Quantitative Kinetic Models from Intravital Microcopy: A Case Study Using Hepatic Transport
arXiv:1908.10564 · doi:10.1021/acs.jpcb.9b04729
Abstract
The liver performs critical physiological functions, including metabolizing and removing substances, such as toxins and drugs, from the bloodstream. Hepatotoxicity itself is intimately linked to abnormal hepatic transport and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market. For this reason, we propose to analyze, across liver compartments, the transport kinetics of fluorescein-a fluorescent marker used as a proxy for drug molecules-using intravital microscopy data. To resolve the transport kinetics quantitatively from fluorescence data, we account for the effect that different liver compartments (with different chemical properties) have on fluorescein's emission rate. To do so, we develop ordinary differential equation transport models from the data where the kinetics are related to the observable fluorescence levels by "measurement parameters" that vary across different liver compartments. On account of the steep non-linearities in the kinetics and stochasticity inherent to the model, we infer kinetic and measurement parameters by generalizing the method of parameter cascades. For this application, the method of parameter cascades ensures fast and precise parameter estimates from noisy time traces.
arXiv comment38 pages, 7 figures,
References in corpus (5)
- Joining Forces of Bayesian and Frequentist Methodology: A Study for Inference in the Presence of Non-Identifiability
- Parameter estimation of ODE's via nonparametric estimators
- An introduction to infinite HMMs for single molecule data analysis
- Probability Measures for Numerical Solutions of Differential Equations
- A derivation of the master equation from path entropy maximization