Abstract
Synthetic biology gives researchers the opportunity to rationally (re-)design cellular activities to achieve a desired function. The design of networks of pathways towards accomplishing this calls for the application of engineering principles, often using model-based tools. Success heavily depends on model reliability. Herein, we present a systematic methodology for developing predictive models comprising model formulation considerations, global sensitivity analysis, model reduction (for highly complex models or where experimental data are limited), optimal experimental design for parameter estimation, and predictive capability checking. Its efficacy and validity are demonstrated using an example from bioprocessing. This approach systematizes the process of developing reliable mathematical models at a minimum experimental cost, enabling in silico simulation and optimization.
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Jimenez Del Val I, Nagy JM, Kontoravdi C (2011) A dynamic mathematical model for monoclonal antibody N-linked glycosylation and nucleotide sugar donor transport within a maturing Golgi apparatus. Biotechnol Prog 27:1730–1743
Selvarasu S, Ho YS et al (2012) Combined in silico modeling and metabolomics analysis to characterize fed-batch CHO cell culture. Biotechnol Bioeng 109:1415–1429
Hildebrandt S, Raden D et al (2008) A top-down approach to mechanistic biological modeling: application to the single-chain antibody folding pathway. Biophys J 95:3535–3558
Saltelli A, Chan K, Scott EM (2000) Sensitivity analysis. Wiley, New York
Kendall M, Stuart A (1979) The advanced theory of statistics, vol 2. Macmillan, New York
Mckay MD (1995) Evaluating prediction uncertainty. US Nuclear Regulatory Commission and Los Alamos National Laboratory, Washington, DC
Cukier RI, Fortuin CM et al (1973) Study of sensitivity of coupled reaction systems to uncertainties in rate coefficients. 1. Theory. J Chem Phys 59:3873–3878
Cukier RI, Schaibly JH, Shuler KE (1975) Study of sensitivity of coupled reaction systems to uncertainties in rate coefficients. 3. Analysis of approximations. J Chem Phys 63:1140–1149
Cukier RI, Levine HB, Shuler KE (1978) Non-linear sensitivity analysis of multi-parameter model systems. J Comput Phys 26:1–42
Schaibly JH, Shuler KE (1973) Study of sensitivity of coupled reaction systems to uncertainties in rate coefficients. 2. Applications. J Chem Phys 59:3879–3888
Sobol IM (2001) Global sensitivity indices for nonlinear mathematical models and their Monte Carlo estimates. Math Comput Simul 55:271–280
Sobol IM, Kucherenko S (2009) Derivative based global sensitivity measures and their link with global sensitivity indices. Math Comput Simul 79:3009–3017
Kiparissides A, Kucherenko SS et al (2009) Global sensitivity analysis challenges in biological systems modeling. Ind Eng Chem Res 48:7168–7180
Versyck KJ, Claes JE, Vanimpe JF (1997) Practical identification of unstructured growth kinetics by application of optimal experimental design. Biotechnol Prog 13:524–531
Nathanson MH, Saidel GM (1985) Multiple-objective criteria for optimal experimental design—application to ferrokinetics. Am J Physiol 248:R378–R386
Munack A (1989) Optimal feeding strategy for identification of monod-type models by fed-batch experiments. Computer applications in fermentation technology: modelling and control of biotechnological processes. Elsevier Applied Science Publishers Ltd, Barking Essex
Van Derlinden E, Bernaerts K, Van Impe JF (2008) Accurate estimation of cardinal growth temperatures of Escherichia coli from optimal dynamic experiments. Int J Food Microbiol 128:89–100
Bernaerts K, Gysemans KPM et al (2006) Optimal experiment design for cardinal values estimation: guidelines for data collection (vol 100, pg 153, 2005). Int J Food Microbiol 110:112–113
Jacques JA (1998) Design of experiments. J Franklin Inst 335:259–279
Sidoli FR, Mantalaris A, Asprey SP (2004) Modelling of Mammalian cells and cell culture processes. Cytotechnology 44:27–46
Kontoravdi C, Asprey SP et al (2005) Application of global sensitivity analysis to determine goals for design of experiments: an example study on antibody-producing cell cultures. Biotechnol Progress 21:1128–1135
Process Systems Enterprise (2002) gPROMS Advanced User Guide, London, UK
Kontoravdi C, Pistikopoulos EN, Mantalaris A (2010) Systematic development of predictive mathematical models for animal cell cultures. Comput Chem Eng 34:1192–1198
Glacken MW, Fleischaker RJ, Sinskey AJ (1986) Reduction of waste product excretion via nutrient control: Possible strategies for maximizing product and cell yields on serum in cultures of mammalian cells. Biotechnol Bioeng 28:1376–1389
Miller WM, Blanch HW, Wilke CR (1988) A kinetic analysis of hybridoma growth and metabolism in batch and continuous suspension culture: Effect of nutrient concentration, dilution rate, and pH Biotechnology and Bioengineering 32(8):947–965
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Kontoravdi, C. (2013). Systematic Methodology for the Development of Mathematical Models for Biological Processes. In: Polizzi, K., Kontoravdi, C. (eds) Synthetic Biology. Methods in Molecular Biology, vol 1073. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-625-2_15
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DOI: https://doi.org/10.1007/978-1-62703-625-2_15
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Publisher Name: Humana Press, Totowa, NJ
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