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	Author	Sinisi, S.; Alimguzhin, V.; Mancini, T.; Tronci, E.; Leeners, B.
	Title	Complete populations of virtual patients for in silico clinical trials			Type	Journal Article
	Year	2021	Publication	Bioinformatics	Abbreviated Journal
	Volume		Issue		Pages	1-8
	Keywords
	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).
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	1367-4803	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @ ref10.1093/bioinformatics/btaa1026			Serial	182
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	Author	Mancini, T.; Mari, F.; Massini, A.; Melatti, I.; Tronci, E.
	Title	On Checking Equivalence of Simulation Scripts			Type	Journal Article
	Year	2021	Publication	Journal of Logical and Algebraic Methods in Programming	Abbreviated Journal
	Volume		Issue		Pages	100640
	Keywords	Formal verification, Simulation based formal verification, Formal Verification of cyber-physical systems, System-level formal verification
	Abstract	To support Model Based Design of Cyber-Physical Systems (CPSs) many simulation based approaches to System Level Formal Verification (SLFV) have been devised. Basically, these are Bounded Model Checking approaches (since simulation horizon is of course bounded) relying on simulators to compute the system dynamics and thereby verify the given system properties. The main obstacle to simulation based SLFV is the large number of simulation scenarios to be considered and thus the huge amount of simulation time needed to complete the verification task. To save on computation time, simulation based SLFV approaches exploit the capability of simulators to save and restore simulation states. Essentially, such a time saving is obtained by optimising the simulation script defining the simulation activity needed to carry out the verification task. Although such approaches aim to (bounded) formal verification, as a matter of fact, the proof of correctness of the methods to optimise simulation scripts basically relies on an intuitive semantics for simulation scripting languages. This hampers the possibility of formally showing that the optimisations introduced to speed up the simulation activity do not actually omit checking of relevant behaviours for the system under verification. The aim of this paper is to fill the above gap by presenting an operational semantics for simulation scripting languages and by proving soundness and completeness properties for it. This, in turn, enables formal proofs of equivalence between unoptimised and optimised simulation scripts.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	2352-2208	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @ Mancini2021100640			Serial	183
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	Author	Leeners, B.; Krueger, T.; Geraedts, K.; Tronci, E.; Mancini, T.; Ille, F.; Egli, M.; Roeblitz, S.; Wunder, D.; Saleh, L.; Schippert, C.; Hengartner, M.P.
	Title	Cognitive function in association with high estradiol levels resulting from fertility treatment			Type	Journal Article
	Year	2021	Publication	Hormones and Behavior	Abbreviated Journal
	Volume	130	Issue		Pages	104951
	Keywords	Cognition, Estrogen, Estradiol, Fertility treatment, Attention, Cognitive bias
	Abstract	The putative association between hormones and cognitive performance is controversial. While there is evidence that estradiol plays a neuroprotective role, hormone treatment has not been shown to improve cognitive performance. Current research is flawed by the evaluation of combined hormonal effects throughout the menstrual cycle or in the menopausal transition. The stimulation phase of a fertility treatment offers a unique model to study the effect of estradiol on cognitive function. This quasi-experimental observational study is based on data from 44 women receiving IVF in Zurich, Switzerland. We assessed visuospatial working memory, attention, cognitive bias, and hormone levels at the beginning and at the end of the stimulation phase of ovarian superstimulation as part of a fertility treatment. In addition to inter-individual differences, we examined intra-individual change over time (within-subject effects). The substantial increases in estradiol levels resulting from fertility treatment did not relate to any considerable change in cognitive functioning. As the tests applied represent a broad variety of cognitive functions on different levels of complexity and with various brain regions involved, we can conclude that estradiol does not show a significant short-term effect on cognitive function.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	0018-506x	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @ Leeners2021104951			Serial	185
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	Author	Sinisi, S.; Alimguzhin, V.; Mancini, T.; Tronci, E.
	Title	Reconciling interoperability with efficient Verification and Validation within open source simulation environments			Type	Journal Article
	Year	2021	Publication	Simulation Modelling Practice and Theory	Abbreviated Journal
	Volume		Issue		Pages	102277
	Keywords	Simulation, Verification and Validation, Interoperability, FMI/FMU, Model Exchange, Cyber-Physical Systems
	Abstract	A Cyber-Physical System (CPS) comprises physical as well as software subsystems. Simulation-based approaches are typically used to support design and Verification and Validation (V&V) of CPSs in several domains such as: aerospace, defence, automotive, smart grid and healthcare. Accordingly, many simulation-based tools are available to support CPS design. This, on one side, enables designers to choose the toolchain that best suits their needs, on the other side poses huge interoperability challenges when one needs to simulate CPSs whose subsystems have been designed and modelled using different toolchains. To overcome such an interoperability problem, in 2010 the Functional Mock-up Interface (FMI) has been proposed as an open standard to support both Model Exchange (ME) and Co-Simulation (CS) of simulation models created with different toolchains. FMI has been adopted by several modelling and simulation environments. Models adhering to such a standard are called Functional Mock-up Units (FMUs). Indeed FMUs play an essential role in defining complex CPSs through, e.g., the System Structure and Parametrization (SSP) standard. Simulation-based V&V of CPSs typically requires exploring different simulation scenarios (i.e., exogenous input sequences to the CPS under design). Many such scenarios have a shared prefix. Accordingly, to avoid simulating many times such shared prefixes, the simulator state at the end of a shared prefix is saved and then restored and used as a start state for the simulation of the next scenario. In this context, an important FMI feature is the capability to save and restore the internal FMU state on demand. This is crucial to increase efficiency of simulation-based V&V. Unfortunately, the implementation of this feature is not mandatory and it is available only within some commercial software. As a result, the interoperability enabled by the FMI standard cannot be fully exploited for V&V when using open-source simulation environments. This motivates developing such a feature for open-source CPS simulation environments. Accordingly, in this paper, we focus on JModelica, an open-source modelling and simulation environment for CPSs based on an open standard modelling language, namely Modelica. We describe how we have endowed JModelica with our open-source implementation of the FMI 2.0 functions needed to save and restore internal states of FMUs for ME. Furthermore, we present experimental results evaluating, through 934 benchmark models, correctness and efficiency of our extended JModelica. Our experimental results show that simulation-based V&V is, on average, 22 times faster with our get/set functionality than without it.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	1569-190x	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @ Sinisi2021102277			Serial	186
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	Author	Fischer, S.; Ehrig, R.; Schaefer, S.; Tronci, E.; Mancini, T.; Egli, M.; Ille, F.; Krueger, T.H.C.; Leeners, B.; Roeblitz, S.
	Title	Mathematical Modeling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation			Type	Journal Article
	Year	2021	Publication	Frontiers in Endocrinology	Abbreviated Journal
	Volume	12	Issue		Pages	117
	Keywords
	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.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	1664-2392	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @ ref10.3389/fendo.2021.613048			Serial	189
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	Author	Melatti, I.; Mari, F.; Mancini, T.; Prodanovic, M.; Tronci, E.
	Title	A Two-Layer Near-Optimal Strategy for Substation Constraint Management via Home Batteries			Type	Journal Article
	Year	2021	Publication	IEEE Transactions on Industrial Electronics	Abbreviated Journal
	Volume		Issue		Pages	1-1
	Keywords
	Abstract	Within electrical distribution networks, substation constraints management requires that aggregated power demand from residential users is kept within suitable bounds. Efficiency of substation constraints management can be measured as the reduction of constraints violations w.r.t. unmanaged demand. Home batteries hold the promise of enabling efficient and user-oblivious substation constraints management. Centralized control of home batteries would achieve optimal efficiency. However, it is hardly acceptable by users, since service providers (e.g., utilities or aggregators) would directly control batteries at user premises. Unfortunately, devising efficient hierarchical control strategies, thus overcoming the above problem, is far from easy. We present a novel two-layer control strategy for home batteries that avoids direct control of home devices by the service provider and at the same time yields near-optimal substation constraints management efficiency. Our simulation results on field data from 62 households in Denmark show that the substation constraints management efficiency achieved with our approach is at least 82% of the one obtained with a theoretical optimal centralized strategy.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN		ISBN		Medium
	Area		Expedition		Conference
	Notes	To appear			Approved	no
	Call Number	MCLab @ davi @ ref9513535			Serial	190
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	Author	Mancini, T.; Melatti, I.; Tronci, E.
	Title	Any-horizon uniform random sampling and enumeration of constrained scenarios for simulation-based formal verification			Type	Journal Article
	Year	2021	Publication	IEEE Transactions on Software Engineering	Abbreviated Journal
	Volume		Issue		Pages	1-1
	Keywords
	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.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	1939-3520	ISBN		Medium
	Area		Expedition		Conference
	Notes	To appear			Approved	no
	Call Number	MCLab @ davi @ ref9527998			Serial	191
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	Author	Tortora, L.; Meynen, G.; Bijlsma, J.; Tronci, E.; Ferracuti, S.
	Title	Neuroprediction and A.I. in Forensic Psychiatry and Criminal Justice: A Neurolaw Perspective			Type	Journal Article
	Year	2020	Publication	Frontiers in Psychology	Abbreviated Journal
	Volume	11	Issue		Pages	220
	Keywords
	Abstract	Advances in the use of neuroimaging in combination with A.I., and specifically the use of machine learning techniques, have led to the development of brain-reading technologies which, in the nearby future, could have many applications, such as lie detection, neuromarketing or brain-computer interfaces. Some of these could, in principle, also be used in forensic psychiatry. The application of these methods in forensic psychiatry could, for instance, be helpful to increase the accuracy of risk assessment and to identify possible interventions. This technique could be referred to as Ã‚â€˜A.I. neuroprediction,Ã‚â€™ and involves identifying potential neurocognitive markers for the prediction of recidivism. However, the future implications of this technique and the role of neuroscience and A.I. in violence risk assessment remain to be established. In this paper, we review and analyze the literature concerning the use of brain-reading A.I. for neuroprediction of violence and rearrest to identify possibilities and challenges in the future use of these techniques in the fields of forensic psychiatry and criminal justice, considering legal implications and ethical issues. The analysis suggests that additional research is required on A.I. neuroprediction techniques, and there is still a great need to understand how they can be implemented in risk assessment in the field of forensic psychiatry. Besides the alluring potential of A.I. neuroprediction, we argue that its use in criminal justice and forensic psychiatry should be subjected to thorough harms/benefits analyses not only when these technologies will be fully available, but also while they are being researched and developed.
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	1664-1078	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @ Neuroprediction-2020			Serial	180
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	Author	Pappagallo, A.; Massini, A.; Tronci, E.
	Title	Monte Carlo Based Statistical Model Checking of Cyber-Physical Systems: A Review			Type	Journal Article
	Year	2020	Publication	Information	Abbreviated Journal
	Volume	11	Issue	558	Pages
	Keywords
	Abstract
	Address
	Corporate Author				Thesis
	Publisher		Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN		ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @			Serial	181
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	Author	Sinisi, S.; Alimguzhin, V.; Mancini, T.; Tronci, E.; Mari, F.; Leeners, B.
	Title	Optimal Personalised Treatment Computation through In Silico Clinical Trials on Patient Digital Twins			Type	Journal Article
	Year	2020	Publication		Abbreviated Journal	Fundamenta Informaticae
	Volume	174	Issue		Pages	283-310
	Keywords	Artificial Intelligence; Virtual Physiological Human; In Silico Clinical Trials; Simulation; Personalised Medicine; In Silico Treatment Optimisation
	Abstract	In Silico Clinical Trials (ISCT), i.e. clinical experimental campaigns carried out by means of computer simulations, hold the promise to decrease time and cost for the safety and efficacy assessment of pharmacological treatments, reduce the need for animal and human testing, and enable precision medicine. In this paper we present methods and an algorithm that, by means of extensive computer simulation-based experimental campaigns (ISCT) guided by intelligent search, optimise a pharmacological treatment for an individual patient (precision medicine ). We show the effectiveness of our approach on a case study involving a real pharmacological treatment, namely the downregulation phase of a complex clinical protocol for assisted reproduction in humans.
	Address
	Corporate Author				Thesis
	Publisher	IOS Press	Place of Publication		Editor
	Language		Summary Language		Original Title
	Series Editor		Series Title		Abbreviated Series Title
	Series Volume		Series Issue		Edition
	ISSN	1875-8681	ISBN		Medium
	Area		Expedition		Conference
	Notes				Approved	no
	Call Number	MCLab @ davi @			Serial	187
Permanent link to this record