The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.

Autor:	Petrikin JE; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA.; 2Department of Pediatrics, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA., Cakici JA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA., Clark MM; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA., Willig LK; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA.; 2Department of Pediatrics, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA., Sweeney NM; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA.; 5Department of Pediatrics, University of California, Rady Children's Hospital, San Diego, CA 92123 USA., Farrow EG; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA.; 2Department of Pediatrics, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA., Saunders CJ; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA.; 6Department of Pathology, Children's Mercy, Kansas City, MO 64108 USA., Thiffault I; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA.; 6Department of Pathology, Children's Mercy, Kansas City, MO 64108 USA., Miller NA; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA., Zellmer L; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA., Herd SM; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA., Holmes AM; 2Department of Pediatrics, Children's Mercy, Kansas City, MO 64108 USA., Batalov S; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA., Veeraraghavan N; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA., Smith LD; 1Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA.; 7Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599 USA., Dimmock DP; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA., Leeder JS; 2Department of Pediatrics, Children's Mercy, Kansas City, MO 64108 USA.; 3School of Medicine, University of Missouri, Kansas City, MO 64108 USA., Kingsmore SF; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA.
Jazyk:	angličtina
Zdroj:	NPJ genomic medicine [NPJ Genom Med] 2018 Feb 09; Vol. 3, pp. 6. Date of Electronic Publication: 2018 Feb 09 (Print Publication: 2018).
DOI:	10.1038/s41525-018-0045-8
Abstrakt:	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. Competing Interests: The authors declare no competing financial interests.
Databáze:	MEDLINE
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