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Verena Wolf

Publications and source records attributed to Verena Wolf.

At least 37 records · Page 2Linked to original sources
arXiv2019

A Stochastic Automata Network Description for Spatial DNA-Methylation Models

DNA methylation is an important biological mechanism to regulate gene expression and control cell development. Mechanistic modeling has become a popular approach to enhance our understanding of the dynamics of methylation pattern formation in living cells. Recent findings suggest that the methylation state of a cytosine base can be influenced by its DNA neighborhood. Therefore, it is necessary to generalize existing mathematical models that consider only one cytosine and its partner on the opposite DNA-strand (CpG), in order to include such neighborhood dependencies. One approach is to describe the system as a stochastic automata network (SAN) with functional transitions. We show that single-CpG models can successfully be generalized to multiple CpGs using the SAN description and verify the results by comparing them to results from extensive Monte-Carlo simulations.

q-bio.GN↗
arXiv2019

Rejection-Based Simulation of Non-Markovian Agents on Complex Networks

Stochastic models in which agents interact with their neighborhood according to a network topology are a powerful modeling framework to study the emergence of complex dynamic patterns in real-world systems. Stochastic simulations are often the preferred - sometimes the only feasible - way to investigate such systems. Previous research focused primarily on Markovian models where the random time until an interaction happens follows an exponential distribution. In this work, we study a general framework to model systems where each agent is in one of several states. Agents can change their state at random, influenced by their complete neighborhood, while the time to the next event can follow an arbitrary probability distribution. Classically, these simulations are hindered by high computational costs of updating the rates of interconnected agents and sampling the random residence times from arbitrary distributions. We propose a rejection-based, event-driven simulation algorithm to overcome these limitations. Our method over-approximates the instantaneous rates corresponding to inter-event times while rejection events counterbalance these over-approximations. We demonstrate the effectiveness of our approach on models of epidemic and information spreading.

cs.SI↗
arXiv2019

Control Variates for Stochastic Simulation of Chemical Reaction Networks

Stochastic simulation is a widely used method for estimating quantities in models of chemical reaction networks where uncertainty plays a crucial role. However, reducing the statistical uncertainty of the corresponding estimators requires the generation of a large number of simulation runs, which is computationally expensive. To reduce the number of necessary runs, we propose a variance reduction technique based on control variates. We exploit constraints on the statistical moments of the stochastic process to reduce the estimators' variances. We develop an algorithm that selects appropriate control variates in an on-line fashion and demonstrate the efficiency of our approach on several case studies.

q-bio.QM↗
arXiv2019

A Hybrid HMM Approach for the Dynamics of DNA Methylation

The understanding of mechanisms that control epigenetic changes is an important research area in modern functional biology. Epigenetic modifications such as DNA methylation are in general very stable over many cell divisions. DNA methylation can however be subject to specific and fast changes over a short time scale even in non-dividing (i.e. not-replicating) cells. Such dynamic DNA methylation changes are caused by a combination of active demethylation and de novo methylation processes which have not been investigated in integrated models. Here we present a hybrid (hidden) Markov model to describe the cycle of methylation and demethylation over (short) time scales. Our hybrid model decribes several molecular events either happening at deterministic points (i.e. describing mechanisms that occur only during cell division) and other events occurring at random time points. We test our model on mouse embryonic stem cells using time-resolved data. We predict methylation changes and estimate the efficiencies of the different modification steps related to DNA methylation and demethylation.

q-bio.GN↗
arXiv2019

Rejection-Based Simulation of Stochastic Spreading Processes on Complex Networks

Stochastic processes can model many emerging phenomena on networks, like the spread of computer viruses, rumors, or infectious diseases. Understanding the dynamics of such stochastic spreading processes is therefore of fundamental interest. In this work we consider the wide-spread compartment model where each node is in one of several states (or compartments). Nodes change their state randomly after an exponentially distributed waiting time and according to a given set of rules. For networks of realistic size, even the generation of only a single stochastic trajectory of a spreading process is computationally very expensive. Here, we propose a novel simulation approach, which combines the advantages of event-based simulation and rejection sampling. Our method outperforms state-of-the-art methods in terms of absolute run-time and scales significantly better, while being statistically equivalent.

cs.SI↗
arXiv2018

Stochastic Hybrid Models of Gene Regulatory Networks - A PDE Approach

A widely used approach to describe the dynamics of gene regulatory networks is based on the chemical master equation, which considers probability distributions over all possible combinations of molecular counts. The analysis of such models is extremely challenging due to their large discrete state space. We therefore propose a hybrid approximation approach based on a system of partial differential equations, where we assume a continuous-deterministic evolution for the protein counts. We discuss efficient analysis methods for both modeling approaches and compare their performance. We show that the hybrid approach yields accurate results for sufficiently large molecule counts, while reducing the computational effort from one ordinary differential equation for each state to one partial differential equation for each mode of the system. Furthermore, we give an analytical steady-state solution of the hybrid model for the case of a self-regulatory gene.

q-bio.MN↗
arXiv2018

Lumping the Approximate Master Equation for Multistate Processes on Complex Networks

Complex networks play an important role in human society and in nature. Stochastic multistate processes provide a powerful framework to model a variety of emerging phenomena such as the dynamics of an epidemic or the spreading of information on complex networks. In recent years, mean-field type approximations gained widespread attention as a tool to analyze and understand complex network dynamics. They reduce the model's complexity by assuming that all nodes with a similar local structure behave identically. Among these methods the approximate master equation (AME) provides the most accurate description of complex networks' dynamics by considering the whole neighborhood of a node. The size of a typical network though renders the numerical solution of multistate AME infeasible. Here, we propose an efficient approach for the numerical solution of the AME that exploits similarities between the differential equations of structurally similar groups of nodes. We cluster a large number of similar equations together and solve only a single lumped equation per cluster. Our method allows the application of the AME to real-world networks, while preserving its accuracy in computing estimates of global network properties, such as the fraction of nodes in a state at a given time.

cs.SI↗
arXiv2017

Lumping of Degree-Based Mean Field and Pair Approximation Equations for Multi-State Contact Processes

Contact processes form a large and highly interesting class of dynamic processes on networks, including epidemic and information spreading. While devising stochastic models of such processes is relatively easy, analyzing them is very challenging from a computational point of view, particularly for large networks appearing in real applications. One strategy to reduce the complexity of their analysis is to rely on approximations, often in terms of a set of differential equations capturing the evolution of a random node, distinguishing nodes with different topological contexts (i.e., different degrees of different neighborhoods), like degree-based mean field (DBMF), approximate master equation (AME), or pair approximation (PA). The number of differential equations so obtained is typically proportional to the maximum degree kmax of the network, which is much smaller than the size of the master equation of the underlying stochastic model, yet numerically solving these equations can still be problematic for large kmax. In this paper, we extend AME and PA, which has been proposed only for the binary state case, to a multi-state setting and provide an aggregation procedure that clusters together nodes having similar degrees, treating those in the same cluster as indistinguishable, thus reducing the number of equations while preserving an accurate description of global observables of interest. We also provide an automatic way to build such equations and to identify a small number of degree clusters that give accurate results. The method is tested on several case studies, where it shows a high level of compression and a reduction of computational time of several orders of magnitude for large networks, with minimal loss in accuracy.

cs.SI↗
arXiv2017

A Stochastic Model for the Formation of Spatial Methylation Patterns

DNA methylation is an epigenetic mechanism whose important role in development has been widely recognized. This epigenetic modification results in heritable changes in gene expression not encoded by the DNA sequence. The underlying mechanisms controlling DNA methylation are only partly understood and recently different mechanistic models of enzyme activities responsible for DNA methylation have been proposed. Here we extend existing Hidden Markov Models (HMMs) for DNA methylation by describing the occurrence of spatial methylation patterns over time and propose several models with different neighborhood dependencies. We perform numerical analysis of the HMMs applied to bisulfite sequencing measurements and accurately predict wild-type data. In addition, we find evidence that the enzymes' activities depend on the left 5' neighborhood but not on the right 3' neighborhood.

q-bio.GN↗
arXiv2016

Generalized Method of Moments for Estimating Parameters of Stochastic Reaction Networks

Discrete-state stochastic models have become a well-established approach to describe biochemical reaction networks that are influenced by the inherent randomness of cellular events. In the last years severalmethods for accurately approximating the statistical moments of such models have become very popular since they allow an efficient analysis of complex networks. We propose a generalized method of moments approach for inferring the parameters of reaction networks based on a sophisticated matching of the statistical moments of the corresponding stochastic model and the sample moments of population snapshot data. The proposed parameter estimation method exploits recently developed moment-based approximations and provides estimators with desirable statistical properties when a large number of samples is available. We demonstrate the usefulness and efficiency of the inference method on two case studies. The generalized method of moments provides accurate and fast estimations of unknown parameters of reaction networks. The accuracy increases when also moments of order higher than two are considered. In addition, the variance of the estimator decreases, when more samples are given or when higher order moments are included.

q-bio.MN↗
arXiv2016

H(O)TA: estimation of DNA methylation and hydroxylation levels and efficiencies from time course data

Methylation and hydroxylation of cytosines to form 5-methylcytosine (5mC) and 5-droxymethylcytosine (5hmC) belong to the most important epigenetic modifications and their vital role in the regulation of gene expression has been widely recognized. Recent experimental techniques allow to infer methylation and hydroxylation levels at CpG dinucleotides but require a sophisticated statistical analysis to achieve accurate estimates.

q-bio.GN↗
arXiv2015

Distribution approximations for the chemical master equation: comparison of the method of moments and the system size expansion

The stochastic nature of chemical reactions involving randomly fluctuating population sizes has lead to a growing research interest in discrete-state stochastic models and their analysis. A widely-used approach is the description of the temporal evolution of the system in terms of a chemical master equation (CME). In this paper we study two approaches for approximating the underlying probability distributions of the CME. The first approach is based on an integration of the statistical moments and the reconstruction of the distribution based on the maximum entropy principle. The second approach relies on an analytical approximation of the probability distribution of the CME using the system size expansion, considering higher-order terms than the linear noise approximation. We consider gene expression networks with unimodal and multimodal protein distributions to compare the accuracy of the two approaches. We find that both methods provide accurate approximations to the distributions of the CME while having different benefits and limitations in applications.

q-bio.QM↗
arXiv2015

Reconstruction of Multimodal Distributions for Hybrid Moment-based Chemical Kinetics, Supporting Information

The stochastic dynamics of biochemical reaction networks can be accurately described by discrete-state Markov processes where each chemical reaction corresponds to a state transition of the process. Due to the largeness problem of the state space, analysis techniques based on an exploration of the state space are often not feasible and the integration of the moments of the underlying probability distribution has become a very popular alternative. In this paper the focus is on a comparison of reconstructed distributions from their moments obtained by two different moment-based analysis methods, the method of moments (MM) and the method of conditional moments (MCM). We use the maximum entropy principle to derive a distribution that fits best to a given sequence of (conditional) moments. For the two gene regulatory networks that we consider we find that the MCM approach is more suitable to describe multimodal distributions and that the reconstruction is more accurate if conditional distributions are considered.

math.NA↗
arXiv2014

Optimal Observation Time Points in Stochastic Chemical Kinetics

Wet-lab experiments, in which the dynamics within living cells are observed, are usually costly and time consuming. This is particularly true if single-cell measurements are obtained using experimental techniques such as flow-cytometry or fluorescence microscopy. It is therefore important to optimize experiments with respect to the information they provide about the system. In this paper we make a priori predictions of the amount of information that can be obtained from measurements. We focus on the case where the measurements are made to estimate parameters of a stochastic model of the underlying biochemical reactions. We propose a numerical scheme to approximate the Fisher information of future experiments at different observation time points and determine optimal observation time points. To illustrate the usefulness of our approach, we apply our method to two interesting case studies.

q-bio.CB↗
arXiv2011

On-the-fly Uniformization of Time-Inhomogeneous Infinite Markov Population Models

This paper presents an on-the-fly uniformization technique for the analysis of time-inhomogeneous Markov population models. This technique is applicable to models with infinite state spaces and unbounded rates, which are, for instance, encountered in the realm of biochemical reaction networks. To deal with the infinite state space, we dynamically maintain a finite subset of the states where most of the probability mass is located. This approach yields an underapproximation of the original, infinite system. We present experimental results to show the applicability of our technique.

math.PR↗
arXiv2011

Parameter Identification for Markov Models of Biochemical Reactions

We propose a numerical technique for parameter inference in Markov models of biological processes. Based on time-series data of a process we estimate the kinetic rate constants by maximizing the likelihood of the data. The computation of the likelihood relies on a dynamic abstraction of the discrete state space of the Markov model which successfully mitigates the problem of state space largeness. We compare two variants of our method to state-of-the-art, recently published methods and demonstrate their usefulness and efficiency on several case studies from systems biology.

q-bio.QM↗
arXiv2010

Bounding the Equilibrium Distribution of Markov Population Models

Arguing about the equilibrium distribution of continuous-time Markov chains can be vital for showing properties about the underlying systems. For example in biological systems, bistability of a chemical reaction network can hint at its function as a biological switch. Unfortunately, the state space of these systems is infinite in most cases, preventing the use of traditional steady state solution techniques. In this paper we develop a new approach to tackle this problem by first retrieving geometric bounds enclosing a major part of the steady state probability mass, followed by a more detailed analysis revealing state-wise bounds.

math.PR↗