Inter-species pathway perturbation prediction via data-driven detection of functional homology

Christoph Hafemeister, Roberto Romero, Erhan Bilal, Pablo Meyer, Raquel Norel, Kahn Rhrissorrakrai, Richard Bonneau, Adi L. Tarca

Research output: Contribution to journalArticlepeer-review

Abstract

Motivation: Experiments in animal models are often conducted to infer how humans will respond to stimuli by assuming that the same biological pathways will be affected in both organisms. The limitations of this assumption were tested in the IMPROVER Species Translation Challenge, where 52 stimuli were applied to both human and rat cells and perturbed pathways were identified. In the Inter-species Pathway Perturbation Prediction sub-challenge, multiple teams proposedmethods to use rat transcription data from 26 stimuli to predict human gene set and pathway activity under the same perturbations. Submissions were evaluated using three performance metrics on data from the remaining 26 stimuli. Results: We present two approaches, ranked second in this challenge, that do not rely on sequence-based orthology between rat and human genes to translate pathway perturbation state but instead identify transcriptional response orthologs across a set of training conditions. The translation from rat to human accomplished by these socalled direct methods is not dependent on the particular analysis method used to identify perturbed gene sets. In contrast, machine learning-based methods require performing a pathway analysis initially and then mapping the pathway activity between organisms. Unlike most machine learning approaches, direct methods can be used to predict the activation of a human pathway for a new (test) stimuli, even when that pathway was never activated by a training stimuli.

Original languageEnglish (US)
Pages (from-to)501-508
Number of pages8
JournalBioinformatics
Volume31
Issue number4
DOIs
StatePublished - Feb 15 2015

ASJC Scopus subject areas

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

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