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Given the importance of these outcomes, refining their assessment is paramount for improving prevention and care. Here we aim to enhance the assessment of these often correlated and multifaceted neonatal outcomes. To achieve this, we employ factor analysis to identify common and unique effects and further confirm these effects using criterion-related validity testing. This validation leverages methylome-wide profiles from neonatal blood. Specifically, we investigate nine neonatal health risk variables, including gestational age, Apgar score, three indicators of body size, jaundice, birth diagnosis, maternal preeclampsia, and maternal age. The methylomic profiles used for this research capture data from nearly all 28 million methylation sites in human blood, derived from the blood spot collected from 333 neonates, within 72\u00a0h post-birth. Our factor analysis revealed two common factors, size factor, that captured the shared effects of weight, head size, height, and gestational age and disease factor capturing the orthogonal shared effects of gestational age, combined with jaundice and birth diagnosis. To minimize false positives in the validation studies, validation was limited to variables with significant cumulative association as estimated through an in-sample replication procedure. This screening resulted in that the two common factors and the unique effects for gestational age, jaundice and Apgar were further investigated with full-scale cell-type specific methylome-wide association analyses. Highly significant, cell-type specific, associations were detected for both common effect factors and for Apgar. Gene Ontology analyses revealed multiple significant biologically relevant terms for the five fully investigated neonatal health risk variables. Given the established links between adverse neonatal outcomes and both immediate and long-term health, the distinct factor effects (representing the common and unique effects of the risk variables) and their biological profiles confirmed in our work, suggest their potential role as clinical biomarkers for assessing health risks and enhancing personalized care.<\/jats:p>","DOI":"10.1186\/s13148-024-01681-3","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T15:02:37Z","timestamp":1716390157000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigating neonatal health risk variables through cell-type specific methylome-wide association studies"],"prefix":"10.1186","volume":"16","author":[{"given":"Thomas L.","family":"Campbell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin Y.","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralen H.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Hultman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin J. 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