Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia

Alida S.D. Kindt, Kai M. Förster, Suzan C.M. Cochius-den Otter, Andreas W. Flemmer, Stefanie M. Hauck, Andrew Flatley, Juliette Kamphuis, Stefan Karrasch, Jürgen Behr, Axel Franz, Christoph Härtel, Jan Krumsiek, Dick Tibboel, Anne Hilgendorff*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)625-632
Number of pages8
JournalPediatric Research
Volume93
Issue number3
Early online date20 May 2022
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
The work was supported by the Grant NWG VH-NG-829 (Helmholtz Association), German Center for Lung Research (Federal Ministry of Science). Open Access funding enabled and organized by Projekt DEAL.

Publisher Copyright: © 2022, The Author(s).

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