Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization

Abstract

Genetic 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. We report a retrospective 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 also 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. The diagnostic sensitivity of rWGS was 43% (eighteen of 42 infants) and 10% (four of 42 infants) for standard genetic tests (P = .0005). The rate of clinical utility of rWGS (31%, thirteen of 42 infants) was significantly greater than for standard genetic tests (2%, one of 42; P = .0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had a 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–$2,000,000. These 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.

Introduction

Genetic disorders and congenital anomalies affect ~6% of live births, and are the leading reason for hospitalization and mortality in infants.

Of 14% of US newborns admitted to neonatal intensive care units (NICU), those with genetic disorders have longer hospitalizations and higher resource utilization.While early etiologic diagnosis in such infants enables optimal outcomes, it is exceptionally difficult to deliver for genetic diseases since they number over 8000 and presentations are often atypical from classical descriptions.

Moreover, they represent the leading cause of NICU and paediatric intensive care unit (PICU) mortality, with most deaths following palliative care decisions. Family counselling regarding palliative care often is impeded by absence of etiologic diagnosis.

Rapid whole-genome sequencing (rWGS) provides a faster diagnosis, enabling precision medicine interventions in time to decrease the morbidity and mortality of infants with genetic diseases. Furthermore, rWGS facilitates end-of-life care decisions that can alleviate suffering and aid the grieving process. However, published evidence demonstrating the effectiveness of rWGS in improving outcomes in infants is insufficient to endorse large-scale implementation;

It is limited to case reports, and one retrospective study (Level III evidence). Examination of reproducibility is imperative. Here, we report such an examination.

Results

Parents provided consent for 42 of 48 eligible infants (88%, Fig. 1). While the intent was trio rWGS (parents and affected infant), rWGS was performed on 29 trios and 1 quad (parents and two affected siblings), nine mother–infant duos, and three singletons.

Flow diagram of the proportion of inpatient infants who were enrolled, received genetic disease diagnoses by rWGS or by standard tests, had consequent acute changes in management (precision medicine), resultant change in outcome, and analysis of impact on acute healthcare utilization. *Include: diagnosis obtained via clinical testing, symptoms determined to not likely be due to a genetic etiology, and/or parents unavailable for consent

Data: 04/04/2018

Lo Staff / The Staff 

American Europen Medical Center 

(americaneuropeanmedicalcenter.blogspot.com) 

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