Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial

Abstract

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management.

Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US.

Design, setting, and participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020.

Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study.

Main outcomes and measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality.

Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed.

Conclusions and relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population.

Trail registration: ClinicalTrials.gov Identifier: NCT03290469.

Figure 1.. Consolidated Standards of Reporting Trials (CONSORT) Flow Diagram of Enrollment and Randomization of Patients in the NICUSeq Clinical Trial

The NICUSeq study used a randomized time-delayed design to investigate the effect of whole-genome sequencing (WGS) on changes of management. The patient attrition noted here does not include 2 deaths in the early group that occurred after day 90 but within the study window.

Figure 2.. Change of Management (COM) Types, Effect by Clinical Classification, and Occurrence Relative to Discharge

A, Types of COM observed at day 60 (black and dark blue bars) and at day 90 (light blue and white bars). COM categories are provided as horizontal x-axis labels. B, The number of patients with a COM across sites classified by the primary indication for testing. The greatest number of patients with a COM were observed in patients with multiple congenital anomalies, and the greatest proportion in those with a neurologic disorder. C, The time from a patient’s first discharge to the return of whole-genome sequencing (WGS) results, with the majority showing short length of stays followed by WGS return of results outside the NICU setting. Orange and blue dots denote patients with a COM (orange) or no COM (blue).

Figure 3.. Secondary Outcomes Including Whole-Genome Sequencing (WGS) Findings, Length of Stay, and Survival

A, The distribution of positive WGS diagnoses by indication for testing. Dark blue shading indicates patients with a positive WGS finding, and light blue shading indicates those with no WGS finding. B, The distribution of variant types and their associated inheritance state detected by WGS (eTable 5 in Supplement 3). C, Total length of stay from the time of enrollment in the NICUSeq study to discharge (eFigure 7 in Supplement 2). D, Patient survival probability stratified by arm. Data collection extended to 115 days to complete final study visit assessments (eFigure 8 in Supplement 2). CNV indicates copy number variation; Indel, insertion/deletion polymorphism; MNV, multinucleotide variant; SNV, single-nucleotide variant.