{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T20:03:02Z","timestamp":1757620982234,"version":"3.44.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["72293581","72274152","62402376"],"award-info":[{"award-number":["72293581","72274152","62402376"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Basic Research Program of Shaanxi","award":["2020JC-01"],"award-info":[{"award-number":["2020JC-01"]}]},{"name":"Natural Science Basic Research Program of Shaanxi","award":["2020JC-01"],"award-info":[{"award-number":["2020JC-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Accurate tumor mutation burden (TMB) quantification is critical for immunotherapy stratification, yet remains challenging due to variability across sequencing platforms, tumor heterogeneity, and variant calling pipelines. Here, we introduce TMBquant, an explainable AI-powered caller designed to optimize TMB estimation through dynamic feature selection, ensemble learning, and automated strategy adaptation. Built upon the H2O AutoML framework, TMBquant integrates variant features, minimizes classification errors, and enhances both accuracy and stability across diverse datasets. We benchmarked TMBquant against nine widely used variant callers, including traditional tools (e.g. Mutect2, VarScan2, Strelka2) and recent AI-based methods (DeepSomatic, Octopus), using 706 whole-exome sequencing tumor\u2013control pairs. To evaluate clinical relevance, we further assessed TMBquant through survival analyses across immunotherapy-treated cohorts of non\u2013small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), and the two NSCLC subtypes: lung adenocarcinoma and lung squamous cell carcinoma. In each cohort, TMBquant consistently achieved the highest hazard ratios, demonstrating superior patient stratification compared to all other methods. Importantly, TMBquant maintained robust predictive performance across both high-TMB (NSCLC) and low-TMB (NPC) settings, highlighting its generalizability across cancer types with distinct biological characteristics. These findings establish TMBquant as a reliable, reproducible, and clinically actionable tool for precision oncology. The software is open source and freely available at https:\/\/github.com\/SomaticCaller\/SomaticCaller. To enhance reproducibility, we provide detailed usage instructions and representative code snippets for TMBquant in the Methods section (see Code Availability).<\/jats:p>","DOI":"10.1093\/bib\/bbaf455","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T11:42:58Z","timestamp":1757331778000},"source":"Crossref","is-referenced-by-count":0,"title":["TMBquant: an explainable AI-powered caller advancing tumor mutation burden quantification across heterogeneous samples"],"prefix":"10.1093","volume":"26","author":[{"given":"Shenjie","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , No. 157, Xiwu Road, Xincheng District, Xi'an 710004 ,","place":["China"]},{"name":"School of Computer Science and Technology, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]},{"name":"Shaanxi Engineering Research Center of Medical and Health Big Data, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaonan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]},{"name":"Nanjing Geneseeq Technology Inc. , 128 Huakang Road, Pukou, Nanjing 211800 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]},{"name":"Shaanxi Engineering Research Center of Medical and Health Big Data, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , No. 157, Xiwu Road, Xincheng District, Xi'an 710004 ,","place":["China"]},{"name":"School of Computer Science and Technology, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]},{"name":"Shaanxi Engineering Research Center of Medical and Health Big Data, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]},{"name":"Shaanxi Engineering Research Center of Medical and Health Big Data, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minchao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nanjing Geneseeq Technology Inc. , 128 Huakang Road, Pukou, Nanjing 211800 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhili","family":"Chang","sequence":"additional","affiliation":[{"name":"Nanjing Geneseeq Technology Inc. , 128 Huakang Road, Pukou, Nanjing 211800 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4585-1792","authenticated-orcid":false,"given":"Yang","family":"Shao","sequence":"additional","affiliation":[{"name":"Nanjing Geneseeq Technology Inc. , 128 Huakang Road, Pukou, Nanjing 211800 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine , Tangdu Hospital, , 569 Xinsi Road, Baqiao District, Xi'an, Shaanxi 710038 ,","place":["China"]},{"name":"The Fourth Military Medical University , Tangdu Hospital, , 569 Xinsi Road, Baqiao District, Xi'an, Shaanxi 710038 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuanying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , No. 157, Xiwu Road, Xincheng District, Xi'an 710004 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3862-6557","authenticated-orcid":false,"given":"Jiayin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , No. 157, Xiwu Road, Xincheng District, Xi'an 710004 ,","place":["China"]},{"name":"School of Computer Science and Technology, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]},{"name":"Shaanxi Engineering Research Center of Medical and Health Big Data, Xi\u2019an Jiaotong University , 28 Xianning West Road, Beilin, Xi\u2019an 710049 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"2025090807425040200_ref1","first-page":"1","article-title":"Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic","volume":"3","author":"Chan","year":"2019","journal-title":"JCO Precis Oncol"},{"key":"2025090807425040200_ref2","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/s41588-018-0312-8","article-title":"Tumor mutational load predicts survival after immunotherapy across multiple cancer types","volume":"51","author":"Samstein","year":"2019","journal-title":"Nat Genet"},{"key":"2025090807425040200_ref3","doi-asserted-by":"publisher","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"2025090807425040200_ref4","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1200\/JCO.2017.75.3384","article-title":"Molecular determinants of response to anti-programmed cell death (PD-1) and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing","volume":"36","author":"Rizvi","year":"2018","journal-title":"J Clin Oncol"},{"key":"2025090807425040200_ref5","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13073-017-0424-2","article-title":"Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden","volume":"9","author":"Chalmers","year":"2017","journal-title":"Genome Med"},{"key":"2025090807425040200_ref6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s13073-020-00791-w","article-title":"Best practices for variant calling in clinical sequencing","volume":"12","author":"Koboldt","year":"2020","journal-title":"Genome Med"},{"key":"2025090807425040200_ref7","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res"},{"key":"2025090807425040200_ref8","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/s41592-018-0051-x","article-title":"Strelka2: fast and accurate calling of germline and somatic variants","volume":"15","author":"Kim","year":"2018","journal-title":"Nat Methods"},{"key":"2025090807425040200_ref9","doi-asserted-by":"publisher","first-page":"e108","DOI":"10.1093\/nar\/gkw227","article-title":"VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research","volume":"44","author":"Lai","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2025090807425040200_ref10","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.scib.2024.01.025","article-title":"Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy","volume":"69","author":"Qian","year":"2024","journal-title":"Sci Bull"},{"key":"2025090807425040200_ref11","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.ccell.2018.04.001","article-title":"Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer","volume":"33","author":"Hellmann","year":"2018","journal-title":"Cancer Cell"},{"key":"2025090807425040200_ref12","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nature13385","article-title":"Comprehensive molecular profiling of lung adenocarcinoma","volume":"511","author":"The Cancer Genome Atlas Research Network","year":"2014","journal-title":"Nature"},{"key":"2025090807425040200_ref13","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 blockade in tumors with mismatch-repair deficiency","volume":"372","author":"Le","year":"2017","journal-title":"N Engl J Med"},{"key":"2025090807425040200_ref14","doi-asserted-by":"publisher","first-page":"e002435","DOI":"10.1136\/jitc-2021-002435","article-title":"Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events","volume":"9","author":"Brahmer","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2025090807425040200_ref15","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1016\/S0140-6736(15)01281-7","article-title":"Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial","volume":"387","author":"Herbst","year":"2016","journal-title":"Lancet (London, England)"},{"key":"2025090807425040200_ref16","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N Engl J Med"},{"key":"2025090807425040200_ref17","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1016\/S0140-6736(18)32409-7","article-title":"Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial","volume":"393","author":"Mok","year":"2019","journal-title":"Lancet (London, England)"},{"key":"2025090807425040200_ref18","doi-asserted-by":"publisher","first-page":"bbae159","DOI":"10.1093\/bib\/bbae159","article-title":"TMBstable: a variant caller controls performance variation across heterogeneous sequencing samples","volume":"25","author":"Wang","year":"2024","journal-title":"Brief Bioinform"},{"key":"2025090807425040200_ref19","doi-asserted-by":"publisher","first-page":"6125","DOI":"10.1016\/j.cell.2024.09.022","article-title":"Empowering biomedical discovery with AI agents","volume":"187","author":"Gao","year":"2024","journal-title":"Cell"},{"key":"2025090807425040200_ref20","first-page":"4765","article-title":"A unified approach to interpreting model predictions","volume":"30","author":"Lundberg","year":"2017","journal-title":"Adv Neural Inf Process Syst"},{"volume-title":"Interpretable Machine Learning: A Guide for Making Black Box Models Explainable","author":"Molnar","key":"2025090807425040200_ref21"},{"key":"2025090807425040200_ref22","doi-asserted-by":"publisher","first-page":"106668","DOI":"10.1016\/j.compbiomed.2023.106668","article-title":"Survey of explainable artificial intelligence techniques for biomedical imaging with deep neural networks","volume":"156","author":"Nazir","year":"2023","journal-title":"Comput Biol Med"},{"key":"2025090807425040200_ref23","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1200\/JCO.2017.76.9901","article-title":"Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient\/microsatellite instability-high metastatic colorectal cancer","volume":"36","author":"Overman","year":"2017","journal-title":"J Clin Oncol"},{"key":"2025090807425040200_ref24","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1056\/NEJMoa1406498","article-title":"Genetic basis for clinical response to CTLA-4 blockade in melanoma","volume":"371","author":"Snyder","year":"2014","journal-title":"N Engl J Med"},{"key":"2025090807425040200_ref25","first-page":"612","article-title":"Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high endometrial cancer","volume":"152","author":"Schrock","year":"2019","journal-title":"Gynecol Oncol"},{"key":"2025090807425040200_ref26","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1126\/science.aaa1348","article-title":"Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer","volume":"348","author":"Rizvi","year":"2015","journal-title":"Science"},{"key":"2025090807425040200_ref27","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cell.2016.02.065","article-title":"Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma","volume":"165","author":"Hugo","year":"2016","journal-title":"Cell"},{"key":"2025090807425040200_ref28","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1056\/NEJMoa1716078","article-title":"Neoadjuvant PD-1 blockade in resectable lung cancer","volume":"378","author":"Forde","year":"2018","journal-title":"N Engl J Med"},{"key":"2025090807425040200_ref29","doi-asserted-by":"publisher","first-page":"e002014","DOI":"10.1136\/jitc-2020-002014","article-title":"Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma","volume":"9","author":"Ma","year":"2021","journal-title":"J Immunother Cancer"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf455\/64220278\/bbaf455.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf455\/64220278\/bbaf455.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T11:42:59Z","timestamp":1757331779000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaf455\/8249065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,31]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,8,31]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf455","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"type":"print","value":"1467-5463"},{"type":"electronic","value":"1477-4054"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,8,31]]},"article-number":"bbaf455"}}