{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:04:08Z","timestamp":1790701448504,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Innovation 2030 - \u201cCancer"},{"name":"Cardiovascular and Cerebrovascular, Respiratory and Metabolic Diseases Prevention and Treatment Research\u201d","award":["2023ZD0506403"],"award-info":[{"award-number":["2023ZD0506403"]}]},{"name":"Medical and Health Science and Technology Development Research Center"},{"name":"National Health Commission of the People\u2019s Republic of China","id":[{"id":"https:\/\/ror.org\/04bdenw41","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011787","name":"Heilongjiang Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["2022ZX103C01"],"award-info":[{"award-number":["2022ZX103C01"]}],"id":[{"id":"10.13039\/501100011787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Paired spatial assays now measure the transcriptome and the proteome on the same tissue section. Existing integration methods commit to a structural choice at the outset: a separate graph per modality, early fusion that folds the measured protein into the embedding so it can no longer be predicted, or intersection rules that discard most similarity edges. Each choice limits what one trained model can do afterwards.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We present MultiSpaceNet, a graph-based framework for joint representation learning from paired spatial transcriptomic and proteomic data. A section is represented as one cell graph over a shared node set, with spatial, transcriptomic and proteomic relations carried as typed edges and the two modality branches kept separate until a per-cell attention fusion. On five benchmark datasets, MultiSpaceNet outperforms nine published state-of-the-art methods in spatial domain identification (mean adjusted Rand index 0.472). Its leakage-free RNA-to-protein imputation matches or exceeds established methods for signal-bearing proteins, and it preserves biological structure across replicate sections better than all compared alternatives. A single trained model thus provides spatial domains, protein imputation, cross-section joint embedding and descriptive per-cell modality-dominance maps.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>Source code is available at https:\/\/github.com\/yongzhuangliulab\/MultiSpaceNet and archived at Zenodo (DOI 10.5281\/zenodo.22667390 and 10.5281\/zenodo.21488824). The scripts that regenerate the reported tables and figures, together with their machine-readable result summaries, are included in the repository (directory resubmission\/) and its Zenodo archive.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btag676","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:15:02Z","timestamp":1790334902000},"source":"Crossref","is-referenced-by-count":0,"title":["MultiSpaceNet: graph-based joint representation learning for paired spatial transcriptome\u2013proteome data"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3195-5645","authenticated-orcid":false,"given":"Zhengqian","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Computer Science and Technology, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binghong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Mathematics, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Mathematics, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialiang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjun","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongyao","family":"Liu","sequence":"additional","affiliation":[{"name":"The School of Future Technology, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Mathematics, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikun","family":"Cao","sequence":"additional","affiliation":[{"name":"The School of Future Technology, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2572-7420","authenticated-orcid":false,"given":"Yongzhuang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Harbin Institute of Technology , Heilongjiang, 150001,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"2026092912180877900_btag676-B1","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s13059-020-02015-1","article-title":"MOFA+: a statistical framework for comprehensive integration of multi-modal single-cell data","volume":"21","author":"Argelaguet","year":"2020","journal-title":"Genome Biol"},{"key":"2026092912180877900_btag676-B2","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1038\/s41592-023-01909-9","article-title":"MultiVI: deep generative model for the integration of multimodal data","volume":"20","author":"Ashuach","year":"2023","journal-title":"Nat Methods"},{"key":"2026092912180877900_btag676-B3","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/s41587-022-01536-3","article-title":"Integration of whole transcriptome spatial profiling with protein markers","volume":"41","author":"Ben-Chetrit","year":"2023","journal-title":"Nat Biotechnol"},{"key":"2026092912180877900_btag676-B4","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1038\/s41467-022-29439-6","article-title":"Deciphering spatial domains from spatially resolved transcriptomics with an adaptive graph attention auto-encoder","volume":"13","author":"Dong","year":"2022","journal-title":"Nat Commun"},{"key":"2026092912180877900_btag676-B5","doi-asserted-by":"publisher","first-page":"2876","DOI":"10.1038\/s41467-026-70821-5","article-title":"SMART: spatial multi-omic aggregation using graph neural networks and metric learning","volume":"17","author":"Du","year":"2026","journal-title":"Nat Commun"},{"key":"2026092912180877900_btag676-B6","doi-asserted-by":"publisher","first-page":"e1013546","DOI":"10.1371\/journal.pcbi.1013546","article-title":"A graph neural network-based spatial multi-omics data integration method for deciphering spatial domains","volume":"21","author":"Gao","year":"2025","journal-title":"PLoS Comput Biol"},{"key":"2026092912180877900_btag676-B7","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/s41592-020-01050-x","article-title":"Joint probabilistic modeling of single-cell multi-omic data with totalVI","volume":"18","author":"Gayoso","year":"2021","journal-title":"Nat Methods"},{"key":"2026092912180877900_btag676-B8","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/s41587-023-01766-z","article-title":"Stabilized mosaic single-cell data integration using unshared features","volume":"42","author":"Ghazanfar","year":"2024","journal-title":"Nat Biotechnol"},{"key":"2026092912180877900_btag676-B9","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.2869","article-title":"Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry","volume":"11","author":"Giesen","year":"2014","journal-title":"Nat Methods"},{"key":"2026092912180877900_btag676-B10","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.cell.2018.07.010","article-title":"Deep profiling of mouse splenic architecture with CODEX multiplexed imaging","volume":"174","author":"Goltsev","year":"2018","journal-title":"Cell"},{"key":"2026092912180877900_btag676-B11","doi-asserted-by":"publisher","first-page":"bbag192","DOI":"10.1093\/bib\/bbag192","article-title":"Spatial multi-omics integration by cross-modal graph contrastive learning","volume":"27","author":"Gui","year":"2026","journal-title":"Brief Bioinform"},{"key":"2026092912180877900_btag676-B12","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"2026092912180877900_btag676-B13","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1038\/s41587-022-01483-z","article-title":"High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging","volume":"40","author":"He","year":"2022","journal-title":"Nat Biotechnol"},{"key":"2026092912180877900_btag676-B14","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1038\/s41592-021-01255-8","article-title":"SpaGCN: integrating gene expression, spatial location and histology to identify spatial domains and spatially variable genes by graph convolutional network","volume":"18","author":"Hu","year":"2021","journal-title":"Nat Methods"},{"key":"2026092912180877900_btag676-B15","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.cell.2020.05.039","article-title":"Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma","volume":"182","author":"Ji","year":"2020","journal-title":"Cell"},{"key":"2026092912180877900_btag676-B16","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1109\/TCBBIO.2026.3690748","article-title":"DiffuST: a latent diffusion model for spatial transcriptomics denoising","volume":"23","author":"Jiao","year":"2026","journal-title":"IEEE Trans Comput Biol Bioinform"},{"key":"2026092912180877900_btag676-B17","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1016\/j.cell.2018.08.039","article-title":"A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging","volume":"174","author":"Keren","year":"2018","journal-title":"Cell"},{"key":"2026092912180877900_btag676-B18","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1038\/s42256-022-00545-w","article-title":"A multi-use deep learning method for CITE-seq and single-cell RNA-seq data integration with cell surface protein prediction and imputation","volume":"4","author":"Lakkis","year":"2022","journal-title":"Nat Mach Intell"},{"key":"2026092912180877900_btag676-B19","doi-asserted-by":"publisher","first-page":"5268","DOI":"10.1038\/s41467-026-71882-2","article-title":"SpatialCOC: an integrative framework for spatial continuous mapping and cross-omics correction in spatial multi-omics data","volume":"17","author":"Li","year":"2026","journal-title":"Nat Commun"},{"key":"2026092912180877900_btag676-B20","doi-asserted-by":"publisher","first-page":"btag457","DOI":"10.1093\/bioinformatics\/btag457","article-title":"SpaMFG: a spatial multi-omics integration method based on feature grouping","volume":"42","author":"Li","year":"2026","journal-title":"Bioinformatics"},{"key":"2026092912180877900_btag676-B21","doi-asserted-by":"publisher","author":"Liao","year":"2023","DOI":"10.1101\/2023.04.28.538364"},{"key":"2026092912180877900_btag676-B22","doi-asserted-by":"publisher","first-page":"e202201701","DOI":"10.26508\/lsa.202201701","article-title":"Concordance of MERFISH spatial transcriptomics with bulk and single-cell RNA sequencing","volume":"6","author":"Liu","year":"2023","journal-title":"Life Sci Alliance"},{"key":"2026092912180877900_btag676-B23","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1016\/j.cell.2020.10.026","article-title":"High-spatial-resolution multi-omics sequencing via deterministic barcoding in tissue","volume":"183","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"2026092912180877900_btag676-B24","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1038\/s41587-023-01676-0","article-title":"High-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq","volume":"41","author":"Liu","year":"2023","journal-title":"Nat Biotechnol"},{"key":"2026092912180877900_btag676-B25","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/s41467-023-36796-3","article-title":"Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST","volume":"14","author":"Long","year":"2023","journal-title":"Nat Commun"},{"key":"2026092912180877900_btag676-B26","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1038\/s41592-024-02316-4","article-title":"Deciphering spatial domains from spatial multi-omics with SpatialGlue","volume":"21","author":"Long","year":"2024","journal-title":"Nat Methods"},{"key":"2026092912180877900_btag676-B27","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41580-018-0094-y","article-title":"Spatial proteomics: a powerful discovery tool for cell biology","volume":"20","author":"Lundberg","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026092912180877900_btag676-B28","author":"Madhu","year":"2026"},{"key":"2026092912180877900_btag676-B29","doi-asserted-by":"publisher","first-page":"100071","DOI":"10.1016\/j.crmeth.2021.100071","article-title":"A mixture-of-experts deep generative model for integrated analysis of single-cell multiomics data","volume":"1","author":"Minoura","year":"2021","journal-title":"Cell Rep Methods"},{"key":"2026092912180877900_btag676-B30","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1038\/s41587-022-01302-5","article-title":"Deep visual proteomics defines single-cell identity and heterogeneity","volume":"40","author":"Mund","year":"2022","journal-title":"Nat Biotechnol"},{"key":"2026092912180877900_btag676-B31","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1126\/science.aaw1219","article-title":"Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution","volume":"363","author":"Rodriques","year":"2019","journal-title":"Science"},{"key":"2026092912180877900_btag676-B32","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/j.cell.2020.07.005","article-title":"Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front","volume":"182","author":"Sch\u00fcrch","year":"2020","journal-title":"Cell"},{"key":"2026092912180877900_btag676-B33","doi-asserted-by":"publisher","first-page":"289","DOI":"10.32614\/RJ-2016-021","article-title":"Mclust 5: clustering, classification and density estimation using gaussian finite mixture models","volume":"8","author":"Scrucca","year":"2016","journal-title":"R J"},{"key":"2026092912180877900_btag676-B34","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41587-020-0739-1","article-title":"Highly sensitive spatial transcriptomics at near-cellular resolution with slide-seqV2","volume":"39","author":"Stickels","year":"2021","journal-title":"Nat Biotechnol"},{"key":"2026092912180877900_btag676-B35","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1038\/s41592-019-0548-y","article-title":"High-definition spatial transcriptomics for in situ tissue profiling","volume":"16","author":"Vickovic","year":"2019","journal-title":"Nat Methods"},{"key":"2026092912180877900_btag676-B36","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/s41467-022-28445-y","article-title":"SM-Omics is an automated platform for high-throughput spatial multi-omics","volume":"13","author":"Vickovic","year":"2022","journal-title":"Nat Commun"},{"key":"2026092912180877900_btag676-B37","doi-asserted-by":"publisher","first-page":"bbag122","DOI":"10.1093\/bib\/bbag122","article-title":"STGNET: extending panel coverage in imaging-based spatial transcriptomics using deep generative adversarial networks","volume":"27","author":"Wang","year":"2026","journal-title":"Brief Bioinform"},{"key":"2026092912180877900_btag676-B38","doi-asserted-by":"publisher","author":"Wang","year":"2019","DOI":"10.1145\/3308558.3313562"},{"key":"2026092912180877900_btag676-B39","doi-asserted-by":"publisher","first-page":"btag465","DOI":"10.1093\/bioinformatics\/btag465","article-title":"ARISE: RNA-anchored shared-edge topology and hierarchical fusion for spatial multi-omics integration","volume":"42","author":"Wang","year":"2026","journal-title":"Bioinformatics"},{"key":"2026092912180877900_btag676-B40","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: large-scale single-cell gene expression data analysis","volume":"19","author":"Wolf","year":"2018","journal-title":"Genome Biol"},{"key":"2026092912180877900_btag676-B41","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1038\/s41588-026-02573-3","article-title":"Mosaic integration of spatial multi-omics with spamosaic","volume":"58","author":"Yan","year":"2026","journal-title":"Nat Genet"},{"key":"2026092912180877900_btag676-B42","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41586-023-05795-1","article-title":"Spatial epigenome\u2013transcriptome co-profiling of mammalian tissues","volume":"616","author":"Zhang","year":"2023","journal-title":"Nature"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btag676\/71395228\/btag676.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/42\/9\/btag676\/71395228\/btag676.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/42\/9\/btag676\/71395228\/btag676.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:18:19Z","timestamp":1790698699000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btag676\/8835683"}},"subtitle":[],"editor":[{"given":"Macha","family":"Nikolski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":42,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,8,31]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btag676","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,31]]},"article-number":"btag676"}}