Alida S D Kindt1,2, Kai M Förster3,4,5, Suzan C M Cochius-den Otter6, Andreas W Flemmer3,4, Stefanie M Hauck7, Andrew Flatley8, Juliette Kamphuis5, Stefan Karrasch9, Jürgen Behr4,10, Axel Franz11, Christoph Härtel12,13, Jan Krumsiek1,14, Dick Tibboel6, Anne Hilgendorff15,16,17. 1. Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany. 2. Department of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands. 3. Member of the German Lung Research Center (DZL), Department of Neonatology, Perinatal Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, LMU Hospital, Munich, Germany. 4. Member of the German Lung Research Center (DZL), Institute for Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, bioArchive, Helmholtz Zentrum München, Munich, Germany. 5. Center for Comprehensive Developmental Care (CDeCLMU), Ludwig-Maximilians University, LMU Hospital, Munich, Germany. 6. Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands. 7. Research Unit Protein Science, Helmholtz Zentrum München, Munich, Germany. 8. Monoclonal Antibody Core Facility, Helmholtz Zentrum München, Neuherberg, Germany. 9. Institute of Epidemiology, Helmholtz Zentrum München, Munich, Germany. 10. Member of the German Lung Research Center (DZL), Department of Internal Medicine V, Ludwig-Maximilians University, LMU Hospital, Munich, Germany. 11. Department for Pediatrics, University of Tübingen, Tübingen, Germany. 12. Department for Pediatrics, University of Schleswig-Holstein, Campus Luebeck, Germany. 13. Department for Pediatrics, University of Würzburg, Würzburg, Germany. 14. Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. 15. Member of the German Lung Research Center (DZL), Institute for Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, bioArchive, Helmholtz Zentrum München, Munich, Germany. A.Hilgendorff@med.uni-muenchen.de. 16. Center for Comprehensive Developmental Care (CDeCLMU), Ludwig-Maximilians University, LMU Hospital, Munich, Germany. A.Hilgendorff@med.uni-muenchen.de. 17. Institute for Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Munich, Germany. A.Hilgendorff@med.uni-muenchen.de.
Abstract
OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic®, Olink-Proteomics®) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD.
OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic®, Olink-Proteomics®) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD.
Authors: Kai Förster; Steffen Sass; Harald Ehrhardt; Daphne S Mous; Robbert J Rottier; Prajakta Oak; Andreas Schulze; Andreas W Flemmer; Judith Gronbach; Christoph Hübener; Tushar Desai; Oliver Eickelberg; Fabian J Theis; Anne Hilgendorff Journal: Am J Respir Crit Care Med Date: 2018-04-15 Impact factor: 21.405
Authors: Kitty G Snoek; Irma Capolupo; Joost van Rosmalen; Lieke de Jongste-van den Hout; Sanne Vijfhuize; Anne Greenough; René M Wijnen; Dick Tibboel; Irwin K M Reiss Journal: Ann Surg Date: 2016-05 Impact factor: 12.969
Authors: John C Rohloff; Amy D Gelinas; Thale C Jarvis; Urs A Ochsner; Daniel J Schneider; Larry Gold; Nebojsa Janjic Journal: Mol Ther Nucleic Acids Date: 2014-10-07 Impact factor: 10.183