F. Maggioli, T. Mancini, and E. Tronci. "SBML2Modelica: Integrating biochemical models within open-standard simulation ecosystems." Bioinformatics 36, no. 7 (2019): 2165â2172. ISSN: 1367-4803. DOI: 10.1093/bioinformatics/btz860.
Abstract: SBML is the most widespread language for the definition of biochemical models. Although dozens of SBML simulators are available, there is a general lack of support to the integration of SBML models within open-standard general-purpose simulation ecosystems. This hinders co-simulation and integration of SBML models within larger model networks, in order to, e.g., enable in-silico clinical trials of drugs, pharmacological protocols, or engineering artefacts such as biomedical devices against Virtual Physiological Human models.Modelica is one of the most popular existing open-standard general-purpose simulation languages, supported by many simulators. Modelica models are especially suited for the definition of complex networks of heterogeneous models from virtually all application domains. Models written in Modelica (and in 100+ other languages) can be readily exported into black-box Functional Mock-Up Units (FMUs), and seamlessly co-simulated and integrated into larger model networks within open-standard language-independent simulation ecosystems.In order to enable SBML model integration within heterogeneous model networks, we present SBML2Modelica, a software system translating SBML models into well-structured, user-intelligible, easily modifiable Modelica models. SBML2Modelica is SBML Level 3 Version 2 -compliant and succeeds on 96.47% of the SBML Test Suite Core (with a few rare, intricate, and easily avoidable combinations of constructs unsupported and cleanly signalled to the user). Our experimental campaign on 613 models from the BioModels database (with up to 5438 variables) shows that the major open-source (general-purpose) Modelica and FMU simulators achieve performance comparable to state-of-the-art specialised SBML simulators.SBML2Modelica is written in Java and is freely available for non-commercial use at https://bitbucket.org/mclab/sbml2modelica
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S. Sinisi, V. Alimguzhin, T. Mancini, E. Tronci, and B. Leeners. "Complete populations of virtual patients for in silico clinical trials." Bioinformatics (2021): 1–8. ISSN: 1367-4803. DOI: 10.1093/bioinformatics/btaa1026.
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).
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Enrico Tronci. "Defining Data Structures via Böhm-Out." J. Funct. Program. 5, no. 1 (1995): 51–64. DOI: 10.1017/S0956796800001234.
Abstract: We show that any recursively enumerable subset of a data structure can be regarded as the solution set to a B??hm-out problem.
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Amedeo Cesta, Alberto Finzi, Simone Fratini, Andrea Orlandini, and Enrico Tronci. "Validation and verification issues in a timeline-based planning system." The Knowledge Engineering Review 25, no. 03 (2010): 299–318. Cambridge University Press. DOI: 10.1017/S0269888910000160.
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 ââ¬Åobviousââ¬Â 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.
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Riccardo Focardi, Roberto Gorrieri, Ruggero Lanotte, Andrea Maggiolo-Schettini, Fabio Martinelli, Simone Tini, and Enrico Tronci. "Formal Models of Timing Attacks on Web Privacy." Electronic Notes in Theoretical Computer Science 62 (2002): 229–243. Notes: TOSCA 2001, Theory of Concurrency, Higher Order Languages and Types. DOI: 10.1016/S1571-0661(04)00329-9.
Abstract: We model a timing attack on web privacy proposed by Felten and Schneider by using three different approaches: HL-Timed Automata, SMV model checker, and tSPA Process Algebra. Some comparative analysis on the three approaches is derived.
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Marco Gribaudo, Andras Horváth, Andrea Bobbio, Enrico Tronci, Ester Ciancamerla, and Michele Minichino. "Fluid Petri Nets and hybrid model checking: a comparative case study." Int. Journal on: Reliability Engineering & System Safety 81, no. 3 (2003): 239–257. Elsevier. DOI: 10.1016/S0951-8320(03)00089-9.
Abstract: The modeling and analysis of hybrid systems is a recent and challenging research area which is actually dominated by two main lines: a functional analysis based on the description of the system in terms of discrete state (hybrid) automata (whose goal is to ascertain conformity and reachability properties), and a stochastic analysis (whose aim is to provide performance and dependability measures). This paper investigates a unifying view between formal methods and stochastic methods by proposing an analysis methodology of hybrid systems based on Fluid Petri Nets (FPNs). FPNs can be analyzed directly using appropriate tools. Our paper shows that the same FPN model can be fed to different functional analyzers for model checking. In order to extensively explore the capability of the technique, we have converted the original FPN into languages for discrete as well as hybrid as well as stochastic model checkers. In this way, a first comparison among the modeling power of well known tools can be carried out. Our approach is illustrated by means of a ââ¬â¢real worldââ¬â¢ hybrid system: the temperature control system of a co-generative plant.
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B. Leeners, T. Krueger, K. Geraedts, E. Tronci, T. Mancini, F. Ille, M. Egli, S. Roeblitz, D. Wunder, L. Saleh et al. "Cognitive function in association with high estradiol levels resulting from fertility treatment." Hormones and Behavior 130 (2021): 104951. ISSN: 0018-506x. DOI: 10.1016/j.yhbeh.2021.104951.
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.
Keywords: Cognition, Estrogen, Estradiol, Fertility treatment, Attention, Cognitive bias
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S. Sinisi, V. Alimguzhin, T. Mancini, and E. Tronci. "Reconciling interoperability with efficient Verification and Validation within open source simulation environments." Simulation Modelling Practice and Theory (2021): 102277. ISSN: 1569-190x. DOI: 10.1016/j.simpat.2021.102277.
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.
Keywords: Simulation, Verification and Validation, Interoperability, FMI/FMU, Model Exchange, Cyber-Physical Systems
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T. Mancini, F. Mari, A. Massini, I. Melatti, and E. Tronci. "Anytime system level verification via parallel random exhaustive hardware in the loop simulation." Microprocessors and Microsystems 41 (2016): 12–28. ISSN: 0141-9331. DOI: 10.1016/j.micpro.2015.10.010.
Abstract: Abstract System level verification of cyber-physical systems has the goal of verifying that the whole (i.e., software + hardware) system meets the given specifications. Model checkers for hybrid systems cannot handle system level verification of actual systems. Thus, Hardware In the Loop Simulation (HILS) is currently the main workhorse for system level verification. By using model checking driven exhaustive HILS, System Level Formal Verification (SLFV) can be effectively carried out for actual systems. We present a parallel random exhaustive HILS based model checker for hybrid systems that, by simulating all operational scenarios exactly once in a uniform random order, is able to provide, at any time during the verification process, an upper bound to the probability that the System Under Verification exhibits an error in a yet-to-be-simulated scenario (Omission Probability). We show effectiveness of the proposed approach by presenting experimental results on SLFV of the Inverted Pendulum on a Cart and the Fuel Control System examples in the Simulink distribution. To the best of our knowledge, no previously published model checker can exhaustively verify hybrid systems of such a size and provide at any time an upper bound to the Omission Probability.
Keywords: Model Checking of Hybrid Systems; Model checking driven simulation; Hardware in the loop simulation
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M. P. Hengartner, T. H. C. Kruger, K. Geraedts, E. Tronci, T. Mancini, F. Ille, M. Egli, S. Röblitz, R. Ehrig, L. Saleh et al. "Negative affect is unrelated to fluctuations in hormone levels across the menstrual cycle: Evidence from a multisite observational study across two successive cycles." Journal of Psychosomatic Research 99 (2017): 21–27. DOI: 10.1016/j.jpsychores.2017.05.018.
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