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Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023
Katherine M Rodriguez1,2,3, Jordan Vaught1,2, Lisa Salz3
1Rady Children's Hospital, San Diego, CA.
Insights
Rapid whole-genome sequencing (rWGS) in pediatric intensive care units (PICUs) and cardiovascular ICUs (CICUs) achieved a 59% diagnostic yield. This genetic testing significantly altered patient management and prognostication in critically ill children.
Area of Science:
- Genomics
- Pediatric Critical Care
- Clinical Utility
Background:
- Rapid whole-genome sequencing (rWGS) is increasingly used in neonates, but its utility in older pediatric patients in intensive care settings is less understood.
- Limited data exists on the clinical impact of rWGS in pediatric intensive care units (PICUs) and cardiovascular intensive care units (CICUs).
Purpose of the Study:
- To analyze the clinical utility and diagnostic yield of rWGS in critically ill children outside the neonatal period.
- To assess the impact of rWGS on clinical management decisions in pediatric intensive care settings.
Main Methods:
- A multisite cohort study involving four tertiary children's hospitals.
- Included were 133 children (0-18 years) in PICU or CICU who underwent phenotype-driven rWGS between May 2016 and June 2023.
- Data collected included diagnostic yield, time to results, and changes in patient management.
Main Results:
- A molecular diagnosis was identified in 59% (79/133) of patients, with a median turnaround time of 3 days.
- Genetic diagnosis led to changes in ICU management for 24% and overall clinical management for 80% of diagnosed patients.
- Dysmorphic features and congenital heart disease were associated with higher diagnostic rates. rWGS enhanced prognostication and informed palliative care decisions.
Conclusions:
- Timely genetic diagnosis using rWGS is feasible and effective across multiple pediatric critical care institutions.
- rWGS demonstrates a substantial diagnostic yield and significantly influences critical care and long-term patient management strategies.
- The study supports the expanded application of rWGS in pediatric intensive care for improved patient outcomes.
Objectives:
Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions.
Design:
Ambidirectional multisite cohort study.
Setting:
Four tertiary children's hospitals.
Patients:
Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023.
Interventions:
None.
Measurements And Main Results:
A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication ( p < 0.0001) and contributed to a decision to consult palliative care ( p < 0.02).
Conclusions:
In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management.
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