Splice Expression Variation Analysis (SEVA) for inter-tumor heterogeneity of gene isoform usage in cancer

Bahman Afsari, Theresa Guo, Michael Considine, Liliana Florea, Luciane T. Kagohara, Genevieve L. Stein-O'Brien, Dylan Kelley, Emily Flam, Kristina D. Zambo, Patrick K. Ha, Donald Geman, Michael F. Ochs, Joseph A. Califano, Daria A. Gaykalova, Alexander V. Favorov, Elana J. Fertig

Research output: Contribution to journalArticlepeer-review

Abstract

Motivation Current bioinformatics methods to detect changes in gene isoform usage in distinct phenotypes compare the relative expected isoform usage in phenotypes. These statistics model differences in isoform usage in normal tissues, which have stable regulation of gene splicing. Pathological conditions, such as cancer, can have broken regulation of splicing that increases the heterogeneity of the expression of splice variants. Inferring events with such differential heterogeneity in gene isoform usage requires new statistical approaches. Results We introduce Splice Expression Variability Analysis (SEVA) to model increased heterogeneity of splice variant usage between conditions (e.g. tumor and normal samples). SEVA uses a rank-based multivariate statistic that compares the variability of junction expression profiles within one condition to the variability within another. Simulated data show that SEVA is unique in modeling heterogeneity of gene isoform usage, and benchmark SEVA's performance against EBSeq, DiffSplice and rMATS that model differential isoform usage instead of heterogeneity. We confirm the accuracy of SEVA in identifying known splice variants in head and neck cancer and perform cross-study validation of novel splice variants. A novel comparison of splice variant heterogeneity between subtypes of head and neck cancer demonstrated unanticipated similarity between the heterogeneity of gene isoform usage in HPV-positive and HPV-negative subtypes and anticipated increased heterogeneity among HPV-negative samples with mutations in genes that regulate the splice variant machinery. These results show that SEVA accurately models differential heterogeneity of gene isoform usage from RNA-seq data.

Original languageEnglish (US)
Pages (from-to)1859-1867
Number of pages9
JournalBioinformatics
Volume34
Issue number11
DOIs
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Statistics and Probability
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Computational Mathematics

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