Parameter inference in mechanistic models of cellular regulation and signalling pathways using gradient matching

A challenging problem in systems biology is parameter inference in mechanistic models of signalling pathways. In the present article, we investigate an approach based on gradient matching and nonparametric Bayesian modelling with Gaussian processes. We evaluate the method on two biological systems, related to the regulation of PIF4/5 in Arabidopsis thaliana, and the JAK/STAT signal transduction pathway

Parameter estimation of stochastic differential equation

Non-parametric modeling is a method which relies heavily on data and motivated by the smoothness properties in estimating a function which involves spline and non-spline approaches. Spline approach consists of regression spline and smoothing spline. Regression spline with Bayesian approach is considered in the first step of a two-step method in estimating the structural parameters for stochastic differential equation (SDE). The selection of knot and order of spline can be done heuristically based on the scatter plot. To overcome the subjective and tedious process of selecting the optimal knot and order of spline, an algorithm was proposed. A single optimal knot is selected out of all the points with exception of the first and the last data which gives the least value of Generalized Cross Validation (GCV) for each order of spline. The use is illustrated using observed data of opening share prices of Petronas Gas Bhd. The results showed that the Mean Square Errors (MSE) for stochastic model with parameters estimated using optimal knot for 1,000, 5,000 and 10,000 runs of Brownian motions are smaller than the SDE models with estimated parameters using knot selected heuristically. This verified the viability of the two-step method in the estimation of the drift and diffusion parameters of SDE with an improvement of a single knot selection

Estimation of constant and time-varying dynamic parameters of HIV infection in a nonlinear differential equation model

Modeling viral dynamics in HIV/AIDS studies has resulted in a deep understanding of pathogenesis of HIV infection from which novel antiviral treatment guidance and strategies have been derived. Viral dynamics models based on nonlinear differential equations have been proposed and well developed over the past few decades. However, it is quite challenging to use experimental or clinical data to estimate the unknown parameters (both constant and time-varying parameters) in complex nonlinear differential equation models. Therefore, investigators usually fix some parameter values, from the literature or by experience, to obtain only parameter estimates of interest from clinical or experimental data. However, when such prior information is not available, it is desirable to determine all the parameter estimates from data. In this paper we intend to combine the newly developed approaches, a multi-stage smoothing-based (MSSB) method and the spline-enhanced nonlinear least squares (SNLS) approach, to estimate all HIV viral dynamic parameters in a nonlinear differential equation model. In particular, to the best of our knowledge, this is the first attempt to propose a comparatively thorough procedure, accounting for both efficiency and accuracy, to rigorously estimate all key kinetic parameters in a nonlinear differential equation model of HIV dynamics from clinical data. These parameters include the proliferation rate and death rate of uninfected HIV-targeted cells, the average number of virions produced by an infected cell, and the infection rate which is related to the antiviral treatment effect and is time-varying. To validate the estimation methods, we verified the identifiability of the HIV viral dynamic model and performed simulation studies.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS290 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Parameter estimation of ODE's via nonparametric estimators

Ordinary differential equations (ODE's) are widespread models in physics, chemistry and biology. In particular, this mathematical formalism is used for describing the evolution of complex systems and it might consist of high-dimensional sets of coupled nonlinear differential equations. In this setting, we propose a general method for estimating the parameters indexing ODE's from times series. Our method is able to alleviate the computational difficulties encountered by the classical parametric methods. These difficulties are due to the implicit definition of the model. We propose the use of a nonparametric estimator of regression functions as a first-step in the construction of an M-estimator, and we show the consistency of the derived estimator under general conditions. In the case of spline estimators, we prove asymptotic normality, and that the rate of convergence is the usual $\sqrt{n}$-rate for parametric estimators. Some perspectives of refinements of this new family of parametric estimators are given.Comment: Published in at http://dx.doi.org/10.1214/07-EJS132 the Electronic Journal of Statistics (http://www.i-journals.org/ejs/) by the Institute of Mathematical Statistics (http://www.imstat.org

Sieve estimation of constant and time-varying coefficients in nonlinear ordinary differential equation models by considering both numerical error and measurement error

This article considers estimation of constant and time-varying coefficients in nonlinear ordinary differential equation (ODE) models where analytic closed-form solutions are not available. The numerical solution-based nonlinear least squares (NLS) estimator is investigated in this study. A numerical algorithm such as the Runge--Kutta method is used to approximate the ODE solution. The asymptotic properties are established for the proposed estimators considering both numerical error and measurement error. The B-spline is used to approximate the time-varying coefficients, and the corresponding asymptotic theories in this case are investigated under the framework of the sieve approach. Our results show that if the maximum step size of the $p$-order numerical algorithm goes to zero at a rate faster than $n^{-1/(p\wedge4)}$, the numerical error is negligible compared to the measurement error. This result provides a theoretical guidance in selection of the step size for numerical evaluations of ODEs. Moreover, we have shown that the numerical solution-based NLS estimator and the sieve NLS estimator are strongly consistent. The sieve estimator of constant parameters is asymptotically normal with the same asymptotic co-variance as that of the case where the true ODE solution is exactly known, while the estimator of the time-varying parameter has the optimal convergence rate under some regularity conditions. The theoretical results are also developed for the case when the step size of the ODE numerical solver does not go to zero fast enough or the numerical error is comparable to the measurement error. We illustrate our approach with both simulation studies and clinical data on HIV viral dynamics.Comment: Published in at http://dx.doi.org/10.1214/09-AOS784 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Robust Parameter Estimation for Rational Ordinary Differential Equations

We present a new approach for estimating parameters in rational ODE models from given (measured) time series data. In typical existing approaches, an initial guess for the parameter values is made from a given search interval. Then, in a loop, the corresponding outputs are computed by solving the ODE numerically, followed by computing the error from the given time series data. If the error is small, the loop terminates and the parameter values are returned. Otherwise, heuristics/theories are used to possibly improve the guess and continue the loop. These approaches tend to be non-robust in the sense that their accuracy depend on the search interval and the true parameter values; furthermore, they cannot handle the case where the parameters are locally identifiable. In this paper, we propose a new approach, which does not suffer from the above non-robustness. In particular, it does not require making good initial guesses for the parameter values or specifying search intervals. Instead, it uses differential algebra, interpolation of the data using rational functions, and multivariate polynomial system solving. We also compare the performance of the resulting software with several other estimation software packages.Comment: Updates regarding robustnes

Reconstructing nonlinear dynamic models of gene regulation using stochastic sampling

<p>Abstract</p> <p>Background</p> <p>The reconstruction of gene regulatory networks from time series gene expression data is one of the most difficult problems in systems biology. This is due to several reasons, among them the combinatorial explosion of possible network topologies, limited information content of the experimental data with high levels of noise, and the complexity of gene regulation at the transcriptional, translational and post-translational levels. At the same time, quantitative, dynamic models, ideally with probability distributions over model topologies and parameters, are highly desirable.</p> <p>Results</p> <p>We present a novel approach to infer such models from data, based on nonlinear differential equations, which we embed into a stochastic Bayesian framework. We thus address both the stochasticity of experimental data and the need for quantitative dynamic models. Furthermore, the Bayesian framework allows it to easily integrate prior knowledge into the inference process. Using stochastic sampling from the Bayes' posterior distribution, our approach can infer different likely network topologies and model parameters along with their respective probabilities from given data. We evaluate our approach on simulated data and the challenge #3 data from the DREAM 2 initiative. On the simulated data, we study effects of different levels of noise and dataset sizes. Results on real data show that the dynamics and main regulatory interactions are correctly reconstructed.</p> <p>Conclusions</p> <p>Our approach combines dynamic modeling using differential equations with a stochastic learning framework, thus bridging the gap between biophysical modeling and stochastic inference approaches. Results show that the method can reap the advantages of both worlds, and allows the reconstruction of biophysically accurate dynamic models from noisy data. In addition, the stochastic learning framework used permits the computation of probability distributions over models and model parameters, which holds interesting prospects for experimental design purposes.</p