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Local Parametric Sensitivity Analysis AMATH 882 Lecture 4, Jan 17, 2013

Local Parametric Sensitivity Analysis AMATH 882 Lecture 4, Jan 17, 2013. Parametric Sensitivity Analysis. Parameters 1. Enzyme activity levels 2. Kinetics constants 3. Decay rates 4. Boundary conditions 5. Variables 1. Concentrations 2. Pathway fluxes 3. Dynamic response

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Local Parametric Sensitivity Analysis AMATH 882 Lecture 4, Jan 17, 2013

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  1. Local Parametric Sensitivity Analysis AMATH 882 Lecture 4, Jan 17, 2013

  2. Parametric Sensitivity Analysis Parameters 1. Enzyme activity levels 2. Kinetics constants 3. Decay rates 4. Boundary conditions 5. .... Variables 1. Concentrations 2. Pathway fluxes 3. Dynamic response 4. Growth rate 5. .... Parametric sensitivity analysis investigates the relationship between the variables and parameters in a biochemical network.

  3. Parametric Sensitivity Analysis:Example reaction kinetics: steady state:

  4. steady state: local sensitivity analysis: effect of perturbation/ intervention: relative sensitivity:

  5. sensitivity analysis: vector notation implicit differentiation steady state:

  6. complete sensitivity analysis:

  7. Sensitivity Analysis: General Computation model: steady state: differentiate: absolute sensitivity:

  8. Time-Varying Sensitivities Sensitivities can be addressed over transient or oscillatory behaviour Computation:

  9. Example Perturbation in S1(0) Perturbation in k1

  10. Application to Phototransduction Pathway

  11. Global Sensitivity Analysis • Addresses system behaviour over a wide range of parameter values • Primarily statistical tools: efficient sampling methods • Provides a broader view of behaviour, but… • Results often difficult to interpret

  12. Applications of Sensitivity Analysis • Predicting the effect of interventions • Drug development Trypanosome metabolism. Bakker et al., 1999,J. Biol. Chem

  13. Applications of Sensitivity Analysis • Predicting the effect of interventions • Drug development • Medicine • Tumour growth and thiamine, Comin-Anduix et al., 2001, Eur. J. Biochem.

  14. Applications of Sensitivity Analysis • Predicting the effect of interventions • Drug development • Medicine • Metabolic engineering • Diacetyl production in Lactococcus lactis, Hoefnagel et al. 2002, Microbiology

  15. Applications of Sensitivity Analysis • Predicting the effect of interventions • Drug development • Medicine • Metabolic engineering • Model construction and analysis • Identifying key variables • NF-B pathway. Ihekwaba et al., 2004, IEE Sys. Biol.

  16. Applications of Sensitivity Analysis • Predicting the effect of interventions • Drug development • Medicine • Metabolic engineering • Model construction and analysis • Identifying key variables • Model calibration • Identifiability. Zak et al. 2003, Genome. Res.

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