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Low malignancy rates in early-development PNs and variable image acquisition hinder development of radiomic models for diagnosing these PNs. To address these challenges, we augmented training using later-development PNs and harmonized for acquisition effects. We examine early-development benign and malignant PNs (n\u2009=\u2009106) below the sensitivity of standard-of-care diagnosis. Classifiers predicting malignancy performed near chance when trained on ComBat-harmonized radiomic features from only early-development PNs. We then augmented training with later-development benign and malignant PNs (n\u2009=\u2009225). We evaluated whether harmonization must incorporate biology that impacts acquisition effects in added training data. To correct variability from four acquisition protocols, we compared: (1) biology-unaware harmonization, (2) harmonizing with a covariate distinguishing early-development, later-development benign, later-development malignant datasets, (3) harmonizing each dataset separately. Models trained using augmentation, but biology-unaware harmonization, failed to improve consistently. Augmented training data harmonized with a covariate (ROC-AUC 0.74 [0.69\u20130.79]) or separately (ROC-AUC 0.71 [0.66\u20130.77]) yielded higher test ROC-AUC (Delong,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.05) and PR-AUC (Wilcoxon,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.05). In a proof-of-principle methodological study, we demonstrate with a small single-center dataset that combining radiomic features from later-development benign and malignant PNs requires biology-aware harmonization.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-57670-4","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T10:03:28Z","timestamp":1781949808000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Training set augmentation and biology-aware harmonization improve radiomic models for lung cancer prediction in indeterminate nodules"],"prefix":"10.1038","volume":"16","author":[{"given":"Claire","family":"Huchthausen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"de Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Larner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einsley","family":"Janowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Colen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishni","family":"Wijesooriya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"57670_CR1","unstructured":"American Cancer Society. 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