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A new efficient approach to fit stochastic models on the basis of high-throughput experimental data using a model of IRF7 gene expression as case study

Aguilera, Luis U. ; Zimmer, Christoph ; Kummer, Ursula

In: BMC Systems Biology, 11 (2017), Nr. 26. pp. 1-14. ISSN 1752-0509

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Background: Mathematical models are used to gain an integrative understanding of biochemical processes and networks. Commonly the models are based on deterministic ordinary differential equations. When molecular counts are low, stochastic formalisms like Monte Carlo simulations are more appropriate and well established. However, compared to the wealth of computational methods used to fit and analyze deterministic models, there is only little available to quantify the exactness of the fit of stochastic models compared to experimental data or to analyze different aspects of the modeling results. Results: Here, we developed a method to fit stochastic simulations to experimental high-throughput data, meaning data that exhibits distributions. The method uses a comparison of the probability density functions that are computed based on Monte Carlo simulations and the experimental data. Multiple parameter values are iteratively evaluated using optimization routines. The method improves its performance by selecting parameters values after comparing the similitude between the deterministic stability of the system and the modes in the experimental data distribution. As a case study we fitted a model of the IRF7 gene expression circuit to time-course experimental data obtained by flow cytometry. IRF7 shows bimodal dynamics upon IFN stimulation. This dynamics occurs due to the switching between active and basal states of the IRF7 promoter. However, the exact molecular mechanisms responsible for the bimodality of IRF7 is not fully understood. Conclusions: Our results allow us to conclude that the activation of the IRF7 promoter by the combination of IRF7 and ISGF3 is sufficient to explain the observed bimodal dynamics.

Item Type: Article
Journal or Publication Title: BMC Systems Biology
Volume: 11
Number: 26
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 28 Feb 2017 14:15
Date: 2017
ISSN: 1752-0509
Page Range: pp. 1-14
Faculties / Institutes: Service facilities > Interdisciplinary Center for Scientific Computing
Service facilities > Cluster of Excellence Cellular Networks
Service facilities > Centre for Organismal Studies Heidelberg (COS)
Service facilities > Graduiertenschulen > Graduiertenschule Molekulare und Zelluläre Biologie
Service facilities > Zentrum für Modellierung und Simulation in der Biowiss.
Subjects: 310 General statistics
570 Life sciences
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