Scalable and flexible inference framework for stochastic dynamic single-cell models
(2022) In PLoS Computational Biology 18(5).- Abstract
Understanding the inherited nature of how biological processes dynamically change over time and exhibit intra- and inter-individual variability, due to the different responses to environmental stimuli and when interacting with other processes, has been a major focus of systems biology. The rise of single-cell fluorescent microscopy has enabled the study of those phenomena. The analysis of single-cell data with mechanistic models offers an invaluable tool to describe dynamic cellular processes and to rationalise cell-to-cell variability within the population. However, extracting mechanistic information from single-cell data has proven difficult. This requires statistical methods to infer unknown model parameters from dynamic,... (More)
Understanding the inherited nature of how biological processes dynamically change over time and exhibit intra- and inter-individual variability, due to the different responses to environmental stimuli and when interacting with other processes, has been a major focus of systems biology. The rise of single-cell fluorescent microscopy has enabled the study of those phenomena. The analysis of single-cell data with mechanistic models offers an invaluable tool to describe dynamic cellular processes and to rationalise cell-to-cell variability within the population. However, extracting mechanistic information from single-cell data has proven difficult. This requires statistical methods to infer unknown model parameters from dynamic, multi-individual data accounting for heterogeneity caused by both intrinsic (e.g. variations in chemical reactions) and extrinsic (e.g. variability in protein concentrations) noise. Although several inference methods exist, the availability of efficient, general and accessible methods that facilitate modelling of single-cell data, remains lacking. Here we present a scalable and flexible framework for Bayesian inference in state-space mixed-effects single-cell models with stochastic dynamic. Our approach infers model parameters when intrinsic noise is modelled by either exact or approximate stochastic simulators, and when extrinsic noise is modelled by either time-varying, or time-constant parameters that vary between cells. We demonstrate the relevance of our approach by studying how cell-to-cell variation in carbon source utilisation affects heterogeneity in the budding yeast Saccharomyces cerevisiae SNF1 nutrient sensing pathway. We identify hexokinase activity as a source of extrinsic noise and deduce that sugar availability dictates cell-to-cell variability.
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- author
- Persson, Sebastian ; Welkenhuysen, Niek ; Shashkova, Sviatlana ; Wiqvist, Samuel LU ; Reith, Patrick ; Schmidt, Gregor W. ; Picchini, Umberto and Cvijovic, Marija
- organization
- publishing date
- 2022-05-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS Computational Biology
- volume
- 18
- issue
- 5
- article number
- e1010082
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- scopus:85130816880
- pmid:35588132
- ISSN
- 1553-734X
- DOI
- 10.1371/journal.pcbi.1010082
- language
- English
- LU publication?
- yes
- id
- a99b8ea2-8c4a-433a-8a63-a82730a13d13
- date added to LUP
- 2022-09-30 13:40:13
- date last changed
- 2024-04-14 13:25:11
@article{a99b8ea2-8c4a-433a-8a63-a82730a13d13,
abstract = {{<p>Understanding the inherited nature of how biological processes dynamically change over time and exhibit intra- and inter-individual variability, due to the different responses to environmental stimuli and when interacting with other processes, has been a major focus of systems biology. The rise of single-cell fluorescent microscopy has enabled the study of those phenomena. The analysis of single-cell data with mechanistic models offers an invaluable tool to describe dynamic cellular processes and to rationalise cell-to-cell variability within the population. However, extracting mechanistic information from single-cell data has proven difficult. This requires statistical methods to infer unknown model parameters from dynamic, multi-individual data accounting for heterogeneity caused by both intrinsic (e.g. variations in chemical reactions) and extrinsic (e.g. variability in protein concentrations) noise. Although several inference methods exist, the availability of efficient, general and accessible methods that facilitate modelling of single-cell data, remains lacking. Here we present a scalable and flexible framework for Bayesian inference in state-space mixed-effects single-cell models with stochastic dynamic. Our approach infers model parameters when intrinsic noise is modelled by either exact or approximate stochastic simulators, and when extrinsic noise is modelled by either time-varying, or time-constant parameters that vary between cells. We demonstrate the relevance of our approach by studying how cell-to-cell variation in carbon source utilisation affects heterogeneity in the budding yeast Saccharomyces cerevisiae SNF1 nutrient sensing pathway. We identify hexokinase activity as a source of extrinsic noise and deduce that sugar availability dictates cell-to-cell variability.</p>}},
author = {{Persson, Sebastian and Welkenhuysen, Niek and Shashkova, Sviatlana and Wiqvist, Samuel and Reith, Patrick and Schmidt, Gregor W. and Picchini, Umberto and Cvijovic, Marija}},
issn = {{1553-734X}},
language = {{eng}},
month = {{05}},
number = {{5}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS Computational Biology}},
title = {{Scalable and flexible inference framework for stochastic dynamic single-cell models}},
url = {{http://dx.doi.org/10.1371/journal.pcbi.1010082}},
doi = {{10.1371/journal.pcbi.1010082}},
volume = {{18}},
year = {{2022}},
}