{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T15:15:47Z","timestamp":1771341347262,"version":"3.50.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T00:00:00Z","timestamp":1645401600000},"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\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2017YFA0505500"],"award-info":[{"award-number":["2017YFA0505500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Strategic Priority Research Program of the Chinese Academy of Sciences","award":["XDB38040400"],"award-info":[{"award-number":["XDB38040400"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31930022"],"award-info":[{"award-number":["31930022"]}],"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":["12131020"],"award-info":[{"award-number":["12131020"]}],"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":["12026608"],"award-info":[{"award-number":["12026608"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>Single-cell RNA sequencing (scRNA-seq) technology provides the possibility to study cell heterogeneity and cell development on the resolution of individual cells. Arguably, three of the most important computational targets on scRNA-seq data analysis are data visualization, cell clustering and trajectory inference. Although a substantial number of algorithms have been developed, most of them do not treat the three targets in a systematic or consistent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this article, we propose an efficient scRNA-seq analysis framework, which accomplishes the three targets consistently by non-uniform \u03b5\u2212neighborhood (NEN) network. First, a network is generated by our NEN method, which combines the advantages of both k-nearest neighbors (KNN) and \u03b5\u2212neighborhood (EN) to represent the manifold that data points reside in gene space. Then from such a network, we use its layout, its community and further its shortest path to achieve the purpose of scRNA-seq data visualization, clustering and trajectory inference. The results on both synthetic and real datasets indicate that our NEN method not only can visually provide the global topological structure of a dataset accurately compared with t-SNE (t-Distributed Stochastic Neighbor Embedding) and UMAP (Uniform Manifold Approximation and Projection), but also has superior performances on clustering and pseudotime ordering of cells over the existing approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>This analysis method has been made into a python package called ccnet and is freely available at https:\/\/github.com\/Just-Jia\/ccNet.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btac114","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T12:09:20Z","timestamp":1645099760000},"page":"2459-2465","source":"Crossref","is-referenced-by-count":3,"title":["<b>Single-cell RNA sequencing data analysis based on non-uniform<\/b>\u03b5\u2212<b>neighborhood network<\/b>"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-2676","authenticated-orcid":false,"given":"Junbo","family":"Jia","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , Hangzhou 310024, China"},{"name":"Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences , Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luonan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , Hangzhou 310024, China"},{"name":"Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences , Shanghai 200031, China"},{"name":"School of Life Science and Technology, ShanghaiTech University , Shanghai 201210, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,2,21]]},"reference":[{"key":"2023041402555259500_","volume-title":"Modern Multidimensional Scaling: Theory and Applications","author":"Borg","year":"2005"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/srep00342","article-title":"Detecting early-warning signals for sudden deterioration of complex diseases by dynamical network biomarkers","volume":"2","author":"Chen","year":"2012","journal-title":"Sci. Rep"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nmeth.2769","article-title":"The promise of single-cell sequencing","volume":"11","author":"Eberwine","year":"2014","journal-title":"Nat. Methods"},{"key":"2023041402555259500_","volume-title":"Computational Topology: An Introduction","author":"Edelsbrunner","year":"2010"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.devcel.2010.02.012","article-title":"Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst","volume":"18","author":"Guo","year":"2010","journal-title":"Dev. Cell"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nmeth.3971","article-title":"Diffusion pseudotime robustly reconstructs lineage branching","volume":"13","author":"Haghverdi","year":"2016","journal-title":"Nat. Methods"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nbt.4091","article-title":"Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors","volume":"36","author":"Haghverdi","year":"2018","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/wics.1343","article-title":"Visualizing large graphs","volume":"7","author":"Hu","year":"2015","journal-title":"Wiley Interdiscip. Rev. Comput. Stat"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"e98679","DOI":"10.1371\/journal.pone.0098679","article-title":"ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software","volume":"9","author":"Jacomy","year":"2014","journal-title":"PLoS One"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1093\/nar\/gkw430","article-title":"TSCAN: pseudo-time reconstruction and evaluation in single-cell RNA-seq analysis","volume":"44","author":"Ji","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1145\/321765.321768","article-title":"A note on Dijkstra\u2019s shortest path algorithm","volume":"20","author":"Johnson","year":"1973","journal-title":"J. ACM"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.cell.2015.05.047","article-title":"Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis","volume":"162","author":"Levine","year":"2015","journal-title":"Cell"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"e8746","DOI":"10.15252\/msb.20188746","article-title":"Current best practices in single-cell RNA-seq analysis: a tutorial","volume":"15","author":"Luecken","year":"2019","journal-title":"Mol. Syst. Biol"},{"key":"2023041402555259500_","article-title":"Umap: uniform manifold approximation and projection for dimension reduction","author":"McInnes","year":"2018"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1038\/s41587-019-0336-3","article-title":"Visualizing structure and transitions in high-dimensional biological data","volume":"37","author":"Moon","year":"2019","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198805090.001.0001","volume-title":"Networks","author":"Newman","year":"2018"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"026102","DOI":"10.1103\/PhysRevE.79.026102","article-title":"Modularity clustering is force-directed layout","volume":"79","author":"Noack","year":"2009","journal-title":"Phys. Rev. E Stat. Nonlin. Soft. Matter. Phys"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/j.cell.2015.11.013","article-title":"Transcriptional heterogeneity and lineage commitment in myeloid progenitors","volume":"163","author":"Paul","year":"2015","journal-title":"Cell"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/nmeth.4402","article-title":"Reversed graph embedding resolves complex single-cell trajectories","volume":"14","author":"Qiu","year":"2017","journal-title":"Nat. Methods"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/nbt0308-303","article-title":"What is principal component analysis?","volume":"26","author":"Ringn\u00e9r","year":"2008","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1126\/science.290.5500.2323","article-title":"Nonlinear dimensionality reduction by locally linear embedding","volume":"290","author":"Roweis","year":"2000","journal-title":"Science"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41587-019-0071-9","article-title":"A comparison of single-cell trajectory inference methods","volume":"37","author":"Saelens","year":"2019","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/nbt.3569","article-title":"Wishbone identifies bifurcating developmental trajectories from single-cell data","volume":"34","author":"Setty","year":"2016","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12864-018-4772-0","article-title":"Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics","volume":"19","author":"Street","year":"2018","journal-title":"BMC Genomics"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nmeth.1315","article-title":"mRNA-seq whole-transcriptome analysis of a single cell","volume":"6","author":"Tang","year":"2009","journal-title":"Nat. Methods"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1126\/science.290.5500.2319","article-title":"A global geometric framework for nonlinear dimensionality reduction","volume":"290","author":"Tenenbaum","year":"2000","journal-title":"Science"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-41695-z","article-title":"From Louvain to Leiden: guaranteeing well-connected communities","volume":"9","author":"Traag","year":"2019","journal-title":"Sci. Rep"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"Pseudo-temporal ordering of individual cells reveals dynamics and regulators of cell fate decisions","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat. Biotechnol"},{"key":"2023041402555259500_","article-title":"Visualizing data using t-SNE","volume":"9, 2579\u20132605","author":"Van der Maaten","year":"2008","journal-title":"J. Mach. Learn. Res"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1093\/bioinformatics\/btx792","article-title":"Spring: a kinetic interface for visualizing high dimensional single-cell expression data","volume":"34","author":"Weinreb","year":"2018","journal-title":"Bioinformatics"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-016-0975-3","article-title":"Slicer: inferring branched, nonlinear cellular trajectories from single cell RNA-seq data","volume":"17","author":"Welch","year":"2016","journal-title":"Genome Biol"},{"key":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"1","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":"2023041402555259500_","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13059-019-1663-x","article-title":"PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells","volume":"20","author":"Wolf","year":"2019","journal-title":"Genome Biol"},{"key":"2023041402555259500_","first-page":"1","article-title":"Dynamic network biomarker indicates pulmonary metastasis at the tipping point of hepatocellular carcinoma","volume":"9","author":"Yang","year":"2018","journal-title":"Nat. Commun"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btac114\/42675470\/btac114.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/9\/2459\/49874602\/btac114.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/9\/2459\/49874602\/btac114.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T17:17:06Z","timestamp":1700241426000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/38\/9\/2459\/6533440"}},"subtitle":[],"editor":[{"given":"Anthony","family":"Mathelier","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,21]]},"references-count":36,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,4,28]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btac114","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5,1]]},"published":{"date-parts":[[2022,2,21]]}}}