title: Urine protein biomarkers for the diagnosis and prognosis of necrotizing enterocolitis in infants.
abstract: OBJECTIVE
  To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC).
  
  
  METHODS
  Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation.
  
  
  RESULTS
  A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC.
  
  
  CONCLUSIONS
  We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.
authors.affiliation: Division of Pediatric Surgery, Lucile Packard Children's Hospital, Palo Alto, CA; Department of Surgery, Stanford University School of Medicine, Stanford, CA. Electronic address: sylvester@stanford.edu.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Sylvester
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: Xuefeng B
authors.initials: XB
authors.lastname: Ling
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA; Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD.
authors.forename: Gigi Yuen-Gee
authors.initials: GY
authors.lastname: Liu
authors.affiliation: Division of Pediatric Surgery, Lucile Packard Children's Hospital, Palo Alto, CA; Department of Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Kastenberg
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: Zhongkai
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: Shuaibin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: Sihua
authors.initials: S
authors.lastname: Peng
authors.affiliation: Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD.
authors.forename: Fizan
authors.initials: F
authors.lastname: Abdullah
authors.affiliation: Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, TX.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Brandt
authors.affiliation: Department of Pediatrics, Division of Neonatology, Yale University School of Medicine, New Haven, CT.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ehrenkranz
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Mary Catherine
authors.initials: MC
authors.lastname: Harris
authors.affiliation: Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, TX.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Division of Neonatology, Yale University School of Medicine, New Haven, CT.
authors.forename: B Joyce
authors.initials: BJ
authors.lastname: Simpson
authors.affiliation: Pediatric Surgery, Department of Surgery, Nationwide Children's Hospital, Columbus, OH.
authors.forename: Corinna
authors.initials: C
authors.lastname: Bowers
authors.affiliation: Pediatric Surgery, Department of Surgery, Nationwide Children's Hospital, Columbus, OH.
authors.forename: R Lawrence
authors.initials: RL
authors.lastname: Moss
mesh_terms: D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D055316:Cystatin C / Q000652:urine; D015536:Down-Regulation; D020345:Enterocolitis, Necrotizing / Q000175:diagnosis*; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000652:urine; D005260:Female; D005340:Fibrinogen / Q000652:urine; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000175:diagnosis; D018950:Lipopolysaccharide Receptors / Q000652:urine; D008297:Male; D013058:Mass Spectrometry; D009414:Nerve Growth Factors / Q000652:urine; D010446:Peptide Fragments / Q000652:urine; D011379:Prognosis; D011446:Prospective Studies; D054839:Retinol-Binding Proteins, Plasma / Q000652:urine; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000175:diagnosis; D015843:Serpins / Q000652:urine; D015854:Up-Regulation; D000511:alpha-Macroglobulins / Q000652:urine; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D015415:Biomarkers; D055316:Cystatin C; D005136:Eye Proteins; D005340:Fibrinogen; D018950:Lipopolysaccharide Receptors; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D054839:Retinol-Binding Proteins, Plasma; D015843:Serpins; D000511:alpha-Macroglobulins; D000099174:Pigment Epithelium-Derived Factor; C510358:A2ML1 protein, human; C101326:RBP4 protein, human; C098000:fibrinogen alphaC