Isolating structural errors in reaction networks in systems biology

Motivation: The growing complexity of reaction-based models necessitates early detection and resolution of model errors. Considerable work has been done on the detection of mass balance errors, especially atomic mass analysis (AMA) (which compares the counts of atoms in the reactants and products) and Linear Programming analysis (which detects stoichiometric inconsistencies). This article extends model error checking to include: (i) certain structural errors in reaction networks and (ii) error isolation. First, we consider the balance of chemical structures (moieties) between reactants and products. This balance is expected in many biochemical reactions, but the imbalance of chemical structures cannot be detected if the analysis is done in units of atomic masses. Second, we improve on error isolation for stoichiometric inconsistencies by identifying a small number of reactions and/or species that cause the error. Doing so simplifies error remediation. Results: We propose two algorithms that address isolating structural errors in reaction networks. Moiety analysis finds imbalances of moieties using the same algorithm as AMA, but moiety analysis works in units of moieties instead of atomic masses. We argue for the value of checking moiety balance, and discuss two approaches to decomposing chemical species into moieties. Graphical Analysis of Mass Equivalence Sets (GAMES) provides isolation for stoichiometric inconsistencies by constructing explanations that relate errors in the structure of the reaction network to elements of the reaction network. We study the effectiveness of moiety analysis and GAMES on curated models in the BioModels repository. We have created open source codes for moiety analysis and GAMES.