Shaping and Dilating the Fitness Landscape for Parameter Estimation in Stochastic Biochemical Models

The parameter estimation (PE) of biochemical reactions is one of the most challenging tasks in systems biology given the pivotal role of these kinetic constants in driving the behavior of biochemical systems. PE is a non-convex, multi-modal, and non-separable optimization problem with an unknown fitness landscape; moreover, the quantities of the biochemical species appearing in the system can be low, making biological noise a non-negligible phenomenon and mandating the use of stochastic simulation. Finally, the values of the kinetic parameters typically follow a log-uniform distribution; thus, the optimal solutions are situated in the lowest orders of magnitude of the search space. In this work, we further elaborate on a novel approach to address the PE problem based on a combination of adaptive swarm intelligence and dilation functions (DFs). DFs require prior knowledge of the characteristics of the fitness landscape; therefore, we leverage an alternative solution to evolve optimal DFs. On top of this approach, we introduce surrogate Fourier modeling to simplify the PE, by producing a smoother version of the fitness landscape that excludes the high frequency components of the fitness function. Our results show that the PE exploiting evolved DFs has a performance comparable with that of the PE run with a custom DF. Moreover, surrogate Fourier modeling allows for improving the convergence speed. Finally, we discuss some open problems related to the scalability of our methodology

A hydrometeorological model intercomparison as a tool to quantify the forecast uncertainty in a medium size basin

Abstract. In the framework of AMPHORE, an INTERREG III B EU project devoted to the hydrometeorological modeling study of heavy precipitation episodes resulting in flood events and the improvement of the operational hydrometeorological forecasts for the prediction and prevention of flood risks in the Western Mediterranean area, a hydrometeorological model intercomparison has been carried out, in order to estimate the uncertainties associated with the discharge predictions. The analysis is performed for an intense precipitation event selected as a case study within the project, which affected northern Italy and caused a flood event in the upper Reno river basin, a medium size catchment in the Emilia-Romagna Region. Two different hydrological models have been implemented over the basin: HEC-HMS and TOPKAPI which are driven in two ways. Firstly, stream-flow simulations obtained by using precipitation observations as input data are evaluated, in order to be aware of the performance of the two hydrological models. Secondly, the rainfall-runoff models have been forced with rainfall forecast fields provided by mesoscale atmospheric model simulations in order to evaluate the reliability of the discharge forecasts resulting by the one-way coupling. The quantitative precipitation forecasts (QPFs) are provided by the numerical mesoscale models COSMO and MM5. Furthermore, different configurations of COSMO and MM5 have been adopted, trying to improve the description of the phenomena determining the precipitation amounts. In particular, the impacts of using different initial and boundary conditions, different mesoscale models and of increasing the horizontal model resolutions are investigated. The accuracy of QPFs is assessed in a threefold procedure. First, these are checked against the observed spatial rainfall accumulations over northern Italy. Second, the spatial and temporal simulated distributions are also examined over the catchment of interest. And finally, the discharge simulations resulting from the one-way coupling with HEC-HMS and TOPKAPI are evaluated against the rain-gauge driven simulated flows, thus employing the hydrological models as a validation tool. The different scenarios of the simulated river flows – provided by an independent implementation of the two hydrological models each one forced with both COSMO and MM5 – enable a quantification of the uncertainties of the precipitation outputs, and therefore, of the discharge simulations. Results permit to highlight some hydrological and meteorological modeling factors which could help to enhance the hydrometeorological modeling of such hazardous events. Main conclusions are: (1) deficiencies in precipitation forecasts have a major impact on flood forecasts; (2) large-scale shift errors in precipitation patterns are not improved by only enhancing the mesoscale model resolution; and (3) weak differences in flood forecasting performance are found by using either a distributed continuous or a semi-distributed event-based hydrological model for this catchment

Use of artificial intelligence to automatically predict the optimal patient-specific inversion time for late gadolinium enhancement imaging. Tool development and clinical validation

Introduction With the worldwide diffusion of cardiac magnetic resonance (CMR), demand on image quality has grown. CMR late gadolinium enhancement (LGE) imaging provides critical diagnostic and prognostic information, and guides management. The identification of optimal Inversion Time (TI), a time-sensitive parameter closely linked to contrast kinetics, is pivotal for correct myocardium nulling. However, determining the optimal TI can be challenging in some diseases and for less experienced operators. Purpose To develop and test an artificial intelligence tool to automatically predict the personalised optimal TI in LGE imaging. Methods The tool, named THAITI, consists of a Random Forest regression model. It considers, as input parameters, patient-specific TI determinants (age, gender, weight, height, kidney function, heart rate) and CMR scan-specific TI determinants (B0, contrast type and dose, time elapsed from contrast injection). THAITI was trained on 219 patients (3585 images) with mixed conditions who underwent CMR (1.5T; Gadobutrol; averaged, MOCO, free-breathing true-FISP IR [1]) for clinical reasons. The dataset was split with a 90–10 policy: 90% of data for training, and 10% for testing. THAITI’s hyperparameters were optimised by embedding k-fold cross validation into an evolutionary computation algorithm, and the best performing model was finally evaluated on the test set. A graphical user interface was also developed. Clinical validation was performed on 55 consecutive patients, randomised to experimental (THAITI-set TI) vs control (operator-set TI) group. Image quality was assessed blindly by 2 independent experienced operators by a 4-points Likert scale, and by means of the contrast/enhancement ratio (CER) (i.e., signal intensity of enhanced/remote myocardium ratio). Results In the testing set, the TI predicted by THAITI differed from the ground truth by ≥ 5ms in 16% of cases. At clinical validation, myocardial nulling quality did not differ between the experimental vs the control group either by CER or visual assessment, with an overall "optimal" or "good" nulling in 96% vs 93%, respectively. Conclusions Using main determinants of contrast kinetics, THAITI efficiently predicted the optimal TI for CMR-LGE imaging. The tool works as a stand-alone on laptops/mobile devices, not requiring adjunctive scanner technology and thus has great potential for diffusion, including in small or recently opened CMR services, and in low-resource settings. Additional development is ongoing to increase generalisability (multi-vendor, multi-sequence, multi-contrast) and to test its potential to further improve CMR-LGE image quality and reduce the need for repeated imaging for inexperienced operators. Figure 1. Top: THAITI interface. Bottom: examples of experimental group CMR-LGE imaging. Table 1. Control vs experimental group. Data expressed as absolute number (%), mean ± SD, median [IQR]. ⧧ T-test; * Chi-square

Might as well jump: sound affects muscle activation in skateboarding.

The aim of the study is to reveal the role of sound in action anticipation and performance, and to test whether the level of precision in action planning and execution is related to the level of sensorimotor skills and experience that listeners possess about a specific action. Individuals ranging from 18 to 75 years of age - some of them without any skills in skateboarding and others experts in this sport - were compared in their ability to anticipate and simulate a skateboarding jump by listening to the sound it produces. Only skaters were able to modulate the forces underfoot and to apply muscle synergies that closely resembled the ones that a skater would use if actually jumping on a skateboard. More importantly we showed that only skaters were able to plan the action by activating anticipatory postural adjustments about 200 ms after the jump event. We conclude that expert patterns are guided by auditory events that trigger proper anticipations of the corresponding patterns of movements

Dark blood ischemic LGE segmentation using a deep learning approach

The extent of ischemic scar detected by Cardiac Magnetic Resonance (CMR) with late gadolinium enhancement (LGE) is linked with long-term prognosis, but scar quantification is time-consuming. Deep Learning (DL) approaches appear promising in CMR segmentation. Purpose: To train and apply a deep learning approach to dark blood (DB) CMR-LGE for ischemic scar segmentation, comparing results to 4-Standard Deviation (4-SD) semi-automated method. Methods: We trained and validated a dual neural network infrastructure on a dataset of DB-LGE short-axis stacks, acquired at 1.5T from 33 patients with ischemic scar. The DL architectures were an evolution of the U-Net Convolutional Neural Network (CNN), using data augmentation to increase generalization. The CNNs worked together to identify and segment 1) the myocardium and 2) areas of LGE. The first CNN simultaneously cropped the region of interest (RoI) according to the bounding box of the heart and calculated the area of myocardium. The cropped RoI was then processed by the second CNN, which identified the overall LGE area. The extent of scar was calculated as the ratio of the two areas. For comparison, endo- and epi-cardial borders were manually contoured and scars segmented by a 4-SD technique with a validated software. Results: The two U-Net networks were implemented with two free and open-source software library for machine learning. We performed 5-fold cross-validation over a dataset of 108 and 385 labelled CMR images of the myocardium and scar, respectively. We obtained high performance (> ∼0.85) as measured by the Intersection over Union metric (IoU) on the training sets, in the case of scar segmentation. With regards to heart recognition, the performance was lower (> ∼0.7), although improved (∼ 0.75) by detecting the cardiac area instead of heart boundaries. On the validation set, performances oscillated between 0.8 and 0.85 for scar tissue recognition, and dropped to ∼0.7 for myocardium segmentation. We believe that underrepresented samples and noise might be affecting the overall performances, so that additional data might be beneficial. Figure1: examples of heart segmentation (upper left panel: training; upper right panel: validation) and of scar segmentation (lower left panel: training; lower right panel: validation). Conclusion: Our CNNs show promising results in automatically segmenting LV and quantify ischemic scars on DB-LGE-CMR images. The performances of our method can further improve by expanding the data set used for the training. If implemented in a clinical routine, this process can speed up the CMR analysis process and aid in the clinical decision-making

T-cell depleted HLA-haploidentical HSCT in a child with neuromyelitis optica

Neuromyelitis optica is an immune-mediated disease characterized by a relapsing course, resulting in progressive disability. In children, given the long life expectancy, a disease-modifying treatment could be particularly desirable. Unfortunately, the currently available treatment strategies with this potential are scarce. Very limited data are available about the use of allogeneic hematopoietic stem cell transplantation (HSCT) for autoimmune neurological diseases. In this report, we present a pediatric case successfully treated with allogeneic HSCT from an HLA-haploidentical donor, after ex vivo TCR/CD19-depletion of the graft. To the best of our knowledge, this is the first case of a pediatric patient to benefit from such a treatment