Abstract
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.
Highlights
INTRODUCTIONA premise of pediatric precision medicine is that outcomes are improved by replacement of clinical diagnosis and empiric management with genetic diagnosis and genotypedifferentiated treatment.[1,2,3,4,5,6,7,8,9] The evidence base for pediatric precision medicine is still underdeveloped.[10,11] Ill infants are especially in need of precision medicine since genetic diseases are a leading cause of mortality, in neonatal intensive care units (NICU) and pediatric intensive care units (PICU).[5,6,7,12,13,14,15,16] Among high-cost health care, NICU treatment is one of the most cost-effective.[17,18,19] Since disease progression can be very rapid in infants, genetic diagnoses must be made quickly to permit consideration of precision interventions in time to decrease morbidity and mortality.[5,6,20,21,22,23] For a few genetic diseases, newborn screening has shown early neonatal diagnosis and rapid, precise intervention to dramatically improve outcomes.[24,25] The potential expansion to newborn diagnosis for symptomatic infants for all 5000 genetic diseases[26] has been made technically possible by the advent of clinical genomic sequencing (whole-genome sequencing (WGS) or whole-exome sequencing (WES), and nextgeneration sequencing gene panel tests (NGS)
NICU and PICU infants receiving trio rapid whole-genome sequencing (rWGS) plus standard clinical testing had a higher rate of genetic diagnosis and shorter time to diagnosis than infants receiving standard tests alone
Among infants with suspected genetic diseases in a regional NICU or PICU, the addition of rWGS decreased the time to diagnosis
Summary
A premise of pediatric precision medicine is that outcomes are improved by replacement of clinical diagnosis and empiric management with genetic diagnosis and genotypedifferentiated treatment.[1,2,3,4,5,6,7,8,9] The evidence base for pediatric precision medicine is still underdeveloped.[10,11] Ill infants are especially in need of precision medicine since genetic diseases are a leading cause of mortality, in neonatal intensive care units (NICU) and pediatric intensive care units (PICU).[5,6,7,12,13,14,15,16] Among high-cost health care, NICU treatment is one of the most cost-effective.[17,18,19] Since disease progression can be very rapid in infants, genetic diagnoses must be made quickly to permit consideration of precision interventions in time to decrease morbidity and mortality.[5,6,20,21,22,23] For a few genetic diseases, newborn screening has shown early neonatal diagnosis and rapid, precise intervention to dramatically improve outcomes.[24,25] The potential expansion to newborn diagnosis for symptomatic infants for all 5000 genetic diseases[26] has been made technically possible by the advent of clinical genomic sequencing (whole-genome sequencing (WGS) or whole-exome sequencing (WES), and nextgeneration sequencing gene panel tests (NGS). Published NICU or PICU experience with rWGS, is limited to case reports and one retrospective study.[5,6,20,21,22,23] In the latter, 57% of infants received genetic diagnoses in a median of 23 days (day of life 49).[6] it has not yet been unequivocally demonstrated whether rWGS improves timeliness of genetic diagnosis relative to standard genetic tests. We report results of newborn sequencing in genomic medicine and public health randomized controlled trial (RCT) 1 (NSIGHT1), an RCT of genomic testing in patients (ClinicalTrials.gov Identifier: NCT02225522).[24] NSIGHT1 compared rates of genetic diagnosis in NICU and PICU infants with possible genetic diseases at 28 days from.
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