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The NSIGHT1-randomized Controlled Trial: Rapid Whole-Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants


The NSIGHT1-randomized Controlled Trial: Rapid Whole-Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

Josh E Petrikin et al. NPJ Genom Med.


Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests (n = 32, cases) or standard genetic tests alone (n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10-46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11-53%];p = 0.004). Median age at diagnosis (25 days [range 14-90] in cases vs. 130 days [range 37-451] in controls) and median time to diagnosis (13 days [range 1-84] in cases, vs. 107 days [range 21-429] in controls) were significantly less in cases than controls (p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases.

Conflict of interest statement

The authors declare no competing financial interests.


Fig. 1
Fig. 1
Design of “Newborn Sequencing In Genomic medicine and public HealTh” study 1 (NSIGHT1; accession NCT02225522). Time (t) is in days. WGS whole-genome sequencing, EHR Electronic Health Record
Fig. 2
Fig. 2
CONSORT flow diagram of NSIGHT1 enrollment and randomization. Major reasons for non-enrollment were family refusal (13%), the infant had a diagnosis that explained the phenotype (9%), and incomplete nominations (9%). At unblinding of clinicians (by 10 days after enrollment), a provision was made whereby clinicians could request compassionate cross-over to the rWGS group if the infant was critically ill. Cross-over was requested for 7 (21%) of 33 infants who randomized to standard tests alone, of which 5 met these criteria and were granted
Fig. 3
Fig. 3
Kaplan–Meier curves of time to diagnosis in cases and controls. The cumulative probability of a diagnosis (Dx) in cases (infants randomized to receive rWGS plus standard genetic tests; shown in red; n = 32) and controls (infants randomized to standard genetic tests alone; shown in blue; n = 33). Differences in probability of receiving a diagnosis were significant between the two arms from day 12–67 after enrollment (a asterisks) and DOL 19 - 99 (b asterisks)

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