Dataset Information

A Nonlinear Mixed Effects Approach for Modeling the Cell-To-Cell Variability of Mig1 Dynamics in Yeast.

ABSTRACT: The last decade has seen a rapid development of experimental techniques that allow data collection from individual cells. These techniques have enabled the discovery and characterization of variability within a population of genetically identical cells. Nonlinear mixed effects (NLME) modeling is an established framework for studying variability between individuals in a population, frequently used in pharmacokinetics and pharmacodynamics, but its potential for studies of cell-to-cell variability in molecular cell biology is yet to be exploited. Here we take advantage of this novel application of NLME modeling to study cell-to-cell variability in the dynamic behavior of the yeast transcription repressor Mig1. In particular, we investigate a recently discovered phenomenon where Mig1 during a short and transient period exits the nucleus when cells experience a shift from high to intermediate levels of extracellular glucose. A phenomenological model based on ordinary differential equations describing the transient dynamics of nuclear Mig1 is introduced, and according to the NLME methodology the parameters of this model are in turn modeled by a multivariate probability distribution. Using time-lapse microscopy data from nearly 200 cells, we estimate this parameter distribution according to the approach of maximizing the population likelihood. Based on the estimated distribution, parameter values for individual cells are furthermore characterized and the resulting Mig1 dynamics are compared to the single cell times-series data. The proposed NLME framework is also compared to the intuitive but limited standard two-stage (STS) approach. We demonstrate that the latter may overestimate variabilities by up to almost five fold. Finally, Monte Carlo simulations of the inferred population model are used to predict the distribution of key characteristics of the Mig1 transient response. We find that with decreasing levels of post-shift glucose, the transient response of Mig1 tend to be faster, more extended, and displays an increased cell-to-cell variability.

SUBMITTER: Almquist J

PROVIDER: S-EPMC4404321 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A Nonlinear Mixed Effects Approach for Modeling the Cell-To-Cell Variability of Mig1 Dynamics in Yeast.

Almquist Joachim J Bendrioua Loubna L Adiels Caroline Beck CB Goksör Mattias M Hohmann Stefan S Jirstrand Mats M

PloS one 20150420 4

The last decade has seen a rapid development of experimental techniques that allow data collection from individual cells. These techniques have enabled the discovery and characterization of variability within a population of genetically identical cells. Nonlinear mixed effects (NLME) modeling is an established framework for studying variability between individuals in a population, frequently used in pharmacokinetics and pharmacodynamics, but its potential for studies of cell-to-cell variability ...[more]

PMID: 25893847

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Project description:Increasingly, often ecologist collects data with nonlinear trends, heterogeneous variances, temporal correlation, and hierarchical structure. Nonlinear mixed-effects models offer a flexible approach to such data, but the estimation and interpretation of these models present challenges, partly associated with the lack of worked examples in the ecological literature.We illustrate the nonlinear mixed-effects modeling approach using temporal dynamics of vegetation moisture with field data from northwestern Patagonia. This is a Mediterranean-type climate region where modeling temporal changes in live fuel moisture content are conceptually relevant (ecological theory) and have practical implications (fire management). We used this approach to answer whether moisture dynamics varies among functional groups and aridity conditions, and compared it with other simpler statistical models. The modeling process is set out "step-by-step": We start translating the ideas about the system dynamics to a statistical model, which is made increasingly complex in order to include different sources of variability and correlation structures. We provide guidelines and R scripts (including a new self-starting function) that make data analyses reproducible. We also explain how to extract the parameter estimates from the R output.Our modeling approach suggests moisture dynamic to vary between grasses and shrubs, and between grasses facing different aridity conditions. Compared to more classical models, the nonlinear mixed-effects model showed greater goodness of fit and met statistical assumptions. While the mixed-effects approach accounts for spatial nesting, temporal dependence, and variance heterogeneity; the nonlinear function allowed to model the seasonal pattern.Parameters of the nonlinear mixed-effects model reflected relevant ecological processes. From an applied perspective, the model could forecast the time when fuel moisture becomes critical to fire occurrence. Due to the lack of worked examples for nonlinear mixed-effects models in the literature, our modeling approach could be useful to diverse ecologists dealing with complex data.

Dataset Information

A Nonlinear Mixed Effects Approach for Modeling the Cell-To-Cell Variability of Mig1 Dynamics in Yeast.

Publications

A Nonlinear Mixed Effects Approach for Modeling the Cell-To-Cell Variability of Mig1 Dynamics in Yeast.

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