Assessing uncertainty in model parameters based on sparse and noisy experimental data

Noriko Hiroi, Maciej Swat, Akira Funahashi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

To perform parametric identification of mathematical models of biological events, experimental data are rare to be sufficient to estimate target behaviors produced by complex non-linear systems. We performed parameter fitting to a cell cycle model with experimental data as an in silico experiment. We calibrated model parameters with the generalized least squares method with randomized initial values and checked local and global sensitivity of the model. Sensitivity analyses showed that parameter optimization induced less sensitivity except for those related to the metabolism of the transcription factors c-Myc and E2F, which are required to overcome a restriction point (R-point). We performed bifurcation analyses with the optimized parameters and found the bimodality was lost. This result suggests that accumulation of c-Myc and E2F induced dysfunction of R-point. We performed a second parameter optimization based on the results of sensitivity analyses and incorporating additional derived from recent in vivo data. This optimization returned the bimodal characteristics of the model with a narrower range of hysteresis than the original. This result suggests that the optimized model can more easily go through R-point and come back to the gap phase after once having overcome it. Two parameter space analyses showed metabolism of c-Myc is transformed as it can allow cell bimodal behavior with weak stimuli of growth factors. This result is compatible with the character of the cell line used in our experiments. At the same time, Rb, an inhibitor of E2F, can allow cell bimodal behavior with only a limited range of stimuli when it is activated, but with a wider range of stimuli when it is inactive. These results provide two insights; biologically, the two transcription factors play an essential role in malignant cells to overcome R-point with weaker growth factor stimuli, and theoretically, sparse time-course data can be used to change a model to a biologically expected state.

Original languageEnglish
Article numberArticle 128
JournalFrontiers in Physiology
Volume5 APR
DOIs
Publication statusPublished - 2014

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Uncertainty
Intercellular Signaling Peptides and Proteins
Transcription Factors
Theoretical Models
Least-Squares Analysis
Computer Simulation
Cell Cycle
Cell Line

Keywords

  • Bifurcation analysis
  • Fisher information matrix
  • Generalized least squares
  • Parametric identification
  • Sensitivity analysis

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Assessing uncertainty in model parameters based on sparse and noisy experimental data. / Hiroi, Noriko; Swat, Maciej; Funahashi, Akira.

In: Frontiers in Physiology, Vol. 5 APR, Article 128, 2014.

Research output: Contribution to journalArticle

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