{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T02:06:11Z","timestamp":1767924371982,"version":"3.49.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012877","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000}}],"reference-count":93,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370233"],"award-info":[{"award-number":["82370233"]}],"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":["82341122"],"award-info":[{"award-number":["82341122"]}],"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":["92369116"],"award-info":[{"award-number":["92369116"]}],"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":["82300133"],"award-info":[{"award-number":["82300133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012542","name":"Sichuan Province Science and Technology Support Program","doi-asserted-by":"publisher","award":["2021YFS0027"],"award-info":[{"award-number":["2021YFS0027"]}],"id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2017YFA0106800"],"award-info":[{"award-number":["2017YFA0106800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Neutrophils, an essential innate immune cell type with a short lifespan, rely on continuous replenishment from bone marrow (BM) precursors. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the molecular regulators involved in the differentiation process remain poorly understood. Here we developed a random forest-based machine-learning pipeline, NeuRGI (Neutrophil Regulatory Gene Identifier), which utilized Positive-Unlabeled Learning (PU-learning) and neural network-based <jats:italic>in silico<\/jats:italic> gene knockout to identify neutrophil regulators. We interrogated features including gene expression dynamics, physiological characteristics, pathological relatedness, and gene conservation for the model training. Our identified pipeline leads to identifying Mitogen-Activated Protein Kinase-4 (<jats:italic>MAP4K4<\/jats:italic>) as a novel neutrophil differentiation regulator. The loss of MAP4K4 in hematopoietic stem cells and progenitors in mice induced neutropenia and impeded the differentiation of neutrophils in the bone marrow. By modulating the phosphorylation level of proteins involved in cell apoptosis, such as STAT5A, MAP4K4 delicately regulates cell apoptosis during the process of neutrophil differentiation. Our work presents a novel regulatory mechanism in neutrophil differentiation and provides a robust prediction model that can be applied to other cellular differentiation processes.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012877","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T17:39:36Z","timestamp":1742233176000},"page":"e1012877","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Machine learning-based prediction reveals kinase MAP4K4 regulates neutrophil differentiation through phosphorylating apoptosis-related proteins"],"prefix":"10.1371","volume":"21","author":[{"given":"Guihua","family":"Wang","sequence":"first","affiliation":[]},{"given":"Dan","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Zhifeng","family":"He","sequence":"additional","affiliation":[]},{"given":"Bin","family":"Mao","sequence":"additional","affiliation":[]},{"given":"Xiao","family":"Hu","sequence":"additional","affiliation":[]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[]},{"given":"Qingxin","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Zhen","family":"Zhou","sequence":"additional","affiliation":[]},{"given":"Yating","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Kepan","family":"Linghu","sequence":"additional","affiliation":[]},{"given":"Chao","family":"Tang","sequence":"additional","affiliation":[]},{"given":"Zijie","family":"Xu","sequence":"additional","affiliation":[]},{"given":"Defu","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Junwei","family":"Song","sequence":"additional","affiliation":[]},{"given":"Huiying","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Yishan","family":"Lin","sequence":"additional","affiliation":[]},{"given":"Ruihan","family":"Li","sequence":"additional","affiliation":[]},{"given":"Jing-Wen","family":"Lin","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1083-9729","authenticated-orcid":true,"given":"Lu","family":"Chen","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"issue":"3","key":"pcbi.1012877.ref001","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil 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Doncevic","year":"2023","journal-title":"Bioinformatics"},{"issue":"9","key":"pcbi.1012877.ref014","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1242\/dev.128.9.1559","article-title":"Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK)","volume":"128","author":"Y Xue","year":"2001","journal-title":"Development"},{"issue":"7544","key":"pcbi.1012877.ref015","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nature14323","article-title":"MAP4K4 regulates integrin-FERM binding to control endothelial cell motility","volume":"519","author":"P Vitorino","year":"2015","journal-title":"Nature"},{"issue":"45","key":"pcbi.1012877.ref016","doi-asserted-by":"crossref","first-page":"eaay2245","DOI":"10.1126\/sciimmunol.aay2245","article-title":"MAP4K4 negatively regulates CD8 T cell-mediated antitumor and antiviral immunity","volume":"5","author":"E Esen","year":"2020","journal-title":"Sci 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Wang","year":"2021","journal-title":"Blood"},{"issue":"6204","key":"pcbi.1012877.ref020","doi-asserted-by":"crossref","first-page":"1251033","DOI":"10.1126\/science.1251033","article-title":"Transcriptional diversity during lineage commitment of human blood progenitors","volume":"345","author":"L Chen","year":"2014","journal-title":"Science"},{"issue":"6679","key":"pcbi.1012877.ref021","doi-asserted-by":"crossref","first-page":"eadf6493","DOI":"10.1126\/science.adf6493","article-title":"Deterministic reprogramming of neutrophils within tumors","volume":"383","author":"MSF Ng","year":"2024","journal-title":"Science"},{"issue":"8","key":"pcbi.1012877.ref022","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1038\/nprot.2009.97","article-title":"Mapping identifiers for the integration of genomic datasets with the R\/Bioconductor package biomaRt","volume":"4","author":"S Durinck","year":"2009","journal-title":"Nat 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conserved elements in vertebrate, insect, worm, and yeast genomes","volume":"15","author":"A Siepel","year":"2005","journal-title":"Genome Res"},{"issue":"1","key":"pcbi.1012877.ref027","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1038\/s41467-021-22973-9","article-title":"The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments","volume":"12","author":"R Grieshaber-Bouyer","year":"2021","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1012877.ref028","doi-asserted-by":"crossref","first-page":"8133","DOI":"10.1038\/s41467-023-43573-9","article-title":"Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts","volume":"14","author":"NS Hackert","year":"2023","journal-title":"Nat Commun"},{"issue":"3","key":"pcbi.1012877.ref029","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/JLB.1RU1219-504RR","article-title":"Transcriptional regulation of neutrophil differentiation and function during inflammation","volume":"107","author":"Z Ai","year":"2020","journal-title":"J Leukoc Biol"},{"issue":"10","key":"pcbi.1012877.ref030","doi-asserted-by":"crossref","first-page":"e0276460","DOI":"10.1371\/journal.pone.0276460","article-title":"Revealing key regulators of neutrophil function during inflammation by re-analysing single-cell RNA-seq","volume":"17","author":"Z Ai","year":"2022","journal-title":"PLoS One"},{"issue":"8","key":"pcbi.1012877.ref031","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1002\/for.3003","article-title":"Deep learning on mixed frequency data","volume":"42","author":"Q Xu","year":"2023","journal-title":"J Forecast"},{"key":"pcbi.1012877.ref032","unstructured":"Ryan JA UJ. quantmod: Quantitative Financial Modelling Framework. R Packag version 04261. 2025."},{"issue":"1","key":"pcbi.1012877.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1055\/s-2008-1039060","article-title":"Neutrophil apoptosis by Fas\/FasL: harmful or advantageous in cardiac surgery?","volume":"57","author":"P Kunes","year":"2009","journal-title":"Thorac Cardiovasc Surg"},{"issue":"33","key":"pcbi.1012877.ref034","doi-asserted-by":"crossref","first-page":"16513","DOI":"10.1073\/pnas.1821601116","article-title":"STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation","volume":"116","author":"S Nepal","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pcbi.1012877.ref035","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1159\/000430197","article-title":"Interleukin-17 stimulates STAT3-mediated endothelial cell activation for neutrophil recruitment","volume":"36","author":"S Yuan","year":"2015","journal-title":"Cell Physiol Biochem"},{"issue":"6","key":"pcbi.1012877.ref036","doi-asserted-by":"crossref","first-page":"954","DOI":"10.4049\/jimmunol.2200705","article-title":"DNAM-1 immunoreceptor protects mice from concanavalin A-induced acute liver injury by reducing neutrophil infiltration","volume":"211","author":"S Matsuo","year":"2023","journal-title":"J Immunol"},{"issue":"6","key":"pcbi.1012877.ref037","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.4049\/jimmunol.1201114","article-title":"The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions","volume":"189","author":"SK Raghuwanshi","year":"2012","journal-title":"J Immunol"},{"issue":"11","key":"pcbi.1012877.ref038","first-page":"3006-3021.e17","article-title":"Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases","volume":"184","author":"M Ota","year":"2021","journal-title":"Cell"},{"key":"pcbi.1012877.ref039","doi-asserted-by":"crossref","first-page":"150051","DOI":"10.1038\/sdata.2015.51","article-title":"De novo transcriptome profiling of highly purified human lymphocytes primary cells","volume":"2","author":"RJP Bonnal","year":"2015","journal-title":"Sci Data"},{"issue":"5","key":"pcbi.1012877.ref040","first-page":"833-845.e5","article-title":"Dissecting ELANE neutropenia pathogenicity by human HSC gene editing","volume":"28","author":"S Rao","year":"2021","journal-title":"Cell Stem Cell"},{"issue":"1","key":"pcbi.1012877.ref041","doi-asserted-by":"crossref","first-page":"104257","DOI":"10.1016\/j.drudis.2024.104257","article-title":"Targeting spleen tyrosine kinase (SYK): structure, mechanisms and drug discovery","volume":"30","author":"S Zhang","year":"2025","journal-title":"Drug Discov Today"},{"issue":"6884","key":"pcbi.1012877.ref042","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/417091a","article-title":"Neutrophil elastase targets virulence factors of enterobacteria","volume":"417","author":"Y Weinrauch","year":"2002","journal-title":"Nature"},{"issue":"13","key":"pcbi.1012877.ref043","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1182\/blood-2010-10-311704","article-title":"Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane","volume":"117","author":"S Nanua","year":"2011","journal-title":"Blood"},{"issue":"10","key":"pcbi.1012877.ref044","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.4049\/jimmunol.1500461","article-title":"Syk tyrosine kinase is critical for B cell antibody responses and memory B cell survival","volume":"194","author":"JA Ackermann","year":"2015","journal-title":"J Immunol"},{"issue":"4","key":"pcbi.1012877.ref045","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1182\/blood-2007-07-100115","article-title":"SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma","volume":"111","author":"L Chen","year":"2008","journal-title":"Blood"},{"issue":"4","key":"pcbi.1012877.ref046","doi-asserted-by":"crossref","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","article-title":"MAGMA: generalized gene-set analysis of GWAS data","volume":"11","author":"CA de Leeuw","year":"2015","journal-title":"PLoS Comput Biol"},{"issue":"10","key":"pcbi.1012877.ref047","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":"X Qiu","year":"2017","journal-title":"Nat Methods"},{"issue":"10","key":"pcbi.1012877.ref048","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/j.cellsig.2008.06.018","article-title":"G-CSF stimulates Jak2-dependent Gab2 phosphorylation leading to Erk1\/2 activation and cell proliferation","volume":"20","author":"L Wang","year":"2008","journal-title":"Cell Signal"},{"issue":"9","key":"pcbi.1012877.ref049","doi-asserted-by":"crossref","first-page":"e232","DOI":"10.1161\/CIRCRESAHA.120.317200","article-title":"Dynamics of cardiac neutrophil diversity in murine myocardial infarction","volume":"127","author":"E Vafadarnejad","year":"2020","journal-title":"Circ Res"},{"issue":"5","key":"pcbi.1012877.ref050","doi-asserted-by":"crossref","first-page":"e13169","DOI":"10.14814\/phy2.13169","article-title":"CLIC1 null mice demonstrate a role for CLIC1 in macrophage superoxide production and tissue injury","volume":"5","author":"B Ulmasov","year":"2017","journal-title":"Physiol Rep"},{"key":"pcbi.1012877.ref051","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.crimmu.2020.01.001","article-title":"Myeloid cell responsiveness to interferon-gamma is sufficient for initial resistance to Listeria monocytogenes","volume":"1","author":"EM Eshleman","year":"2020","journal-title":"Curr Res Immunol"},{"key":"pcbi.1012877.ref052","doi-asserted-by":"crossref","first-page":"155077","DOI":"10.1016\/j.cyto.2020.155077","article-title":"The mechanism of Tyk2 deficiency-induced immunosuppression in mice involves robust IL-10 production in macrophages","volume":"130","author":"K Hirashima","year":"2020","journal-title":"Cytokine"},{"issue":"41","key":"pcbi.1012877.ref053","doi-asserted-by":"crossref","first-page":"37868","DOI":"10.1074\/jbc.M103381200","article-title":"SHP1 protein-tyrosine phosphatase inhibits gp91PHOX and p67PHOX expression by inhibiting interaction of PU.1, IRF1, interferon consensus sequence-binding protein, and CREB-binding protein with homologous Cis elements in the CYBB and NCF2 genes","volume":"276","author":"B Kautz","year":"2001","journal-title":"J Biol Chem"},{"issue":"9","key":"pcbi.1012877.ref054","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1002\/art.41704","article-title":"Neutrophil phospholipase c\u03b32 drives autoantibody-induced arthritis through the generation of the inflammatory microenvironment","volume":"73","author":"K Futosi","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"pcbi.1012877.ref055","doi-asserted-by":"crossref","first-page":"1304529","DOI":"10.3389\/fimmu.2023.1304529","article-title":"Neutrophil infiltration associated genes on the prognosis and tumor immune microenvironment of lung adenocarcinoma","volume":"14","author":"R Liu","year":"2023","journal-title":"Front Immunol"},{"key":"pcbi.1012877.ref056","doi-asserted-by":"crossref","first-page":"1119064","DOI":"10.3389\/fimmu.2023.1119064","article-title":"Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population","volume":"14","author":"A Kawasaki","year":"2023","journal-title":"Front Immunol"},{"key":"pcbi.1012877.ref057","first-page":"41","article-title":"The HL60 cell line: a model system for studying human myeloid cell differentiation","volume":"9","author":"GD Birnie","year":"1988","journal-title":"Br J Cancer Suppl"},{"issue":"7","key":"pcbi.1012877.ref058","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"T Stuart","year":"2019","journal-title":"Cell"},{"issue":"6","key":"pcbi.1012877.ref059","doi-asserted-by":"crossref","first-page":"100498","DOI":"10.1016\/j.crmeth.2023.100498","article-title":"hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data","volume":"3","author":"S Morabito","year":"2023","journal-title":"Cell Rep 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Cardoso-Moreira","year":"2019","journal-title":"Nature"},{"issue":"1","key":"pcbi.1012877.ref063","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1038\/s41467-023-38389-6","article-title":"Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways","volume":"14","author":"P Demela","year":"2023","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1012877.ref064","doi-asserted-by":"crossref","first-page":"8366","DOI":"10.1038\/s41598-023-35597-4","article-title":"A publication-wide association study (PWAS), historical language models to prioritise novel therapeutic drug targets","volume":"13","author":"D Narganes-Carl\u00f3n","year":"2023","journal-title":"Sci Rep"},{"issue":"5675","key":"pcbi.1012877.ref065","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1126\/science.1098119","article-title":"Ultraconserved elements in the human genome","volume":"304","author":"G Bejerano","year":"2004","journal-title":"Science"},{"issue":"1","key":"pcbi.1012877.ref066","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: from bench to clinic","volume":"6","author":"X Hu","year":"2021","journal-title":"Signal Transduct Target Ther"},{"issue":"7","key":"pcbi.1012877.ref067","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/s41419-022-05094-z","article-title":"SALIS transcriptionally represses IGFBP3\/Caspase-7-mediated apoptosis by associating with STAT5A to promote hepatocellular carcinoma","volume":"13","author":"X Liu","year":"2022","journal-title":"Cell Death Dis"},{"issue":"5","key":"pcbi.1012877.ref068","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/s41401-019-0333-6","article-title":"The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation","volume":"41","author":"W-L Zhao","year":"2020","journal-title":"Acta Pharmacol Sin"},{"issue":"2","key":"pcbi.1012877.ref069","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41419-020-2335-1","article-title":"Suppressing STAT5 signaling affects osteosarcoma growth and stemness","volume":"11","author":"D Subramaniam","year":"2020","journal-title":"Cell Death Dis"},{"issue":"1","key":"pcbi.1012877.ref070","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13046-019-1502-7","article-title":"De-regulated STAT5A\/miR-202-5p\/USP15\/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance","volume":"39","author":"Z-Y Nie","year":"2020","journal-title":"J Exp Clin Cancer Res"},{"issue":"7990","key":"pcbi.1012877.ref071","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s41586-023-06733-x","article-title":"Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer","volume":"624","author":"P Zhou","year":"2023","journal-title":"Nature"},{"issue":"3","key":"pcbi.1012877.ref072","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nmeth.4177","article-title":"Pooled CRISPR screening with single-cell transcriptome readout","volume":"14","author":"P Datlinger","year":"2017","journal-title":"Nat Methods"},{"issue":"12","key":"pcbi.1012877.ref073","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/nrg3980","article-title":"Single-cell epigenomics: techniques and emerging applications","volume":"16","author":"O Schwartzman","year":"2015","journal-title":"Nat Rev Genet"},{"issue":"3","key":"pcbi.1012877.ref074","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s41592-023-01828-9","article-title":"Single-cell proteomics: challenges and prospects","volume":"20","year":"2023","journal-title":"Nat Methods"},{"issue":"9","key":"pcbi.1012877.ref075","first-page":"592","article-title":"An Evaluation of Two-Step Techniques for Positive-Unlabeled Learning in Text Classification","volume":"3","author":"A Kaboutari","year":"2014","journal-title":"Int J Comput Appl Technol Res"},{"issue":"2","key":"pcbi.1012877.ref076","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s11222-009-9153-8","article-title":"Estimation of prediction error by using K-fold cross-validation","volume":"21","author":"T Fushiki","year":"2009","journal-title":"Stat Comput"},{"issue":"1","key":"pcbi.1012877.ref077","doi-asserted-by":"crossref","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":"L Scrucca","year":"2016","journal-title":"R J"},{"issue":"D1","key":"pcbi.1012877.ref078","doi-asserted-by":"crossref","first-page":"D1082","DOI":"10.1093\/nar\/gkad987","article-title":"The UCSC genome browser database: 2024 update","volume":"52","author":"BJ Raney","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pcbi.1012877.ref079","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1093\/bioinformatics\/bti042","article-title":"Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification","volume":"21","author":"I Yanai","year":"2005","journal-title":"Bioinformatics"},{"issue":"1","key":"pcbi.1012877.ref080","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s10618-012-0295-5","article-title":"Training and assessing classification rules with imbalanced data","volume":"28","author":"G Menardi","year":"2012","journal-title":"Data Min Knowl Disc"},{"key":"pcbi.1012877.ref081","article-title":"Class imbalance, and cost sensitivity: why under-sampling beats over-sampling","volume":"91","author":"C Drummond","year":"2003","journal-title":"Phys Rev Lett"},{"key":"pcbi.1012877.ref082","article-title":"Classification and regression by randomForest","volume":"23","author":"A Liaw","year":"2001","journal-title":"Forest"},{"key":"pcbi.1012877.ref083","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: an open-source package for R and S+ to analyze and compare ROC curves","volume":"12","author":"X Robin","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1012877.ref084","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"L Breiman","year":"2001","journal-title":"Mach Learn"},{"issue":"1","key":"pcbi.1012877.ref085","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: large-scale single-cell gene expression data analysis","volume":"19","author":"FA Wolf","year":"2018","journal-title":"Genome Biol"},{"issue":"5","key":"pcbi.1012877.ref086","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"OMICS"},{"issue":"1","key":"pcbi.1012877.ref087","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.gpb.2022.04.008","article-title":"simplifyEnrichment: A Bioconductor Package for Clustering and Visualizing Functional Enrichment Results","volume":"21","author":"Z Gu","year":"2023","journal-title":"Genom Proteom Bioinform"},{"key":"pcbi.1012877.ref088","first-page":"426","article-title":"Cytoscape: a software environment for integrated models","volume":"13","author":"P Shannon","year":"1971","journal-title":"Genome Res"},{"issue":"6004","key":"pcbi.1012877.ref089","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1126\/science.330.6004.574","article-title":"Genomics. 1000 genomes project gives new map of genetic diversity","volume":"330","author":"E Pennisi","year":"2010","journal-title":"Science"},{"issue":"4","key":"pcbi.1012877.ref090","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","article-title":"DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors","volume":"8","author":"CS McGinnis","year":"2019","journal-title":"Cell Syst"},{"key":"pcbi.1012877.ref091","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"P Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"issue":"D1","key":"pcbi.1012877.ref092","doi-asserted-by":"crossref","first-page":"D330","DOI":"10.1093\/nar\/gky1055","article-title":"The gene ontology resource: 20 years and still GOing strong","volume":"47","year":"2019","journal-title":"Nucleic Acids 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