{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:56:21Z","timestamp":1791305781019,"version":"4.3.1"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Oncology","reference-count":9,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01CA272991"],"award-info":[{"award-number":["R01CA272991"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DE033512"],"award-info":[{"award-number":["R01DE033512"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54CA274513"],"award-info":[{"award-number":["U54CA274513"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01EB032680"],"award-info":[{"award-number":["R01EB032680"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Digital-twin frameworks can potentially offer a pathway toward individualized treatment but remain largely untested in radiation oncology. We present a causal digital-twin model for head-and-neck (H&amp;N) cancer that estimates patient-specific survival benefit from chemoradiotherapy (CRT) versus radiotherapy (RT) alone, stratified by HPV status.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Using the public RADCURE cohort (n = 3,346), we developed a causal digital-twin framework in which patients were divided into HPV-positive and HPV-negative groups and assigned to training (RT start year \u2264 2007) and test sets (RT start year &gt; 2007). Bayesian-network structure learning identified each cohort\u2019s Markov Blanket around the 2-year survival endpoint (SVy2), yielding the minimal causally relevant feature set. A causal-forest model (double machine learning, DML framework) estimated the individualized treatment effect\n                    <jats:italic>\u03c4<\/jats:italic>\n                    =\n                    <jats:italic>P<\/jats:italic>\n                    (\n                    <jats:italic>Svy2<\/jats:italic>\n                    |\n                    <jats:italic>CRT,X<\/jats:italic>\n                    ) \u2212\n                    <jats:italic>P<\/jats:italic>\n                    (\n                    <jats:italic>Svy2<\/jats:italic>\n                    |\n                    <jats:italic>RT,X<\/jats:italic>\n                    ), with\n                    <jats:inline-formula>\n                      <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"26363910v1_inline1.gif\"\/>\n                    <\/jats:inline-formula>\n                    denoting the model-estimated effect. Overlap restrictions were applied to mitigate extrapolation. Predictive discrimination (AUC, C-index), average treatment effects (ATE), individualized effects (ITE), and decision-curve analyses were computed.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    For HPV-negative disease, internal evaluation demonstrated strong discriminative performance (test AUC = 0.72; C-index = 0.81, p &lt; 0.01). The estimated test-set ATE favored CRT with a modest but positive improvement in SVy2 (mean\n                    <jats:inline-formula>\n                      <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"26363910v1_inline2.gif\"\/>\n                    <\/jats:inline-formula>\n                    ). Patterns in\n                    <jats:inline-formula>\n                      <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"26363910v1_inline3.gif\"\/>\n                    <\/jats:inline-formula>\n                    were clinically coherent, including increased benefit in node-positive and good-performance patients and reduced benefit in high-burden or poor-performance presentations. Decision-curve analysis showed that a\n                    <jats:inline-formula>\n                      <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"26363910v1_inline4.gif\"\/>\n                    <\/jats:inline-formula>\n                    -guided selective-CRT strategy provided higher net benefit than uniform treatment policies. HPV-positive disease exhibited substantially greater but less clinically structured treatment-effect heterogeneity, accompanied by reduced overlap and greater uncertainty.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study demonstrates a proof-of-concept causal digital-twin framework for interpretable, patient-specific survival simulation in H&amp;N cancer. The model captures clinically plausible treatment-effect heterogeneity and establishes a foundation for multi-cohort validation and future integration into individualized treatment decision support.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.30.26363910","type":"posted-content","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:50:12Z","timestamp":1790988612000},"source":"Crossref","is-referenced-by-count":0,"title":["HPV-Stratified Causal Digital Twins for Personalized Survival Benefit Estimation in Head and Neck Cancer"],"prefix":"10.64898","author":[{"given":"Keyur D.","family":"Shah","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Wei","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anees","family":"Dhabaan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hania A.","family":"Al-Hallaq","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Bates","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Stokes","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9023-5855","authenticated-orcid":false,"given":"Xiaofeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100609251160000_2026.09.30.26363910v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032646"},{"key":"2026100609251160000_2026.09.30.26363910v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2021.01.013"},{"key":"2026100609251160000_2026.09.30.26363910v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.patter.2024.101028"},{"key":"2026100609251160000_2026.09.30.26363910v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14103574"},{"key":"2026100609251160000_2026.09.30.26363910v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq439"},{"key":"2026100609251160000_2026.09.30.26363910v1.6","doi-asserted-by":"publisher","DOI":"10.48550\/ARXIV.1510.04342"},{"key":"2026100609251160000_2026.09.30.26363910v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2024.07.002"},{"key":"2026100609251160000_2026.09.30.26363910v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/mp.16972"},{"key":"2026100609251160000_2026.09.30.26363910v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2025.09.063"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.30.26363910","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:25:20Z","timestamp":1791303920000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.30.26363910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":9,"URL":"https:\/\/doi.org\/10.64898\/2026.09.30.26363910","relation":{},"subject":[],"published":{"date-parts":[[2026,10,2]]},"subtype":"preprint"}}