Null diffusion-based enrichment for metabolomics data

PLoS One. 2017 Dec 6;12(12):e0189012. doi: 10.1371/journal.pone.0189012. eCollection 2017.

Abstract

Metabolomics experiments identify metabolites whose abundance varies as the conditions under study change. Pathway enrichment tools help in the identification of key metabolic processes and in building a plausible biological explanation for these variations. Although several methods are available for pathway enrichment using experimental evidence, metabolomics does not yet have a comprehensive overview in a network layout at multiple molecular levels. We propose a novel pathway enrichment procedure for analysing summary metabolomics data based on sub-network analysis in a graph representation of a reference database. Relevant entries are extracted from the database according to statistical measures over a null diffusive process that accounts for network topology and pathway crosstalk. Entries are reported as a sub-pathway network, including not only pathways, but also modules, enzymes, reactions and possibly other compound candidates for further analyses. This provides a richer biological context, suitable for generating new study hypotheses and potential enzymatic targets. Using this method, we report results from cells depleted for an uncharacterised mitochondrial gene using GC and LC-MS data and employing KEGG as a knowledge base. Partial validation is provided with NMR-based tracking of 13C glucose labelling of these cells.

Publication types

  • Validation Study

MeSH terms

  • Algorithms
  • Magnetic Resonance Spectroscopy
  • Metabolomics*
  • Models, Theoretical*

Grants and funding

This work was supported by the Spanish Ministry of Economy and Competitiveness (www.mineco.gob.es) [BFU2012-39521 and BFU2015-68354 to T.S., TEC2014-60337-R to A.P., SAF2011-30578 and BFU2014-57466 to O.Y.]. O.Y., A.P. and S.P. thank for funding the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and the Networking Biomedical Research Centre in the subject area of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), both initiatives of Instituto de Investigación Carlos III (ISCIII). S.A. was supported by a Finnish Cultural Society Fellowship. S.P. thanks the AGAUR FI-scholarship programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Takeda Cambridge Ltd provided support in the form of salaries for authors [FF], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.