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Biol."],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Identifying patient\u2010specific flow of signal transduction perturbed by multiple single\u2010nucleotide alterations is critical for improving patient outcomes in cancer cases. However, accurate estimation of mutational effects at the pathway level for such patients remains an open problem. While probabilistic pathway topology methods are gaining interest among the scientific community, the overwhelming majority do not account for network perturbation effects from multiple single\u2010nucleotide alterations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here we present an improvement of the mutational forks formalism to infer the patient\u2010specific flow of signal transduction based on multiple single\u2010nucleotide alterations, including non\u2010synonymous and synonymous mutations. The lung adenocarcinoma and skin cutaneous melanoma datasets from TCGA Pan\u2010Cancer Atlas have been employed to show the utility of the proposed method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We have comprehensively characterized six mutational forks. The number of mutated nodes ranged from one to four depending on the topological characteristics of a fork. Transitional confidences (TCs) have been computed for every possible combination of single\u2010nucleotide alterations in the fork. The performed analysis demonstrated the capacity of the mutational forks formalism to follow a biologically explainable logic in the identification of high\u2010likelihood signaling routes in lung adenocarcinoma and skin cutaneous melanoma patients. The findings have been largely supported by the evidence from the biomedical literature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We conclude that the formalism has a great chance to enable an assessment of patient\u2010specific flow by leveraging information from multiple single\u2010nucleotide alterations to adjust the transitional likelihoods that are solely based on the canonical view of a disease.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s40484-020-0227-0","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T16:03:20Z","timestamp":1608653000000},"page":"336-346","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identifying patient\u2010specific flow of signal transduction perturbed by multiple single\u2010nucleotide alterations"],"prefix":"10.1002","volume":"8","author":[{"given":"Olha","family":"Kholod","sequence":"first","affiliation":[{"name":"<!--1--> MU Institute for Data Science and Informatics University of Missouri Columbia MO 65201 USA"},{"name":"<!--2--> Department Pathology and Anatomical Sciences School of Medicine University of Missouri Columbia MO 65212 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi\u2010Ren","family":"Shyu","sequence":"additional","affiliation":[{"name":"<!--1--> MU Institute for Data Science and Informatics University of Missouri Columbia MO 65201 USA"},{"name":"<!--5--> Department of Electrical Engineering &amp; Computer Science University of Missouri Columbia MO 65212 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Mitchem","sequence":"additional","affiliation":[{"name":"<!--1--> MU Institute for Data Science and Informatics University of Missouri Columbia MO 65201 USA"},{"name":"<!--3--> Department of Surgery School of Medicine University of Missouri Columbia MO 65212 USA"},{"name":"<!--4--> Harry S. Truman Memorial Veterans\u2019 Hospital Columbia MO 65201 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jussuf","family":"Kaifi","sequence":"additional","affiliation":[{"name":"<!--3--> Department of Surgery School of Medicine University of Missouri Columbia MO 65212 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitriy","family":"Shin","sequence":"additional","affiliation":[{"name":"<!--1--> MU Institute for Data Science and Informatics University of Missouri Columbia MO 65201 USA"},{"name":"<!--2--> Department Pathology and Anatomical Sciences School of Medicine University of Missouri Columbia MO 65212 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,12]]},"reference":[{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006098"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002375"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5MB00815H"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes10020143"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2011.0154"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102105\u201011\u2010505"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201023643\u20105"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201050790\u20100"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1720589115"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201048391\u2010y"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.056"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09860"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.244"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.12.10.1265"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5445.1741"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202004200"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201006\u20104788"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304212200"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101694\u20101"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425\u2010019\u20100659\u20100"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.21037\/jtd.2018.09.35"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201010489\u20102"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2825"},{"key":"e_1_2_8_25_2","doi-asserted-by":"crossref","unstructured":"Kholod O. 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