Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants. However, before wide-spread adoption and implementation, its effect on clinical management in a diverse population must be determined. Therefore, researchers from carried out a randomised clinical study to determine the effect of WGS on clinical management in a population of racially and ethnically diverse acutely ill infants in the US.
Clinical management of acutely ill infants
Critically ill infants in intensive care units (ICUs) are at a high risk of morbidity and mortality. It is estimated that in the US around 400,000 newborns are admitted to a neonatal ICU annually.
Genetic disorders are a leading cause of ICU admission. This has led to several investigations into the efficacy of genomic testing in populations of acutely ill infants. The types of genomic testing being investigated include whole-exome sequencing and whole-genome sequencing (WGS). Whole exome sequencing surveys approximately 2% of the genome that encodes proteins. While WGS evaluates approximately 95% of nuclear and mitochondrial DNA. These studies have reported 20% to 50% diagnostic efficacy with high variability. This variability is largely due to differing inclusion criteria and comprehensiveness of genomic tests. The highest efficacy results have been observed in cohorts of critically ill infants with clinical features suggestive of genetic disease.
Observational investigations of clinical utility of genetic tests have also shown that up to two-thirds of molecularly diagnosed infants receive an alteration in care. However, the widespread implementation of WGS and other genomic tests in the ICU is hampered by a lack of controlled studies investigating their effect on change of management (COM) using matched comparator groups, real-world inclusion criteria, and diverse populations.
Randomised clinical trial to assess the effect of WGS on COM
In this study, published in JAMA Pediatrics, researchers reported the results of a multicentre, randomised, time-delayed investigation of the effect of clinical WGS on infants admitted to an ICU at five US children’s hospitals.
A total of 354 infants were randomised in the early or delayed arms. Patient selection was based on admittance to the ICU with a suspected genetic disease. The mean participant age was 15 days. Overall, 201 participants were boys; 19 were of Asian descent, 47 were black, 250 were white, and 38 were of other descent.
Patients were randomised to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrolment. The observation period was extended to 90 days to assess the effect of the results on care. Usual care was also continued throughout the study, including molecular testing, allowing assessment of the real-world effectiveness of WGS.
Is there an effect of WGS on COM?
At 60 days, twice as many infants in the early group versus the delayed group received molecular diagnosis and COM. At 90 days, the delayed group showed a doubling of diagnostic efficacy, as well as COM. Overall, the most common COMs across all observation windows were subspecialty referrals, surgery or other invasive procedures, condition-specific medications, or other supportive alterations in medication. However, no differences were observed in length of stay or survival.
Conclusions and future implications
Overall, this study has detailed the results of a randomised clinical trial, using a cohort of acutely ill infants in intensive care units, to assess the effect of WGS on COM. Introduction of WGS was associated with a significant increase in focused clinical management compared with normal care. This work therefore helps to support the growing body of literature that access to first-line WGS may reduce healthcare disparities by enabling diagnostic equity.
We recently interviewed Stephen Kingsmore, President and CEO of Rady’s Children’s Institute for Genomic Medicine, who spoke about the importance of WGS for early and accurate diagnosis in critically ill newborns.
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