{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:49:24Z","timestamp":1773103764524,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Secretar\u00eda de Investigaci\u00f3n y Posgrado-IPN","award":["SIP-20250212"],"award-info":[{"award-number":["SIP-20250212"]}]},{"name":"Secretar\u00eda de Investigaci\u00f3n y Posgrado-IPN","award":["SIP-20250231"],"award-info":[{"award-number":["SIP-20250231"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Conventional omics analysis often treats outliers as noise, yet they may harbor critical biological insights. Objetive: This study proposes a paradigm shift: actively investigating outliers to discover biologically relevant subtypes within metabolic\u2013inflammatory syndromes. Methods: We applied a comprehensive analytical framework for outlier detection based on a multi-algorithm consensus (IQR, MAD, Isolation Forest) to a clinical cohort of diabetic neuropathy (n = 93) and an in vitro 3T3-L1 adipocyte model (n = 39). The identified outliers were characterized using robust PCA, co-expression networks, unsupervised clustering, and Random Forest predictive modeling. Results: In the clinical cohort, an outlier subgroup (47.3%) exhibited an extreme immune\u2013metabolic phenotype characterized by hyperactivation of Th1\/Th17 pathways (elevated T-bet and IL-17; p &lt; 0.001), hypertriglyceridemia, and network reconfiguration (TGF\u03b2 and STAT4 hubs). In the cellular model, outlier samples (12.8%) showed autonomous pro-inflammatory behavior characterized by IL-6 overproduction (p = 0.002) and IL-10 suppression. Conclusions: Multivariate analysis confirmed spatial segregation of these profiles. Systematic outlier investigation revealed discrete pathophysiological subtypes invisible to mean-focused analyses, demonstrating that extreme values encapsulate potent biological signals. This framework offers a generalizable approach for uncovering clinical heterogeneity and identifying therapeutic targets in complex diseases.<\/jats:p>","DOI":"10.3390\/medsci14010128","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T13:27:18Z","timestamp":1773062838000},"page":"128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Signal in the Extreme: A Systematic Outlier Framework Identifies Discrete Immunometabolic Subtypes in Human and Cellular Models"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4627-5213","authenticated-orcid":false,"given":"Julio Jes\u00fas","family":"Garcia-Coste","sequence":"first","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Gen\u00e9tica de Enfermedades Metab\u00f3licas, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla Aidee","family":"Aguayo-Cer\u00f3n","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Gen\u00e9tica de Enfermedades Metab\u00f3licas, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-2920","authenticated-orcid":false,"given":"Judith","family":"Espinosa-Raya","sequence":"additional","affiliation":[{"name":"Laboratorio Multidisciplinario en Ciencias Biom\u00e9dicas, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis Alejandro","family":"Garc\u00eda-Rivero","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7191-0884","authenticated-orcid":false,"given":"Carina","family":"L\u00f3pez-Leyva","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Gen\u00e9tica de Enfermedades Metab\u00f3licas, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0376-5037","authenticated-orcid":false,"given":"Roc\u00edo Alejandra","family":"Guti\u00e9rrez-Rojas","sequence":"additional","affiliation":[{"name":"Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9428-3619","authenticated-orcid":false,"given":"Cruz","family":"Vargas-De-Le\u00f3n","sequence":"additional","affiliation":[{"name":"Laboratorio de Modelaci\u00f3n Bioestad\u00edstica para la Salud, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"},{"name":"Divisi\u00f3n de Investigaci\u00f3n, Hospital Ju\u00e1rez de M\u00e9xico, Ciudad de M\u00e9xico 07760, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-5736","authenticated-orcid":false,"given":"Rodrigo","family":"Romero-Nava","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Gen\u00e9tica de Enfermedades Metab\u00f3licas, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R1901","DOI":"10.1152\/ajpregu.00847.2007","article-title":"Gene expression profiling in human skeletal muscle during recovery from eccentric exercise","volume":"294","author":"Mahoney","year":"2008","journal-title":"Am. 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