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 ¼ 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.

Polymerase Gamma Mitochondrial DNA Depletion Syndrome Initially Presenting as Disproportionate Respiratory Distress in a Moderately Premature Neonate: A Case Report

“…It also shows patients with complex neonatal diseases with significant family history may benefit from rES to allow for expedited diagnosis and early termination of the diagnostic odyssey. Indeed, this conclusion is concordant with the findings of both the NSIGHT2 randomized controlled trial ( Dimmock et al, 2020 ) as well as the Australian Acute Care Genomics Study ( Australian Genomics Health Alliance Acute Care Flagship et al, 2020 ). However, those findings had not been published, let alone made it into widespread practice when this patient presented and so this patient initially underwent panel-based genetic testing based on the respiratory failure phenotype then apparent and the causal variants in POLG were not interrogated.…”

Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)

“…Most parents in this study perceived being adequately informed to consent, understood their child's results, and denied regret or harm from undergoing sequencing. 79 Lewis et al interviewed parents of children with rare diseases participating in the 10,000 Genomes project. Overall, parents were positive about completing the testing for diagnostic purposes.…”

Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.

“…Improved diagnostic performance is anticipated to enable faster and more cost-effective, tiered reviews. These features hold promise for reduced time-to-diagnosis and greater scalability for critical applications, such as in seriously ill children in the NICU/PICU [27,66].…”