{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:43Z","timestamp":1772138083829,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T00:00:00Z","timestamp":1490140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"BMBF","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) is a widely used approach to study protein\u2013DNA interactions. Often, the quantities of interest are the differential occupancies relative to controls, between genetic backgrounds, treatments, or combinations thereof. Current methods for differential occupancy of ChIP-Seq data rely however on binning or sliding window techniques, for which the choice of the window and bin sizes are subjective.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we present GenoGAM (Genome-wide Generalized Additive Model), which brings the well-established and flexible generalized additive models framework to genomic applications using a data parallelism strategy. We model ChIP-Seq read count frequencies as products of smooth functions along chromosomes. Smoothing parameters are objectively estimated from the data by cross-validation, eliminating ad hoc binning and windowing needed by current approaches. GenoGAM provides base-level and region-level significance testing for full factorial designs. Application to a ChIP-Seq dataset in yeast showed increased sensitivity over existing differential occupancy methods while controlling for type I error rate. By analyzing a set of DNA methylation data and illustrating an extension to a peak caller, we further demonstrate the potential of GenoGAM as a generic statistical modeling tool for genome-wide assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and Implementation<\/jats:title>\n                    <jats:p>Software is available from Bioconductor: https:\/\/www.bioconductor.org\/packages\/release\/bioc\/html\/GenoGAM.html.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary information is available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btx150","type":"journal-article","created":{"date-parts":[[2017,3,20]],"date-time":"2017-03-20T08:13:29Z","timestamp":1489997609000},"page":"2258-2265","source":"Crossref","is-referenced-by-count":7,"title":["GenoGAM: genome-wide generalized additive models for ChIP-Seq analysis"],"prefix":"10.1093","volume":"33","author":[{"given":"Georg","family":"Stricker","sequence":"first","affiliation":[{"name":"Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"},{"name":"Department of Informatics, Technische Universit\u00e4t M\u00fcnchen, Garching, Germany"}]},{"given":"Alexander","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}]},{"given":"Daniel","family":"Schulz","sequence":"additional","affiliation":[{"name":"Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}]},{"given":"Matthias","family":"Schmid","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Biometrie, Informatik und Epidemiologie, University Hospital Bonn, Bonn, Germany"}]},{"given":"Achim","family":"Tresch","sequence":"additional","affiliation":[{"name":"Institute for Genetics, University of Cologne, Cologne, Germany"}]},{"given":"Julien","family":"Gagneur","sequence":"additional","affiliation":[{"name":"Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"},{"name":"Department of Informatics, Technische Universit\u00e4t M\u00fcnchen, Garching, Germany"}]}],"member":"286","published-online":{"date-parts":[[2017,3,22]]},"reference":[{"key":"2023063012502643900_btx150-B1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nature05632","article-title":"Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome","volume":"446","author":"Albert","year":"2007","journal-title":"Nature"},{"key":"2023063012502643900_btx150-B2","first-page":"e153","article-title":"Differential peak calling of Chip-Seq signals with replicates with thor","volume":"44","author":"Allhoff","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023063012502643900_btx150-B3","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol"},{"key":"2023063012502643900_btx150-B4","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.cell.2007.05.009","article-title":"High-resolution profiling of histone methylations in the human genome","volume":"129","author":"Barski","year":"2007","journal-title":"Cell"},{"key":"2023063012502643900_btx150-B5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. B"},{"key":"2023063012502643900_btx150-B6","doi-asserted-by":"crossref","first-page":"9546","DOI":"10.1073\/pnas.0914005107","article-title":"Independent filtering increases detection power for high-throughput experiments","volume":"107","author":"Bourgon","year":"2010","journal-title":"Proc. Natl. Acad. Sci"},{"key":"2023063012502643900_btx150-B8","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4612-6333-3","volume-title":"A Practical Guide to Splines","author":"De Boor","year":"1978"},{"key":"2023063012502643900_btx150-B9","first-page":"89","article-title":"Flexible smoothing with B-splines and penalties","author":"Eilers","year":"1996","journal-title":"Stat. Sci"},{"key":"2023063012502643900_btx150-B12","first-page":"297","article-title":"Generalized additive models","volume":"1","author":"Hastie","year":"1986","journal-title":"Stat. Sci"},{"key":"2023063012502643900_btx150-B13","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/515198d","article-title":"Data analysis: approximation aids handling of big data","volume":"515","author":"Heinis","year":"2014","journal-title":"Nature"},{"key":"2023063012502643900_btx150-B14","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1093\/biomet\/75.4.800","article-title":"A sharper Bonferroni procedure for multiple tests of significance","volume":"75","author":"Hochberg","year":"1988","journal-title":"Biometrika"},{"key":"2023063012502643900_btx150-B15","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1093\/bioinformatics\/btu568","article-title":"JAMM: a peak finder for joint analysis of NGS replicates","volume":"31","author":"Ibrahim","year":"2015","journal-title":"Bioinformatics"},{"key":"2023063012502643900_btx150-B16","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1126\/science.1141319","article-title":"Genome-wide mapping of in vivo protein-DNA interactions","volume":"316","author":"Johnson","year":"2007","journal-title":"Science"},{"key":"2023063012502643900_btx150-B17","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2023063012502643900_btx150-B18","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.1093\/nar\/gku351","article-title":"De novo detection of differentially bound regions for ChIP-Seq data using peaks and windows: controlling error rates correctly","volume":"42","author":"Lun","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023063012502643900_btx150-B19","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1467-9469.2011.00760.x","article-title":"Coverage properties of confidence intervals for generalized additive model components","volume":"39","author":"Marra","year":"2012","journal-title":"Scand. J. Stat"},{"key":"2023063012502643900_btx150-B20","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrg3788","article-title":"Identifying and mitigating bias in next-generation sequencing methods for chromatin biology","volume":"15","author":"Meyer","year":"2014","journal-title":"Nat. Rev. Genet"},{"key":"2023063012502643900_btx150-B21","doi-asserted-by":"crossref","first-page":"370","DOI":"10.2307\/2344614","article-title":"Generalized linear models","volume":"135","author":"Nelder","year":"1972","journal-title":"J. R. Stat. Soc. A"},{"key":"2023063012502643900_btx150-B22","doi-asserted-by":"crossref","first-page":"R67","DOI":"10.1186\/gb-2011-12-7-r67","article-title":"ZINBA integrates local covariates with DNA-Seq data to identify broad and narrow regions of enrichment, even within amplified genomic regions","volume":"12","author":"Rashid","year":"2011","journal-title":"Genome Biol"},{"key":"2023063012502643900_btx150-B23","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nmeth1068","article-title":"Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing","volume":"4","author":"Robertson","year":"2007","journal-title":"Nat. Methods"},{"key":"2023063012502643900_btx150-B24","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1186\/1471-2164-14-826","article-title":"MMDiff: quantitative testing for shape changes in ChIP-Seq data sets","volume":"14","author":"Schweikert","year":"2013","journal-title":"BMC Genomics"},{"key":"2023063012502643900_btx150-B26","doi-asserted-by":"crossref","first-page":"e65598","DOI":"10.1371\/journal.pone.0065598","article-title":"diffReps: detecting differential chromatin modification sites from ChIP-Seq data with biological replicates","volume":"8","author":"Shen","year":"2013","journal-title":"PLoS One"},{"key":"2023063012502643900_btx150-B27","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/nmeth.3035","article-title":"Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity","volume":"11","author":"Smallwood","year":"2014","journal-title":"Nat. Methods"},{"key":"2023063012502643900_btx150-B28","first-page":"953","article-title":"A comprehensive comparison of tools for differential ChIP-Seq analysis","volume":"17","author":"Steinhauser","year":"2016","journal-title":"Brief. Bioinformatics"},{"key":"2023063012502643900_btx150-B29","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1101\/gad.232215.113","article-title":"Context dependency of Set1\/COMPASS-mediated histone H3 Lys4 trimethylation","volume":"28","author":"Thornton","year":"2014","journal-title":"Genes Dev"},{"key":"2023063012502643900_btx150-B30","first-page":"439","article-title":"Quasi-likelihood functions, generalized linear models, and the Gauss Newton method","volume":"61","author":"Wedderburn","year":"1974","journal-title":"Biometrika"},{"key":"2023063012502643900_btx150-B31","first-page":"2802","article-title":"Multiple testing in genome-wide association studies via hidden Markov models","volume":"25","author":"Wei","year":"2009","journal-title":"Bioinformatics (Oxford, England)"},{"key":"2023063012502643900_btx150-B32","doi-asserted-by":"crossref","DOI":"10.1201\/9781420010404","volume-title":"Generalized Additive Models: An Introduction with R","author":"Wood","year":"2006"},{"key":"2023063012502643900_btx150-B33","first-page":"1","article-title":"Generalized additive models for gigadata: modelling the UK black smoke network daily data","author":"Wood","year":"2016","journal-title":"J. Am. Stat. Assoc"},{"key":"2023063012502643900_btx150-B34","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/nature07728","article-title":"Bidirectional promoters generate pervasive transcription in yeast","volume":"457","author":"Xu","year":"2009","journal-title":"Nature"},{"key":"2023063012502643900_btx150-B35","author":"Zaharia","year":"2010"},{"key":"2023063012502643900_btx150-B36","doi-asserted-by":"crossref","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Zhang","year":"2008","journal-title":"Genome Biol"},{"key":"2023063012502643900_btx150-B37","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1093\/bioinformatics\/btu372","article-title":"Pepr: A peak-calling prioritization pipeline to identify consistent or differential peaks from replicated ChIP-Seq data","volume":"30","author":"Zhang","year":"2014","journal-title":"Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/33\/15\/2258\/50756539\/bioinformatics_33_15_2258.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/33\/15\/2258\/50756539\/bioinformatics_33_15_2258.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T23:57:58Z","timestamp":1719100678000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/33\/15\/2258\/3078602"}},"subtitle":[],"editor":[{"given":"Janet","family":"Kelso","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2017,3,22]]},"references-count":33,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2017,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btx150","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/047464","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":[[2017,8,1]]},"published":{"date-parts":[[2017,3,22]]}}}