An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm

Abstract

The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of clinician surveys of the clinical utility of rapid genomic sequencing (RGS). The primary end-point-clinician perception that RGS was useful- was met for 154 (77%) of 201 infants. Both positive and negative tests were rated as having clinical utility (42 of 45 [93%] and 112 of 156 [72%], respectively). Physicians reported that RGS changed clinical management in 57 (28%) infants, particularly in those receiving urWGS (p = 0.0001) and positive tests (p < 0.00001). Outcomes of 32 (15%) infants were perceived to be changed by RGS. Positive tests changed outcomes more frequently than negative tests (p < 0.00001). In logistic regression models, the likelihood that RGS was perceived as useful increased 6.7-fold when associated with changes in management (95% CI 1.8-43.3). Changes in management were 10.1-fold more likely when results were positive (95% CI 4.7-22.4) and turnaround time was shorter (odds ratio 0.92, 95% CI 0.85-0.99). RGS seldom led to clinician-perceived confusion or distress among families (6 of 207 [3%]). In summary, clinicians perceived high clinical utility and low likelihood of harm with first-tier RGS of infants in ICUs with diseases of unknown etiology. RGS was perceived as beneficial irrespective of whether results were positive or negative.

Keywords: NSIGHT2; clinical utility; diagnostic testing outcomes; healthcare cost-benefit analysis; neonatal intensive care unit; pediatric intensive care unit; rapid whole-exome sequencing; rapid whole-genome sequencing; ultra-rapid whole-genome sequencing.

Conflict of interest statement

D.D. received funding from Biomarin (consultant for Pegvaliase trials), Audentes Therapeutics (Scientific Advisory Board), and Ichorion Therapeutics (consultant for mitochondrial disease drugs).

Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

CONSORT Flow Diagram of Infants Who Were Screened for Eligibility in NSIGHT2, Sequenced, Received a Genetic Disease Diagnosis, and Were Surveyed for Clinician Perception of Clinical Utility The primary end point was clinician perception that diagnostic genomic sequencing was useful or very useful (clinical utility or no clinical utility, blue shading).

Figure 2

A Flow Diagram of NSIGHT2-Informed Proposed Best Practices and Expected Outcomes for Genome-Informed Intensive Care of Infants with Diseases of Unknown Etiology Δ, change; urWGS, ultra-rapid whole-genome sequencing.