Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders

Abstract

Background: Genomic assessment previously took months to result and was unable to impact clinical care in the pediatric intensive care unit (PICU). The advent of rapid exome sequencing potentially changes this. We investigated the impact of rapid exome sequencing in a pilot study on pediatric patients admitted to a single PICU with new onset metabolic/neurologic disease. Methods: Rapid exome sequencing (7 days to verbal result) was performed on (n=10) PICU patients age <6 years admitted with new onset metabolic/neurologic disease. The primary outcome of interest was inpatient LOS, which served as a proxy for inpatient cost. Results: A significant reduction in median LOS was identified when comparing PICU patients who underwent rapid exome sequencing to historical controls. From those patients who underwent rapid sequencing, 5 had likely pathogenic variants. In 3 cases with diagnostic genetic results, there was a modification to clinical care attributable to information provided by exome sequencing. Conclusions: This pilot study demonstrates that rapid exome sequencing is feasible to do in the PICU, that genetic results can be returned quickly enough to impact critical care decision-making and management. In a select population of PICU patients, this technology may contribute to a decrease in hospital length of stay.

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care

“…With the exception of one non-randomized retrospective study looking at a longer turnaround time exome test, 27 studies performed in the carefully controlled environment of clinical research have reproducibly found genome-wide sequencing to be effective for diagnosis and management of undiagnosed infants in ICUs and to result in reductions in health care costs. 6,8,11,[14][15][16][20][21][22][28][29][30][31][32][33][34] PBB demonstrates the feasibility of deploying rWGS-informed RPM into routine care across multiple sites to help vulnerable patients in a cost-effective manner while achieving diagnosis and change-in-medical-care rates comparable to previously published studies. Test results influenced the decisions physicians and families made about the care of babies with rare genetic diseases.…”

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)

“…Cost-effectiveness should be reassessed as well using systematic review as the literature increases but interim findings are encouraging. 91 Workforce considerations will change including ordering providers, need of clinical geneticists/ genetic counselors, and lab availability.…”

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

“…[8][9][10] Previous work has demonstrated that rapid genome-wide sequencing (ultra-rapid whole-genome sequencing [urWGS], rapid whole-genome sequencing [rWGS], or rapid whole-exome sequencing [rWES]) is associated with both a shorter time to diagnosis and an increased diagnostic yield when compared with standard-of-care testing, including gene panels and chromosome microarrays. 6,7,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] However, earlier diagnosis of genetic disorders is a process measure and not a definitive mark of clinical utility.…”

“…26 Although 15 studies to date have shown, by varying definitions, the clinical utility of rapid genome-wide sequencing in the NICU, PICU, and CVICU, it is not yet clear what the specific indications for such testing should be, nor, beyond case series, in what situations urWGS, rWGS, or rWES are associated with improved outcomes. 6,7,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]33 Moreover, modeling of previously published data suggests that both the cost and clinical utility of urWGS, rWGS, and rWES vary inversely with time to result. 14,16 However, the optimal match of presentations, timeliness, and cost effectiveness is not yet known.…”