A novel urine peptide biomarker-based algorithm for the prognosis of necrotising enterocolitis in human infants

Abstract

Objective Necrotising enterocolitis (NEC) is a major source of neonatal morbidity and mortality. The management of infants with NEC is currently complicated by our inability to accurately identify those at risk for progression of disease prior to the development of irreversible intestinal necrosis. We hypothesised that integrated analysis of clinical parameters in combination with urine peptide biomarkers would lead to improved prognostic accuracy in the NEC population. Design Infants under suspicion of having NEC (n=550) were prospectively enrolled from a consortium consisting of eight university-based paediatric teaching hospitals. Twenty-seven clinical parameters were used to construct a multivariate predictor of NEC progression. Liquid chromatography/mass spectrometry was used to profile the urine peptidomes from a subset of this population (n=65) to discover novel biomarkers of NEC progression. An ensemble model for the prediction of disease progression was then created using clinical and biomarker data. Results The use of clinical parameters alone resulted in a receiver-operator characteristic curve with an area under the curve of 0.817 and left 40.1% of all patients in an ‘indeterminate’ risk group. Three validated urine peptide biomarkers (fibrinogen peptides: FGA1826, FGA1883 and FGA2659) produced a receiver-operator characteristic area under the curve of 0.856. The integration of clinical parameters with urine biomarkers in an ensemble model resulted in the correct prediction of NEC outcomes in all cases tested. Conclusions Ensemble modelling combining clinical parameters with biomarker analysis dramatically improves our ability to identify the population at risk for developing progressive NEC.

Necrotizing enterocolitis: new insights into pathogenesis and mechanisms

“…Furthermore, a promising strategy in the identification of progressive NEC that requires surgical intervention has been formulated as a novel algorithm combining 27 clinical parameters and three urine fibrinogen peptide biomarkers, FGA1826, FGA1883 and FGA2659. This algorithm was reported to accurately predict the need for surgery in infants with suspected NEC in 100% of the cases analysed as opposed to only 40.1% when using the clinical parameters alone 49,50 , but it remains to be validated independently and in larger population studies. These and other biomarkers, therefore, could be considered for use in association with noninvasive monitoring techniques that assess intestinal tissue perfusion (for example, near-infrared spectroscopy) 51 to identify those infants at risk of developing NEC.…”

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

“…The same group performed another study identifying three urinary coagulation cascade fibrinogen peptides that discriminated between medical and surgical NEC (AUC 0.86). When combined with clinical variables, these accurately predicted all infants requiring surgical intervention (65). Furthermore, they recently identified fibrinogen-γ dimers in plasma discriminated NEC (N=40) from sepsis (N=20), with an AUC 0.95.…”

Current Research on the Epidemiology, Pathogenesis, and Management of Necrotizing Enterocolitis

“…Recently, biomarker discovery studies of the urinary proteome [16] and peptidome [17] have identified proteins and peptides associated with poor outcome (i.e., disease progression). Importantly, the biomarkers alone were not able to completely distinguish progressors from non-progressors, but were able to when clinical factors were incorporated into the prediction model.…”