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Single-cell differential expression analysis faces challenges like sample correlation, individual variation, and scalability. We develop a fast and scalable linear mixed-effects model (LMM) estimation algorithm, FLASH-MM, to address these issues. We reformulate aspects of the linear mixed model estimation procedure to make it faster, by reducing computational complexity and memory usage. Simulation studies with scRNA-seq data show that FLASH-MM is accurate, computationally efficient, effectively controls false positive rates, and maintains high statistical power in differential expression analysis. Tests on tuberculosis immune and kidney single cell data demonstrate FLASH-MM\u2019s utility in accelerating single-cell differential expression analysis across diverse biological contexts.<\/jats:p>","DOI":"10.1038\/s41467-026-69063-2","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T06:25:45Z","timestamp":1770272745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["FLASH-MM: fast and scalable single-cell differential expression analysis using linear mixed-effects models"],"prefix":"10.1038","volume":"17","author":[{"given":"Changjiang","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-8067","authenticated-orcid":false,"given":"Delaram","family":"Pouyabahar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3405-9532","authenticated-orcid":false,"given":"Veronique","family":"Voisin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6708-9116","authenticated-orcid":false,"given":"Hamed","family":"Heydari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0185-8861","authenticated-orcid":false,"given":"Gary D.","family":"Bader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"69063_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21038-1","volume":"12","author":"KD Zimmerman","year":"2021","unstructured":"Zimmerman, K. 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