Search

Automation is becoming ubiquitous in all laboratory activities, leading towards precisely defined and codified laboratory protocols. However, the integration between laboratory protocols and mathematical models is still lacking. Models describe physical processes, while protocols define the steps carried out during an experiment: neither cover the domain of the other, although they both attempt to characterize the same phenomena. We should ideally start from an integrated description of both the model and the steps carried out to test it, to concurrently analyze uncertainties in model parameters, equipment tolerances, and data collection. To this end, we present a language to model and optimize experimental biochemical protocols that facilitates such an integrated description, and that can be combined with experimental data. We provide a probabilistic semantics for our language based on a Bayesian interpretation that formally characterizes the uncertainties in both the data collection, the underlying model, and the protocol operations. On a set of case studies we illustrate how the resulting framework allows for automated analysis and optimization of experimental protocols, including Gibson assembly protocols.

With recent high-throughput technology we can synthesize large heterogeneous collections of DNA structures, and also read them all out precisely in a single procedure. Can we use these tools, not only to do things faster, but also to devise new techniques and algorithms? In this paper we examine some DNA algorithms that assume high-throughput synthesis and sequencing. We aim to monitor, record, and read out the order in which a number $N$ of events occur, using $N^2$ redundant detectors, and (after sequencing) reconstructing the order by transitive reduction.

Gaussian processes (GPs) enable principled computation of model uncertainty, making them attractive for safety-critical applications. Such scenarios demand that GP decisions are not only accurate, but also robust to perturbations. In this paper we present a framework to analyse adversarial robustness of GPs, defined as invariance of the model's decision to bounded perturbations. Given a compact subset of the input space $T\subseteq \mathbb{R}^d$, a point $x^*$ and a GP, we provide provable guarantees of adversarial robustness of the GP by computing lower and upper bounds on its prediction range in $T$. We develop a branch-and-bound scheme to refine the bounds and show, for any $\epsilon > 0$, that our algorithm is guaranteed to converge to values $\epsilon$-close to the actual values in finitely many iterations. The algorithm is anytime and can handle both regression and classification tasks, with analytical formulation for most kernels used in practice. We evaluate our methods on a collection of synthetic and standard benchmark datasets, including SPAM, MNIST and FashionMNIST. We study the effect of approximate inference techniques on robustness and demonstrate how our method can be used for interpretability. Our empirical results suggest that the adversarial robustness of GPs increases with accurate posterior estimation., Comment: Submitted for publication

Motivation: Stochastic reaction networks are a widespread model to describe biological systems where the presence of noise is relevant, such as in cell regulatory processes. Unfortu-nately, in all but simplest models the resulting discrete state-space representation hinders analytical tractability and makes numerical simulations expensive. Reduction methods can lower complexity by computing model projections that preserve dynamics of interest to the user. Results: We present an exact lumping method for stochastic reaction networks with mass-action kinetics. It hinges on an equivalence relation between the species, resulting in a reduced network where the dynamics of each macro-species is stochastically equivalent to the sum of the original species in each equivalence class, for any choice of the initial state of the system. Furthermore, by an appropriate encoding of kinetic parameters as additional species, the method can establish equivalences that do not depend on specific values of the parameters. The method is supported by an efficient algorithm to compute the largest species equivalence, thus the maximal lumping. The effectiveness and scalability of our lumping technique, as well as the physical interpretability of resulting reductions, is demonstrated in several models of signaling pathways and epidemic processes on complex networks. Availability: The algorithms for species equivalence have been implemented in the software tool ERODE, freely available for download from https://www.erode.eu.

Kaemika is an app available on the four major app stores. It provides deterministic and stochastic simulation, supporting natural chemical notation enhanced with recursive and conditional generation of chemical reaction networks. It has a liquid-handling protocol sublanguage compiled to a virtual digital microfluidic device. Chemical and microfluidic simulations can be interleaved for full experimental-cycle modeling. A novel and unambiguous representation of directed multigraphs is used to lay out chemical reaction networks in graphical form.

Almost two centuries ago Pierre-Joseph Proudhon proposed social contracts -- voluntary agreements among free people -- as a foundation from which an egalitarian and just society can emerge. A \emph{digital social contract} is the novel incarnation of this concept for the digital age: a voluntary agreement between people that is specified, undertaken, and fulfilled in the digital realm. It embodies the notion of "code-is-law" in its purest form, in that a digital social contract is in fact a program -- code in a social contracts programming language, which specifies the digital actions parties to the social contract may take; and the parties to the contract are entrusted, equally, with the task of ensuring that each party abides by the contract. Parties to a social contract are identified via their public keys, and the one and only type of action a party to a digital social contract may take is a "digital speech act" -- signing an utterance with her private key and sending it to the other parties to the contract. Here, we present a formal definition of a digital social contract as agents that communicate asynchronously via crypto-speech acts, where the output of each agent is the input of all the other agents. We outline an abstract design for a social contracts programming language and show, via programming examples, that key application areas, including social community; simple sharing-economy applications; egalitarian currency networks; and democratic community governance, can all be expressed elegantly and efficiently as digital social contracts.

Gaussian Processes (GPs) are widely employed in control and learning because of their principled treatment of uncertainty. However, tracking uncertainty for iterative, multi-step predictions in general leads to an analytically intractable problem. While approximation methods exist, they do not come with guarantees, making it difficult to estimate their reliability and to trust their predictions. In this work, we derive formal probability error bounds for iterative prediction and planning with GPs. Building on GP properties, we bound the probability that random trajectories lie in specific regions around the predicted values. Namely, given a tolerance $\epsilon > 0 $, we compute regions around the predicted trajectory values, such that GP trajectories are guaranteed to lie inside them with probability at least $1-\epsilon$. We verify experimentally that our method tracks the predictive uncertainty correctly, even when current approximation techniques fail. Furthermore, we show how the proposed bounds can be employed within a safe reinforcement learning framework to verify the safety of candidate control policies, guiding the synthesis of provably safe controllers., Comment: An earlier version of this work presented in NeurIPS-2019 Workshop on Safety and Robustness in Decision Making. A shorter (but otherwise equivalent) paper was accepted to the 59th Conference on Decision and Control (CDC2020)

Deep neural network controllers for autonomous driving have recently benefited from significant performance improvements, and have begun deployment in the real world. Prior to their widespread adoption, safety guarantees are needed on the controller behaviour that properly take account of the uncertainty within the model as well as sensor noise. Bayesian neural networks, which assume a prior over the weights, have been shown capable of producing such uncertainty measures, but properties surrounding their safety have not yet been quantified for use in autonomous driving scenarios. In this paper, we develop a framework based on a state-of-the-art simulator for evaluating end-to-end Bayesian controllers. In addition to computing pointwise uncertainty measures that can be computed in real time and with statistical guarantees, we also provide a method for estimating the probability that, given a scenario, the controller keeps the car safe within a finite horizon. We experimentally evaluate the quality of uncertainty computation by several Bayesian inference methods in different scenarios and show how the uncertainty measures can be combined and calibrated for use in collision avoidance. Our results suggest that uncertainty estimates can greatly aid decision making in autonomous driving., Comment: 7 pages, 3 figures, submitted to ICRA 2020

We investigate adversarial robustness of Gaussian Process Classification (GPC) models. Given a compact subset of the input space $T\subseteq \mathbb{R}^d$ enclosing a test point $x^*$ and a GPC trained on a dataset $\mathcal{D}$, we aim to compute the minimum and the maximum classification probability for the GPC over all the points in $T$. In order to do so, we show how functions lower- and upper-bounding the GPC output in $T$ can be derived, and implement those in a branch and bound optimisation algorithm. For any error threshold $\epsilon > 0$ selected a priori, we show that our algorithm is guaranteed to reach values $\epsilon$-close to the actual values in finitely many iterations. We apply our method to investigate the robustness of GPC models on a 2D synthetic dataset, the SPAM dataset and a subset of the MNIST dataset, providing comparisons of different GPC training techniques, and show how our method can be used for interpretability analysis. Our empirical analysis suggests that GPC robustness increases with more accurate posterior estimation., Comment: 10 pages, 6 figures + Supplementary Material

Principles of feedback control have been shown to naturally arise in biological systems and successfully applied to build synthetic circuits. In this work we consider Biochemical Reaction Networks (CRNs) as a paradigm for modelling biochemical systems and provide the first implementation of a derivative component in CRNs. That is, given an input signal represented by the concentration level of some species, we build a CRN that produces as output the concentration of two species whose difference is the derivative of the input signal. By relying on this component, we present a CRN implementation of a feedback control loop with Proportional-Integral-Derivative (PID) controller and apply the resulting control architecture to regulate the protein expression in a microRNA regulated gene expression model., Comment: 8 Pages, 4 figures, Submitted to CDC 2019

We introduce a probabilistic robustness measure for Bayesian Neural Networks (BNNs), defined as the probability that, given a test point, there exists a point within a bounded set such that the BNN prediction differs between the two. Such a measure can be used, for instance, to quantify the probability of the existence of adversarial examples. Building on statistical verification techniques for probabilistic models, we develop a framework that allows us to estimate probabilistic robustness for a BNN with statistical guarantees, i.e., with a priori error and confidence bounds. We provide experimental comparison for several approximate BNN inference techniques on image classification tasks associated to MNIST and a two-class subset of the GTSRB dataset. Our results enable quantification of uncertainty of BNN predictions in adversarial settings., Comment: 9 pages, 6 figures

This work targets the development of an efficient abstraction method for formal analysis and control synthesis of discrete-time stochastic hybrid systems (SHS) with linear dynamics. The focus is on temporal logic specifications, both over finite and infinite time horizons. The framework constructs a finite abstraction as a class of uncertain Markov models known as interval Markov decision process (IMDP). Then, a strategy that maximizes the satisfaction probability of the given specification is synthesized over the IMDP and mapped to the underlying SHS. In contrast to existing formal approaches, which are by and large limited to finite-time properties and rely on conservative over-approximations, we show that the exact abstraction error can be computed as a solution of convex optimization problems and can be embedded into the IMDP abstraction. This is later used in the synthesis step over both finite- and infinite-horizon specifications, mitigating the known state-space explosion problem. Our experimental validation of the new approach compared to existing abstraction-based approaches shows: (i) significant (orders of magnitude) reduction of the abstraction error; (ii) marked speed-ups; and (iii) boosted scalability, allowing in particular to verify models with more than 10 continuous variables.

Electric circuits manipulate electric charge and magnetic flux via a small set of discrete components to implement useful functionality over continuous time-varying signals represented by currents and voltages. Much of the same functionality is useful to biological organisms, where it is implemented by a completely different set of discrete components (typically proteins) and signal representations (typically via concentrations). We describe how to take a linear electric circuit and systematically convert it to a chemical reaction network of the same functionality, as a dynamical system. Both the structure and the components of the electric circuit are dissolved in the process, but the resulting chemical network is intelligible. This approach provides access to a large library of well-studied devices, from analog electronics, whose chemical network realization can be compared to natural biochemical networks, or used to engineer synthetic biochemical networks.

Bayesian inference and Gaussian processes are widely used in applications ranging from robotics and control to biological systems. Many of these applications are safety-critical and require a characterization of the uncertainty associated with the learning model and formal guarantees on its predictions. In this paper we define a robustness measure for Bayesian inference against input perturbations, given by the probability that, for a test point and a compact set in the input space containing the test point, the prediction of the learning model will remain $\delta-$close for all the points in the set, for $\delta>0.$ Such measures can be used to provide formal guarantees for the absence of adversarial examples. By employing the theory of Gaussian processes, we derive tight upper bounds on the resulting robustness by utilising the Borell-TIS inequality, and propose algorithms for their computation. We evaluate our techniques on two examples, a GP regression problem and a fully-connected deep neural network, where we rely on weak convergence to GPs to study adversarial examples on the MNIST dataset.

It is well known that exact notions of model abstraction and reduction for dynamical systems may not be robust enough in practice because they are highly sensitive to the specific choice of parameters. In this paper we consider this problem for nonlinear ordinary differential equations (ODEs) with polynomial derivatives. We introduce approximate differential equivalence as a more permissive variant of a recently developed exact counterpart, allowing ODE variables to be related even when they are governed by nearby derivatives. We develop algorithms to (i) compute the largest approximate differential equivalence; (ii) construct an approximate quotient model from the original one via an appropriate parameter perturbation; and (iii) provide a formal certificate on the quality of the approximation as an error bound, computed as an over-approximation of the reachable set of the perturbed model. Finally, we apply approximate differential equivalences to study the effect of parametric tolerances in models of symmetric electric circuits., Comment: Accepted for publication at QEST 2018

We consider probabilistic model checking for continuous-time Markov chains (CTMCs) induced from Stochastic Reaction Networks (SRNs) against a fragment of Continuous Stochastic Logic (CSL) extended with reward operators. Classical numerical algorithms for CSL model checking based on uniformisation are limited to finite CTMCs and suffer from the state sapce explosion problem. On the other hand, approximate techniques such as mean-field approximations and simulations combined with statistical inference are more scalable, but can be time consuming and do not support the full expressiveness of CSL. In this paper we employ a continuous-space approximation of the CTMC in terms of a Gaussian process based on the Central Limit Approximation (CLA), also known as the Linear Noise Approximation (LNA), whose solution requires solving a number of differential equations that is quadratic in the number of species and independent of the population size. We then develop efficient and scalable approximate model checking algorithms on the resulting Gaussian process, where we restrict the target regions for probabilistic reachability to convex polytopes. This allows us to derive an abstraction in terms of a time-inhomogeneous discrete-time Markov chain (DTMC), whose dimension is independent of the number of species, on which model checking is performed. Using results from probability theory, we prove the convergence in distribution of our algorithms to the corresponding measures on the original CTMC. We implement the techniques and, on a set of examples, demonstrate that they allow us to overcome the state space explosion problem, while still correctly characterizing the stochastic behaviour of the system. Our methods can be used for formal analysis of a wide range of distributed stochastic systems, including biochemical systems, sensor networks and population protocols.

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.

In chemical reaction networks (CRNs) with stochastic semantics based on continuous-time Markov chains (CTMCs), the typically large populations of species cause combinatorially large state spaces. This makes the analysis very difficult in practice and represents the major bottleneck for the applicability of minimization techniques based, for instance, on lumpability. In this paper we present syntactic Markovian bisimulation (SMB), a notion of bisimulation developed in the Larsen-Skou style of probabilistic bisimulation, defined over the structure of a CRN rather than over its underlying CTMC. SMB identifies a lumpable partition of the CTMC state space a priori, in the sense that it is an equivalence relation over species implying that two CTMC states are lumpable when they are invariant with respect to the total population of species within the same equivalence class. We develop an efficient partition-refinement algorithm which computes the largest SMB of a CRN in polynomial time in the number of species and reactions. We also provide an algorithm for obtaining a quotient network from an SMB that induces the lumped CTMC directly, thus avoiding the generation of the state space of the original CRN altogether. In practice, we show that SMB allows significant reductions in a number of models from the literature. Finally, we study SMB with respect to the deterministic semantics of CRNs based on ordinary differential equations (ODEs), where each equation gives the time-course evolution of the concentration of a species. SMB implies forward CRN bisimulation, a recently developed behavioral notion of equivalence for the ODE semantics, in an analogous sense: it yields a smaller ODE system that keeps track of the sums of the solutions for equivalent species., Comment: Extended version (with proofs), of the corresponding paper published at KimFest 2017 (http://kimfest.cs.aau.dk/)

We explore the range of probabilistic behaviours that can be engineered with Chemical Reaction Networks (CRNs). We show that at steady state CRNs are able to "program" any distribution with finite support in $\mathbb{N}^m$, with $m \geq 1$. Moreover, any distribution with countable infinite support can be approximated with arbitrarily small error under the $L^1$ norm. We also give optimized schemes for special distributions, including the uniform distribution. Finally, we formulate a calculus to compute on distributions that is complete for finite support distributions, and can be compiled to a restricted class of CRNs that at steady state realize those distributions.

We present two quantitative behavioral equivalences over species of a chemical reaction network (CRN) with semantics based on ordinary differential equations. Forward CRN bisimulation identifies a partition where each equivalence class represents the exact sum of the concentrations of the species belonging to that class. Backward CRN bisimulation relates species that have the identical solutions at all time points when starting from the same initial conditions. Both notions can be checked using only CRN syntactical information, i.e., by inspection of the set of reactions. We provide a unified algorithm that computes the coarsest refinement up to our bisimulations in polynomial time. Further, we give algorithms to compute quotient CRNs induced by a bisimulation. As an application, we find significant reductions in a number of models of biological processes from the literature. In two cases we allow the analysis of benchmark models which would be otherwise intractable due to their memory requirements., Comment: Extended version of the CONCUR 2015 paper

Stochastic evolution of Chemical Reactions Networks (CRNs) over time is usually analysed through solving the Chemical Master Equation (CME) or performing extensive simulations. Analysing stochasticity is often needed, particularly when some molecules occur in low numbers. Unfortunately, both approaches become infeasible if the system is complex and/or it cannot be ensured that initial populations are small. We develop a probabilistic logic for CRNs that enables stochastic analysis of the evolution of populations of molecular species. We present an approximate model checking algorithm based on the Linear Noise Approximation (LNA) of the CME, whose computational complexity is independent of the population size of each species and polynomial in the number of different species. The algorithm requires the solution of first order polynomial differential equations. We prove that our approach is valid for any CRN close enough to the thermodynamical limit. However, we show on four case studies that it can still provide good approximation even for low molecule counts. Our approach enables rigorous analysis of CRNs that are not analyzable by solving the CME, but are far from the deterministic limit. Moreover, it can be used for a fast approximate stochastic characterization of a CRN.

Continuous Markovian Logic (CML) is a multimodal logic that expresses quantitative and qualitative properties of continuous-time labelled Markov processes with arbitrary (analytic) state-spaces, henceforth called continuous Markov processes (CMPs). The modalities of CML evaluate the rates of the exponentially distributed random variables that characterize the duration of the labeled transitions of a CMP. In this paper we present weak and strong complete axiomatizations for CML and prove a series of metaproperties, including the finite model property and the construction of canonical models. CML characterizes stochastic bisimilarity and it supports the definition of a quantified extension of the satisfiability relation that measures the "compatibility" between a model and a property. In this context, the metaproperties allows us to prove two robustness theorems for the logic stating that one can perturb formulas and maintain "approximate satisfaction"., Comment: Extended version of a paper presented at CSL2011

We study the Pi-calculus, enriched with pairing and non-blocking input, and define a notion of type assignment that uses the type constructor "arrow". We encode the circuits of the calculus X into this variant of Pi, and show that all reduction (cut-elimination) and assignable types are preserved. Since X enjoys the Curry-Howard isomorphism for Gentzen's calculus LK, this implies that all proofs in LK have a representation in Pi., Comment: International Workshop on Classical Logic and Computation (CL&C'08), Reykjavik, Iceland, July 2008

Reversing a (forward) computation history means undoing the history. In concurrent systems, undoing the history is not performed in a deterministic way but in a causally consistent fashion, where states that are reached during a backward computation are states that could have been reached during the computation history by just performing independent actions in a different order., Comment: Presented at MeCBIC 2011

We investigate the computing power of a restricted class of DNA strand displacement structures: those that are made of double strands with nicks (interruptions) in the top strand. To preserve this structural invariant, we impose restrictions on the single strands they interact with: we consider only two-domain single strands consisting of one toehold domain and one recognition domain. We study fork and join signal-processing gates based on these structures, and we show that these systems are amenable to formalization and to mechanical verification.

We introduce a natural language interface for building stochastic pi calculus models of biological systems. In this language, complex constructs describing biochemical events are built from basic primitives of association, dissociation and transformation. This language thus allows us to model biochemical systems modularly by describing their dynamics in a narrative-style language, while making amendments, refinements and extensions on the models easy. We demonstrate the language on a model of Fc-gamma receptor phosphorylation during phagocytosis. We provide a tool implementation of the translation into a stochastic pi calculus language, Microsoft Research's SPiM.