Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

Abstract

BACKGROUNDGenetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.METHODSRetrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.FINDINGSThe diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.DISCUSSIONThese findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases

“…The proportion of children receiving a change in clinical management by WGS results was 0.27 (95% Cl 0.17-0.40, I 2 =54%, four studies of 136 children), compared with 0.18 (95% Cl 0.13-0.24, I 2 -77%,twelve studies of 992 children) by WES, and 0.06 (95% Cl 0.05-0.07, I 2 =42%, eight studies of 4,271 children) by CMA (Figure 5). Meta-analysis of WGS and CMA groups, for which heterogeneity was not significant ( P =.09 and P =.10, respectively), demonstrated that the rate of clinical utility of WGS was higher than CMA ( P <.0001) 25,32,34,35,37,45,59-61 . Meta-analysis of four studies that reported comparisons of rates of clinical utility by WGS/WES and CMA within cohorts 25,32,37,45 .…”

“…Heterogeneity within WGS and CMA groups was mild following removal of variance associated with year of publication. In eleven studies of 1,962 children published in 2017, the pooled diagnostic sensitivity of WGS (0.42, 95% Cl 0.34-0.51, I 2 =13%) was significantly greater than CMA (0.05, 95% Cl 0.03-0.09, I 2 =40%; P<.0001, Figure 1b ) 22,24,25,32,34,35,37,39,40,41,43 .…”

“…Both hospital and reference laboratory subgroups demonstrated significant heterogeneity. However, heterogeneity was reduced in ten studies published in 2017 (I 2 =34%, P =.14, and I 2 =26%, P =.26, respectively) 22,24, 25,32,34,35,37,39,40,43 . In these, the diagnostic sensitivity of hospital genomic sequencing was 0.42 (95% Cl 0.38-0.46, I 2 =34%), which was significantly higher than reference laboratories (0.31, 95% Cl 0.27-0.34, I 2 =26%; P=.004 , Figure 4b).…”

“…Since the diagnostic sensitivity of WES and WGS was not significantly different, we pooled WGS and WES studies in remaining subgroup analyses. Seven studies directly compared the proportion diagnosed by WGS or WES and CMA in 697 children; in each study, the diagnostic sensitivity of WGS/WES was at least three-fold higher than CMA 22,25,32,3,35,37,45 . Four of these manuscripts contained enough information to estimate the marginal odds ratios of receiving a diagnosis among subjects that received both WGS/WES and CMA 25,32,33,45 .…”

“…Since only thirteen (35%) of these reported results of a comparator test, pooling made comparisons susceptible to confounding from factors including clinical setting, patient factors, eligibility criteria, study quality, clinical expertise, and testing procedures. Meta-analysis of studies published in 2017, which removed variance associated with year of publication, showed that the diagnostic sensitivity of WGS (0.42, 95% Cl 0.34-0.51, I 2 =13%) was significantly greater than CMA (0.05, 95% Cl 0.03-0.09, I 2 =40%; P <.0001) 22,24,25,32,34,35,37,39,40,41,43 . Similarly, meta-analysis of studies featuring within-cohort comparisons showed that the odds of a diagnosis by WGS or WES was 8.3 times greater than CMA (95% Cl, 4.7-14.9, I 2 =36%; P <.0001) 25,32,33,45 .…”