Abstract: Model-based approaches to safety and efficacy assessment of pharmacological drugs, treatment strategies, or medical devices (In Silico Clinical Trial, ISCT) aim to decrease time and cost for the needed experimentations, reduce animal and human testing, and enable precision medicine. Unfortunately, in presence of non-identifiable models (e.g., reaction networks), parameter estimation is not enough to generate complete populations of Virtual Patient (VPs), i.e., populations guaranteed to show the entire spectrum of model behaviours (phenotypes), thus ensuring representativeness of the trial.We present methods and software based on global search driven by statistical model checking that, starting from a (non-identifiable) quantitative model of the human physiology (plus drugs PK/PD) and suitable biological and medical knowledge elicited from experts, compute a population of VPs whose behaviours are representative of the whole spectrum of phenotypes entailed by the model (completeness) and pairwise distinguishable according to user-provided criteria. This enables full granularity control on the size of the population to employ in an ISCT, guaranteeing representativeness while avoiding over-representation of behaviours.We proved the effectiveness of our algorithm on a non-identifiable ODE-based model of the female Hypothalamic-Pituitary-Gonadal axis, by generating a population of 4 830 264 VPs stratified into 7 levels (at different granularity of behaviours), and assessed its representativeness against 86 retrospective health records from Pfizer, Hannover Medical School and University Hospital of Lausanne. The datasets are respectively covered by our VPs within Average Normalised Mean Absolute Error of 15%, 20%, and 35% (90% of the latter dataset is covered within 20% error).

Abstract: Model-based approaches to the verification of non-terminating Cyber-Physical Systems (CPSs) usually rely on numerical simulation of the System Under Verification (SUV) model under input scenarios of possibly varying duration, chosen among those satisfying given constraints. Such constraints typically stem from requirements (or assumptions) on the SUV inputs and its operational environment as well as from the enforcement of additional conditions aiming at, e.g., prioritising the (often extremely long) verification activity, by, e.g., focusing on scenarios explicitly exercising selected requirements, or avoiding </i>vacuity</i> in their satisfaction. In this setting, the possibility to efficiently sample at random (with a known distribution, e.g., uniformly) within, or to efficiently enumerate (possibly in a uniformly random order) scenarios among those satisfying all the given constraints is a key enabler for the practical viability of the verification process, e.g., via simulation-based statistical model checking. Unfortunately, in case of non-trivial combinations of constraints, iterative approaches like Markovian random walks in the space of sequences of inputs in general fail in extracting scenarios according to a given distribution (e.g., uniformly), and can be very inefficient to produce at all scenarios that are both legal (with respect to SUV assumptions) and of interest (with respect to the additional constraints). For example, in our case studies, up to 91% of the scenarios generated using such iterative approaches would need to be neglected. In this article, we show how, given a set of constraints on the input scenarios succinctly defined by multiple finite memory monitors, a data structure (scenario generator) can be synthesised, from which any-horizon scenarios satisfying the input constraints can be efficiently extracted by (possibly uniform) random sampling or (randomised) enumeration. Our approach enables seamless support to virtually all simulation-based approaches to CPS verification, ranging from simple random testing to statistical model checking and formal (i.e., exhaustive) verification, when a suitable bound on the horizon or an iterative horizon enlargement strategy is defined, as in the spirit of bounded model checking.

Abstract: One of the key points to take into account to foster effective introduction of AI planning and scheduling systems in real world is to develop end user trust in the related technologies. Automated planning and scheduling systems often brings solutions to the users which are neither “obvious� nor immediately acceptable for them. This is due to the ability of these tools to take into account quite an amount of temporal and causal constraints and to employ resolution processes often designed to optimize the solution with respect to non trivial evaluation functions. To increase technology trust, the study of tools for verifying and validating plans and schedules produced by AI systems might be instrumental. In general, validation and verification techniques represent a needed complementary technology in developing domain independent architectures for automated problem solving. This paper presents a preliminary report of the issues concerned with the use of two software tools for formal verification of finite state systems to the validation of the solutions produced by MrSPOCK, a recent effort for building a timeline based planning tool in an ESA project.

Abstract: System Level Analysis calls for a language comprehensible to experts with different background and yet precise enough to support meaningful analyses. SysML is emerging as an effective balance between such conflicting goals. In this paper we outline some the results obtained as for SysML based system level functional formal verification by an ESA/ESTEC study, with a collaboration among INTECS and La Sapienza University of Roma. The study focuses on SysML based system level functional requirements techniques.