{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T08:49:47Z","timestamp":1773305387501,"version":"3.50.1"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T00:00:00Z","timestamp":1510704000000},"content-version":"vor","delay-in-days":126,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["Grant 1425\/13"],"award-info":[{"award-number":["Grant 1425\/13"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Epigenome-wide association studies can provide novel insights into the regulation of genes involved in traits and diseases. The rapid emergence of bisulfite-sequencing technologies enables performing such genome-wide studies at the resolution of single nucleotides. However, analysis of data produced by bisulfite-sequencing poses statistical challenges owing to low and uneven sequencing depth, as well as the presence of confounding factors. The recently introduced Mixed model Association for Count data via data AUgmentation (MACAU) can address these challenges via a generalized linear mixed model when confounding can be encoded via a single variance component. However, MACAU cannot be used in the presence of multiple variance components. Additionally, MACAU uses a computationally expensive Markov Chain Monte Carlo (MCMC) procedure, which cannot directly approximate the model likelihood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We present a new method, Mixed model Association via a Laplace ApproXimation (MALAX), that is more computationally efficient than MACAU and allows to model multiple variance components. MALAX uses a Laplace approximation rather than MCMC based approximations, which enables to directly approximate the model likelihood. Through an extensive analysis of simulated and real data, we demonstrate that MALAX successfully addresses statistical challenges introduced by bisulfite-sequencing while controlling for complex sources of confounding, and can be over 50% faster than 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 full source code of MALAX is available at https:\/\/github.com\/omerwe\/MALAX.<\/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\/btx248","type":"journal-article","created":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T07:52:13Z","timestamp":1492674733000},"page":"i325-i332","source":"Crossref","is-referenced-by-count":12,"title":["Association testing of bisulfite-sequencing methylation data via a Laplace approximation"],"prefix":"10.1093","volume":"33","author":[{"given":"Omer","family":"Weissbrod","sequence":"first","affiliation":[{"name":"Statistics Department, Tel Aviv University, Tel Aviv, Israel"},{"name":"Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel"}]},{"given":"Elior","family":"Rahmani","sequence":"additional","affiliation":[{"name":"Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel"}]},{"given":"Regev","family":"Schweiger","sequence":"additional","affiliation":[{"name":"Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel"}]},{"given":"Saharon","family":"Rosset","sequence":"additional","affiliation":[{"name":"Statistics Department, Tel Aviv University, Tel Aviv, Israel"}]},{"given":"Eran","family":"Halperin","sequence":"additional","affiliation":[{"name":"Computer Science Department, University of California Los Angeles, Los Angeles, CA, USA"},{"name":"Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, Los Angeles, CA, USA"}]}],"member":"286","published-online":{"date-parts":[[2017,7,12]]},"reference":[{"key":"2023051506501538800_btx248-B1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/BF01441146","article-title":"A method for quantifying differentiation between populations at multi-allelic loci and its implications for investigating identity and paternity","volume":"96","author":"Balding","year":"1995","journal-title":"Genetica"},{"key":"2023051506501538800_btx248-B2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1109\/MCSE.2010.118","article-title":"Cython: the best of both worlds","volume":"13","author":"Behnel","year":"2011","journal-title":"Comput. 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