{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T01:51:41Z","timestamp":1764813101491,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Parker B. Francis","award":["K23HD101701","5R25HL126140-06"],"award-info":[{"award-number":["K23HD101701","5R25HL126140-06"]}]},{"name":"National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["K23HD101701","5R25HL126140-06"],"award-info":[{"award-number":["K23HD101701","5R25HL126140-06"]}]},{"name":"NIH National Heart, Lung, and Blood Institute","award":["K23HD101701","5R25HL126140-06"],"award-info":[{"award-number":["K23HD101701","5R25HL126140-06"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: Extremely premature neonates are at increased risk for respiratory complications, often resulting in recurrent hospitalizations during early childhood. Early identification of preterm infants at highest risk of respiratory hospitalizations could enable targeted preventive interventions. While clinical and demographic factors offer some prognostic value, integrating transcriptomic data may improve predictive accuracy. Objective: To determine whether early-life gene expression profiles can predict respiratory-related hospitalizations within the first four years of life in extremely preterm neonates. Methods: We conducted a retrospective cohort study of 58 neonates born at &lt;32 weeks\u2019 gestational age, using publicly available transcriptomic data from peripheral blood samples collected on days 5, 14, and 28 of life. Random forest models were trained to predict unplanned respiratory readmissions. Model performance was evaluated using sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC). Results: All three models, built using transcriptomic data from days 5, 14, and 28, demonstrated strong predictive performance (AUC = 0.90), though confidence intervals were wide due to small sample size. We identified 31 genes and eight biological pathways that were differentially expressed between preterm neonates with and without subsequent respiratory readmissions. Conclusions: Transcriptomic data from the neonatal period, combined with machine learning, accurately predicted respiratory-related rehospitalizations in extremely preterm neonates. The identified gene signatures offer insight into early biological disruptions that may predispose preterm neonates to chronic respiratory morbidity. Validation in larger, diverse cohorts is needed to support clinical translation.<\/jats:p>","DOI":"10.3390\/children12080996","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T12:39:29Z","timestamp":1753792769000},"page":"996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Predicting Future Respiratory Hospitalizations in Extremely Premature Neonates Using Transcriptomic Data and Machine Learning"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9510-2875","authenticated-orcid":false,"given":"Bryan G.","family":"McOmber","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lois","family":"Randolph","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"II","given":"Patrick","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3017-0348","authenticated-orcid":false,"given":"Przemko","family":"Kwinta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4285-1562","authenticated-orcid":false,"given":"Jordan","family":"Kuiper","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, George Washington University, Washington, DC 20052, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kartikeya","family":"Makker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khyzer B.","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvaro","family":"Moreira","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref_1","unstructured":"(2025, April 07). Preterm Birth. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/preterm-birth."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1055\/s-0035-1571202","article-title":"Short- and Long-Term Outcomes for Extremely Preterm Neonates","volume":"33","author":"Patel","year":"2016","journal-title":"Am. J. Perinatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105187","DOI":"10.1016\/j.earlhumdev.2020.105187","article-title":"An overview of adult health outcomes after preterm birth","volume":"150","author":"Crump","year":"2020","journal-title":"Early Hum. Dev."},{"key":"ref_4","first-page":"87","article-title":"Persistent and progressive long-term lung disease in survivors of preterm birth","volume":"28","author":"Urs","year":"2018","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Srinivasjois, R., Slimings, C., Einarsd\u00f3ttir, K., Burgner, D., and Leonard, H. (2015). Association of Gestational Age at Birth with Reasons for Subsequent Hospitalisation: 18 Years of Follow-Up in a Western Australian Population Study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130535"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/S1473-3099(16)00150-X","article-title":"Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: A population-based, data-linkage study from Western Australia","volume":"16","author":"Miller","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Feng, X., Dong, H., Li, B., Yu, L., Zhu, J., Lou, C., and Zhang, J. (2023). Integrative analysis of the expression profiles of whole coding and non-coding RNA transcriptomes and construction of the competing endogenous RNA networks for chronic obstructive pulmonary disease. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1050783"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Huang, Y., Talwar, A., Chatterjee, S., and Aparasu, R.R. (2021). Application of machine learning in predicting hospital readmissions: A scoping review of the literature. BMC Med. Res. Methodol., 21.","DOI":"10.1186\/s12874-021-01284-z"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pietrzyk, J.J., Kwinta, P., Wollen, E.J., Bik-Multanowski, M., Madetko-Talowska, A., G\u00fcnther, C.-C., Jag\u0142a, M., Tomasik, T., Saugstad, O.D., and Krauss-Etschmann, S. (2013). Gene expression profiling in preterm neonates: New aspects of bronchopulmonary dysplasia development. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078585"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1164\/ajrccm.163.7.2011060","article-title":"Bronchopulmonary dysplasia","volume":"163","author":"Jobe","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Davidson, L., and Berkelhamer, S. (2017). Bronchopulmonary Dysplasia: Chronic Lung Disease of Infancy and Long-Term Pulmonary Outcomes. J. Clin. Med., 6.","DOI":"10.3390\/jcm6010004"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.siny.2009.08.004","article-title":"Long-term outcomes of bronchopulmonary dysplasia","volume":"14","author":"Doyle","year":"2009","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jain, D., Feldman, A., and Sangam, S. (2020). Predicting Long-Term Respiratory Outcomes in Premature Neonates: Is It Time to Move beyond Bronchopulmonary Dysplasia?. Children, 7.","DOI":"10.3390\/children7120283"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1002\/ppul.25301","article-title":"Bronchopulmonary dysplasia as a determinant of respiratory outcomes in adult life","volume":"56","author":"Collaco","year":"2021","journal-title":"Pediatr. Pulmonol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sun, L., Zhang, H., Bao, Y., Li, W., Wu, J., He, Y., and Zhu, J. (2021). Long-Term Outcomes of Bronchopulmonary Dysplasia Under Two Different Diagnostic Criteria: A Retrospective Cohort Study at a Chinese Tertiary Center. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.648972"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.earlhumdev.2018.10.003","article-title":"Predictors of hospitalization for acute lower respiratory infections during the first two years of life in a population of preterm neonates with bronchopulmonary dysplasia","volume":"127","year":"2018","journal-title":"Early Hum. Dev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chen, D., Chen, J., Cui, N., Cui, M., Chen, X., Zhu, X., and Zhu, X. (2020). Respiratory Morbidity and Lung Function Analysis During the First 36 Months of Life in Neonates with Bronchopulmonary Dysplasia (BPD). Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00540"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40348-022-00137-z","article-title":"When inflammation meets lung development-an update on the pathogenesis of bronchopulmonary dysplasia","volume":"9","author":"Holzfurtner","year":"2022","journal-title":"Mol. Cell. Pediatr."},{"key":"ref_19","first-page":"700","article-title":"Mitochondrial dysfunction contributes to alveolar developmental arrest in a mouse model of bronchopulmonary dysplasia","volume":"45","author":"Collins","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/pr.2016.216","article-title":"Mitochondrial dysfunction in alveolar and white matter developmental failure in premature neonates","volume":"81","author":"Ten","year":"2017","journal-title":"Pediatr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cui, T.X., Brady, A.E., Zhang, Y.-J., Anderson, C., and Popova, A.P. (2023). IL-17a-producing \u03b3\u03b4T cells and NKG2D signaling mediate bacterial endotoxin-induced neonatal lung injury. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1156842"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Pagel, J., Twisselmann, N., Rausch, T.K., Waschina, S., Hartz, A., Steinbeis, M., Olbertz, J., Nagel, K., Steinmetz, A., and Faust, K. (2020). Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Neonates. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.565257"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1172\/JCI36130","article-title":"The cytokine network in asthma and chronic obstructive pulmonary disease","volume":"118","author":"Barnes","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kraik, K., Tota, M., Laska, J., \u0141acwik, J., Pa\u017adzierz, \u0141., S\u0119dek, \u0141., and Gomu\u0142ka, K. (2024). The Role of Transforming Growth Factor-\u03b2 (TGF-\u03b2) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells, 13.","DOI":"10.3390\/cells13151271"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"L285","DOI":"10.1152\/ajplung.00106.2021","article-title":"Complex roles of TGF-\u03b2 signaling pathways in lung development and bronchopulmonary dysplasia","volume":"324","author":"Calthorpe","year":"2023","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1165\/ajrcmb.22.4.3854","article-title":"Neuregulin-1 and human epidermal growth factor receptors 2 and 3 play a role in human lung development in vitro","volume":"22","author":"Patel","year":"2000","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"L1101","DOI":"10.1152\/ajplung.00343.2017","article-title":"Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia","volume":"313","author":"Ahlbrecht","year":"2017","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mi\u017e\u00edkov\u00e1, I., and Morty, R.E. (2015). The Extracellular Matrix in Bronchopulmonary Dysplasia: Target and Source. Front. Med., 2.","DOI":"10.3389\/fmed.2015.00091"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wu, T.-J., Jing, X., Teng, M., Pritchard, K.A., Day, B.W., Naylor, S., and Teng, R.-J. (2024). Role of Myeloperoxidase, Oxidative Stress, and Inflammation in Bronchopulmonary Dysplasia. Antioxidants, 13.","DOI":"10.3390\/antiox13080889"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yue, L., Lu, X., Dennery, P.A., and Yao, H. (2021). Metabolic dysregulation in bronchopulmonary dysplasia: Implications for identification of biomarkers and therapeutic approaches. Redox Biol., 48.","DOI":"10.1016\/j.redox.2021.102104"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"L734","DOI":"10.1152\/ajplung.00183.2018","article-title":"Lung omics signatures in a bronchopulmonary dysplasia and pulmonary hypertension-like murine model","volume":"315","author":"Shrestha","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e071018","DOI":"10.1136\/bmj-2022-071018","article-title":"Transparent reporting of multivariable prediction models developed or validated using clustered data: TRIPOD-Cluster checklist","volume":"380","author":"Debray","year":"2023","journal-title":"BMJ"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e078378","DOI":"10.1136\/bmj-2023-078378","article-title":"TRIPOD+AI statement: Updated guidance for reporting clinical prediction models that use regression or machine learning methods","volume":"385","author":"Collins","year":"2024","journal-title":"BMJ"}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/8\/996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:17:58Z","timestamp":1760033878000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/8\/996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["children12080996"],"URL":"https:\/\/doi.org\/10.3390\/children12080996","relation":{},"ISSN":["2227-9067"],"issn-type":[{"type":"electronic","value":"2227-9067"}],"subject":[],"published":{"date-parts":[[2025,7,29]]}}}