{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:04:48Z","timestamp":1784905488909,"version":"3.55.0"},"posted":{"date-parts":[[2025,3,6]]},"group-title":"Genomics","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Multimodal single-cell assays profile complementary layers of cell state, but integration is complicated by modality mismatch, sparsity, and uneven cohort coverage. We present UniVI (\n                  <jats:bold>Uni<\/jats:bold>\n                  fied\n                  <jats:bold>V<\/jats:bold>\n                  ariational\n                  <jats:bold>I<\/jats:bold>\n                  nference), a scalable mixture-of-experts\n                  <jats:italic>\u03b2<\/jats:italic>\n                  -variational autoencoder that learns a shared latent space while preserving modality-specific structure. UniVI couples modality-specific encoders\/de-coders with a shared latent prior and a symmetric cross-modal alignment objective, enabling consistent integration of paired measurements without curated feature-link graphs or pre-annotated reference atlases; optional supervised heads can be added when labels are available. Across paired RNA\u2013protein (CITE-seq) and RNA\u2013chromatin (10x Multiome, SHARE-seq) data spanning human PBMCs and mouse back skin\u2014a non-hematopoietic tissue with continuous differentiation hierarchies\u2014UniVI produces coherent embeddings, improves label transfer, and enables cross-modal reconstruction and denoising. Extending to tri-modal measurements, UniVI maintains robust three-way alignment among RNA, chromatin accessibility, and surface proteins (TEA-seq), and accommodates DNA methylation in a paired scNMT-seq mouse gastrulation proof-of-concept under beta-binomial likelihoods. Performance degrades gracefully under severe cell-type imbalance and in the presence of modality-exclusive populations. In an acute myeloid leukemia mosaic design, a paired RNA\u2013protein bridge anchors independent RNA-only and protein+genotype cohorts, revealing genotype-associated neighborhoods that sharpen with mutation-aware fine-tuning. UniVI thus provides a flexible, interpretable framework for multimodal integration across paired, tri-modal, and mosaic study designs and supports practical reference-to-query projection in partially observed studies.\n                <\/jats:p>","DOI":"10.1101\/2025.02.28.640429","type":"posted-content","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:40:34Z","timestamp":1741333234000},"source":"Crossref","is-referenced-by-count":0,"title":["Unifying multimodal single-cell data with a mixture-of-experts\n                  <i>\u03b2<\/i>\n                  -variational autoencoder framework"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1234-2118","authenticated-orcid":false,"given":"Andrew J.","family":"Ashford","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"Computational Biology Department, Oregon Health & Science University, Portland, OR 97201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4367-2386","authenticated-orcid":false,"given":"Trevor","family":"Enright","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Oregon Health & Science University, Portland, OR 97201, USA"},{"name":"Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-2246","authenticated-orcid":false,"given":"Julia","family":"Somers","sequence":"additional","affiliation":[{"name":"Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA"},{"name":"Biomedical Engineering Department, Oregon Health & Science University, Portland, OR 97201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8105-2440","authenticated-orcid":false,"given":"Olga","family":"Nikolova","sequence":"additional","affiliation":[{"name":"Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-7113","authenticated-orcid":false,"given":"Emek","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"Computational Biology Department, Oregon Health & Science University, Portland, OR 97201, USA"},{"name":"Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA"},{"name":"Biomedical Engineering Department, Oregon Health & Science University, Portland, OR 97201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072407150783000_2025.02.28.640429v3.1","unstructured":"10x Genomics 2021a. 10k human PBMCs, multiome v1.0, Chromium X, single-cell multiome ATAC + gene expression dataset generated by a Chromium X series instrument, analyzed using Cell Ranger ARC 2.0.0."},{"key":"2026072407150783000_2025.02.28.640429v3.2","unstructured":"10x Genomics 2021b. 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