Kruidenier², Megan Sikes², Alexandra Keefe¹, Kati J Buckingham³, Colby T Marvin³, Kathryn M Shively³, Tamara Bacus³, Olivia M Sommerland³, Kailyn Anderson³, Heidi Gildersleeve³, Chayna J Davis³, Jamie Love-Nichols², Katherine E MacDuffie⁴, Danny E Miller⁵, Joon-Ho Yu⁶, Amy Snook⁷, Britt Johnson⁷, David L Veenstra⁸, Julia Parish-Morris⁹, Kirsty McWalter⁷, Kyle Retterer¹⁰, Deborah Copenheaver⁷, Bethany Friedman⁷, Jane Juusola⁷, Erin Ryan⁷, Renee Varga⁷, Daniel A Doherty¹¹, Katrina Dipple¹, Jessica X Chong¹², Paul Kruszka⁷, Michael J Bamshad¹³

Affiliations

¹ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA.
² Seattle Children's Hospital, Seattle, WA 98105, USA.
³ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
⁴ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Treuman Katz Center for Pediatric Bioethics and Palliative Care, Seattle Children's Research Institute, Seattle, WA 98121, USA.
⁵ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Bay Institute, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
⁶ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Treuman Katz Center for Pediatric Bioethics and Palliative Care, Seattle Children's Research Institute, Seattle, WA 98121, USA; Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA.
⁷ GeneDx, Gaithersburg, MD 20877, USA.
⁸ Department of Pharmacy, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Biomedical and Health Informatics, Perelman School of Medicine, Philadelphia, PA 19146, USA.
¹⁰ GeneDx, Gaithersburg, MD 20877, USA; Geisinger, Danville, PA 17822, USA.
¹¹ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Bay Institute, Seattle, WA 98195, USA.
¹² Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman Bay Institute, Seattle, WA 98195, USA.
¹³ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Bay Institute, Seattle, WA 98195, USA. Electronic address: mbamshad@uw.edu.

Abstract

Access to a precise genetic diagnosis (PrGD) in critically ill newborns is limited and inequitable because the complex inclusion criteria used to prioritize testing eligibility omit many patients at high risk for a genetic condition. SeqFirst-neo is a program to test whether a genotype-driven workflow using simple, broad exclusion criteria to assess eligibility for rapid genome sequencing (rGS) increases access to a PrGD in critically ill newborns. All 408 newborns admitted to a neonatal intensive care unit between January 2021 and February 2022 were assessed, and of 240 eligible infants, 126 were offered rGS (i.e., intervention group [IG]) and compared to 114 infants who received conventional care in parallel (i.e., conventional care group [CCG]). A PrGD was made in 62/126 (49.2%) IG neonates compared to 11/114 (9.7%) CCG infants. The odds of receiving a PrGD were ∼9 times greater in the IG vs. the CCG, and this difference was maintained at 12 months follow-up. Access to a PrGD in the IG vs. CCG differed significantly between infants identified as non-White (34/74, 45.9% vs. 6/29, 20.7%; p = 0.024) and Black (8/10, 80.0% vs. 0/4; p = 0.015). Neonatologists were significantly less successful at predicting a PrGD in non-White than non-Hispanic White infants. The use of a standard workflow in the IG with a PrGD revealed that a PrGD would have been missed in 26/62 (42%) infants. The use of simple, broad exclusion criteria that increase access to genetic testing significantly increases access to a PrGD, improves access equity, and results in fewer missed diagnoses.

Keywords: equity; genetic diagnosis; health disparity; rapid whole-genome sequencing; rare disease.

MeSH terms

Critical Illness*
Female
Genetic Testing* / methods
Genotype
Health Services Accessibility*
Humans
Infant, Newborn
Intensive Care Units, Neonatal
Male