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Holistic view on cell survival and DNA damage: how model-based data analysis supports exploration of dynamics in Biological systems


Weyland, Mathias S; Thumser-Henner, Pauline; Nytko, Katarzyna J; Rohrer Bley, Carla; Ulzega, Simone; Petri-Fink, Alke; Lattuada, Marco; Füchslin, Rudolf M; Scheidegger, Stephan (2020). Holistic view on cell survival and DNA damage: how model-based data analysis supports exploration of dynamics in Biological systems. Computational and Mathematical Methods in Medicine, 2020:5972594.

Abstract

In this work, a method is established to calibrate a model that describes the basic dynamics of DNA damage and repair. The model can be used to extend planning for radiotherapy and hyperthermia in order to include the biological effects. In contrast to “syntactic” models (e.g., describing molecular kinetics), the model used here describes radiobiological semantics, resulting in a more powerful model but also in a far more challenging calibration. Model calibration is attempted from clonogenic assay data (doses of 0–6 Gy) and from time-resolved comet assay data obtained within 6 h after irradiation with 6 Gy. It is demonstrated that either of those two sources of information alone is insufficient for successful model calibration, and that both sources of information combined in a holistic approach are necessary to find viable model parameters. Approximate Bayesian computation (ABC) with simulated annealing is used for parameter search, revealing two aspects that are beneficial to resolving the calibration problem: (1) assessing posterior parameter distributions instead of point-estimates and (2) combining calibration runs from different assays by joining posterior distributions instead of running a single calibration run with a combined, computationally very expensive objective function.

Abstract

In this work, a method is established to calibrate a model that describes the basic dynamics of DNA damage and repair. The model can be used to extend planning for radiotherapy and hyperthermia in order to include the biological effects. In contrast to “syntactic” models (e.g., describing molecular kinetics), the model used here describes radiobiological semantics, resulting in a more powerful model but also in a far more challenging calibration. Model calibration is attempted from clonogenic assay data (doses of 0–6 Gy) and from time-resolved comet assay data obtained within 6 h after irradiation with 6 Gy. It is demonstrated that either of those two sources of information alone is insufficient for successful model calibration, and that both sources of information combined in a holistic approach are necessary to find viable model parameters. Approximate Bayesian computation (ABC) with simulated annealing is used for parameter search, revealing two aspects that are beneficial to resolving the calibration problem: (1) assessing posterior parameter distributions instead of point-estimates and (2) combining calibration runs from different assays by joining posterior distributions instead of running a single calibration run with a combined, computationally very expensive objective function.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Veterinary Clinic > Department of Small Animals
05 Vetsuisse Faculty > Center for Applied Biotechnology and Molecular Medicine
05 Vetsuisse Faculty > Center for Clinical Studies
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Physical Sciences > Modeling and Simulation
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Immunology and Microbiology
Physical Sciences > Applied Mathematics
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, Modelling and Simulation, General Immunology and Microbiology, Applied Mathematics, General Medicine
Language:English
Date:6 July 2020
Deposited On:02 Dec 2020 16:20
Last Modified:23 Jun 2024 01:46
Publisher:Hindawi Publishing Corporation
ISSN:1748-670X
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1155/2020/5972594
Project Information:
  • : FunderSNSF
  • : Grant ID320030_163435
  • : Project TitleDynamic Thermal Dosimetric Concept for Evaluating Synergistic Effect of Combined Hyperthermia-Radiotherapy (HT-RT)
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)