{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T01:59:28Z","timestamp":1772503168950,"version":"3.50.1"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T00:00:00Z","timestamp":1550016000000},"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\/100000893","name":"Simons Foundation","doi-asserted-by":"publisher","award":["SFARI 416835"],"award-info":[{"award-number":["SFARI 416835"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Whole exome sequencing (WES) studies for autism spectrum disorder (ASD) could identify only around six dozen risk genes to date because the genetic architecture of the disorder is highly complex. To speed the gene discovery process up, a few network-based ASD gene discovery algorithms were proposed. Although these methods use static gene interaction networks, functional clustering of genes is bound to evolve during neurodevelopment and disruptions are likely to have a cascading effect on the future associations. Thus, approaches that disregard the dynamic nature of neurodevelopment are limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we present a spatio-temporal gene discovery algorithm, which leverages information from evolving gene co-expression networks of neurodevelopment. The algorithm solves a prize-collecting Steiner forest-based problem on co-expression networks, adapted to model neurodevelopment and transfer information from precursor neurodevelopmental windows. The decisions made by the algorithm can be traced back, adding interpretability to the results. We apply the algorithm on ASD WES data of 3871 samples and identify risk clusters using BrainSpan co-expression networks of early- and mid-fetal periods. On an independent dataset, we show that incorporation of the temporal dimension increases the predictive power: predicted clusters are hit more and show higher enrichment in ASD-related functions compared with the state-of-the-art.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The code is available at http:\/\/ciceklab.cs.bilkent.edu.tr\/st-steiner.<\/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\/btz110","type":"journal-article","created":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T16:17:36Z","timestamp":1550074656000},"page":"3433-3440","source":"Crossref","is-referenced-by-count":12,"title":["ST-Steiner: a spatio-temporal gene discovery algorithm"],"prefix":"10.1093","volume":"35","author":[{"given":"Utku","family":"Norman","sequence":"first","affiliation":[{"name":"Computer Engineering Department, Bilkent University , Ankara, Turkey"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8613-6619","authenticated-orcid":false,"given":"A Ercument","family":"Cicek","sequence":"additional","affiliation":[{"name":"Computer Engineering Department, Bilkent University , Ankara, Turkey"},{"name":"Computational Biology Department, School of Computer Science, Carnegie Mellon University , Pittsburgh, PA, USA"}]}],"member":"286","published-online":{"date-parts":[[2019,2,13]]},"reference":[{"key":"2023013108045456600_btz110-B1","doi-asserted-by":"crossref","first-page":"a022863","DOI":"10.1101\/cshperspect.a022863","article-title":"Glutamatergic mechanisms associated with seizures and epilepsy","volume":"5","author":"Barker-Haliski","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med"},{"key":"2023013108045456600_btz110-B2","doi-asserted-by":"crossref","first-page":"1417.","DOI":"10.1038\/mp.2015.207","article-title":"Prenatal \u03b2-catenin\/brn2\/tbr2 transcriptional cascade regulates adult social and stereotypic behaviors","volume":"21","author":"Belinson","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"2023013108045456600_btz110-B3","doi-asserted-by":"crossref","first-page":"36.","DOI":"10.1186\/1749-8104-4-36","article-title":"Notch activity in the nervous system: to switch or not switch?","volume":"4","author":"Cau","year":"2009","journal-title":"Neural Dev"},{"key":"2023013108045456600_btz110-B4","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/mp.2013.16","article-title":"Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system","volume":"19","author":"Cristino","year":"2014","journal-title":"Mol. Psychiatry"},{"key":"2023013108045456600_btz110-B5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature13772","article-title":"Synaptic, transcriptional and chromatin genes disrupted in autism","volume":"515","author":"De Rubeis","year":"2014","journal-title":"Nature"},{"key":"2023013108045456600_btz110-B6","first-page":"1","article-title":"Prevalence of autism spectrum disorder among children aged 8 years\u2014autism and developmental disabilities monitoring network, 11 sites, United States, 2010","volume":"63","year":"(2014)","journal-title":"MMWR Surveill. Summ"},{"key":"2023013108045456600_btz110-B7","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.ins.2008.11.017","article-title":"A layout algorithm for undirected compound graphs","volume":"179","author":"Dogrusoz","year":"2009","journal-title":"Inf. Sci"},{"key":"2023013108045456600_btz110-B8","first-page":"276","volume-title":"Sem. Cell Dev. Biol","author":"Ems-McClung","year":"2010"},{"key":"2023013108045456600_btz110-B9","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.neuron.2011.05.021","article-title":"Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses","volume":"70","author":"Gilman","year":"2011","journal-title":"Neuron"},{"key":"2023013108045456600_btz110-B10","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1038\/nn.3261","article-title":"Diverse types of genetic variation converge on functional gene networks involved in schizophrenia","volume":"15","author":"Gilman","year":"2012","journal-title":"Nat. Neurosci"},{"key":"2023013108045456600_btz110-B11","first-page":"39","volume-title":"Biocomputing 2014: Proceedings of the Pacific Symposium","author":"Gitter","year":"2014"},{"key":"2023013108045456600_btz110-B12","doi-asserted-by":"crossref","first-page":"569.","DOI":"10.1038\/ng.3259","article-title":"Understanding multicellular function and disease with human tissue-specific networks","volume":"47","author":"Greene","year":"2015","journal-title":"Nat. Genet"},{"key":"2023013108045456600_btz110-B13","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1084\/jem.20030566","article-title":"Truncation of c-mip (tc-mip), a new proximal signaling protein, induces c-maf th2 transcription factor and cytoskeleton reorganization","volume":"198","author":"Grimbert","year":"2003","journal-title":"J. Exp. Med"},{"key":"2023013108045456600_btz110-B14","doi-asserted-by":"crossref","first-page":"e1003671","DOI":"10.1371\/journal.pgen.1003671","article-title":"Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes","volume":"9","author":"He","year":"2013","journal-title":"PLoS Genet"},{"key":"2023013108045456600_btz110-B15","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1101\/gr.178855.114","article-title":"The discovery of integrated gene networks for autism and related disorders","volume":"25","author":"Hormozdiari","year":"2015","journal-title":"Genome Res"},{"key":"2023013108045456600_btz110-B16","doi-asserted-by":"crossref","first-page":"1516.","DOI":"10.1038\/ncb2870","article-title":"A network of epigenetic regulators guides developmental haematopoiesis in vivo","volume":"15","author":"Huang","year":"2013","journal-title":"Nat. Cell Biol"},{"key":"2023013108045456600_btz110-B17","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neuron.2012.04.009","article-title":"De novo gene disruptions in children on the autistic spectrum","volume":"74","author":"Iossifov","year":"2012","journal-title":"Neuron"},{"key":"2023013108045456600_btz110-B18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature13908","article-title":"The contribution of de novo coding mutations to autism spectrum disorder","volume":"515","author":"Iossifov","year":"2014","journal-title":"Nature"},{"key":"2023013108045456600_btz110-B19","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1177\/0883073815601501","article-title":"Autism spectrum disorder and epilepsy: two sides of the same coin?","volume":"30","author":"Jeste","year":"2015","journal-title":"J. Child Neurol"},{"key":"2023013108045456600_btz110-B20","first-page":"D767","article-title":"Human protein reference database-2009 update","volume":"37(Suppl. 1)","author":"Keshava Prasad","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"2023013108045456600_btz110-B21","doi-asserted-by":"crossref","first-page":"D337","DOI":"10.1093\/nar\/gkr1125","article-title":"Histome\u2014a relational knowledgebase of human histone proteins and histone modifying enzymes","volume":"40","author":"Khare","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023013108045456600_btz110-B22","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1038\/nn.4353","article-title":"Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder","volume":"19","author":"Krishnan","year":"2016","journal-title":"Nat. Neurosci"},{"key":"2023013108045456600_btz110-B23","doi-asserted-by":"crossref","first-page":"e94408.","DOI":"10.1371\/journal.pone.0094408","article-title":"Tcf3 represses wnt\u2013\u03b2-catenin signaling and maintains neural stem cell population during neocortical development","volume":"9","author":"Kuwahara","year":"2014","journal-title":"PLoS One"},{"key":"2023013108045456600_btz110-B24","doi-asserted-by":"crossref","first-page":"61.","DOI":"10.1038\/nmeth.4083","article-title":"A scored human protein\u2013protein interaction network to catalyze genomic interpretation","volume":"14","author":"Li","year":"2017","journal-title":"Nat. Methods"},{"key":"2023013108045456600_btz110-B25","doi-asserted-by":"crossref","first-page":"3669","DOI":"10.1074\/jbc.M511725200","article-title":"Involvement of myosin vb in glutamate receptor trafficking","volume":"281","author":"Lis\u00e9","year":"2006","journal-title":"J. Biol. Chem"},{"key":"2023013108045456600_btz110-B26","doi-asserted-by":"crossref","first-page":"22.","DOI":"10.1186\/2040-2392-5-22","article-title":"Dawn: a framework to identify autism genes and subnetworks using gene expression and genetics","volume":"5","author":"Liu","year":"2014","journal-title":"Mol. Autism"},{"key":"2023013108045456600_btz110-B27","doi-asserted-by":"crossref","first-page":"1571.","DOI":"10.1214\/15-AOAS844","article-title":"Network assisted analysis to reveal the genetic basis of autism","volume":"9","author":"Liu","year":"2015","journal-title":"Ann. Appl. Stat"},{"key":"2023013108045456600_btz110-B28","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1002\/ajmg.a.38277","article-title":"cmip haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues","volume":"173","author":"Luo","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"2023013108045456600_btz110-B29","doi-asserted-by":"crossref","first-page":"12741","DOI":"10.1038\/ncomms12741","article-title":"Transport of a Kinesin-Cargo pair along microtubules into dendritic spines undergoing synaptic plasticity","volume":"7","author":"McVicker","year":"2016","journal-title":"Nat. Commun"},{"key":"2023013108045456600_btz110-B30","doi-asserted-by":"crossref","first-page":"709.","DOI":"10.1038\/349709a0","article-title":"Novel myosin heavy chain encoded by murine dilute coat colour locus","volume":"349","author":"Mercer","year":"1991","journal-title":"Nature"},{"key":"2023013108045456600_btz110-B31","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1101\/gad.891401","article-title":"Tcf3 and lef1 regulate lineage differentiation of multipotent stem cells in skin","volume":"15","author":"Merrill","year":"2001","journal-title":"Genes Dev"},{"key":"2023013108045456600_btz110-B32","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/nature11011","article-title":"Patterns and rates of exonic de novo mutations in autism spectrum disorders","volume":"485","author":"Neale","year":"2012","journal-title":"Nature"},{"key":"2023013108045456600_btz110-B33","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.cell.2006.07.036","article-title":"Tcf3 governs stem cell features and represses cell fate determination in skin","volume":"127","author":"Nguyen","year":"2006","journal-title":"Cell"},{"key":"2023013108045456600_btz110-B34","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13073-017-0497-y","article-title":"Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders","volume":"9","author":"Nguyen","year":"2017","journal-title":"Genome Med"},{"key":"2023013108045456600_btz110-B35","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1002\/stem.731","article-title":"Gene expression profiling of neural stem cells and identification of regulators of neural differentiation during cortical development","volume":"29","author":"Ohtsuka","year":"2011","journal-title":"Stem Cells"},{"key":"2023013108045456600_btz110-B36","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nature10989","article-title":"Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations","volume":"485","author":"O\u2019Roak","year":"2012","journal-title":"Nature"},{"key":"2023013108045456600_btz110-B37","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.cell.2013.10.031","article-title":"Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism","volume":"155","author":"Parikshak","year":"2013","journal-title":"Cell"},{"key":"2023013108045456600_btz110-B38","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1474-4422(02)00073-X","article-title":"Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy","volume":"1","author":"Pitk\u00e4nen","year":"2002","journal-title":"Lancet Neurol"},{"key":"2023013108045456600_btz110-B39","volume-title":"Models of Seizures and Epilepsy","author":"Pitk\u00e4nen","year":"2017"},{"key":"2023013108045456600_btz110-B40","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature10945","article-title":"De novo mutations revealed by whole-exome sequencing are strongly associated with autism","volume":"485","author":"Sanders","year":"2012","journal-title":"Nature"},{"key":"2023013108045456600_btz110-B41","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.neuron.2015.09.016","article-title":"Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci","volume":"87","author":"Sanders","year":"2015","journal-title":"Neuron"},{"key":"2023013108045456600_btz110-B42","first-page":"77","article-title":"Prenatal contributions to epilepsy: lessons from the bedside","volume":"5","author":"Scher","year":"2003","journal-title":"Epileptic Dis"},{"key":"2023013108045456600_btz110-B43","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"2023013108045456600_btz110-B44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: from gene data mining to disease genome sequence analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"2023013108045456600_btz110-B45","doi-asserted-by":"crossref","first-page":"D996","DOI":"10.1093\/nar\/gks1042","article-title":"Allen brain atlas: an integrated spatio-temporal portal for exploring the central nervous system","volume":"41","author":"Sunkin","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023013108045456600_btz110-B46","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gkq973","article-title":"The string database in 2011: functional interaction networks of proteins, globally integrated and scored","volume":"39","author":"Szklarczyk","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2023013108045456600_btz110-B47","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1046\/j.1528-1157.2001.042suppl.3008.x","article-title":"Gabaergic mechanisms in epilepsy","volume":"42","author":"Treiman","year":"2001","journal-title":"Epilepsia"},{"key":"2023013108045456600_btz110-B48","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/978-3-642-29627-7_31","article-title":"Simultaneous reconstruction of multiple signaling pathways via the prize-collecting Steiner forest problem","author":"Tuncbag","year":"2012","journal-title":"Lecture Notes in Computer Science Research in Computational Molecular Biology"},{"key":"2023013108045456600_btz110-B49","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1089\/cmb.2012.0092","article-title":"Simultaneous reconstruction of multiple signaling pathways via the prize-collecting Steiner forest problem","volume":"20","author":"Tuncbag","year":"2013","journal-title":"J. Comput. Biol"},{"key":"2023013108045456600_btz110-B50","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1056\/NEJMoa0910752","article-title":"Timing of de novo mutagenesis\u2014a twin study of sodium-channel mutations","volume":"363","author":"Vadlamudi","year":"2010","journal-title":"N. Engl. J. Med"},{"key":"2023013108045456600_btz110-B51","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/aur.1240","article-title":"Haploinsufficiency of cmip in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23. 2","volume":"5","author":"Van der Aa","year":"2012","journal-title":"Autism Res"},{"key":"2023013108045456600_btz110-B52","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.cell.2013.10.020","article-title":"Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism","volume":"155","author":"Willsey","year":"2013","journal-title":"Cell"},{"key":"2023013108045456600_btz110-B53","author":"Wolter","year":"2013"},{"key":"2023013108045456600_btz110-B54","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1038\/s41598-017-02348-1","article-title":"Genetic variants in the transcription regulatory region of megf10 are associated with autism in Chinese Han population","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Rep"},{"key":"2023013108045456600_btz110-B55","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.braindev.2015.04.006","article-title":"Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients","volume":"38","author":"Yang","year":"2016","journal-title":"Brain Dev"},{"key":"2023013108045456600_btz110-B56","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/humu.23147","article-title":"A cell type-specific expression signature predicts haploinsufficient autism-susceptibility genes","volume":"38","author":"Zhang","year":"2017","journal-title":"Hum. Mutat"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/18\/3433\/48975021\/bioinformatics_35_18_3433.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/18\/3433\/48975021\/bioinformatics_35_18_3433.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T08:33:00Z","timestamp":1675153980000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/18\/3433\/5317161"}},"subtitle":[],"editor":[{"given":"Bonnie","family":"Berger","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2019,2,13]]},"references-count":56,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2019,9,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz110","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/256693","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,9,15]]},"published":{"date-parts":[[2019,2,13]]}}}