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

Abstract

ImportanceGenetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.ObjectiveTo test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.DesignAn investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.SettingA regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.ParticipantsSixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.InterventionParent and infant trio rWGS.Main Outcome and MeasureThe hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.ResultsTwenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).CONCLUSIONSrWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.

Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants

“…Farnaes et al reported 38% of patients received a full explanation for their symptoms by rGS while 43% received at least a partial explanation (Farnaes et al, ). Additionally Petrikin et al reported a clinical sensitivity of 31% by rGS (Petrikin et al, ). The reason for the favorable sensitivity for RapSeq may be due to the fact that all genes known to be causative of Mendelian disorders were targeted by the panel.…”

Genetic counseling in pediatric acute care: Reflections on ultra‐rapid genomic diagnoses in neonates

“…Multiple studies have shown that a definitive molecular diagnosis in the pediatric acute care setting can provide prognostic information, altering management decisions and clinical outcomes (Farnaes et al, ; Meng et al, ; Mestek‐Boukhibar et al, ; Stark, Lunke, et al, Stark, Lunke, et al, ; Stark, Schofield, et al, Stark, Schofield, et al, ; Stark et al, ; van Diemen et al, ; Willig et al, ), and evidence is emerging that turnaround times impact clinical utility (Meng et al, ; Stark, Lunke, et al, Stark, Lunke, et al, ; van Diemen et al, ; Willig et al, ). However, the clinical value of rapid genomic sequencing can be difficult to rigorously demonstrate (Friedman et al, ; Grosse & Farnaes, ; Petrikin et al, ). Furthermore, considerable clinical and laboratory challenges need to be overcome for sustainable implementation of diagnostic genomics at “rapid” (2–3 weeks) or “ultra‐rapid” (<7 days) turnaround times, including the need for medical geneticists, genetic counselors, and medical scientists to be available “on demand” (Friedman et al, ; Stark, Lunke, et al, Stark, Lunke, et al, ).…”

Factors complicating the informed consent process for whole exome sequencing in neonatal and pediatic intensive care units

“…A recent flurry of studies demonstrates the utility and increased use of WES/WGS, especially rapid WES/WGS, for critically ill patients in neonatal and pediatric intensive care unit (ICU) settings (Meng et al, ; Petrikin et al, ; Petrikin, Willig, Smith, & Kingsmore, ; Smith, Willig, & Kingsmore, ; Stark et al, ). They show broad genetic testing like WES/WGS has meaningful potential to impact care decisions, spanning from identifying treatment of the underlying disease to withdrawing support for incurable disorders.…”