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Pathway-level differential co-expression analysis, a powerful approach for transcriptomics, identifies condition-specific changes in gene-gene interaction networks, offering targeted insights. However, a key challenge is the lack of robust methods and benchmarks specifically for evaluating algorithms\u2019 ability to identify disrupted gene-gene associations across conditions. We introduce <jats:italic>DRaCOoN<\/jats:italic> (Differential Regulatory and Co-expression Networks), a Python package and web tool for pathway-level differential co-expression analysis. <jats:italic>DRaCOoN<\/jats:italic> uniquely integrates multiple association and differential metrics, with a novel, computationally efficient permutation test for significance assessment. Crucially, <jats:italic>DRaCOoN<\/jats:italic> also provides a benchmarking framework for comprehensive method evaluation. Extensive benchmarking on simulated data and three real-world datasets (bone healing, colorectal cancer, and head\/neck carcinoma) showed that <jats:italic>DRaCOoN<\/jats:italic>, particularly with an entropy-based association measure and the <jats:italic>s<\/jats:italic> differential metric, consistently outperforms eight other methods. It remains highly accurate in balanced datasets, robust to varying gene perturbation levels, and identifies biologically relevant regulatory changes. Furthermore, <jats:italic>DRaCOoN<\/jats:italic> serves as both a powerful tool and a benchmarking framework for elucidating disease mechanisms from transcriptomics data, advancing precision medicine by uncovering critical gene regulatory alterations.<\/jats:p>","DOI":"10.1186\/s12859-025-06162-9","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T19:30:01Z","timestamp":1748287801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DRaCOon: a novel algorithm for pathway-level differential co-expression analysis in transcriptomics"],"prefix":"10.1186","volume":"26","author":[{"given":"Fernando M.","family":"Delgado-Chaves","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferdinand","family":"Spurny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Laske","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mhaned","family":"Oubounyt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Baumbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"issue":"1","key":"6162_CR1","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/msb.2011.99","volume":"8","author":"T Ideker","year":"2012","unstructured":"Ideker T, Krogan NJ. 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