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Bioengineering 2017, 4(2), 48; doi:10.3390/bioengineering4020048

Assessing and Resolving Model Misspecifications in Metabolic Flux Analysis

1
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
2
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editor: Xueyang Feng
Received: 14 March 2017 / Revised: 30 April 2017 / Accepted: 22 May 2017 / Published: 24 May 2017
(This article belongs to the Special Issue Applying Systems Biotechnology Tools to Study Cell Metabolism)
View Full-Text   |   Download PDF [851 KB, uploaded 24 May 2017]   |  

Abstract

Metabolic flux analysis (MFA) is an indispensable tool in metabolic engineering. The simplest variant of MFA relies on an overdetermined stoichiometric model of the cell’s metabolism under the pseudo-steady state assumption to evaluate the intracellular flux distribution. Despite its long history, the issue of model error in overdetermined MFA, particularly misspecifications of the stoichiometric matrix, has not received much attention. We evaluated the performance of statistical tests from linear least square regressions, namely Ramsey’s Regression Equation Specification Error Test (RESET), the F-test, and the Lagrange multiplier test, in detecting model misspecifications in the overdetermined MFA, particularly missing reactions. We further proposed an iterative procedure using the F-test to correct such an issue. Using Chinese hamster ovary and random metabolic networks, we demonstrated that: (1) a statistically significant regression does not guarantee high accuracy of the flux estimates; (2) the removal of a reaction with a low flux magnitude can cause disproportionately large biases in the flux estimates; (3) the F-test could efficiently detect missing reactions; and (4) the proposed iterative procedure could robustly resolve the omission of reactions. Our work demonstrated that statistical analysis and tests could be used to systematically assess, detect, and resolve model misspecifications in the overdetermined MFA. View Full-Text
Keywords: metabolic flux analysis; model misspecification; constraint-based model; stoichiometric model; Chinese hamster ovary cell culture metabolic flux analysis; model misspecification; constraint-based model; stoichiometric model; Chinese hamster ovary cell culture
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Gunawan, R.; Hutter, S. Assessing and Resolving Model Misspecifications in Metabolic Flux Analysis. Bioengineering 2017, 4, 48.

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