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


METHODS
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.
Division of Pediatric Surgery, Lucile Packard Children's Hospital, Stanford, USA Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Karl G
KG
Sylvester
Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Xuefeng B
XB
Ling
Department of Surgery, Stanford University School of Medicine, Stanford, USA Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.
G Y
GY
Liu
Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Zachary J
ZJ
Kastenberg
Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Jun
J
Ji
Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Zhongkai
Z
Hu
Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Sihua
S
Peng
Department of Surgery, Stanford University School of Medicine, Stanford, USA.
Ken
K
Lau
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.
Fizan
F
Abdullah
Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, USA.
Mary L
ML
Brandt
Department of Pediatrics, Yale University School of Medicine, New Haven, USA.
Richard A
RA
Ehrenkranz
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, USA.
Mary Catherine
MC
Harris
Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, USA.
Timothy C
TC
Lee
Department of Pediatrics, Yale University School of Medicine, New Haven, USA.
Joyce
J
Simpson
Division of Pediatric Surgery, Nationwide Children's Hospital, Columbus, USA Department of Surgery, Ohio State College of Medicine, Columbus, USA.
Corinna
C
Bowers
Division of Pediatric Surgery, Nationwide Children's Hospital, Columbus, USA Department of Surgery, Ohio State College of Medicine, Columbus, USA.
R Lawrence
RL
Moss
D000465:Algorithms; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine*; D020345:Enterocolitis, Necrotizing / Q000628:therapy / Q000652:urine*; D005260:Female; D005340:Fibrinogen / Q000652:urine*; D006801:Humans; D007223:Infant; D008297:Male; D010455:Peptides / Q000652:urine*; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D018570:Risk Assessment / Q000379:methods
D015415:Biomarkers; D010455:Peptides; D005340:Fibrinogen
Clinical Decision Making; Inflammatory Mediators; Paediatric Gastroenterology; Paediatric Surgery; Peptides