NEW YORK – New research suggests that sequencing-based genetic diagnoses for critically ill newborns can be improved by relying on simple, broad exclusion criteria for testing rather than sifting through potentially complex sets of inclusion criteria.
"[U]se of complex inclusion criteria suggests that some kids with a genetic condition won't get offered genetic testing or precise genetic diagnosis," senior and corresponding author Michael Bamshad, head of the genetic medicine division with the University of Washington and Seattle Children's Hospital's pediatrics department, said in an email. "This is a missed opportunity to offer precise care, reduce morbidity and mortality, and lower healthcare costs."
In a paper appearing in the American Journal of Human Genetics on Monday, Bamshad and colleagues from UW, Seattle Children's, and molecular diagnostics laboratory GeneDx presented findings for 240 newborns treated in a Seattle Children's Hospital neonatal intensive care unit (NICU) between January 2021 and February 2022 who were eligible to receive rapid genome sequencing under their "genotype-driven" workflow, which they dubbed the SeqFirst-neo program.
"SeqFirst is a platform to develop and test strategies for improving access to a precise genetic diagnosis," Bamshad said, noting that "we tested the impact of using simple, broad exclusion criteria instead of complex inclusion criteria on access to a precise genetic diagnosis."
Through the SeqFirst-neo research initiative, for example, families were offered rapid genome sequencing when their critically ill newborns' conditions could not be explained by premature birth, trauma, or an infection. Similar efforts, known as "SeqFirst-Ddi" and "SeqFirst-All Kids Included," respectively, are also underway to assess toddlers with atypical development and children from underserved communities.
In the current SeqFirst-neo study, the team sequenced whole blood collected from the proband, parents, and in some cases other family members using the CLIA-certified, commercially available GenomeXpress test from GeneDx. They reached precise genetic diagnoses in 62 of the 126 infants whose families were offered testing, representing more than 49 percent of cases assessed using exclusion criteria-based rapid genome sequencing. In contrast, precise genetic diagnoses — the identification of a genetic variant that fully or partially explained an infant's clinical symptom — were reached for 11 of 114, or 9.7 percent, of infants receiving conventional care.
The differences in diagnostic rates were particularly pronounced in infants identified as Black or non-White. The investigators reached genetic diagnoses in 80 percent of the critically ill Black infants and nearly 46 percent of the non-White critically ill infants with the SeqFirst approach. None of the four Black infants in the conventional care group reached genetic diagnoses, while genetic diagnoses were made for just six of 29 non-White infants getting conventional care.
"If we generalize our results, it suggests that there are a lot of kids in NICUs around the country who have a genetic condition but aren't being offered testing because … the workflow is too complicated," Bamshad said. "So, this is a lot of kids for whom we're missing the opportunity to provide precision care."
Based on their results so far, he and his colleagues reasoned that the use of relatively simple exclusion criteria for rapid newborn sequencing may not only improve genetic diagnoses overall but can also lead to more equitable access to care in infants enduring critical illness.
With such considerations in mind, the investigators are now developing methods to help providers become more equipped to understand, access, and apply rapid genome sequencing more broadly in the NICU, starting with an online portal established to help neonatologists work with families during the consent and return of results stages of the rapid genome sequencing process.
"We hypothesize that use of the portal will facilitate more autonomy and support for the neonatologists, allow for genetics services to be used more efficiently, and ultimately further increase access to testing and a diagnosis," Bamshad said.
"The step after this is to test the addition of providing clinical genetics services remotely in this workflow," he added, "so as to support NICUs with limited or no clinical genetics services."