Karl G Sylvester1, Xuefeng B Ling2, Gigi Yuen-Gee Liu3, Zachary J Kastenberg4, Jun Ji2, Zhongkai Hu2, Shuaibin Wu2, Sihua Peng2, Fizan Abdullah5, Mary L Brandt6, Richard A Ehrenkranz7, Mary Catherine Harris8, Timothy C Lee6, B Joyce Simpson7, Corinna Bowers9, R Lawrence Moss9. 1. 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. 2. Department of Surgery, Stanford University School of Medicine, Stanford, CA. 3. Department of Surgery, Stanford University School of Medicine, Stanford, CA; Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD. 4. Division of Pediatric Surgery, Lucile Packard Children's Hospital, Palo Alto, CA; Department of Surgery, Stanford University School of Medicine, Stanford, CA. 5. Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD. 6. Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, TX. 7. Department of Pediatrics, Division of Neonatology, Yale University School of Medicine, New Haven, CT. 8. Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA. 9. Pediatric Surgery, Department of Surgery, Nationwide Children's Hospital, Columbus, OH.
Abstract
OBJECTIVES: 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). STUDY DESIGN: 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.
OBJECTIVES: 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). STUDY DESIGN: 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.
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