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We present JOANA (Joint continuous multi-Omics enrichment ANAlysis), a novel Bayesian framework for pathway analysis with three key contributions. First, JOANA enables high specificity through continuous probabilistic modeling of significance scores using Beta mixture distributions, eliminating arbitrary thresholds while maintaining sensitivity. Second, JOANA\u2019s multi-omics integration via Bayesian networks inherently accounts for missing values and reveals pathways invisible to single-layer analyses. Finally, we demonstrate high versatility across diverse experimental paradigms\u2014from proteomics and transcriptomics to single-cell transcriptomics, mutation analysis, and transcriptomics\u2013epigenomics data. In systematic comparisons on synthetic data as well as diverse real-world multi-modal datasets, JOANA achieves up to $\\sim $20-fold reduction in reported pathways compared with existing methods while maintaining sensitivity for true biological signals. We implement JOANA in an open-source Python package, joanapy.<\/jats:p>","DOI":"10.1093\/bib\/bbag328","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:31:15Z","timestamp":1780399875000},"source":"Crossref","is-referenced-by-count":0,"title":["Continuous multi-omics pathway enrichment analysis resolves hidden functional heterogeneity"],"prefix":"10.1093","volume":"27","author":[{"given":"Sareh","family":"Amerifar","sequence":"first","affiliation":[{"name":"MedicineII-Hematology and Oncology, University Hospital Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"Goethe University Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"German Cancer Consortium (DKTK), partner site Frankfurt\/Mainz , a partnership between DKFZ and UCT Frankfurt-Marburg, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kopf","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK), partner site Frankfurt\/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"German Cancer Research Center (DKFZ) , Im Neuenheimer Feld 280, 69120 Heidelberg, Baden-W\u00fcrttemberg,","place":["Germany"]},{"name":"Digitec Galaxus AG , Pfingstweidstrasse 60b, 8005 Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Sass","sequence":"additional","affiliation":[{"name":"Institute of Computational Biology, Helmholtz Munich, Ingolst\u00e4dter Landstra\u00dfe 1 , 85764 Neuherberg, Bavaria,","place":["Germany"]},{"name":"Pharma Technical Development, Roche Diagnostics GmbH , Nonnenwald 2, 82377 Penzberg, 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Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"German Cancer Consortium (DKTK) , partner site Frankfurt\/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"Frankfurt Cancer Institute (FCI) , Georg-Speyer-Haus, Paul-Ehrlich-Stra\u00dfe 42-44, 60596 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health , 9000 Rockville Pike, Bethesda, MD 20892,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel H","family":"Schulz","sequence":"additional","affiliation":[{"name":"Institute for Computational Genomic Medicine, Goethe University Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Oellerich","sequence":"additional","affiliation":[{"name":"MedicineII-Hematology and Oncology, University Hospital Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"Goethe University Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"German Cancer Consortium (DKTK), partner site Frankfurt\/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Hessen,","place":["Germany"]},{"name":"German Cancer Research Center (DKFZ) , Im Neuenheimer Feld 280, 69120 Heidelberg, Baden-W\u00fcrttemberg,","place":["Germany"]},{"name":"Frankfurt Cancer Institute (FCI), Georg-Speyer-Haus , Paul-Ehrlich-Stra\u00dfe 42-44, 60596 Frankfurt am Main, Hessen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian 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