Wenger Tara L, Scott Abbey, Kruidenier Lukas, Sikes Megan, Keefe Alexandra, Buckingham Kati J, Marvin Colby T, Shively Kathryn M, Bacus Tamara, Sommerland Olivia M, Anderson Kailyn, Gildersleeve Heidi, Davis Chayna J, Love-Nichols Jamie, MacDuffie Katherine E, Miller Danny E, Yu Joon-Ho, Snook Amy, Johnson Britt, Veenstra David L, Parish-Morris Julia, McWalter Kirsty, Retterer Kyle, Copenheaver Deborah, Friedman Bethany, Juusola Jane, Ryan Erin, Varga Renee, Doherty Daniel A, Dipple Katrina, Chong Jessica X, Kruszka Paul, Bamshad Michael J
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA.
Seattle Children's Hospital, Seattle, WA 98105, USA.
Am J Hum Genet. 2025 Mar 6;112(3):508-522. doi: 10.1016/j.ajhg.2025.02.003. Epub 2025 Feb 24.
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.
由于用于确定检测资格优先级的复杂纳入标准遗漏了许多患有遗传疾病高风险的患者，危重新生儿获得精确基因诊断（PrGD）的机会有限且不公平。SeqFirst-neo是一个项目，旨在测试使用简单、广泛的排除标准来评估快速基因组测序（rGS）资格的基因型驱动工作流程是否能增加危重新生儿获得PrGD的机会。对2021年1月至2022年2月期间入住新生儿重症监护病房的所有408名新生儿进行了评估，在240名符合条件的婴儿中，126名接受了rGS（即干预组[IG]），并与114名同时接受常规护理的婴儿（即常规护理组[CCG]）进行比较。IG组126名新生儿中有62名（49.2%）获得了PrGD，而CCG组114名婴儿中有11名（9.7%）获得了PrGD。IG组获得PrGD的几率比CCG组高约9倍，且这一差异在12个月随访时仍然存在。IG组和CCG组中，非白人婴儿（34/74，45.9%对6/29，20.7%；p = 0.024）和黑人婴儿（8/10，80.0%对0/4；p = 0.015）获得PrGD的情况存在显著差异。新生儿科医生在预测非白人婴儿的PrGD方面明显不如非西班牙裔白人婴儿成功。对IG组中获得PrGD的婴儿使用标准工作流程发现，26/62（42%）的婴儿会漏诊PrGD。使用简单、广泛的排除标准以增加基因检测机会，可显著增加获得PrGD的机会，改善获取公平性，并减少漏诊情况。
