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We describe a biomarker discovery strategy that exploits monocytes as circulating sentinels to amplify disease-perturbed signals in blood. This strategy leverages monocyteMINER, a mechanistic transcriptional regulatory network inferred from monocyte transcriptomes of 1,202 healthy individuals. As proof-of-concept, we uncovered a 31-gene atherosclerosis-perturbed network that underpins disease etiology, identifying diagnostic signatures for coronary artery disease (ARAP2, P2RY14, FKBP15) and acute myocardial infarction (SERPINA1, ASGR2). For tuberculosis (TB), monocyteMINER uncovered a 5-gene signature (MAS_TB_META5: ANKRD22, AIM2, VAMP5, GBP5, TGM2) from just 438 samples. MAS_TB_META5 outperformed 77 existing signatures across 18 cohorts (&gt;4,400 patients, 12 countries), achieving WHO target product profile for high-sensitivity screening (including in advanced HIV patients), and predicting TB progression up to 5 years before diagnosis. Thus, our findings show that monocyteMINER offers a generalizable platform for discovering clinically actionable biomarkers for diverse diseases.<\/jats:p>","DOI":"10.64898\/2026.07.04.736372","type":"posted-content","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:30:20Z","timestamp":1783344620000},"source":"Crossref","is-referenced-by-count":0,"title":["Monocyte-amplified transcriptional signatures of human diseases"],"prefix":"10.64898","author":[{"given":"Mario L.","family":"Arrieta-Ortiz","sequence":"first","affiliation":[{"name":"Institute for Systems Biology, 401 Terry Ave N, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ju","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute for Systems Biology, 401 Terry Ave N, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin S.","family":"Baliga","sequence":"additional","affiliation":[{"name":"Institute for Systems Biology, 401 Terry Ave N, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080523351074000_2026.07.04.736372v1.1","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1158\/1055-9965.EPI-20-0074","article-title":"Pitfalls in cancer biomarker discovery and validation with emphasis on circulating tumor DNA. 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