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Here we describe MAGICAL (Multiome Accessibility Gene Integration Calling and Looping), a hierarchical Bayesian approach that leverages paired single-cell RNA sequencing and single-cell transposase-accessible chromatin sequencing from different conditions to map disease-associated transcription factors, chromatin sites, and genes as regulatory circuits. By simultaneously modeling signal variation across cells and conditions in both omics data types, MAGICAL achieved high accuracy on circuit inference. We applied MAGICAL to study\n                    <jats:italic>Staphylococcus<\/jats:italic>\n                    \u2009\n                    <jats:italic>aureus<\/jats:italic>\n                    sepsis from peripheral blood mononuclear single-cell data that we generated from subjects with bloodstream infection and uninfected controls. MAGICAL identified sepsis-associated regulatory circuits predominantly in CD14 monocytes, known to be activated by bacterial sepsis. We addressed the challenging problem of distinguishing host regulatory circuit responses to methicillin-resistant and methicillin-susceptible\n                    <jats:italic>S.<\/jats:italic>\n                    \u2009\n                    <jats:italic>aureus<\/jats:italic>\n                    infections. Although differential expression analysis failed to show predictive value, MAGICAL identified epigenetic circuit biomarkers that distinguished methicillin-resistant from methicillin-susceptible\n                    <jats:italic>S.<\/jats:italic>\n                    \u2009\n                    <jats:italic>aureus<\/jats:italic>\n                    infections.\n                  <\/jats:p>","DOI":"10.1038\/s43588-023-00476-5","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T12:04:34Z","timestamp":1690286674000},"page":"644-657","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Mapping disease regulatory circuits at cell-type resolution from single-cell multiomics data"],"prefix":"10.1038","volume":"3","author":[{"given":"Xi","family":"Chen","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7750-3587","authenticated-orcid":false,"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Antonio","family":"Cappuccio","sequence":"additional","affiliation":[]},{"given":"Wan-Sze","family":"Cheng","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2451-8598","authenticated-orcid":false,"given":"Frederique Ruf","family":"Zamojski","sequence":"additional","affiliation":[]},{"given":"Venugopalan D.","family":"Nair","sequence":"additional","affiliation":[]},{"given":"Clare M.","family":"Miller","sequence":"additional","affiliation":[]},{"given":"Aliza B.","family":"Rubenstein","sequence":"additional","affiliation":[]},{"given":"German","family":"Nudelman","sequence":"additional","affiliation":[]},{"given":"Alicja","family":"Tadych","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8379-6600","authenticated-orcid":false,"given":"Chandra L.","family":"Theesfeld","sequence":"additional","affiliation":[]},{"given":"Alexandria","family":"Vornholt","sequence":"additional","affiliation":[]},{"given":"Mary-Catherine","family":"George","sequence":"additional","affiliation":[]},{"given":"Felicia","family":"Ruffin","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Dagher","sequence":"additional","affiliation":[]},{"given":"Daniel G.","family":"Chawla","sequence":"additional","affiliation":[]},{"given":"Alessandra","family":"Soares-Schanoski","sequence":"additional","affiliation":[]},{"given":"Rachel R.","family":"Spurbeck","sequence":"additional","affiliation":[]},{"given":"Lishomwa C.","family":"Ndhlovu","sequence":"additional","affiliation":[]},{"given":"Robert","family":"Sebra","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-1544","authenticated-orcid":false,"given":"Steven H.","family":"Kleinstein","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-5917","authenticated-orcid":false,"given":"Andrew G.","family":"Letizia","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0223-0120","authenticated-orcid":false,"given":"Irene","family":"Ramos","sequence":"additional","affiliation":[]},{"suffix":"Jr","given":"Vance G.","family":"Fowler","sequence":"additional","affiliation":[]},{"given":"Christopher W.","family":"Woods","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4828-7771","authenticated-orcid":false,"given":"Elena","family":"Zaslavsky","sequence":"additional","affiliation":[]},{"given":"Olga G.","family":"Troyanskaya","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5791-1217","authenticated-orcid":false,"given":"Stuart C.","family":"Sealfon","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"476_CR1","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/s41576-019-0128-0","volume":"20","author":"S Schoenfelder","year":"2019","unstructured":"Schoenfelder, S. & Fraser, P. 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This work was prepared as part of his official duties. Title 17, US Code \u00a7105 provides that copyright protection under this title is not available for any work of the US Government. Title 17, US code \u00a7101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person\u2019s official duties. The views expressed in the article are those of the authors and do not necessarily express the official policy and position of the US Navy, the Department of Defense, the US Government, or the institutions affiliated with the authors. V.G.F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; Royalties from UpToDate, stock options from Valanbio and ArcBio, Honoraria from Infectious Diseases of America for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. L.C.N. has received consulting fees from work as a scientific advisor for AbbVie, ViiV Healthcare, and Cytodyn and also serves on the Board of Directors of CytoDyn and has financial interests in Ledidi AS, all for work outside of the submitted work. S.C.S. is a founder of GNOMX Corp and serves as chief scientific officer. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}