{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:47:50Z","timestamp":1791874070884,"version":"4.3.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Central Guided Funds for Local Science and Technology Development"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Metabolomics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>This study aimed to identify serum metabolites independently associated with maximal voluntary ventilation (MVV) among native high\u2011altitude Tibetan adults, and explore metabolic correlates of pulmonary ventilatory function under chronic hypoxic exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Untargeted serum metabolomic profiling comprising 5310 initially detected metabolic features, with 3381 high-quality annotated metabolites retained after strict quality filtering and comprehensive clinical data were collected from 168 native high\u2011altitude Tibetan adults with complete clinical, phenotypic, and metabolomic data (no missing values in the final analytical dataset). Continuous phenotypic and metabolomic variables were Z\u2011score\u2011standardized before analysis. Participants were stratified by MVV quartiles and randomly split into a training set (70%,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009119) and an independent validation set (30%,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200949). A multi\u2011tier metabolite\u2011screening pipeline was implemented solely within the training set: tiered\u2011threshold univariate regression generated candidate metabolites, followed by elastic\u2011net regularized regression (\u03b1\u2009=\u20090.5, lambda.1se). A prespecified fallback rule selected the top\u2011five metabolites with the smallest univariate P\u2011values when elastic\u2011net produced no non\u2011zero\u2011coefficient features. Selected candidates were entered into confounder\u2011adjusted multivariable linear regression, retaining metabolites with\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05. Bootstrap resampling assessed screening stability. Ten\u2011fold cross\u2011validation evaluated internal performance, and the final model was tested on the independent validation set. Sensitivity analysis was performed by excluding the exogenous drug\u2011related metabolite to evaluate robustness of core associations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Three serum metabolites showed independent associations with MVV: N\u2011Undecanoylglycine (\u03b2 = \u22125.237,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.002), Isosorbide Dinitrate (\u03b2\u2009=\u20090.245,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.007), and Hypoglycin B (\u03b2\u2009=\u20094.655,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.006). The metabolite\u2011based model yielded a 10\u2011fold cross\u2011validated R\n                      <jats:sup>2<\/jats:sup>\n                      of 0.191 in the training set, with predictive R\n                      <jats:sup>2<\/jats:sup>\n                      decreasing to 0.090 in the independent validation set. Bootstrap inclusion frequencies for target metabolites were moderate, suggesting relatively weak marginal metabolite\u2011MVV effects. Sensitivity analysis confirmed that core endogenous associations were not driven by the exogenous Isosorbide Dinitrate. Formal pathway enrichment was not conducted due to the small number of significant metabolites.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identified three serum metabolites independently correlated with MVV in native high\u2011altitude Tibetans using a multi\u2011stage metabolome\u2011wide screening workflow. These metabolites represent preliminary metabolic correlates of ventilatory function under chronic high\u2011altitude hypoxia. The marked attenuation of predictive performance from internal cross\u2011validation to external validation reflects limited generalisability of metabolic signatures in moderate\u2011sized population cohorts. This work emphasises the value of prespecified multi\u2011tier screening, stability evaluation and fallback strategies for metabolome\u2011wide association analyses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11306-026-02517-2","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T12:06:12Z","timestamp":1787400372000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum metabolic signatures associated with maximal voluntary ventilation in native high-altitude Tibetans"],"prefix":"10.1007","volume":"22","author":[{"given":"Tao","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lening","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusheng","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghe","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Labasangzhu","family":"Labasangzhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunyou","family":"Dunyou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danbalangjie","family":"Danbalangjie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuetao","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"2517_CR1","doi-asserted-by":"publisher","first-page":"8655","DOI":"10.1073\/pnas.0701985104","volume":"104","author":"CM Beall","year":"2007","unstructured":"Beall, C. 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