Topological augmentation to infer hidden processes in biological systems

Bioinformatics. 2014 Jan 15;30(2):221-7. doi: 10.1093/bioinformatics/btt638. Epub 2013 Dec 2.

Abstract

Motivation: A common problem in understanding a biochemical system is to infer its correct structure or topology. This topology consists of all relevant state variables-usually molecules and their interactions. Here we present a method called topological augmentation to infer this structure in a statistically rigorous and systematic way from prior knowledge and experimental data.

Results: Topological augmentation starts from a simple model that is unable to explain the experimental data and augments its topology by adding new terms that capture the experimental behavior. This process is guided by representing the uncertainty in the model topology through stochastic differential equations whose trajectories contain information about missing model parts. We first apply this semiautomatic procedure to a pharmacokinetic model. This example illustrates that a global sampling of the parameter space is critical for inferring a correct model structure. We also use our method to improve our understanding of glutamine transport in yeast. This analysis shows that transport dynamics is determined by glutamine permeases with two different kinds of kinetics. Topological augmentation can not only be applied to biochemical systems, but also to any system that can be described by ordinary differential equations.

Availability and implementation: Matlab code and examples are available at: http://www.csb.ethz.ch/tools/index

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Amino Acid Transport Systems, Basic / metabolism
  • Bayes Theorem
  • Gastrointestinal Tract / drug effects
  • Glutamine / metabolism
  • Humans
  • Models, Biological*
  • Pharmaceutical Preparations / administration & dosage
  • Pharmacokinetics
  • Saccharomyces cerevisiae / metabolism
  • Systems Biology*

Substances

  • Amino Acid Transport Systems, Basic
  • Pharmaceutical Preparations
  • Glutamine
  • glutamine permease