{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T07:14:34Z","timestamp":1772176474169,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011189","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000}}],"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T00:00:00Z","timestamp":1710374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004853","name":"Chinese University of Hong Kong","doi-asserted-by":"publisher","award":["4930181"],"award-info":[{"award-number":["4930181"]}],"id":[{"id":"10.13039\/501100004853","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021366","name":"Faculty of Science, Chinese University of Hong Kong","doi-asserted-by":"publisher","award":["CRIMS 4620033"],"award-info":[{"award-number":["CRIMS 4620033"]}],"id":[{"id":"10.13039\/501100021366","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004853","name":"Chinese University of Hong Kong","doi-asserted-by":"publisher","award":["4053540, 4053586"],"award-info":[{"award-number":["4053540, 4053586"]}],"id":[{"id":"10.13039\/501100004853","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["GRF 14301120, GRF 14300923"],"award-info":[{"award-number":["GRF 14301120, GRF 14300923"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>RNA sequencing (RNA-Seq) is widely used to capture transcriptome dynamics across tissues, biological entities, and conditions. Currently, few or no methods can handle multiple biological variables (e.g., tissues\/ phenotypes) and their interactions simultaneously, while also achieving dimension reduction (DR).<\/jats:p>\n                  <jats:p>\n                    We propose INSIDER, a general and flexible statistical framework based on matrix factorization, which is freely available at\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/kai0511\/insider\" xlink:type=\"simple\">https:\/\/github.com\/kai0511\/insider<\/jats:ext-link>\n                    . INSIDER decomposes variation from different biological variables and their interactions into a shared low-rank latent space. Particularly, it introduces the elastic net penalty to induce sparsity while considering the grouping effects of genes. It can achieve DR of high-dimensional data (of &gt; = 3 dimensions), as opposed to conventional methods (e.g., PCA\/NMF) which generally only handle 2D data (e.g., sample \u00d7 expression). Besides, it enables computing \u2019adjusted\u2019 expression profiles for specific biological variables while controlling variation from other variables. INSIDER is computationally efficient and accommodates missing data. INSIDER also performed similarly or outperformed a close competing method, SDA, as shown in simulations and can handle complex missing data in RNA-Seq data. Moreover, unlike SDA, it can be used when the data cannot be structured into a tensor. Lastly, we demonstrate its usefulness via real data analysis, including clustering donors for disease subtyping, revealing neuro-development trajectory using the BrainSpan data, and uncovering biological processes contributing to variables of interest (e.g., disease status and tissue) and their interactions.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011189","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T13:50:15Z","timestamp":1710424215000},"page":"e1011189","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["INSIDER: Interpretable sparse matrix decomposition for RNA expression data analysis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2774-6326","authenticated-orcid":true,"given":"Kai","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuichan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-7270","authenticated-orcid":true,"given":"Pak Chung","family":"Sham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hon-Cheong","family":"So","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9301-947X","authenticated-orcid":true,"given":"Zhixiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,3,14]]},"reference":[{"issue":"1","key":"pgen.1011189.ref001","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrg2484","article-title":"RNA-Seq: a revolutionary tool for transcriptomics","volume":"10","author":"Z Wang","year":"2009","journal-title":"Nature reviews genetics"},{"issue":"6","key":"pgen.1011189.ref002","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The genotype-tissue expression (GTEx) project","volume":"45","author":"J Lonsdale","year":"2013","journal-title":"Nat Genet"},{"issue":"7495","key":"pgen.1011189.ref003","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nature13185","article-title":"Transcriptional landscape of the prenatal human brain","volume":"508","author":"JA Miller","year":"2014","journal-title":"Nature"},{"issue":"12","key":"pgen.1011189.ref004","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1038\/nn.4156","article-title":"The psychencode project","volume":"18","author":"S Akbarian","year":"2015","journal-title":"Nat Neurosci"},{"issue":"7351","key":"pgen.1011189.ref005","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature10110","article-title":"Transcriptomic analysis of autistic brain reveals convergent molecular pathology","volume":"474","author":"I Voineagu","year":"2011","journal-title":"Nature"},{"issue":"4","key":"pgen.1011189.ref006","doi-asserted-by":"crossref","first-page":"273","DOI":"10.5607\/en.2015.24.4.273","article-title":"Characteristics of brains in autism spectrum disorder: structure, function and connectivity across the lifespan","volume":"24","author":"S Ha","year":"2015","journal-title":"Experimental neurobiology"},{"issue":"2","key":"pgen.1011189.ref007","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0896-6273(00)00115-X","article-title":"Autism spectrum disorders","volume":"28","author":"C Lord","year":"2000","journal-title":"Neuron"},{"issue":"7","key":"pgen.1011189.ref008","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pgen.1011189.ref009","first-page":"1","article-title":"Differential expression analysis for sequence count data","author":"S Anders","year":"2010","journal-title":"Nature Precedings"},{"issue":"51","key":"pgen.1011189.ref010","doi-asserted-by":"crossref","first-page":"14662","DOI":"10.1073\/pnas.1617317113","article-title":"Simultaneous dimension reduction and adjustment for confounding variation","volume":"113","author":"Z Lin","year":"2016","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pgen.1011189.ref011","article-title":"Batch effects correction with unknown subtypes","author":"X Luo","year":"2018","journal-title":"Journal of the American Statistical Association"},{"issue":"1","key":"pgen.1011189.ref012","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"WE Johnson","year":"2007","journal-title":"Biostatistics"},{"issue":"6755","key":"pgen.1011189.ref013","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":"DD Lee","year":"1999","journal-title":"Nature"},{"issue":"1","key":"pgen.1011189.ref014","first-page":"1","article-title":"scINSIGHT for interpreting single-cell gene expression from biologically heterogeneous data","volume":"23","author":"K Qian","year":"2022","journal-title":"Genome Biol"},{"issue":"11","key":"pgen.1011189.ref015","doi-asserted-by":"crossref","first-page":"3632","DOI":"10.1038\/s41596-020-0391-8","article-title":"Jointly defining cell types from multiple single-cell datasets using LIGER","volume":"15","author":"J Liu","year":"2020","journal-title":"Nature protocols"},{"issue":"10","key":"pgen.1011189.ref016","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.tig.2018.07.003","article-title":"Enter the matrix: factorization uncovers knowledge from omics","volume":"34","author":"GL Stein-O\u2019Brien","year":"2018","journal-title":"Trends in Genetics"},{"issue":"3","key":"pgen.1011189.ref017","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1137\/07070111X","article-title":"Tensor decompositions and applications","volume":"51","author":"TG Kolda","year":"2009","journal-title":"SIAM Rev"},{"issue":"1","key":"pgen.1011189.ref018","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.csda.2010.05.020","article-title":"Hierarchical multilinear models for multiway data","volume":"55","author":"PD Hoff","year":"2011","journal-title":"Comput Stat Data Anal"},{"issue":"1","key":"pgen.1011189.ref019","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1752-0509-2-63","article-title":"Multiway modeling and analysis in stem cell systems biology","volume":"2","author":"B Yener","year":"2008","journal-title":"BMC systems biology"},{"issue":"9","key":"pgen.1011189.ref020","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/ng.3624","article-title":"Tensor decomposition for multiple-tissue gene expression experiments","volume":"48","author":"V Hore","year":"2016","journal-title":"Nat Genet"},{"issue":"2","key":"pgen.1011189.ref021","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1467-9868.2005.00503.x","article-title":"Regularization and variable selection via the elastic net","volume":"67","author":"H Zou","year":"2005","journal-title":"Journal of the royal statistical society: series B (statistical methodology)"},{"issue":"12","key":"pgen.1011189.ref022","doi-asserted-by":"crossref","first-page":"4164","DOI":"10.1073\/pnas.0308531101","article-title":"Metagenes and molecular pattern discovery using matrix factorization","volume":"101","author":"J Brunet","year":"2004","journal-title":"Proceedings of the national academy of sciences"},{"issue":"7370","key":"pgen.1011189.ref023","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature10523","article-title":"Spatio-temporal transcriptome of the human brain","volume":"478","author":"HJ Kang","year":"2011","journal-title":"Nature"},{"issue":"4","key":"pgen.1011189.ref024","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s11065-010-9148-4","article-title":"The basics of brain development","volume":"20","author":"J Stiles","year":"2010","journal-title":"Neuropsychol Rev"},{"issue":"3","key":"pgen.1011189.ref025","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1017\/S095457941800072X","article-title":"Prenatal neural origins of infant motor development: Associations between fetal brain and infant motor development","volume":"30","author":"ME Thomason","year":"2018","journal-title":"Dev Psychopathol"},{"issue":"3","key":"pgen.1011189.ref026","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jadohealth.2009.05.016","article-title":"Adolescent maturity and the brain: the promise and pitfalls of neuroscience research in adolescent health policy","volume":"45","author":"SB Johnson","year":"2009","journal-title":"Journal of adolescent health"},{"issue":"2","key":"pgen.1011189.ref027","doi-asserted-by":"crossref","first-page":"a016824","DOI":"10.1101\/cshperspect.a016824","article-title":"Synaptic signaling in learning and memory","volume":"8","author":"MB Kennedy","year":"2016","journal-title":"Cold Spring Harbor perspectives in biology"},{"key":"pgen.1011189.ref028","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.expneurol.2004.03.027","article-title":"Development of neurotransmitter systems during critical periods","volume":"190","author":"E Herlenius","year":"2004","journal-title":"Exp Neurol"},{"issue":"31","key":"pgen.1011189.ref029","doi-asserted-by":"crossref","first-page":"8161","DOI":"10.1523\/JNEUROSCI.1554-07.2007","article-title":"The role of the dorsal striatum in reward and decision-making","volume":"27","author":"BW Balleine","year":"2007","journal-title":"Journal of Neuroscience"},{"key":"pgen.1011189.ref030","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3389\/fncel.2020.00239","article-title":"The CNS myelin proteome: deep profile and persistence after post-mortem delay","volume":"14","author":"O Jahn","year":"2020","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"pgen.1011189.ref031","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s12035-009-8071-2","article-title":"Myelin proteomics: molecular anatomy of an insulating sheath","volume":"40","author":"O Jahn","year":"2009","journal-title":"Mol Neurobiol"},{"issue":"9","key":"pgen.1011189.ref032","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1523\/JNEUROSCI.1899-11.2012","article-title":"The importance of the NRG-1\/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders","volume":"32","author":"A Shamir","year":"2012","journal-title":"Journal of Neuroscience"},{"issue":"1","key":"pgen.1011189.ref033","doi-asserted-by":"crossref","first-page":"e1004031","DOI":"10.1371\/journal.pcbi.1004031","article-title":"The formation of multi-synaptic connections by the interaction of synaptic and structural plasticity and their functional consequences","volume":"11","author":"M Fauth","year":"2015","journal-title":"PLoS computational biology"},{"key":"pgen.1011189.ref034","doi-asserted-by":"crossref","first-page":"e31126","DOI":"10.7554\/eLife.31126","article-title":"Neuropathological and transcriptomic characteristics of the aged brain","volume":"6","author":"JA Miller","year":"2017","journal-title":"Elife"},{"issue":"3","key":"pgen.1011189.ref035","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1515\/revneuro-2019-0058","article-title":"Synaptic plasticity in Alzheimer\u2019s disease and healthy aging","volume":"31","author":"DMC Torres","year":"2020","journal-title":"Rev Neurosci"},{"issue":"10","key":"pgen.1011189.ref036","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1002\/jnr.22392","article-title":"Synapse loss in dementias","volume":"88","author":"R Clare","year":"2010","journal-title":"J Neurosci Res"},{"issue":"1","key":"pgen.1011189.ref037","first-page":"1","article-title":"The clinical promise of biomarkers of synapse damage or loss in Alzheimer\u2019s disease","volume":"12","author":"M Colom-Cadena","year":"2020","journal-title":"Alzheimer\u2019s research & therapy"},{"issue":"2","key":"pgen.1011189.ref038","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3390\/life13020373","article-title":"Alzheimer\u2019s disease and impaired bone microarchitecture, regeneration and potential genetic links","volume":"13","author":"M Zhang","year":"2023","journal-title":"Life"},{"issue":"11","key":"pgen.1011189.ref039","first-page":"1","article-title":"APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress","volume":"9","author":"J Pan","year":"2018","journal-title":"Cell death & disease"},{"issue":"6","key":"pgen.1011189.ref040","first-page":"835","article-title":"Mapping the Metallo-maze to Memory Loss: Does Neuronal Metal Ion Deficiency Contribute to Dementia? Yakugaku Zasshi","volume":"141","author":"MJ Hackett","year":"2021","journal-title":"Journal of the Pharmaceutical Society of Japan"},{"issue":"1","key":"pgen.1011189.ref041","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41597-019-0183-6","article-title":"CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder","volume":"6","author":"GE Hoffman","year":"2019","journal-title":"Scientific data"},{"issue":"2","key":"pgen.1011189.ref042","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1467-9868.2011.01004.x","article-title":"Strong rules for discarding predictors in lasso-type problems","volume":"74","author":"R Tibshirani","year":"2012","journal-title":"Journal of the Royal Statistical Society: Series B (Statistical Methodology)"},{"issue":"8","key":"pgen.1011189.ref043","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1109\/MC.2009.263","article-title":"Matrix factorization techniques for recommender systems","volume":"42","author":"Y Koren","year":"2009","journal-title":"Computer"},{"issue":"1","key":"pgen.1011189.ref044","first-page":"3367","article-title":"Matrix completion and low-rank SVD via fast alternating least squares","volume":"16","author":"T Hastie","year":"2015","journal-title":"The Journal of Machine Learning Research"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1011189","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1011189","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T13:35:35Z","timestamp":1711460135000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1011189"}},"subtitle":[],"editor":[{"given":"Xiaofeng","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,3,14]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1011189","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.11.10.515904","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,14]]}}}