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

Deep Learning for Abstraction, Control and Monitoring of Complex Cyber-Physical Systems

Cyber-Physical Systems (CPS) consist of digital devices that interact with some physical components. Their popularity and complexity are growing exponentially, giving birth to new, previously unexplored, safety-critical application domains. As CPS permeate our daily lives, it becomes imperative to reason about their reliability. Formal methods provide rigorous techniques for verification, control and synthesis of safe and reliable CPS. However, these methods do not scale with the complexity of the system, thus their applicability to real-world problems is limited. A promising strategy is to leverage deep learning techniques to tackle the scalability issue of formal methods, transforming unfeasible problems into approximately solvable ones. The approximate models are trained over observations which are solutions of the formal problem. In this thesis, we focus on the following tasks, which are computationally challenging: the modeling and the simulation of a complex stochastic model, the design of a safe and robust control policy for a system acting in a highly uncertain environment and the runtime verification problem under full or partial observability. Our approaches, based on deep learning, are indeed applicable to real-world complex and safety-critical systems acting under strict real-time constraints and in presence of a significant amount of uncertainty.Cyber-Physical Systems (CPS) consist of digital devices that interact with some physical components. Their popularity and complexity are growing exponentially, giving birth to new, previously unexplored, safety-critical application domains. As CPS permeate our daily lives, it becomes imperative to reason about their reliability. Formal methods provide rigorous techniques for verification, control and synthesis of safe and reliable CPS. However, these methods do not scale with the complexity of the system, thus their applicability to real-world problems is limited. A promising strategy is to leverage deep learning techniques to tackle the scalability issue of formal methods, transforming unfeasible problems into approximately solvable ones. The approximate models are trained over observations which are solutions of the formal problem. In this thesis, we focus on the following tasks, which are computationally challenging: the modeling and the simulation of a complex stochastic model, the design of a safe and robust control policy for a system acting in a highly uncertain environment and the runtime verification problem under full or partial observability. Our approaches, based on deep learning, are indeed applicable to real-world complex and safety-critical systems acting under strict real-time constraints and in presence of a significant amount of uncertainty

Learning and Designing Stochastic Processes from Logical Constraints

Stochastic processes offer a flexible mathematical formalism to model and reason about systems. Most analysis tools, however, start from the premises that models are fully specified, so that any parameters controlling the system's dynamics must be known exactly. As this is seldom the case, many methods have been devised over the last decade to infer (learn) such parameters from observations of the state of the system. In this paper, we depart from this approach by assuming that our observations are {\it qualitative} properties encoded as satisfaction of linear temporal logic formulae, as opposed to quantitative observations of the state of the system. An important feature of this approach is that it unifies naturally the system identification and the system design problems, where the properties, instead of observations, represent requirements to be satisfied. We develop a principled statistical estimation procedure based on maximising the likelihood of the system's parameters, using recent ideas from statistical machine learning. We demonstrate the efficacy and broad applicability of our method on a range of simple but non-trivial examples, including rumour spreading in social networks and hybrid models of gene regulation

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

Approximation Techniques for Stochastic Analysis of Biological Systems

There has been an increasing demand for formal methods in the design process of safety-critical synthetic genetic circuits. Probabilistic model checking techniques have demonstrated significant potential in analyzing the intrinsic probabilistic behaviors of complex genetic circuit designs. However, its inability to scale limits its applicability in practice. This chapter addresses the scalability problem by presenting a state-space approximation method to remove unlikely states resulting in a reduced, finite state representation of the infinite-state continuous-time Markov chain that is amenable to probabilistic model checking. The proposed method is evaluated on a design of a genetic toggle switch. Comparisons with another state-of-art tool demonstrates both accuracy and efficiency of the presented method

Formal Quantitative Analysis of Reaction Networks Using Chemical Organisation Theory

Proceedings of CMSB 2016 will be published as a volume in Springer's Lecture Notes in Computer Science / Lecture Notes in Bioinformatics series (LNCS/LNBI)