Experimental Biological Protocols with Formal Semantics

Both experimental and computational biology is becoming increasingly automated. Laboratory experiments are now performed automatically on high-throughput machinery, while computational models are synthesized or inferred automatically from data. However, integration between automated tasks in the process of biological discovery is still lacking, largely due to incompatible or missing formal representations. While theories are expressed formally as computational models, existing languages for encoding and automating experimental protocols often lack formal semantics. This makes it challenging to extract novel understanding by identifying when theory and experimental evidence disagree due to errors in the models or the protocols used to validate them. To address this, we formalize the syntax of a core protocol language, which provides a unified description for the models of biochemical systems being experimented on, together with the discrete events representing the liquid-handling steps of biological protocols. We present both a deterministic and a stochastic semantics to this language, both defined in terms of hybrid processes. In particular, the stochastic semantics captures uncertainties in equipment tolerances, making it a suitable tool for both experimental and computational biologists. We illustrate how the proposed protocol language can be used for automated verification and synthesis of laboratory experiments on case studies from the fields of chemistry and molecular programming

Bounding Mean First Passage Times in Population Continuous-Time Markov Chains

We consider the problem of bounding mean first passage times and reachability probabilities for the class of population continuous-time Markov chains, which capture stochastic interactions between groups of identical agents. The quantitative analysis of such 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 novel approach that leverages techniques from martingale theory and stochastic processes to generate constraints on the statistical moments of first passage time distributions. These constraints induce a semi-definite program that can be used to compute exact bounds on reachability probabilities and mean first passage times without numerically solving the transient probability distribution of the process or sampling from it. We showcase the method on some test examples and tailor it to models exhibiting multimodality, a class of particularly challenging scenarios from biology

Numerical analysis of stochastic biochemical reaction networks

Numerical solution of the chemical master equation for stochastic reaction networks typically suffers from the state space explosion problem due to the curse of dimensionality and from stiffness due to multiple time scales. The dimension of the state space equals the number of molecular species involved in the reaction network and the size of the system of differential equations equals the number of states in the corresponding continuous-time Markov chain, which is usually enormously huge and often even infinite. Thus, efficient numerical solution approaches must be able to handle huge, possibly infinite and stiff systems of differential equations efficiently. In this thesis, we present efficient techniques for the numerical analysis of the biochemical reaction networks. We present an approximate numerical integration approach that combines a dynamical state space truncation procedure with efficient numerical integration schemes for systems of ordinary differential equations including adaptive step size selection based on local error estimates. We combine our dynamical state space truncation with the method of conditional moments, and present the implementation details and numerical results. We also incorporate ideas from importance sampling simulations into a non-simulative numerical method that approximates transient rare event probabilities based on a dynamical truncation of the state space. Finally, we present a maximum likelihood method for the estimation of the model parameters given noisy time series measurements of molecular counts. All approaches presented in this thesis are implemented as part of the tool STAR, which allows to model and simulate the biochemical reaction networks. The efficiency and accuracy is demonstrated by numerical examples.Numerische Lösungen der chemischen Master-Gleichung für stochastische Reaktionsnetzwerke leiden typischerweise an dem Zustandsraumexplosionsproblem aufgrund der hohen Dimensionalität und der Steifigkeit durch mehrfache Zeitskalen. Die Dimension des Zustandsraumes entspricht der Anzahl der molekularen Spezies von dem Reaktionsnetzwerk und die Größe des Systems von Differentialgleichungen entspricht der Anzahl der Zustände in der entsprechenden kontinuierlichen Markov-Kette, die in der Regel enorm gross und oft sogar unendlich gross ist. Daher müssen numerische Methoden in der Lage sein, riesige, eventuell unendlich grosse und steife Systeme von Differentialgleichungen effizient lösen zu können. In dieser Arbeit beschreiben wir effiziente Methoden für die numerische Analyse biochemischer Reaktionsnetzwerke. Wir betrachten einen inexakten numerischen Integrationsansatz, bei dem eine dynamische Zustandsraumbeschneidung und ein Verfahren mit einem effizienten numerischen Integrationsschema für Systeme von gewöhnlichen Differentialgleichungen benutzt werden. Wir kombinieren unsere dynamische Zustandsraumbeschneidungsmethode mit der Methode der bedingten Momente und beschreiben die Implementierungdetails und numerischen Ergebnisse. Wir benutzen auch Ideen des importance sampling für eine nicht-simulative numerische Methode, die basierend auf der Zustandsraumbeschneidung die Wahrscheinlichkeiten von seltenen Ereignissen berechnen kann. Schließlich beschreiben wir eine Maximum-Likelihood-Methode für die Schätzung der Modellparameter bei verrauschten Zeitreihenmessungen von molekularen Anzahlen. Alle in dieser Arbeit beschriebenen Ansätze sind in dem Software-Tool STAR implementiert, das erlaubt, biochemische Reaktionsnetzwerke zu modellieren und zu simulieren. Die Effizienz und die Genauigkeit werden durch numerische Beispiele gezeigt

Computer Aided Verification

This open access two-volume set LNCS 11561 and 11562 constitutes the refereed proceedings of the 31st International Conference on Computer Aided Verification, CAV 2019, held in New York City, USA, in July 2019. The 52 full papers presented together with 13 tool papers and 2 case studies, were carefully reviewed and selected from 258 submissions. The papers were organized in the following topical sections: Part I: automata and timed systems; security and hyperproperties; synthesis; model checking; cyber-physical systems and machine learning; probabilistic systems, runtime techniques; dynamical, hybrid, and reactive systems; Part II: logics, decision procedures; and solvers; numerical programs; verification; distributed systems and networks; verification and invariants; and concurrency