{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T02:18:54Z","timestamp":1770689934024,"version":"3.49.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["61872300"],"award-info":[{"award-number":["61872300"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["61873214"],"award-info":[{"award-number":["61873214"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["XDJK2019B024"],"award-info":[{"award-number":["XDJK2019B024"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of CQ CSTC","award":["cstc2018jcyjAX0228"],"award-info":[{"award-number":["cstc2018jcyjAX0228"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Isoforms are alternatively spliced mRNAs of genes. They can be translated into different functional proteoforms, and thus greatly increase the functional diversity of protein variants (or proteoforms). Differentiating the functions of isoforms (or proteoforms) helps understanding the underlying pathology of various complex diseases at a deeper granularity. Since existing functional genomic databases uniformly record the annotations at the gene-level, and rarely record the annotations at the isoform-level, differentiating isoform functions is more challenging than the traditional gene-level function prediction.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Several approaches have been proposed to differentiate the functions of isoforms. They generally follow the multi-instance learning paradigm by viewing each gene as a bag and the spliced isoforms as its instances, and push functions of bags onto instances. These approaches implicitly assume the collected annotations of genes are complete and only integrate multiple RNA-seq datasets. As such, they have compromised performance. We propose a data integrative solution (called DisoFun) to Differentiate isoform Functions with collaborative matrix factorization. DisoFun assumes the functional annotations of genes are aggregated from those of key isoforms. It collaboratively factorizes the isoform data matrix and gene-term data matrix (storing Gene Ontology annotations of genes) into low-rank matrices to simultaneously explore the latent key isoforms, and achieve function prediction by aggregating predictions to their originating genes. In addition, it leverages the PPI network and Gene Ontology structure to further coordinate the matrix factorization. Extensive experimental results show that DisoFun improves the area under the receiver operating characteristic curve and area under the precision-recall curve of existing solutions by at least 7.7 and 28.9%, respectively. We further investigate DisoFun on four exemplar genes (LMNA, ADAM15, BCL2L1 and CFLAR) with known functions at the isoform-level, and observed that DisoFun can differentiate functions of their isoforms with 90.5% accuracy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The code of DisoFun is available at mlda.swu.edu.cn\/codes.php?name=DisoFun.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz847","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T12:11:19Z","timestamp":1573560679000},"page":"1864-1871","source":"Crossref","is-referenced-by-count":30,"title":["Differentiating isoform functions with collaborative matrix factorization"],"prefix":"10.1093","volume":"36","author":[{"given":"Keyao","family":"Wang","sequence":"first","affiliation":[{"name":"College of Computer and Information Science, Southwest University , Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5890-0365","authenticated-orcid":false,"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Computer and Information Science, Southwest University , Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlotta","family":"Domeniconi","sequence":"additional","affiliation":[{"name":"Department of Computer Science, George Mason University , Fairfax, VA 22030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology , Thuwal 23955, SA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1667-6705","authenticated-orcid":false,"given":"Guoxian","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Computer and Information Science, Southwest University , Chongqing 400715, China"},{"name":"Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology , Thuwal 23955, SA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"2023060911595048200_btz847-B1","first-page":"577","author":"Andrews","year":"2003"},{"key":"2023060911595048200_btz847-B2","doi-asserted-by":"crossref","first-page":"i284","DOI":"10.1093\/bioinformatics\/btz367","article-title":"DIFFUSE: predicting isoform functions from sequences and expression profiles via deep learning","volume":"35","author":"Chen","year":"2019","journal-title":"Bioinformatics"},{"key":"2023060911595048200_btz847-B3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0004-3702(96)00034-3","article-title":"Solving the multiple instance problem with axis-parallel rectangles","volume":"89","author":"Dietterich","year":"1997","journal-title":"Artif. Intell"},{"key":"2023060911595048200_btz847-B4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1109\/TPAMI.2008.277","article-title":"Convex and semi-nonnegative matrix factorizations","volume":"32","author":"Ding","year":"2008","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell"},{"key":"2023060911595048200_btz847-B5","doi-asserted-by":"crossref","first-page":"e1003314","DOI":"10.1371\/journal.pcbi.1003314","article-title":"Systematically differentiating functions for alternatively spliced isoforms through integrating RNA-seq data","volume":"9","author":"Eksi","year":"2013","journal-title":"PLoS Comput. Biol"},{"key":"2023060911595048200_btz847-B6","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","year":"2012","journal-title":"Nature"},{"key":"2023060911595048200_btz847-B7","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1093\/bioinformatics\/btw366","article-title":"NegGOA: negative GO annotations selection using ontology structure","volume":"32","author":"Fu","year":"2016","journal-title":"Bioinformatics"},{"key":"2023060911595048200_btz847-B8","first-page":"D331","article-title":"Expansion of the Gene Ontology knowledgebase and resources","volume":"45","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023060911595048200_btz847-B9","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/2047-217X-3-4","article-title":"Understanding how and why the Gene Ontology and its annotations evolve: the GO within UniProt","volume":"3","author":"Huntley","year":"2014","journal-title":"Gigascience"},{"key":"2023060911595048200_btz847-B10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13059-016-1037-6","article-title":"An expanded evaluation of protein function prediction methods shows an improvement in accuracy","volume":"17","author":"Jiang","year":"2016","journal-title":"Genome Biol"},{"key":"2023060911595048200_btz847-B11","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023060911595048200_btz847-B12","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"2023060911595048200_btz847-B13","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/44565","article-title":"Learning the parts of objects by non-negative matrix factorization","volume":"401","author":"Lee","year":"1999","journal-title":"Nature"},{"key":"2023060911595048200_btz847-B14","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.tig.2014.05.005","article-title":"The emerging era of genomic data integration for analyzing splice isoform function","volume":"30","author":"Li","year":"2014","journal-title":"Trends Genet"},{"key":"2023060911595048200_btz847-B15","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1093\/nar\/gkt1362","article-title":"High-resolution functional annotation of human transcriptome: predicting isoform functions by a novel multiple instance-based label propagation method","volume":"42","author":"Li","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023060911595048200_btz847-B16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/embr.201338126","article-title":"Antagonistic functions of LMNA isoforms in energy expenditure and lifespan","volume":"15","author":"Lopez-Mejia","year":"2014","journal-title":"EMBO Rep"},{"key":"2023060911595048200_btz847-B17","first-page":"345","author":"Luo","year":"2017"},{"key":"2023060911595048200_btz847-B18","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/ng.259","article-title":"Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing","volume":"40","author":"Pan","year":"2008","journal-title":"Nat. Genet"},{"key":"2023060911595048200_btz847-B19","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1021\/acs.jproteome.5b00883","article-title":"Genome-wide functional annotation of human protein-coding splice variants using multiple instance learning","volume":"15","author":"Panwar","year":"2016","journal-title":"J.\u00a0Proteome Res"},{"key":"2023060911595048200_btz847-B20","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat. Biotechnol"},{"key":"2023060911595048200_btz847-B21","doi-asserted-by":"crossref","first-page":"8431","DOI":"10.1128\/MCB.00565-07","article-title":"Protein kinase C-dependent control of Bcl-x alternative splicing","volume":"27","author":"Revil","year":"2007","journal-title":"Mol. Cell. Biol"},{"key":"2023060911595048200_btz847-B22","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/82360","article-title":"A network of protein-protein interactions in yeast","volume":"18","author":"Schwikowski","year":"2000","journal-title":"Nat. Biotechnol"},{"key":"2023060911595048200_btz847-B23","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1093\/bioinformatics\/bty1017","article-title":"DeepIsoFun: a deep domain adaptation approach to predict isoform functions","volume":"35","author":"Shaw","year":"2019","journal-title":"Bioinformatics"},{"key":"2023060911595048200_btz847-B24","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1016\/j.biocel.2007.02.016","article-title":"Alternative splicing in cancer: noise, functional, or systematic?","volume":"39","author":"Skotheim","year":"2007","journal-title":"Int. J. Biochem. Cell Biol"},{"key":"2023060911595048200_btz847-B25","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/nmeth.2369","article-title":"Proteoform: a single term describing protein complexity","volume":"10","author":"Smith","year":"2013","journal-title":"Nat. Methods"},{"key":"2023060911595048200_btz847-B26","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13059-016-0940-1","article-title":"A benchmark for RNA-seq quantification pipelines","volume":"17","author":"Teng","year":"2016","journal-title":"Genome Biol"},{"key":"2023060911595048200_btz847-B27","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/nature07509","article-title":"Alternative isoform regulation in human tissue transcriptomes","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"2023060911595048200_btz847-B28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrg2484","article-title":"RNA-Seq: a revolutionary tool for transcriptomics","volume":"10","author":"Wang","year":"2009","journal-title":"Nat. Rev. Genet"},{"key":"2023060911595048200_btz847-B29","doi-asserted-by":"crossref","first-page":"1254806","DOI":"10.1126\/science.1254806","article-title":"The human splicing code reveals new insights into the genetic determinants of disease","volume":"347","author":"Xiong","year":"2015","journal-title":"Science"},{"key":"2023060911595048200_btz847-B30","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1186\/s12859-015-0713-y","article-title":"Predicting protein function via downward random walks on a gene ontology","volume":"16","author":"Yu","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"2023060911595048200_btz847-B31","first-page":"1","article-title":"Isoform function prediction based on bi-random walks on a heterogeneous network","volume":"99","author":"Yu","year":"2019","journal-title":"Bioinformatics"},{"key":"2023060911595048200_btz847-B32","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1016\/j.artint.2011.10.002","article-title":"Multi-instance multi-label learning","volume":"176","author":"Zhou","year":"2012","journal-title":"Artif. Intell"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz847\/30739364\/btz847.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/6\/1864\/50554065\/bioinformatics_36_6_1864.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/6\/1864\/50554065\/bioinformatics_36_6_1864.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T12:03:39Z","timestamp":1686312219000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/6\/1864\/5625622"}},"subtitle":[],"editor":[{"given":"Jonathan","family":"Wren","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":32,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz847","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,3,15]]},"published":{"date-parts":[[2019,11,14]]}}}