Abstract: New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts (“waves”) of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modeling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test ovarian stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.

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.