{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:07:03Z","timestamp":1770224823936,"version":"3.49.0"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T00:00:00Z","timestamp":1573171200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T00:00:00Z","timestamp":1573171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["CA124504"],"award-info":[{"award-number":["CA124504"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["CA163251"],"award-info":[{"award-number":["CA163251"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["CA008748"],"award-info":[{"award-number":["CA008748"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n              <jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>We previously introduced a random-effects model to analyze a set of patients, each of which has two distinct tumors. The goal is to estimate the proportion of patients for which one of the tumors is a metastasis of the other, i.e. where the tumors are clonally related. Matches of mutations within a tumor pair provide the evidence for clonal relatedness. In this article, using simulations, we compare two estimation approaches that we considered for our model: use of a constrained quasi-Newton algorithm to maximize the likelihood conditional on the random effect, and an Expectation-Maximization algorithm where we further condition the random-effect distribution on the data.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In some specific settings, especially with sparse information, the estimation of the parameter of interest is at the boundary a non-negligible number of times using the first approach, while the EM algorithm gives more satisfactory estimates. This is of considerable importance for our application, since an estimate of either 0 or 1 for the proportion of cases that are clonal leads to individual probabilities being 0 or 1 in settings where the evidence is clearly not sufficient for such definitive probability estimates.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The EM algorithm is a preferable approach for our clonality random-effect model. It is now the method implemented in our R package <jats:italic>Clonality<\/jats:italic>, making available an easy and fast way to estimate this model on a range of applications.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12859-019-3148-z","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T14:51:47Z","timestamp":1573224707000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An EM algorithm to improve the estimation of the probability of clonal relatedness of pairs of tumors in cancer patients"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-6093","authenticated-orcid":false,"given":"Audrey","family":"Mauguen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venkatraman E.","family":"Seshan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Ostrovnaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin B.","family":"Begg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,11,8]]},"reference":[{"issue":"4","key":"3148_CR1","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/sj.bjc.6602021","volume":"91","author":"MR Teixeira","year":"2004","unstructured":"Teixeira MR, Ribeiro FR, Torres L, Pandis N, Andersen JA, Lothe RA, Heim S. Assessment of clonal relationships in ipsilateral and bilateral multiple breast carcinomas by comparative genomic hybridisation and hierarchical clustering analysis. Br J Cancer. 2004; 91(4):775\u201382. \nhttps:\/\/doi.org\/10.1038\/sj.bjc.6602021\n\n.","journal-title":"Br J Cancer"},{"issue":"6","key":"3148_CR2","doi-asserted-by":"publisher","first-page":"djv427","DOI":"10.1093\/jnci\/djv427","volume":"108","author":"Anne M. Schultheis","year":"2015","unstructured":"Schultheis AM, Ng CKY, De Filippo MR, Piscuoglio S, Macedo GS, Gatius S, Perez Mies B, Soslow RA, Lim RS, Viale A, Huberman KH, Palacios JC, Reis-Filho JS, Matias-Guiu X, Weigelt B. Massively Parallel Sequencing-Based Clonality Analysis of Synchronous Endometrioid Endometrial and Ovarian Carcinomas. J Natl Cancer Inst. 2016;108(6). \nhttps:\/\/doi.org\/10.1093\/jnci\/djv427\n\n.","journal-title":"Journal of the National Cancer Institute"},{"issue":"7","key":"3148_CR3","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1002\/ijc.31761","volume":"144","author":"J Perea","year":"2019","unstructured":"Perea J, Garc\u00eda JL, Corchete L, Lumbreras E, Arriba M, Rueda D, Tapial S, P\u00e9rez J, Vieiro V, Rodr\u00edguez Y, Brand\u00e1riz L, Garc\u00eda-Arranz M, Garc\u00eda-Olmo D, Goel A, Urioste M, Sarmiento RG. Redefining synchronous colorectal cancers based on tumor clonality. Int J Cancer. 2019; 144(7):1596\u2013608. \nhttps:\/\/doi.org\/10.1002\/ijc.31761\n\n.","journal-title":"Int J Cancer"},{"key":"3148_CR4","doi-asserted-by":"publisher","first-page":"12072","DOI":"10.1038\/ncomms12072","volume":"7","author":"M Cereda","year":"2016","unstructured":"Cereda M, Gambardella G, Benedetti L, Iannelli F, Patel D, Basso G, Guerra RF, Mourikis TP, Puccio I, Sinha S, Laghi L, Spencer J, Rodriguez-Justo M, Ciccarelli FD. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes. Nat Commun. 2016; 7:12072. \nhttps:\/\/doi.org\/10.1038\/ncomms12072\n\n.","journal-title":"Nat Commun"},{"issue":"11","key":"3148_CR5","doi-asserted-by":"publisher","first-page":"e0142487","DOI":"10.1371\/journal.pone.0142487","volume":"10","author":"L Bao","year":"2015","unstructured":"Bao L, Messer K, Schwab R, Harismendy O, Pu M, Crain B, Yost S, Frazer KA, Rana B, Hasteh F, Wallace A, Parker BA. Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors. PLoS ONE. 2015; 10(11):e0142487. \nhttps:\/\/doi.org\/10.1371\/journal.pone.0142487\n\n.","journal-title":"PLoS ONE"},{"issue":"1","key":"3148_CR6","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/biom.12710","volume":"74","author":"A Mauguen","year":"2018","unstructured":"Mauguen A, Seshan VE, Ostrovnaya I, Begg CB. Estimating the probability of clonal relatedness of pairs of tumors in cancer patients. Biometrics. 2018; 74(1):321\u2013330. \nhttps:\/\/doi.org\/10.1111\/biom.12710\n\n.","journal-title":"Biometrics"},{"issue":"12","key":"3148_CR7","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1093\/bioinformatics\/btr267","volume":"27","author":"I Ostrovnaya","year":"2011","unstructured":"Ostrovnaya I, Seshan VE, Olshen AB, Begg CB. Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles. Bioinformatics. 2011; 27(12):1698\u20131699. \nhttps:\/\/doi.org\/10.1093\/bioinformatics\/btr267\n\n.","journal-title":"Bioinformatics"},{"issue":"2","key":"3148_CR8","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/ijc.31051","volume":"142","author":"CB Begg","year":"2018","unstructured":"Begg CB, Ostrovnaya I, Geyer FC, Papanastasiou AD, Ng CKY, Sakr RA, Bernstein JL, Burke KA, King TA, Piscuoglio S, Mauguen A, Orlow I, Weigelt B, Seshan VE, Morrow M, Reis-Filho JS. Contralateral breast cancers: Independent cancers or metastases?Int J Cancer. 2018; 142(2):347\u2013356. \nhttps:\/\/doi.org\/10.1002\/ijc.31051\n\n.","journal-title":"Int J Cancer"},{"issue":"3","key":"3148_CR9","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cels.2018.03.002","volume":"6","author":"K Ellrott","year":"2018","unstructured":"Ellrott K, Bailey MH, Saksena G, et al. Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines. Cell Syst. 2018; 6(3):271\u2013281.e7. \nhttps:\/\/doi.org\/10.1016\/j.cels.2018.03.002\n\n.","journal-title":"Cell Syst"},{"key":"3148_CR10","unstructured":"Ostrovnaya I. Clonality: Clonality testing. 2019. R package version 1.32.0."}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12859-019-3148-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12859-019-3148-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12859-019-3148-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T00:08:52Z","timestamp":1604707732000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/s12859-019-3148-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,8]]},"references-count":10,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["3148"],"URL":"https:\/\/doi.org\/10.1186\/s12859-019-3148-z","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,8]]},"assertion":[{"value":"4 February 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The motivating study involved genomic analyses of archived specimens and was conducted under a waiver of consent approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board (WA0388-13).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"N\/A","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"555"}}