Can Clinical and Surgical Parameters Be Combined to Predict How Long It Will Take a Tibia Fracture to Heal? A Prospective Multicentre Observational Study: The FRACTING Study

Healing of tibia fractures occurs over a wide time range of months, with a number of risk factors contributing to prolonged healing. In this prospective, multicentre, observational study, we investigated the capability of FRACTING (tibia FRACTure prediction healING days) score, calculated soon after tibia fracture treatment, to predict healing time. Methods: The study included 363 patients. Information on patient health, fracture morphology, and surgical treatment adopted were combined to calculate the FRACTING score. Fractures were considered healed when the patient was able to fully weight-bear without pain. Results: 319 fractures (88%) healed within 12 months from treatment. Forty-four fractures healed after 12 months or underwent a second surgery. FRACTING score positively correlated with days to healing: r = 0.63 (p < 0.0001). Average score value was 7.3 ± 2.5; ROC analysis showed strong reliability of the score in separating patients healing before versus after 6 months: AUC = 0.823. Conclusions: This study shows that the FRACTING score can be employed both to predict months needed for fracture healing and to identify immediately after treatment patients at risk of prolonged healing. In patients with high score values, new pharmacological and nonpharmacological treatments to enhance osteogenesis could be tested selectively, which may finally result in reduced disability time and health cost savings

Ceramide-transfer protein-mediated ceramide transfer is a structurally tunable flow-inducing mechanism with structural feed-forward loops

This paper considers two models of ceramide-transfer protein (CERT)-mediated ceramide transfer at the trans-Golgi network proposed in the literature, short distance shuttle and neck swinging, and seeks structural (parameter-free) features of the two models, which rely exclusively on the peculiar interaction network and not on specific parameter values. In particular, it is shown that both models can be seen as flow-inducing systems, where the flows between pairs of species are tuned by the concentrations of other species, and suitable external inputs can structurally regulate ceramide transfer. In the short distance shuttle model, the amount of transferred ceramide is structurally tuned by active protein kinase D (PKD), both directly and indirectly, in a coherent feed-forward loop motif. In the neck-swinging model, the amount of transferred ceramide is structurally tuned by active PI4KIIIβ, while active PKD has an ambivalent effect, due to the presence of an incoherent feed-forward loop motif that directly inhibits ceramide transfer and indirectly promotes it; the structural role of active PKD is to favour CERT mobility in the cytosol. It is also shown that the influences among key variables often have structurally determined steady-state signs, which can help falsify the models against experimental traces.Networked Cyber-Physical System

Foreword: The 15th IFAC Symposium on Large Scale Complex Systems (LSS 2019) was held at the Delft University of Technology (TU Delft), on May 26th-28th 2019.

Team Tamas Keviczk

Polyhedral Lyapunov functions structurally ensure global asymptotic stability of dynamical networks iff the Jacobian is non-singular

For a vast class of dynamical networks, including chemical reaction networks (CRNs) with monotonic reaction rates, the existence of a polyhedral Lyapunov function (PLF) implies structural (i.e., parameter-free) local stability. Global structural stability is ensured under the additional assumption that each of the variables (chemical species concentrations in CRNs) is subject to a spontaneous infinitesimal dissipation. This paper solves the open problem of global structural stability in the absence of the infinitesimal dissipation, showing that the existence of a PLF structurally ensures global convergence if and only if the system Jacobian passes a structural non-singularity test. It is also shown that, if the Jacobian is structurally non-singular, under positivity assumptions for the system partial derivatives, the existence of an equilibrium is guaranteed. For systems subject to positivity constraints, it is shown that, if the system admits a PLF, under structural non-singularity assumptions, global convergence within the positive orthant is structurally ensured, while the existence of an equilibrium can be proven by means of a linear programming test and the computation of a piecewise-linear-in-rate Lyapunov function.Accepted Author ManuscriptTeam Tamas Keviczk

Interaction sign patterns in biological networks: From qualitative to quantitative criteria

In stable biological and ecological networks, the steady-state influence matrix gathers the signs of steady-state responses to step-like perturbations affecting the variables. Such signs are difficult to predict a priori, because they result from a combination of direct effects (deducible from the Jacobian of the network dynamics) and indirect effects. For stable monotone or cooperative networks, the sign pattern of the influence matrix can be qualitatively determined based exclusively on the sign pattern of the system Jacobian. For other classes of networks, we show that a semi-qualitative approach yields sufficient conditions for Jacobians with a given sign pattern to admit a fully positive influence matrix, and we also provide quantitative conditions for Jacobians that are translated eventually nonnegative matrices. We present a computational test to check whether the influence matrix has a constant sign pattern in spite of parameter variations, and we apply this algorithm to quasi-Metzler Jacobian matrices, to assess whether positivity of the influence matrix is preserved in spite of deviations from cooperativity. When the influence matrix is fully positive, we give a simple vertex algorithm to test robust stability. The devised criteria are applied to analyse the steady-state behaviour of ecological and biomolecular networks.Team Tamas Keviczk

BDC-Decomposition for global influence analysis

In biochemical networks, the steady-state input-output influence is the sign of the output steady-state variation due to a persistent positive input perturbation; if the sign does not depend on the value of the strictly positive system parameters, the influence is structural. As recently shown for small perturbations, when the linearized system approximation is valid, steady-state input-output influences can be structurally assessed, for biochemical networks with m unknown parameters, by means of a vertex algorithm with complexity 2m. This letter shows that the structural input-output influence of a biochemical network is a global property, which does not require any small-perturbation assumption. It also shows that, using a new algorithm, the complexity can be reduced down to 2m-n , where n is the system order, thus drastically reducing the computation time. Finally, when the uncertain parameters belong to known intervals, non-conservative bounds are given for the steady-state ratio between output and input, allowing for sensitivity analysis.Accepted Author ManuscriptTeam Tamas Keviczk

Optimal duration and planning of switching treatments taking drug toxicity into account: a convex optimisation approach

We consider a multi-compartment evolutionary model representing growth, mutation and migration of cancer cells, as well as the effect of drugs, and we design optimal switching targeted cancer therapies where a single drug, or suitable drug combination, is given at each time so as to minimise not only the overall tumor size over a finite horizon, but also drug-provoked side effects. The strong diagonally- dominant structure of the model allows to solve the problem via convex optimisation. We provide an algorithm that yields optimality throughout the whole treatment duration by solving the convex optimisation problem with different horizons, and show how dwell time can be enforced via heuristics. Also the optimal treatment duration can be computed via convex optimisation. The proposed approaches are applied to a model of ALK-rearranged lung carcinoma.Accepted Author ManuscriptTeam Tamas Keviczk

A framework to analyze opinion formation models

Comparing model predictions with real data is crucial to improve and validate a model. For opinion formation models, validation based on real data is uncommon and difficult to obtain, also due to the lack of systematic approaches for a meaningful comparison. We introduce a framework to assess opinion formation models, which can be used to determine the qualitative outcomes that an opinion formation model can produce, and compare model predictions with real data. The proposed approach relies on a histogram-based classification algorithm, and on transition tables. The algorithm classifies an opinion distribution as perfect consensus, consensus, polarization, clustering, or dissensus; these qualitative categories were identified from World Values Survey data. The transition tables capture the qualitative evolution of the opinion distribution between an initial and a final time. We compute the real transition tables based on World Values Survey data from different years, as well as the predicted transition tables produced by the French-DeGroot, Weighted-Median, Bounded Confidence, and Quantum Game models, and we compare them. Our results provide insight into the evolution of real-life opinions and highlight key directions to improve opinion formation models.Team Tamas Keviczk

Topology-independent robust stability for networks of homogeneous MIMO systems

We study dynamic networks described by a directed graph where the nodes are associated with MIMO systems with transfer-function matrix F(s), representing individual dynamic units, and the arcs are associated with MIMO systems with transfer-function matrix G(s), accounting for the dynamic interactions among the units. In the nominal case, we provide a topology-independent condition for the stability of all possible dynamic networks with a maximum connectivity degree, regardless of their size and interconnection structure. When node and arc transfer-function matrices are affected by norm-bounded homogeneous uncertainties, the robust condition for size- and topology-independent stability depends on the uncertainty magnitude. Both conditions, expressed as constraints for the Nyquist diagram of the poles of the transfer-function matrix H(s) = F(s)G(s), are scalable and can be checked locally to guarantee stability-preserving “plug-and-play” addition of new nodes and arcs.Team Tamas Keviczk

Probabilistic analysis of agent-based opinion formation models

When agent-based models are developed to capture opinion formation in large-scale populations, the opinion update equations often need to embed several complex psychological traits. The resulting models are more realistic, but also challenging to assess analytically, and hence numerical analysis techniques have an increasing importance in their study. Here, we propose the Qualitative Outcome Likelihood (QOL) analysis, a novel probabilistic analysis technique aimed to unravel behavioural patterns and properties of agent-based opinion formation models, and to characterise possible outcomes when only limited information is available. The QOL analysis reveals which qualitative categories of opinion distributions a model can produce, brings to light their relation to model features such as initial conditions, agent parameters and underlying digraph, and allows us to compare the behaviour of different opinion formation models. We exemplify the proposed technique by applying it to four opinion formation models: the classical Friedkin-Johnsen model and Bounded Confidence model, as well as the recently proposed Backfire Effect and Biased Assimilation model and Classification-based model.Team Tamas Keviczk