A spatio-temporal model to reveal oscillator phenotypes in molecular clocks: Parameter estimation elucidates circadian gene transcription dynamics in single-cells.

We propose a stochastic distributed delay model together with a Markov random field prior and a measurement model for bioluminescence-reporting to analyse spatio-temporal gene expression in intact networks of cells. The model describes the oscillating time evolution of molecular mRNA counts through a negative transcriptional-translational feedback loop encoded in a chemical Langevin equation with a probabilistic delay distribution. The model is extended spatially by means of a multiplicative random effects model with a first order Markov random field prior distribution. Our methodology effectively separates intrinsic molecular noise, measurement noise, and extrinsic noise and phenotypic variation driving cell heterogeneity, while being amenable to parameter identification and inference. Based on the single-cell model we propose a novel computational stability analysis that allows us to infer two key characteristics, namely the robustness of the oscillations, i.e. whether the reaction network exhibits sustained or damped oscillations, and the profile of the regulation, i.e. whether the inhibition occurs over time in a more distributed versus a more direct manner, which affects the cells' ability to phase-shift to new schedules. We show how insight into the spatio-temporal characteristics of the circadian feedback loop in the suprachiasmatic nucleus (SCN) can be gained by applying the methodology to bioluminescence-reported expression of the circadian core clock gene Cry1 across mouse SCN tissue. We find that while (almost) all SCN neurons exhibit robust cell-autonomous oscillations, the parameters that are associated with the regulatory transcription profile give rise to a spatial division of the tissue between the central region whose oscillations are resilient to perturbation in the sense that they maintain a high degree of synchronicity, and the dorsal region which appears to phase shift in a more diversified way as a response to large perturbations and thus could be more amenable to entrainment

Stochastic spreading on complex networks

Complex interacting systems are ubiquitous in nature and society. Computational modeling of these systems is, therefore, of great relevance for science and engineering. Complex networks are common representations of these systems (e.g., friendship networks or road networks). Dynamical processes (e.g., virus spreading, traffic jams) that evolve on these networks are shaped and constrained by the underlying connectivity. This thesis provides numerical methods to study stochastic spreading processes on complex networks. We consider the processes as inherently probabilistic and analyze their behavior through the lens of probability theory. While powerful theoretical frameworks (like the SIS-epidemic model and continuous-time Markov chains) already exist, their analysis is computationally challenging. A key contribution of the thesis is to ease the computational burden of these methods. Particularly, we provide novel methods for the efficient stochastic simulation of these processes. Based on different simulation studies, we investigate techniques for optimal vaccine distribution and critically address the usage of mathematical models during the Covid-19 pandemic. We also provide model-reduction techniques that translate complicated models into simpler ones that can be solved without resorting to simulations. Lastly, we show how to infer the underlying contact data from node-level observations.Komplexe, interagierende Systeme sind in Natur und Gesellschaft allgegenwärtig. Die computergestützte Modellierung dieser Systeme ist daher von immenser Bedeutung für Wissenschaft und Technik. Netzwerke sind eine gängige Art, diese Systeme zu repräsentieren (z. B. Freundschaftsnetzwerke, Straßennetze). Dynamische Prozesse (z. B. Epidemien, Staus), die sich auf diesen Netzwerken ausbreiten, werden durch die spezifische Konnektivität geformt. In dieser Arbeit werden numerische Methoden zur Untersuchung stochastischer Ausbreitungsprozesse in komplexen Netzwerken entwickelt. Wir betrachten die Prozesse als inhärent probabilistisch und analysieren ihr Verhalten nach wahrscheinlichkeitstheoretischen Fragestellungen. Zwar gibt es bereits theoretische Grundlagen und Paradigmen (wie das SIS-Epidemiemodell und zeitkontinuierliche Markov-Ketten), aber ihre Analyse ist rechnerisch aufwändig. Ein wesentlicher Beitrag dieser Arbeit besteht darin, die Rechenlast dieser Methoden zu verringern. Wir erforschen Methoden zur effizienten Simulation dieser Prozesse. Anhand von Simulationsstudien untersuchen wir außerdem Techniken für optimale Impfstoffverteilung und setzen uns kritisch mit der Verwendung mathematischer Modelle bei der Covid-19-Pandemie auseinander. Des Weiteren führen wir Modellreduktionen ein, mit denen komplizierte Modelle in einfachere umgewandelt werden können. Abschließend zeigen wir, wie man von Beobachtungen einzelner Knoten auf die zugrunde liegende Netzwerkstruktur schließt

Doctor of Philosophy

dissertationFunctional magnetic resonance imaging (fMRI) measures the change of oxygen consumption level in the blood vessels of the human brain, hence indirectly detecting the neuronal activity. Resting-state fMRI (rs-fMRI) is used to identify the intrinsic functional patterns of the brain when there is no external stimulus. Accurate estimation of intrinsic activity is important for understanding the functional organization and dynamics of the brain, as well as differences in the functional networks of patients with mental disorders. This dissertation aims to robustly estimate the functional connectivities and networks of the human brain using rs-fMRI data of multiple subjects. We use Markov random field (MRF), an undirected graphical model to represent the statistical dependency among the functional network variables. Graphical models describe multivariate probability distributions that can be factorized and represented by a graph. By defining the nodes and the edges along with their weights according to our assumptions, we build soft constraints into the graph structure as prior information. We explore various approximate optimization methods including variational Bayesian, graph cuts, and Markov chain Monte Carlo sampling (MCMC). We develop the random field models to solve three related problems. In the first problem, the goal is to detect the pairwise connectivity between gray matter voxels in a rs-fMRI dataset of the single subject. We define a six-dimensional graph to represent our prior information that two voxels are more likely to be connected if their spatial neighbors are connected. The posterior mean of the connectivity variables are estimated by variational inference, also known as mean field theory in statistical physics. The proposed method proves to outperform the standard spatial smoothing and is able to detect finer patterns of brain activity. Our second work aims to identify multiple functional systems. We define a Potts model, a special case of MRF, on the network label variables, and define von Mises-Fisher distribution on the normalized fMRI signal. The inference is significantly more difficult than the binary classification in the previous problem. We use MCMC to draw samples from the posterior distribution of network labels. In the third application, we extend the graphical model to the multiple subject scenario. By building a graph including the network labels of both a group map and the subject label maps, we define a hierarchical model that has richer structure than the flat single-subject model, and captures the shared patterns as well as the variation among the subjects. All three solutions are data-driven Bayesian methods, which estimate model parameters from the data. The experiments show that by the regularization of MRF, the functional network maps we estimate are more accurate and more consistent across multiple sessions

Tools and Algorithms for the Construction and Analysis of Systems

This open access two-volume set constitutes the proceedings of the 27th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2021, which was held during March 27 – April 1, 2021, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2021. The conference was planned to take place in Luxembourg and changed to an online format due to the COVID-19 pandemic. The total of 41 full papers presented in the proceedings was carefully reviewed and selected from 141 submissions. The volume also contains 7 tool papers; 6 Tool Demo papers, 9 SV-Comp Competition Papers. The papers are organized in topical sections as follows: Part I: Game Theory; SMT Verification; Probabilities; Timed Systems; Neural Networks; Analysis of Network Communication. Part II: Verification Techniques (not SMT); Case Studies; Proof Generation/Validation; Tool Papers; Tool Demo Papers; SV-Comp Tool Competition Papers

Computer aided reliability, availability, and safety modeling for fault-tolerant computer systems with commentary on the HARP program

Many of the most challenging reliability problems of our present decade involve complex distributed systems such as interconnected telephone switching computers, air traffic control centers, aircraft and space vehicles, and local area and wide area computer networks. In addition to the challenge of complexity, modern fault-tolerant computer systems require very high levels of reliability, e.g., avionic computers with MTTF goals of one billion hours. Most analysts find that it is too difficult to model such complex systems without computer aided design programs. In response to this need, NASA has developed a suite of computer aided reliability modeling programs beginning with CARE 3 and including a group of new programs such as: HARP, HARP-PC, Reliability Analysts Workbench (Combination of model solvers SURE, STEM, PAWS, and common front-end model ASSIST), and the Fault Tree Compiler. The HARP program is studied and how well the user can model systems using this program is investigated. One of the important objectives will be to study how user friendly this program is, e.g., how easy it is to model the system, provide the input information, and interpret the results. The experiences of the author and his graduate students who used HARP in two graduate courses are described. Some brief comparisons were made with the ARIES program which the students also used. Theoretical studies of the modeling techniques used in HARP are also included. Of course no answer can be any more accurate than the fidelity of the model, thus an Appendix is included which discusses modeling accuracy. A broad viewpoint is taken and all problems which occurred in the use of HARP are discussed. Such problems include: computer system problems, installation manual problems, user manual problems, program inconsistencies, program limitations, confusing notation, long run times, accuracy problems, etc

Understanding Churn in Decentralized Peer-to-Peer Networks

This dissertation presents a novel modeling framework for understanding the dynamics of peer-to-peer (P2P) networks under churn (i.e., random user arrival/departure) and designing systems more resilient against node failure. The proposed models are applicable to general distributed systems under a variety of conditions on graph construction and user lifetimes. The foundation of this work is a new churn model that describes user arrival and departure as a superposition of many periodic (renewal) processes. It not only allows general (non-exponential) user lifetime distributions, but also captures heterogeneous behavior of peers. We utilize this model to analyze link dynamics and the ability of the system to stay connected under churn. Our results offers exact computation of user-isolation and graph-partitioning probabilities for any monotone lifetime distribution, including heavy-tailed cases found in real systems. We also propose an age-proportional random-walk algorithm for creating links in unstructured P2P networks that achieves zero isolation probability as system size becomes infinite. We additionally obtain many insightful results on the transient distribution of in-degree, edge arrival process, system size, and lifetimes of live users as simple functions of the aggregate lifetime distribution. The second half of this work studies churn in structured P2P networks that are usually built upon distributed hash tables (DHTs). Users in DHTs maintain two types of neighbor sets: routing tables and successor/leaf sets. The former tables determine link lifetimes and routing performance of the system, while the latter are built for ensuring DHT consistency and connectivity. Our first result in this area proves that robustness of DHTs is mainly determined by zone size of selected neighbors, which leads us to propose a min-zone algorithm that significantly reduces link churn in DHTs. Our second result uses the Chen-Stein method to understand concurrent failures among strongly dependent successor sets of many DHTs and finds an optimal stabilization strategy for keeping Chord connected under churn

Modelling and performability evaluation of Wireless Sensor Networks

This thesis presents generic analytical models of homogeneous clustered Wireless Sensor Networks (WSNs) with a centrally located Cluster Head (CH) coordinating cluster communication with the sink directly or through other intermediate nodes. The focus is to integrate performance and availability studies of WSNs in the presence of sensor nodes and channel failures and repair/replacement. The main purpose is to enhance improvement of WSN Quality of Service (QoS). Other research works also considered in this thesis include modelling of packet arrival distribution at the CH and intermediate nodes, and modelling of energy consumption at the sensor nodes. An investigation and critical analysis of wireless sensor network architectures, energy conservation techniques and QoS requirements are performed in order to improve performance and availability of the network. Existing techniques used for performance evaluation of single and multi-server systems with several operative states are investigated and analysed in details. To begin with, existing approaches for independent (pure) performance modelling are critically analysed with highlights on merits and drawbacks. Similarly, pure availability modelling approaches are also analysed. Considering that pure performance models tend to be too optimistic and pure availability models are too conservative, performability, which is the integration of performance and availability studies is used for the evaluation of the WSN models developed in this study. Two-dimensional Markov state space representations of the systems are used for performability modelling. Following critical analysis of the existing solution techniques, spectral expansion method and system of simultaneous linear equations are developed and used to solving the proposed models. To validate the results obtained with the two techniques, a discrete event simulation tool is explored. In this research, open queuing networks are used to model the behaviour of the CH when subjected to streams of traffic from cluster nodes in addition to dynamics of operating in the various states. The research begins with a model of a CH with an infinite queue capacity subject to failures and repair/replacement. The model is developed progressively to consider bounded queue capacity systems, channel failures and sleep scheduling mechanisms for performability evaluation of WSNs. Using the developed models, various performance measures of the considered system including mean queue length, throughput, response time and blocking probability are evaluated. Finally, energy models considering mean power consumption in each of the possible operative states is developed. The resulting models are in turn employed for the evaluation of energy saving for the proposed case study model. Numerical solutions and discussions are presented for all the queuing models developed. Simulation is also performed in order to validate the accuracy of the results obtained. In order to address issues of performance and availability of WSNs, current research present independent performance and availability studies. The concerns resulting from such studies have therefore remained unresolved over the years hence persistence poor system performance. The novelty of this research is a proposed integrated performance and availability modelling approach for WSNs meant to address challenges of independent studies. In addition, a novel methodology for modelling and evaluation of power consumption is also offered. Proposed model results provide remarkable improvement on system performance and availability in addition to providing tools for further optimisation studies. A significant power saving is also observed from the proposed model results. In order to improve QoS for WSN, it is possible to improve the proposed models by incorporating priority queuing in a mixed traffic environment. A model of multi-server system is also appropriate for addressing traffic routing. It is also possible to extend the proposed energy model to consider other sleep scheduling mechanisms other than On-demand proposed herein. Analysis and classification of possible arrival distribution of WSN packets for various application environments would be a great idea for enabling robust scientific research