MOTIVATION: Cancer somatic driver mutations associated with genes within a pathway often show a mutually exclusive pattern across a cohort of patients. This mutually exclusive mutational signal has been frequently used to distinguish driver from passenger mutations and to investigate relationships among driver mutations. Current methods for de novo discovery of mutually exclusive mutational patterns are limited because the heterogeneity in background mutation rate can confound mutational patterns, and the presence of highly mutated genes can lead to spurious patterns. In addition, most methods only focus on a limited number of pre-selected genes and are unable to perform genome-wide analysis due to computational inefficiency. RESULTS: We introduce a statistical framework, MEScan, for accurate and efficient mutual exclusivity analysis at the genomic scale. Our framework contains a fast and powerful statistical test for mutual exclusivity with adjustment of the background mutation rate and impact of highly mutated genes, and a multi-step procedure for genome-wide screening with the control of false discovery rate. We demonstrate that MEScan more accurately identifies mutually exclusive gene sets than existing methods and is at least two orders of magnitude faster than most methods. By applying MEScan to data from four different cancer types and pan-cancer, we have identified several biologically meaningful mutually exclusive gene sets. AVAILABILITY AND IMPLEMENTATION: MEScan is available as an R package at https://github.com/MarkeyBBSRF/MEScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: The Gene Ontology (GO) is the unifying biological vocabulary for codifying, managing and sharing biological knowledge. Quality issues in GO, if not addressed, can cause misleading results or missed biological discoveries. Manual identification of potential quality issues in GO is a challenging and arduous task, given its growing size. We introduce an automated auditing approach for suggesting potentially missing is-a relations, which may further reveal erroneous is-a relations. RESULTS: We developed a Subsumption-based Sub-term Inference Framework (SSIF) by leveraging a novel term-algebra on top of a sequence-based representation of GO concepts along with three conditional rules (monotonicity, intersection and sub-concept rules). Applying SSIF to the October 3, 2018 release of GO suggested 1938 unique potentially missing is-a relations. Domain experts evaluated a random sample of 210 potentially missing is-a relations. The results showed SSIF achieved a precision of 60.61, 60.49 and 46.03% for the monotonicity, intersection and sub-concept rules, respectively. AVAILABILITY AND IMPLEMENTATION: SSIF is implemented in Java. The source code is available at https://github.com/rashmie/SSIF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene Ontology (GO) provides a controlled vocabulary for describing genes and related gene products. Quality assurance of Gene ontology (GO) is a vital aspect of the terminology management lifecycle. In this paper, we introduce a lexical-based inference approach to detecting subtype (or isa) inconsistencies among GO terms (i.e., biological concepts). We first model the name of each concept as a set of words. Then, we generate hierarchically linked and unlinked pairs of concepts (A, B), where A and B have the same number of words, and contain common words as well as a single different word. Each linked concept-pair infers a linked term-pair, and each unlinked concept-pair infers an unlinked term-pair. A term-pair appearing as both linked and unlinked is considered a potential inconsistency, which may represent a subtype inconsistency between the original linked and unlinked concept-pair. Applying this approach to the 03/28/2017 release of GO, a total of 3,715 potential subtype inconsistencies were obtained. Evaluation of a random sample of potential inconsistencies revealed two types of potential errors: missing subtype relations and incorrect subtype relations in GO, and achieved an accuracy of 56.33% for detecting such errors. This indicates that this lexical-based inference approach using the set-of-words model is a promising way to facilitate quality improvement of GO.