Parameter inference for a stochastic kinetic model of expanded polyglutamine proteins

Fisher, H.F.; Boys, R.J.; Gillespie, C.S.; Proctor, C.J.; Golightly, A.

Abstract

The presence of protein aggregates in cells is a known feature of many human age-related diseases, such as Huntington's disease. Simulations using fixed parameter values in a model of the dynamic evolution of expanded polyglutaime (PolyQ) proteins in cells have been used to gain a better understanding of the biological system. However, there is considerable uncertainty about the values of some of the parameters governing the system. Currently, appropriate values are chosen by ad hoc attempts to tune the parameters so that the model output matches experimental data. The problem is further complicated by the fact that the data only offer a partial insight into the underlying biological process: the data consist only of the proportions of cell death and of cells with inclusion bodies at a few time points, corrupted by measurement error. Developing inference procedures to estimate the model parameters in this scenario is a significant task. The model probabilities corresponding to the observed proportions cannot be evaluated exactly, and so they are estimated within the inference algorithm by repeatedly simulating realizations from the model. In general such an approach is computationally very expensive, and we therefore construct Gaussian process emulators for the key quantities and reformulate our algorithm around these fast stochastic approximations. We conclude by highlighting appropriate values of the model parameters leading to new insights into the underlying biological processes.

Citation

Fisher, H., Boys, R., Gillespie, C., Proctor, C., & Golightly, A. (2022). Parameter inference for a stochastic kinetic model of expanded polyglutamine proteins. Biometrics, 78(3), 1195-1208. https://doi.org/10.1111/biom.13467

• Journal Article Type: Article
• Acceptance Date: Mar 24, 2021
• Online Publication Date: May 6, 2021
• Publication Date: 2022-09
• Deposit Date: Feb 9, 2022
• Publicly Available Date: Jan 18, 2023
• Journal: Biometrics
• Print ISSN: 0006-341X
• Electronic ISSN: 1541-0420
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 78
• Issue: 3
• Pages: 1195-1208
• DOI: https://doi.org/10.1111/biom.13467