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In recent years, a wide variety of graph neural network (GNN) architectures have emerged, each with its own strengths, weaknesses, and complexities. Various techniques, including rewiring, lifting, and node annotation with centrality values, have been employed as pre-processing steps to enhance GNN performance. However, there are no universally accepted best practices, and the impact of architecture and pre-processing on performance often remains opaque. This study systematically explores the impact of various graph transformations as pre-processing steps on the performance of common GNN architectures across standard datasets. The models are evaluated based on their ability to distinguish non-isomorphic graphs, referred to as expressivity. Our findings reveal that certain transformations, particularly those augmenting node features with centrality measures, consistently improve expressivity. However, these gains come with trade-offs, as methods like graph encoding, while enhancing expressivity, introduce numerical inaccuracies widely-used python packages. Additionally, we observe that these pre-processing techniques are limited when addressing complex tasks involving 3-WL and 4-WL indistinguishable graphs.

We propose an extension of the reinforcement learning architecture that enables moral decision-making of reinforcement learning agents based on normative reasons. Central to this approach is a reason-based shield generator yielding a moral shield that binds the agent to actions that conform with recognized normative reasons so that our overall architecture restricts the agent to actions that are (internally) morally justified. In addition, we describe an algorithm that allows to iteratively improve the reason-based shield generator through case-based feedback from a moral judge., Comment: 8 pages, 2 figures, Workshop paper accepted to FEAR24 (IFM Workshop)

Young stellar objects (YSOs) accrete up to half of their material in short periods of enhanced mass accretion. For massive YSOs (MYSOs with more than 8 solar masses), accretion outbursts are of special importance, as they serve as diagnostics in highly obscured regions. Within this work, two outbursting MYSOs within different evolutionary stages, the young source G358.93-0.03 MM1 (G358) and the more evolved one G323.46-0.08 (G323), are investigated, and the major burst parameters are derived. For both sources, follow-up observations with the airborne SOFIA observatory were performed to detect the FIR afterglows. All together, we took three burst-/post-observations in the far infrared. The burst parameters are needed to understand the accretion physics and to conclude on the possible triggering mechanisms behind it. Up to today, G323s burst is the most energetic one ever observed for a MYSO. G358s burst was about two orders of magnitude weaker and shorter (2 months instead of 8 years). We suggest that G358s burst was caused by the accretion of a spiral fragment (or a small planet), where G323 accreted a heavy object (a planet or even a potential companion). To model those sources, we use radiative transfer (RT) simulations (static and time-dependent). G323s accretion burst is the first astrophysical science case, that is modeled with time-dependent RT (TDRT). We incorporate a small TDRT parameter-study and develop a time-depending fitting tool (the TFitter) for future modeling., Comment: PhD Thesis

Monte Carlo estimation in plays a crucial role in stochastic reaction networks. However, reducing the statistical uncertainty of the corresponding estimators requires sampling a large number of trajectories. We propose control variates based on the statistical moments of the process to reduce the estimators' variances. We develop an algorithm that selects an efficient subset of infinitely many control variates. To this end, the algorithm uses resampling and a redundancy-aware greedy selection. We demonstrate the efficiency of our approach in several case studies., Comment: arXiv admin note: substantial text overlap with arXiv:1905.00854

Dynamical systems in which local interactions among agents give rise to complex emerging phenomena are ubiquitous in nature and society. This work explores the problem of inferring the unknown interaction structure (represented as a graph) of such a system from measurements of its constituent agents or individual components (represented as nodes). We consider a setting where the underlying dynamical model is unknown and where different measurements (i.e., snapshots) may be independent (e.g., may stem from different experiments). We propose GINA (Graph Inference Network Architecture), a graph neural network (GNN) to simultaneously learn the latent interaction graph and, conditioned on the interaction graph, the prediction of a node's observable state based on adjacent vertices. GINA is based on the hypothesis that the ground truth interaction graph -- among all other potential graphs -- allows to predict the state of a node, given the states of its neighbors, with the highest accuracy. We test this hypothesis and demonstrate GINA's effectiveness on a wide range of interaction graphs and dynamical processes.

To understand the long-run behavior of Markov population models, the computation of the stationary distribution is often a crucial part. We propose a truncation-based approximation that employs a state-space lumping scheme, aggregating states in a grid structure. The resulting approximate stationary distribution is used to iteratively refine relevant and truncate irrelevant parts of the state-space. This way, the algorithm learns a well-justified finite-state projection tailored to the stationary behavior. We demonstrate the method's applicability to a wide range of non-linear problems with complex stationary behaviors., Comment: arXiv admin note: text overlap with arXiv:2010.10096

Many probabilistic inference problems such as stochastic filtering or the computation of rare event probabilities require model analysis under initial and terminal constraints. We propose a solution to this bridging problem for the widely used class of population-structured Markov jump processes. The method is based on a state-space lumping scheme that aggregates states in a grid structure. The resulting approximate bridging distribution is used to iteratively refine relevant and truncate irrelevant parts of the state-space. This way the algorithm learns a well-justified finite-state projection yielding guaranteed lower bounds for the system behavior under endpoint constraints. We demonstrate the method's applicability to a wide range of problems such as Bayesian inference and the analysis of rare events.

Learning-based approaches for solving large sequential decision making problems have become popular in recent years. The resulting agents perform differently and their characteristics depend on those of the underlying learning approach. Here, we consider a benchmark planning problem from the reinforcement learning domain, the Racetrack, to investigate the properties of agents derived from different deep (reinforcement) learning approaches. We compare the performance of deep supervised learning, in particular imitation learning, to reinforcement learning for the Racetrack model. We find that imitation learning yields agents that follow more risky paths. In contrast, the decisions of deep reinforcement learning are more foresighted, i.e., avoid states in which fatal decisions are more likely. Our evaluations show that for this sequential decision making problem, deep reinforcement learning performs best in many aspects even though for imitation learning optimal decisions are considered., Comment: Extended Version of the Conference Paper published in the Proceedings of the 17th International Conference on Quantitative Evaluation of SysTems (QEST)

With recent advances in sequencing technologies, large amounts of epigenomic data have become available and computational methods are contributing significantly to the progress of epigenetic research. As an orthogonal approach to methods based on machine learning, mechanistic modeling aims at a description of the mechanisms underlying epigenetic changes. Here, we propose an efficient method for parameter estimation for stochastic models that describe the dynamics of DNA methylation patterns over time. Our method is based on the Generalized Method of Moments (GMM) and gives results with an accuracy similar to that of maximum likelihood-based estimation approaches. However, in contrast to the latter, the GMM still allows an efficient and accurate calibration of parameters even if the complexity of the model is increased by considering longer methylation patterns. We show the usefulness of our method by applying it to hairpin bisulfite sequencing data from mouse ESCs for varying pattern lengths., Comment: 12 pages, 3 figures, 1 table

We consider the problem of bounding mean first passage times for a class of continuous-time Markov chains that captures stochastic interactions between groups of identical agents. The quantitative analysis of such probabilistic population models is notoriously difficult since typically neither state-based numerical approaches nor methods based on stochastic sampling give efficient and accurate results. Here, we propose a technique that extends recently developed methods using semi-definite programming to determine bounds on mean first passage times. We further apply the technique to hybrid models and demonstrate its accuracy and efficiency for some examples from biology.

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., Comment: 10 pages, 3 figures, 1 table

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., Comment: 14 pages including 2 pages Appendix and 2 pages references

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.

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., Comment: 15 pages, 5 figures, 2 tables

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.

Discrete-state stochastic models are a popular approach to describe the inherent stochasticity of gene expression in single cells. The analysis of such models is hindered by the fact that the underlying discrete state space is extremely large. Therefore hybrid models, in which protein counts are replaced by average protein concentrations, have become a popular alternative. The evolution of the corresponding probability density functions is given by a coupled system of hyperbolic PDEs. This system has Markovian nature but its hyperbolic structure makes it difficult to apply standard functional analytical methods. We are able to prove convergence towards the stationary solution and determine such equilibrium explicitly by combining abstract methods from the theory of positive operators and elementary ideas from potential analysis., Comment: 23 pages, 7 figures

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.

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., Comment: 16 pages, 3 figures, 2 tables, V3: added performance comparison for numerical solution + 1 reference

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., Comment: 18 pages, 7 figures, content of former appendix now included in the main part; accepted by 15th International Conference on Computational Methods in Systems Biology (CMSB), 2017

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., Comment: 16 pages with the Appendix

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.

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., Comment: 18 pages, 5 figures, minor changes concerning measurement errors

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., Comment: 28 pages, 6 figures

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., Comment: The paper has been presented in HSB 2014

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., Comment: 10 pages, 5 figures, supplementary information

The classical problem of moments is addressed by the maximum entropy approach for one-dimensional discrete distributions. The numerical technique of adaptive support approximation is proposed to reconstruct the distributions in the region where the main part of probability mass is located., Comment: 5 pages

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.

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., Comment: 4 pages

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.

The importance of stochasticity within biological systems has been shown repeatedly during the last years and has raised the need for efficient stochastic tools. We present SABRE, a tool for stochastic analysis of biochemical reaction networks. SABRE implements fast adaptive uniformization (FAU), a direct numerical approximation algorithm for computing transient solutions of biochemical reaction networks. Biochemical reactions networks represent biological systems studied at a molecular level and these reactions can be modeled as transitions of a Markov chain. SABRE accepts as input the formalism of guarded commands, which it interprets either as continuous-time or as discrete-time Markov chains. Besides operating in a stochastic mode, SABRE may also perform a deterministic analysis by directly computing a mean-field approximation of the system under study. We illustrate the different functionalities of SABRE by means of biological case studies.

We present a numerical approximation technique for the analysis of continuous-time Markov chains that describe networks of biochemical reactions and play an important role in the stochastic modeling of biological systems. Our approach is based on the construction of a stochastic hybrid model in which certain discrete random variables of the original Markov chain are approximated by continuous deterministic variables. We compute the solution of the stochastic hybrid model using a numerical algorithm that discretizes time and in each step performs a mutual update of the transient probability distribution of the discrete stochastic variables and the values of the continuous deterministic variables. We implemented the algorithm and we demonstrate its usefulness and efficiency on several case studies from systems biology., Comment: 10 pages