{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:08:14Z","timestamp":1793210894173,"version":"4.5.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Major Science and Technology Projects of Henan","award":["161100311500"],"award-info":[{"award-number":["161100311500"]}]},{"name":"Major Science and Technology Projects of Henan","award":["161100311500"],"award-info":[{"award-number":["161100311500"]}]},{"name":"Major Science and Technology Projects of Henan","award":["161100311500"],"award-info":[{"award-number":["161100311500"]}]},{"name":"Major Science and Technology Projects of Henan","award":["161100311500"],"award-info":[{"award-number":["161100311500"]}]},{"name":"Major Science and Technology Projects of Henan","award":["161100311500"],"award-info":[{"award-number":["161100311500"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lung cancer remains the leading cause of cancer deaths worldwide. Although low-dose spiral computed tomography (LDCT) screening is used for the detection of lung cancer in a high-risk population, false-positive results of LDCT remain a clinical problem. Here, we developed a blood test of a novel panel of three established lung cancer methylation biomarkers for lung cancer detection. Short stature homeobox 2 gene (\n                    <jats:italic>SHOX2<\/jats:italic>\n                    ), ras association domain family 1A gene (\n                    <jats:italic>RASSF1A<\/jats:italic>\n                    ), and prostaglandin E receptor 4 gene (\n                    <jats:italic>PTGER4<\/jats:italic>\n                    ) methylation was analyzed in a training cohort of 351 individuals (197 controls, 154 cases) and validated from an independent cohort of 149 subjects (89 controls, 60 cases). The novel panel biomarkers distinguished between malignant and benign lung disease at high sensitivity and specificity: 87.0% sensitivity [95% CI 80.2\u201391.5%], 98.0% specificity [95% CI 94.9\u201399.4%]. Sensitivity in adenocarcinoma, squamous cell carcinoma, small cell lung cancer, and other lung cancer was 89.0%, 87.5%, 85.7%, and 77.8%, respectively. Notably, cancer patients in stage I and II showed high diagnostic sensitivity at 82.5% and 90.5%, respectively. Moreover, the diagnostic efficiency did not show bias toward age, gender, smoking, and the presence of other (nonlung) cancers. The performance of the panel in the validation cohort confirmed the diagnostic value. These findings clearly showed that this panel of DNA methylation biomarkers was effective in detecting lung cancer noninvasively and may provide clinical utility in stand-alone or in combination with current imaging techniques to improve the diagnosis of lung cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-96242-6","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T06:14:09Z","timestamp":1629267249000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["A panel of DNA methylation biomarkers for detection and improving diagnostic efficiency of lung cancer"],"prefix":"10.1038","volume":"11","author":[{"given":"Bing","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqun","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengzhi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"96242_CR1","unstructured":"Key Statistics for Lung Cancer. https:\/\/www.cancer.org\/cancer\/non-small-cell-lung4 cancer\/about\/key-statistics.html. Accessed 9 August 2019."},{"issue":"1","key":"96242_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 71(1), 7\u201333. https:\/\/doi.org\/10.3322\/caac.21654 (2021).","journal-title":"CA Cancer J. Clin."},{"key":"96242_CR3","doi-asserted-by":"publisher","first-page":"CD001991","DOI":"10.1002\/14651858.CD001991.pub3","volume":"6","author":"R Manser","year":"2013","unstructured":"Manser, R. et al. Screening for lung cancer. Cochrane Database Syst. Rev. 6, CD001991. https:\/\/doi.org\/10.1002\/14651858.CD001991.pub3 (2013).","journal-title":"Cochrane Database Syst. Rev."},{"issue":"18 Suppl","key":"96242_CR4","first-page":"83S","volume":"19","author":"PM Marcus","year":"2001","unstructured":"Marcus, P. M. Lung cancer screening: an update. J Clin Oncol. 19(18 Suppl), 83S-86S (2001).","journal-title":"J Clin Oncol."},{"issue":"5","key":"96242_CR5","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1056\/NEJMoa1102873","volume":"365","author":"DR Aberle","year":"2011","unstructured":"National Lung Screening Trial Research Team, Aberle, D. R., Adams, A. M., Berg, C. D., Black, W. C., Clapp, J. D., Fagerstrom, R. M., Gareen, I. F., Gatsonis, C., Marcus, P. M. & Sicks, J. D. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365(5), 395\u2013409. https:\/\/doi.org\/10.1056\/NEJMoa1102873 (2011).","journal-title":"N. Engl. J. Med."},{"issue":"21","key":"96242_CR6","doi-asserted-by":"publisher","first-page":"1980","DOI":"10.1056\/NEJMoa1209120","volume":"368","author":"TR Church","year":"2013","unstructured":"National Lung Screening Trial Research Team, Church, T. R., Black, W. C., Aberle, D. R., Berg, C. D., Clingan, K. L., Duan, F., Fagerstrom, R. M., Gareen, I. F., Gierada, D. S., Jones, G. C., Mahon, I., Marcus, P. M., Sicks, J. D., Jain, A. & Baum, S. Results of initial low-dose computed tomographic screening for lung cancer. N. Engl. J. Med. 368(21), 1980\u20131991. https:\/\/doi.org\/10.1056\/NEJMoa1209120 (2013).","journal-title":"N. Engl. J. Med."},{"issue":"3","key":"96242_CR7","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.jtho.2018.11.023","volume":"14","author":"LM Seijo","year":"2019","unstructured":"Seijo, L. M. et al. Biomarkers in lung cancer screening: Achievements, promises, and challenges. J. Thorac. Oncol. 14(3), 343\u2013357. https:\/\/doi.org\/10.1016\/j.jtho.2018.11.023 (2019).","journal-title":"J. Thorac. Oncol."},{"issue":"8","key":"96242_CR8","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1158\/1940-6207.CAPR-11-0441","volume":"5","author":"M Hassanein","year":"2012","unstructured":"Hassanein, M. et al. The state of molecular biomarkers for the early detection of lung cancer. Cancer Prev. Res. (Phila). 5(8), 992\u20131006. https:\/\/doi.org\/10.1158\/1940-6207.CAPR-11-0441 (2012).","journal-title":"Cancer Prev. Res. (Phila)."},{"key":"96242_CR9","doi-asserted-by":"publisher","unstructured":"Silvestri, G. A., Vachani, A., Whitney, D., Elashoff, M., Porta Smith, K., Ferguson, J. S., Parsons, E., Mitra, N., Brody, J., Lenburg, M. E., Spira, A. & AEGIS Study Team. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N. Engl. J. Med. 373(3), 243\u2013251. https:\/\/doi.org\/10.1056\/NEJMoa1504601 (2015).","DOI":"10.1056\/NEJMoa1504601"},{"issue":"7216","key":"96242_CR10","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nature07423","volume":"455","author":"L Ding","year":"2008","unstructured":"Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216), 1069\u20131075. https:\/\/doi.org\/10.1038\/nature07423 (2008).","journal-title":"Nature"},{"issue":"52","key":"96242_CR11","doi-asserted-by":"publisher","first-page":"21083","DOI":"10.1073\/pnas.1320659110","volume":"110","author":"X Ni","year":"2013","unstructured":"Ni, X. et al. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc. Natl. Acad. Sci. U. S. A. 110(52), 21083\u201321088. https:\/\/doi.org\/10.1073\/pnas.1320659110 (2013).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"9","key":"96242_CR12","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1038\/nrc1432","volume":"4","author":"SA Belinsky","year":"2004","unstructured":"Belinsky, S. A. Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer. 4(9), 707\u2013717. https:\/\/doi.org\/10.1038\/nrc1432 (2004).","journal-title":"Nat Rev Cancer."},{"issue":"10","key":"96242_CR13","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1074\/mcp.M500055-MCP200","volume":"4","author":"T Xiao","year":"2005","unstructured":"Xiao, T. et al. An approach to studying lung cancer-related proteins in human blood. Mol Cell Proteomics. 4(10), 1480\u20131486. https:\/\/doi.org\/10.1074\/mcp.M500055-MCP200 (2005).","journal-title":"Mol Cell Proteomics."},{"key":"96242_CR14","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.3389\/fonc.2019.01281","volume":"9","author":"N Shen","year":"2019","unstructured":"Shen, N. et al. A Diagnostic panel of DNA methylation biomarkers for lung adenocarcinoma. Front. Oncol. 9, 1281. https:\/\/doi.org\/10.3389\/fonc.2019.01281 (2019).","journal-title":"Front. Oncol."},{"issue":"4","key":"96242_CR15","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.cell.2007.01.029","volume":"128","author":"PA Jones","year":"2007","unstructured":"Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128(4), 683\u2013692. https:\/\/doi.org\/10.1016\/j.cell.2007.01.029 (2007).","journal-title":"Cell"},{"issue":"8","key":"96242_CR16","doi-asserted-by":"publisher","first-page":"1998","DOI":"10.1158\/1078-0432.CCR-16-1371","volume":"23","author":"A Hulbert","year":"2017","unstructured":"Hulbert, A. et al. Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum. Clin. Cancer Res. 23(8), 1998\u20132005. https:\/\/doi.org\/10.1158\/1078-0432.CCR-16-1371 (2017).","journal-title":"Clin. Cancer Res."},{"key":"96242_CR17","unstructured":"Food and Drug Administration. Department of Health and Human Services. Letter confirming approval of application for premarket approval of Colorguard. http:\/\/www.accessdata.fda.gov\/cdrh_docs\/pdf13\/p130017a.pdf. Accessed 24 May 2016."},{"key":"96242_CR18","unstructured":"Food and Drug Administration. Department of Health and Human Services. Letter confirming approval of application for premarket approval of Epi proColon test. http:\/\/www.accessdata.fda.gov\/cdrh_docs\/pdf13\/p130001a.pdf. Accessed 24 May 2016."},{"key":"96242_CR19","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1186\/1471-2407-10-600","volume":"10","author":"B Schmidt","year":"2010","unstructured":"Schmidt, B. et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer based on bronchial aspirates. BMC Cancer 10, 600. https:\/\/doi.org\/10.1186\/1471-2407-10-600 (2010).","journal-title":"BMC Cancer"},{"issue":"10","key":"96242_CR20","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1097\/JTO.0b013e318220ef9a","volume":"6","author":"C Kneip","year":"2011","unstructured":"Kneip, C. et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J. Thorac. Oncol. 6(10), 1632\u20131638. https:\/\/doi.org\/10.1097\/JTO.0b013e318220ef9a (2011).","journal-title":"J. Thorac. Oncol."},{"issue":"5","key":"96242_CR21","first-page":"1281","volume":"15","author":"H Chen","year":"2006","unstructured":"Chen, H. et al. Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer. Oncol. Rep. 15(5), 1281\u20131285 (2006).","journal-title":"Oncol. Rep."},{"issue":"12","key":"96242_CR22","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1016\/j.ejca.2009.04.038","volume":"45","author":"P Helmbold","year":"2009","unstructured":"Helmbold, P., Lahtz, C., Herpel, E., Schnabel, P. A. & Dammann, R. H. Frequent hypermethylation of RASSF1A tumour suppressor gene promoter and presence of Merkel cell polyomavirus in small cell lung cancer. Eur. J. Cancer. 45(12), 2207\u20132211. https:\/\/doi.org\/10.1016\/j.ejca.2009.04.038 (2009).","journal-title":"Eur. J. Cancer."},{"issue":"1","key":"96242_CR23","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.jtho.2016.08.123","volume":"12","author":"G Weiss","year":"2017","unstructured":"Weiss, G., Schlegel, A., Kottwitz, D., K\u00f6nig, T. & Tetzner, R. Validation of the SHOX2\/PTGER4 DNA Methylation marker panel for plasma-based discrimination between patients with malignant and nonmalignant lung disease. J. Thorac. Oncol. 12(1), 77\u201384. https:\/\/doi.org\/10.1016\/j.jtho.2016.08.123 (2017).","journal-title":"J. Thorac. Oncol."},{"issue":"1","key":"96242_CR24","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s13048-019-0503-7","volume":"12","author":"V Dochez","year":"2019","unstructured":"Dochez, V. et al. Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review. J. Ovarian Res. 12(1), 28. https:\/\/doi.org\/10.1186\/s13048-019-0503-7 (2019).","journal-title":"J. Ovarian Res."},{"key":"96242_CR25","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.6004\/jnccn.2014.0176","volume":"12","author":"DS Ettinger","year":"2014","unstructured":"Ettinger, D. S. et al. Non-small cell lung cancer, version 1.2015. J Natl. Compr. Cancer Netw. 12, 1738\u20131761. https:\/\/doi.org\/10.6004\/jnccn.2014.0176 (2014).","journal-title":"J Natl. Compr. Cancer Netw."},{"key":"96242_CR26","unstructured":"https:\/\/worldwide.espacenet.com\/patent\/search\/family\/067395231\/publication\/US2021032704A1?q=US20210032704A1"},{"issue":"5","key":"96242_CR27","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1007\/s13277-012-0379-2","volume":"33","author":"CJ Chapman","year":"2012","unstructured":"Chapman, C. J. et al. EarlyCDT-lung test: Improved clinical utility through additional autoantibody assays. Tumour Biol. 33(5), 1319\u20131326. https:\/\/doi.org\/10.1007\/s13277-012-0379-2 (2012).","journal-title":"Tumour Biol."},{"issue":"8","key":"96242_CR28","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1056\/NEJMoa1211776","volume":"368","author":"MC Tammem\u00e4gi","year":"2013","unstructured":"Tammem\u00e4gi, M. C. et al. Selection criteria for lung-cancer screening. N. Engl. J. Med. 368(8), 728\u2013736. https:\/\/doi.org\/10.1056\/NEJMoa1211776 (2013).","journal-title":"N. Engl. J. Med."},{"key":"96242_CR29","doi-asserted-by":"publisher","unstructured":"Blanchon, T., Br\u00e9chot, J. M., Grenier, P. A., Ferretti, G. R., Lemari\u00e9, E., Milleron, B., Chagu\u00e9, D., Laurent, F., Martinet, Y., Beigelman-Aubry, C., Blanchon, F., Revel, M. P., Friard, S., R\u00e9my-Jardin, M., Vasile, M., Santelmo, N., Lecalier, A., Lef\u00e9bure, P., Moro-Sibilot, D., Breton, J. L., Carette, M. F., Brambilla, C., Fournel, F., Kieffer, A., Frija, G., Flahault, A. & D\u00e9piscan Group. Baseline results of the Depiscan study: A French randomized pilot trial of lung cancer screening comparing low dose CT scan (LDCT) and chest X-ray (CXR). Lung Cancer 58(1), 50\u201358. https:\/\/doi.org\/10.1016\/j.lungcan.2007.05.009 (2007).","DOI":"10.1016\/j.lungcan.2007.05.009"},{"key":"96242_CR30","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.3389\/fgene.2019.01150","volume":"10","author":"WJ Locke","year":"2019","unstructured":"Locke, W. J. et al. DNA methylation cancer biomarkers: Translation to the clinic. Front Genet. 10, 1150. https:\/\/doi.org\/10.3389\/fgene.2019.01150 (2019).","journal-title":"Front Genet."},{"issue":"3","key":"96242_CR31","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1620\/tjem.229.173","volume":"229","author":"S Fukushige","year":"2013","unstructured":"Fukushige, S. & Horii, A. DNA methylation in cancer: a gene silencing mechanism and the clinical potential of its biomarkers. Tohoku J. Exp. Med. 229(3), 173\u2013185. https:\/\/doi.org\/10.1620\/tjem.229.173 (2013).","journal-title":"Tohoku J. Exp. Med."},{"issue":"12","key":"96242_CR32","doi-asserted-by":"publisher","first-page":"3446","DOI":"10.1158\/0008-5472.CAN-15-3278","volume":"76","author":"M Klutstein","year":"2016","unstructured":"Klutstein, M., Nejman, D., Greenfield, R. & Cedar, H. DNA methylation in cancer and aging. Cancer Res. 76(12), 3446\u20133450. https:\/\/doi.org\/10.1158\/0008-5472.CAN-15-3278 (2016).","journal-title":"Cancer Res."},{"issue":"22","key":"96242_CR33","doi-asserted-by":"publisher","first-page":"5692","DOI":"10.1158\/0008-5472.CAN-12-2309","volume":"72","author":"G Nikolaidis","year":"2012","unstructured":"Nikolaidis, G. et al. DNA methylation biomarkers offer improved diagnostic efficiency in lung cancer. Cancer Res. 72(22), 5692\u20135701. https:\/\/doi.org\/10.1158\/0008-5472.CAN-12-2309 (2012).","journal-title":"Cancer Res."},{"issue":"17","key":"96242_CR34","doi-asserted-by":"publisher","first-page":"3585","DOI":"10.7150\/jca.21368","volume":"8","author":"C Zhang","year":"2017","unstructured":"Zhang, C. et al. DNA methylation analysis of the SHOX2 and RASSF1A panel in bronchoalveolar lavage fluid for lung cancer diagnosis. J. Cancer. 8(17), 3585\u20133591. https:\/\/doi.org\/10.7150\/jca.21368 (2017).","journal-title":"J. Cancer."},{"issue":"13","key":"96242_CR35","doi-asserted-by":"publisher","first-page":"4494","DOI":"10.1158\/1078-0432.CCR-10-3436","volume":"17","author":"S Begum","year":"2011","unstructured":"Begum, S. et al. An epigenetic marker panel for detection of lung cancer using cell-free serum DNA. Clin Cancer Res. 17(13), 4494\u20134503. https:\/\/doi.org\/10.1158\/1078-0432.CCR-10-3436 (2011).","journal-title":"Clin Cancer Res."},{"issue":"9","key":"96242_CR36","doi-asserted-by":"publisher","first-page":"170070","DOI":"10.1098\/rsob.170070","volume":"7","author":"S Blandin Knight","year":"2017","unstructured":"Blandin Knight, S. et al. Progress and prospects of early detection in lung cancer. Open Biol. 7(9), 170070. https:\/\/doi.org\/10.1098\/rsob.170070 (2017).","journal-title":"Open Biol."},{"issue":"20","key":"96242_CR37","doi-asserted-by":"publisher","first-page":"30299","DOI":"10.1016\/j.jmoldx.2020.04.205","volume":"S1525\u20131578","author":"L de Vos","year":"2020","unstructured":"de Vos, L. et al. Treatment response monitoring in patients with advanced malignancies using cell-free SHOX2 and SEPT9 DNA methylation in blood: An observational prospective study. J. Mol. Diagn. S1525\u20131578(20), 30299\u201330303. https:\/\/doi.org\/10.1016\/j.jmoldx.2020.04.205 (2020).","journal-title":"J. Mol. Diagn."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96242-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96242-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96242-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T07:45:54Z","timestamp":1670053554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96242-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,18]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["96242"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-96242-6","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-416830\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,18]]},"assertion":[{"value":"13 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"FW, YC, and ML are employees of Excellen Medical Technology Co., Ltd. All other authors have no conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16782"}}