{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:52:28Z","timestamp":1776214348353,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["20JC1413800"],"award-info":[{"award-number":["20JC1413800"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Health Science and Technology Key Project of Zhejiang Provincial Health Commission","award":["WKJ-ZJ-2007"],"award-info":[{"award-number":["WKJ-ZJ-2007"]}]},{"name":"Key Research and Development Program of Zhejiang Province of China","award":["2021C03126"],"award-info":[{"award-number":["2021C03126"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072857"],"award-info":[{"award-number":["82072857"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL149620"],"award-info":[{"award-number":["HL149620"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["15SFRN23910002"],"award-info":[{"award-number":["15SFRN23910002"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>DNA methylation plays a crucial role in transcriptional regulation. Reduced representation bisulfite sequencing (RRBS) is a technique of increasing use for analyzing genome-wide methylation profiles. Many computational tools such as Metilene, MethylKit, BiSeq and DMRfinder have been developed to use RRBS data for the detection of the differentially methylated regions (DMRs) potentially involved in epigenetic regulations of gene expression. For DMR detection tools, as for countless other medical applications, P-values and their adjustments are among the most standard reporting statistics used to assess the statistical significance of biological findings. However, P-values are coming under increasing criticism relating to their questionable accuracy and relatively high levels of false positive or negative indications. Here, we propose a method to calculate E-values, as likelihood ratios falling into the null hypothesis over the entire parameter space, for DMR detection in RRBS data. We also provide the R package \u2018metevalue\u2019 as a user-friendly interface to implement E-value calculations into various DMR detection tools. To evaluate the performance of E-values, we generated various RRBS benchmarking datasets using our simulator \u2018RRBSsim\u2019 with eight samples in each experimental group. Our comprehensive benchmarking analyses showed that using E-values not only significantly improved accuracy, area under ROC curve and power, over that of P-values or adjusted P-values, but also reduced false discovery rates and type I errors. In applications using real RRBS data of CRL rats and a clinical trial on low-salt diet, the use of E-values detected biologically more relevant DMRs and also improved the negative association between DNA methylation and gene expression.<\/jats:p>","DOI":"10.1093\/bib\/bbad241","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T08:27:28Z","timestamp":1686731248000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>E<\/i>\n                    -value: a superior alternative to\n                    <i>P<\/i>\n                    -value and its adjustments in DNA methylation studies"],"prefix":"10.1093","volume":"24","author":[{"given":"Yifan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Mathematics, Shanghai Normal University , Shanghai ,","place":["China"]},{"name":"Transwarp Technology Co., LTD , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Shanghai Normal University , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province , Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, , Hangzhou ,","place":["China"]},{"name":"Zhejiang University , Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, , Hangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liyuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province , Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, , Hangzhou ,","place":["China"]},{"name":"Zhejiang University , Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, , Hangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Shanghai Normal University , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongxian","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Shanghai Normal University , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L","family":"Mattson","sequence":"additional","affiliation":[{"name":"Department of Physiology , Medical College of Georgia, , Augusta, GA ,","place":["USA"]},{"name":"Augusta University , Medical College of Georgia, , Augusta, GA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srividya","family":"Kidambi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical College of Wisconsin , Milwaukee, WI ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyu","family":"Liang","sequence":"additional","affiliation":[{"name":"Center of Systems Molecular Medicine , Department of Physiology, , Milwaukee, WI ,","place":["USA"]},{"name":"Medical College of Wisconsin , Department of Physiology, , Milwaukee, WI ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province , Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, , Hangzhou ,","place":["China"]},{"name":"Zhejiang University , Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, , Hangzhou ,","place":["China"]},{"name":"Center of Systems Molecular Medicine , Department of Physiology, , Milwaukee, WI ,","place":["USA"]},{"name":"Medical College of Wisconsin , Department of Physiology, , Milwaukee, WI ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3559-5337","authenticated-orcid":false,"given":"Xiaoqing","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Shanghai Normal University , Shanghai 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