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Purpose Growth factors and inflammatory and angiogenetic proteins are involved in the development of retinopathy of prematurity (ROP). However, no early biochemical markers are in clinical use to predict ROP. By performing cluster analysis of multiple biomarkers, we aimed to determine patient groups with high and low risk for developing ROP. Methods In total, 202 protein markers in plasma were quantified by proximity extension assay from 35 extremely preterm infants on day 2 of life. Infants were sorted in groups by automated two-dimensional hierarchical clustering of all biomarkers. ROP was classified as stages I to III with or without surgical treatment. Predictive biomarkers were evaluated by analysis of variance and detected differences by two-sided paired t-test with Bonferroni corrections for multiple comparisons. Results Differences in 39 biochemical markers divided infants without ROP into two control groups (control 1, n = 7; control 2, n = 5; P < 0.05). Sixty-six biochemical markers defined differences between the control groups (n = 13) and all ROP infants (n = 23; P < 0.05). PARK7, VIM, MPO, CD69, and NEMO were markedly increased in control 1 compared to all ROP infants (P < 0.001). Lower TNFRSF4 and higher HER2 and GAL appeared in infants with ROP as compared to control 1 and/or 2 (P < 0.05, respectively). Conclusions Our data suggest that early elevated levels of PARK7, VIM, MPO, CD69, and NEMO may be associated with lower risk of developing ROP. Lower levels of TNFRSF4 with higher levels of HER2 and GAL may predict ROP development. Translational Relevance Cluster analysis of early postnatal biomarkers may help to identify infants with low or high risk of developing ROP.