{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T03:13:29Z","timestamp":1775445209534,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health under the frame of ERA PerMed JTC2022"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality globally. While multi-modal artificial intelligence (AI) models offer significant predictive potential, their translation into routine clinical practice is delayed by the \u201cblack box\u201d nature of complex algorithms and the fragmentation of heterogeneous data. We present LANTERN-XGB, a hierarchical machine learning workflow designed to bridge this gap by generating interpretable \u201cdigital human avatars\u201d for precision oncology. The methodology employs a multi-stage scalable tree boosting system (XGBoost) architecture utilizing shapley additive explanations (SHAP) for rigorous hierarchical feature selection, missing value management, and patient-specific decision support. The workflow was developed and benchmarked using a retrospective cohort of 437 patients with clinical N0 NSCLC, followed by validation on a prospective dataset (n = 100) and an independent external dataset (n = 100). The pipeline integrates diverse data modalities to predict occult lymph node metastasis (OLM). LANTERN-XGB identified a robust consensus signature driven by non-linear interactions among CT textural fragmentation, PET metabolic heterogeneity, tumor density distribution, and systemic clinical modulators. Exploratory transcriptomic pathway analysis (GSVA) revealed that high-risk predictions strongly correlate with systemic molecular dysregulation, such as the enrichment of immune-inflammatory signaling and metabolic stress pathways. The model achieved robust discrimination in external validation (AUC \u2248 0.77), performing comparably to state-of-the-art nomogram benchmarks. Crucially, the LANTERN-XGB framework demonstrated superior utility in handling diagnostic ambiguity; local force plots allowed for the correct reclassification of \u201cborderline\u201d prediction by visualizing feature interactions that standard linear models fail to capture. LANTERN-XGB provides a validated, open-source framework that successfully balances predictive power with clinical transparency. By empowering clinicians to visualize and verify the logic behind AI predictions, this workflow offers a pragmatic path for integrating reliable multi-modal avatars into daily medical decision-making.<\/jats:p>","DOI":"10.3390\/ijms27073128","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:53Z","timestamp":1774878113000},"page":"3128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LANTERN-XGB: An Interpretable Multi-Modal Machine Learning for Improving Clinical Decision-Making in Lung Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Davide","family":"Dalfovo","sequence":"first","affiliation":[{"name":"OncoRay\u2014National Center for Radiation Research in Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Helmholtz-Zentrum Dresden-Rossendorf, 01067 Dresden, Germany"},{"name":"Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01067 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4654-1577","authenticated-orcid":false,"given":"Carolina","family":"Sassorossi","sequence":"additional","affiliation":[{"name":"Unit of Thoracic Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy"},{"name":"Thoracic Surgery Unit, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"De Paolis","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"},{"name":"Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Campanella","sequence":"additional","affiliation":[{"name":"Unit of Thoracic Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy"},{"name":"Thoracic Surgery Unit, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2937-9678","authenticated-orcid":false,"given":"Dania","family":"Nachira","sequence":"additional","affiliation":[{"name":"Unit of Thoracic Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy"},{"name":"Thoracic Surgery Unit, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-1014","authenticated-orcid":false,"given":"Leonardo","family":"Petracca Ciavarella","sequence":"additional","affiliation":[{"name":"Unit of Thoracic Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy"},{"name":"Thoracic Surgery Unit, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5631-1575","authenticated-orcid":false,"given":"Luca","family":"Boldrini","sequence":"additional","affiliation":[{"name":"Advanced Radiotherapy Center, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther G. C.","family":"Troost","sequence":"additional","affiliation":[{"name":"OncoRay\u2014National Center for Radiation Research in Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Helmholtz-Zentrum Dresden-Rossendorf, 01067 Dresden, Germany"},{"name":"Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01067 Dresden, Germany"},{"name":"Institute of Radiooncology\u2014OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, 01067 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9679-6669","authenticated-orcid":false,"given":"R\u00f3za","family":"\u00c1d\u00e1ny","sequence":"additional","affiliation":[{"name":"ELKH-DE Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4001 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N\u00faria","family":"Farr\u00e9","sequence":"additional","affiliation":[{"name":"Institut de Recerca de L\u2019Hospital de la Santa Creu i Sant Pau (IR-HSCSP), 08001 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8635-0279","authenticated-orcid":false,"given":"Ece","family":"\u00d6zt\u00fcrk","sequence":"additional","affiliation":[{"name":"School of Medicine, Turkey and Ko\u00e7 University Research Center for Translational Medicine (KUTTAM), Ko\u00e7 University, Istanbul 34450, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0833-4334","authenticated-orcid":false,"given":"Angelo","family":"Minucci","sequence":"additional","affiliation":[{"name":"Departmental Unit of Molecular and Genomic Diagnostics, Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"},{"name":"Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1067-4696","authenticated-orcid":false,"given":"Rocco","family":"Trisolini","sequence":"additional","affiliation":[{"name":"Interventional Pulmonology Unit, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Bria","sequence":"additional","affiliation":[{"name":"Medical Oncology, A. Gemelli University Hospital Foundation IRCCS, Largo a. 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Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Lococo","sequence":"additional","affiliation":[{"name":"Unit of Thoracic Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy"},{"name":"Thoracic Surgery Unit, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA. Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer Statistics, 2024. CA","volume":"74","author":"Siegel","year":"2024","journal-title":"Cancer J. 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