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Sick Infants Profiled With WGS See Better Diagnosis, More Care Changes

NEW YORK – New data out this week have added support to a growing push for routine use of whole-genome sequencing in the diagnosis of acutely ill newborns suspected of having a genetic disorder.

Investigators from five US children's hospitals, working with Illumina, published their results Monday in JAMA Pediatrics. Called the NICUSeq Randomized Time-Delayed Trial, the study demonstrated that clinical whole-genome sequencing significantly outperformed standard care practices in providing diagnoses and led to more changes in clinical management for these infants.

According to the authors, the results support the widespread adoption and implementation of clinical WGS in this area of medical practice. Additionally, because the study recruited a relatively diverse cohort, it helps illustrate how pushing WGS into the standard of care for diagnosing sick infants could reduce healthcare disparities by enabling "diagnostic equity," the authors wrote.

"This brings us one important step closer to a precision diagnosis for every child that needs one," corresponding author Ryan Taft, VP of scientific research at Illumina, said in a statement.

In an email, he noted that the "usual care" diagnostic testing that WGS was being compared to in the trial varied widely between patients and institutions.

Overall, a majority of patients received some kind of diagnosis whether by the trial's WGS or other local practices, but those were not evenly distributed.

"The first thing we need to do to make diagnostic equity more likely is to understand which tools to deploy for a given population, and in this study we show that for infants with a suspect genetic disease in the ICU, that is WGS. Next, we need to work with policymakers and insurers to reduce or eliminate barriers to reimbursement. Third, we need professional societies and guideline-producing entities to embrace WGS. Fourth, we need to continue to drive cost-effective sequencing and analysis. None of this is easy, but it is tractable," Taft said.

The study joins a number of others that have assessed comprehensive genomic testing in populations of acutely ill infants, using either whole-exome or whole-genome sequencing. WGS in particular has been pioneered by Stephen Kingsmore, president and CEO of the Rady Children's Institute for Genomic Medicine.

According to the authors of the new JAMA Pediatrics study, prior research has shown that a significant number of molecularly diagnosed infants receive altered care that is associated with improved outcomes, and that parents and clinicians perceive genomic testing as having high utility in the acute care setting.

However, widespread implementation of WGS in the ICU has been hampered "by a lack of controlled studies investigating their effect on change of management using matched comparator groups, real-world inclusion criteria, and diverse populations," the group wrote.

Their new study randomized 354 infants suspected by their doctor of having a genetic disorder to either receive clinical WGS within 15 days or after a 60-day wait. Clinicians otherwise continued their usual care strategies, including using various types of molecular genetic testing, which allowed the team to assess the effect of WGS within a real-world clinical population.

According to the authors, twice as many patients in the 15-day WGS group had received a molecular diagnosis and a change in their management compared with those in the delayed sequencing group.

For those for whom return of WGS results was delayed by 60 days, there was then a further doubling in the number of patients with a change in management and a precision diagnosis.

The majority of management changes that occurred didn't lead to specific interventions, with specialty referrals being the most common, the authors wrote. However, 8 percent of the diagnosed patients had interventions that directly addressed their "etiologic molecular alteration."

Additionally, the investigators followed the cohort up to 90 days in total and found that the proportion of patients with a change of management continued to rise, even for those who received a WGS diagnosis at 15 days. This suggests that "genetic findings may provide a foundation for long-term clinical decision-making," they wrote.

"Having this type of genetic information provides immediate and sustainable benefits that have lifelong value, providing a genetic 'report card' that can be used to help direct medical care throughout life," Chester Brown, genetics division chief of Le Bonheur Children's Hospital and the University of Tennessee Health Science Center, said in a statement.

Although prior observations by Kingsmore and others have suggested outcome and health-economic benefits from rapid WGS in newborns, the JAMA study did not observe differences in length of stay or mortality. According to the authors, this could be either because the main effect of WGS is a refinement of care, rather than improved survival, or because a larger study with shorter WGS testing turnaround times may be necessary to measure outcome effects.

The team did highlight several diagnoses that led to changes in management with "notable clinical effect." For example, a male infant aged 29 days who was randomized to the 15-day WGS group received a diagnosis of Wiskott-Aldrich syndrome by WGS and subsequently received a corrective bone marrow transplant.

In other cases, inappropriate interventions were halted as a result of diagnosis, including in a female infant aged 11 days with epilepsy for whom ineffective administration of pyridoxine was stopped after her diagnosis with an unsuspected KCNQ2 variation.

Overall, the authors argued that even without data showing statistically improved outcomes in the current study, the link between establishing a diagnosis for sick infants and improving their care is clear. As such, the results of the study lend "much weight to the adoption of [clinical] WGS as a first-tier diagnostic test," said lead author Ian Krantz, a professor of pediatrics at the Children's Hospital of Philadelphia, in a statement.

"There is absolutely more we can learn in this population, and long-term longitudinal studies that assess the impact of the 'genomic report card' over the course of a child’s life are going to be essential," Taft added in his email. "The NICUSeq results, however, indicate that we should not wait for further studies to be completed before widespread implementation is seriously considered."

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