Machine learning and XAI approaches highlight the strong connection between O 3 and N O 2 pollutants and Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia with millions of affected patients worldwide. Currently, there is still no cure and AD is often diagnosed long time after onset because there is no clear diagnosis. Thus, it is essential to study the physiology and pathogenesis of AD, investigating the risk factors that could be strongly connected to the disease onset. Despite AD, like other complex diseases, is the result of the combination of several factors, there is emerging agreement that environmental pollution should play a pivotal role in the causes of disease. In this work, we implemented an Artificial Intelligence model to predict AD mortality, expressed as Standardized Mortality Ratio, at Italian provincial level over 5 years. We employed a set of publicly available variables concerning pollution, health, society and economy to feed a Random Forest algorithm. Using methods based on eXplainable Artificial Intelligence (XAI) we found that air pollution (mainly O 3 and N O 2 ) contribute the most to AD mortality prediction. These results could help to shed light on the etiology of Alzheimer's disease and to confirm the urgent need to further investigate the relationship between the environment and the disease.

TISBE: A Public Web Platform for the Consensus-Based Explainable Prediction of Developmental Toxicity.

Despite being extremely relevant for the protection of prenatal and neonatal health, the developmental toxicity (Dev Tox) is a highly complex endpoint whose molecular rationale is still largely unknown. The lack of availability of high-quality data as well as robust nontesting methods makes its understanding even more difficult. Thus, the application of new explainable alternative methods is of utmost importance, with Dev Tox being one of the most animal-intensive research themes of regulatory toxicology. Descending from TIRESIA (Toxicology Intelligence and Regulatory Evaluations for Scientific and Industry Applications), the present work describes TISBE (TIRESIA Improved on Structure-Based Explainability), a new public web platform implementing four fundamental advancements for in silico analyses: a three times larger dataset, a transparent XAI (explainable artificial intelligence) framework employing a fragment-based fingerprint coding, a novel consensus classifier based on five independent machine learning models, and a new applicability domain (AD) method based on a double top-down approach for better estimating the prediction reliability. The training set (TS) includes as many as 1008 chemicals annotated with experimental toxicity values. Based on a 5-fold cross-validation, a median value of 0.410 for the Matthews correlation coefficient was calculated; TISBE was very effective, with a median value of sensitivity and specificity equal to 0.984 and 0.274, respectively. TISBE was applied on two external pools made of 1484 bioactive compounds and 85 pediatric drugs taken from ChEMBL (Chemical European Molecular Biology Laboratory) and TEDDY (Task-Force in Europe for Drug Development in the Young) repositories, respectively. Notably, TISBE gives users the option to clearly spot the molecular fragments responsible for the toxicity or the safety of a given chemical query and is available for free at https://prometheus.farmacia.uniba.it/tisbe.

Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research.

Every year, 11% of infants are born preterm with significant health consequences, with the vaginal microbiome a risk factor for preterm birth. We crowdsource models to predict (1) preterm birth (PTB; <37 weeks) or (2) early preterm birth (ePTB; <32 weeks) from 9 vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from public raw data via phylogenetic harmonization. The predictive models are validated on two independent unpublished datasets representing 331 samples from 148 pregnant individuals. The top-performing models (among 148 and 121 submissions from 318 teams) achieve area under the receiver operator characteristic (AUROC) curve scores of 0.69 and 0.87 predicting PTB and ePTB, respectively. Alpha diversity, VALENCIA community state types, and composition are important features in the top-performing models, most of which are tree-based methods. This work is a model for translation of microbiome data into clinically relevant predictive models and to better understand preterm birth.

Making sense of chemical space network shows signs of criticality.

Chemical space modelling has great importance in unveiling and visualising latent information, which is critical in predictive toxicology related to drug discovery process. While the use of traditional molecular descriptors and fingerprints may suffer from the so-called curse of dimensionality, complex networks are devoid of the typical drawbacks of coordinate-based representations. Herein, we use chemical space networks (CSNs) to analyse the case of the developmental toxicity (Dev Tox), which remains a challenging endpoint for the difficulty of gathering enough reliable data despite very important for the protection of the maternal and child health. Our study proved that the Dev Tox CSN has a complex non-random organisation and can thus provide a wealth of meaningful information also for predictive purposes. At a phase transition, chemical similarities highlight well-established toxicophores, such as aryl derivatives, mostly neurotoxic hydantoins, barbiturates and amino alcohols, steroids, and volatile organic compounds ether-like chemicals, which are strongly suspected of the Dev Tox onset and can thus be employed as effective alerts for prioritising chemicals before testing.

Where developmental toxicity meets explainable artificial intelligence: state-of-the-art and perspectives.

INTRODUCTION: The application of Artificial Intelligence (AI) to predictive toxicology is rapidly increasing, particularly aiming to develop non-testing methods that effectively address ethical concerns and reduce economic costs. In this context, Developmental Toxicity (Dev Tox) stands as a key human health endpoint, especially significant for safeguarding maternal and child well-being. AREAS COVERED: This review outlines the existing methods employed in Dev Tox predictions and underscores the benefits of utilizing New Approach Methodologies (NAMs), specifically focusing on eXplainable Artificial Intelligence (XAI), which proves highly efficient in constructing reliable and transparent models aligned with recommendations from international regulatory bodies. EXPERT OPINION: The limited availability of high-quality data and the absence of dependable Dev Tox methodologies render XAI an appealing avenue for systematically developing interpretable and transparent models, which hold immense potential for both scientific evaluations and regulatory decision-making.

A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

BACKGROUND: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. METHODS: Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). RESULTS: In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. CONCLUSIONS: The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

Deep learning approach for denoising low-SNR correlation plenoptic images.

Correlation Plenoptic Imaging (CPI) is a novel volumetric imaging technique that uses two sensors and the spatio-temporal correlations of light to detect both the spatial distribution and the direction of light. This novel approach to plenoptic imaging enables refocusing and 3D imaging with significant enhancement of both resolution and depth of field. However, CPI is generally slower than conventional approaches due to the need to acquire sufficient statistics for measuring correlations with an acceptable signal-to-noise ratio (SNR). We address this issue by implementing a Deep Learning application to improve image quality with undersampled frame statistics. We employ a set of experimental images reconstructed by a standard CPI architecture, at three different sampling ratios, and use it to feed a CNN model pre-trained through the transfer learning paradigm U-Net architecture with VGG-19 net for the encoding part. We find that our model reaches a Structural Similarity (SSIM) index value close to 1 both for the test sample (SSIM = [Formula: see text]) and in 5-fold cross validation (SSIM = [Formula: see text]); the results are also shown to outperform classic denoising methods, in particular for images with lower SNR. The proposed work represents the first application of Artificial Intelligence in the field of CPI and demonstrates its high potential: speeding-up the acquisition by a factor 20 over the fastest CPI so far demonstrated, enabling recording potentially 200 volumetric images per second. The presented results open the way to scanning-free real-time volumetric imaging at video rate, which is expected to achieve a substantial influence in various applications scenarios, from monitoring neuronal activity to machine vision and security.

Artificial Intelligence and Complex Network Approaches Reveal Potential Gene Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the number of cases is constantly increasing. Early and accurate HCC diagnosis is crucial to improving the effectiveness of treatment. The aim of the study is to develop a supervised learning framework based on hierarchical community detection and artificial intelligence in order to classify patients and controls using publicly available microarray data. With our methodology, we identified 20 gene communities that discriminated between healthy and cancerous samples, with an accuracy exceeding 90%. We validated the performance of these communities on an independent dataset, and with two of them, we reached an accuracy exceeding 80%. Then, we focused on two communities, selected because they were enriched with relevant biological functions, and on these we applied an explainable artificial intelligence (XAI) approach to analyze the contribution of each gene to the classification task. In conclusion, the proposed framework provides an effective methodological and quantitative tool helping to find gene communities, which may uncover pivotal mechanisms responsible for HCC and thus discover new biomarkers.

An eXplainable Artificial Intelligence analysis of Raman spectra for thyroid cancer diagnosis.

Raman spectroscopy shows great potential as a diagnostic tool for thyroid cancer due to its ability to detect biochemical changes during cancer development. This technique is particularly valuable because it is non-invasive and label/dye-free. Compared to molecular tests, Raman spectroscopy analyses can more effectively discriminate malignant features, thus reducing unnecessary surgeries. However, one major hurdle to using Raman spectroscopy as a diagnostic tool is the identification of significant patterns and peaks. In this study, we propose a Machine Learning procedure to discriminate healthy/benign versus malignant nodules that produces interpretable results. We collect Raman spectra obtained from histological samples, select a set of peaks with a data-driven and label independent approach and train the algorithms with the relative prominence of the peaks in the selected set. The performance of the considered models, quantified by area under the Receiver Operating Characteristic curve, exceeds 0.9. To enhance the interpretability of the results, we employ eXplainable Artificial Intelligence and compute the contribution of each feature to the prediction of each sample.

CIRCE: Web-Based Platform for the Prediction of Cannabinoid Receptor Ligands Using Explainable Machine Learning.

The endocannabinoid system, which includes cannabinoid receptor 1 and 2 subtypes (CB1R and CB2R, respectively), is responsible for the onset of various pathologies including neurodegeneration, cancer, neuropathic and inflammatory pain, obesity, and inflammatory bowel disease. Given the high similarity of CB1R and CB2R, generating subtype-selective ligands is still an open challenge. In this work, the Cannabinoid Iterative Revaluation for Classification and Explanation (CIRCE) compound prediction platform has been generated based on explainable machine learning to support the design of selective CB1R and CB2R ligands. Multilayer classifiers were combined with Shapley value analysis to facilitate explainable predictions. In test calculations, CIRCE predictions reached ∼80% accuracy and structural features determining ligand predictions were rationalized. CIRCE was designed as a web-based prediction platform that is made freely available as a part of our study.

An eXplainability Artificial Intelligence approach to brain connectivity in Alzheimer's disease.

The advent of eXplainable Artificial Intelligence (XAI) has revolutionized the way human experts, especially from non-computational domains, approach artificial intelligence; this is particularly true for clinical applications where the transparency of the results is often compromised by the algorithmic complexity. Here, we investigate how Alzheimer's disease (AD) affects brain connectivity within a cohort of 432 subjects whose T1 brain Magnetic Resonance Imaging data (MRI) were acquired within the Alzheimer's Disease Neuroimaging Initiative (ADNI). In particular, the cohort included 92 patients with AD, 126 normal controls (NC) and 214 subjects with mild cognitive impairment (MCI). We show how graph theory-based models can accurately distinguish these clinical conditions and how Shapley values, borrowed from game theory, can be adopted to make these models intelligible and easy to interpret. Explainability analyses outline the role played by regions like putamen, middle and superior temporal gyrus; from a class-related perspective, it is possible to outline specific regions, such as hippocampus and amygdala for AD and posterior cingulate and precuneus for MCI. The approach is general and could be adopted to outline how brain connectivity affects specific brain regions.

A Dementia mortality rates dataset in Italy (2012-2019).

Dementia is on the rise in the world population and has been defined by the World Health Organization as a global public health priority. In Italy, according to demographic projections, in 2051 there will be 280 elderly people for every 100 young people, with an increase in all age-related chronic diseases, including dementia. Currently the total number of patients with dementia is estimated to be over 1 million (mainly with Alzheimer's disease (AD) and Parkinson's disease (PD)). In-depth studies of the etiology and physiology of dementia are complicated due to the complexity of these diseases and their long duration. In this work we present a dataset on mortality rates (in the form of Standardized Mortality Ratios, SMR) for AD e PD in Italy at provincial level over a period of 8 years (2012-2019). Access to long-term, spatially detailed and ready-to-use data could favor both health monitoring and the research of new treatments and new drugs as well as innovative methodologies for early diagnosis of dementia.

Study of Alternative Imaging Methods for In Vivo Boron Neutron Capture Therapy.

Boron Neutron Capture Therapy (BNCT) is an innovative and highly selective treatment against cancer. Nowadays, in vivo boron dosimetry is an important method to carry out such therapy in clinical environments. In this work, different imaging methods were tested for dosimetry and tumor monitoring in BNCT based on a Compton camera detector. A dedicated dataset was generated through Monte Carlo tools to study the imaging capabilities. We first applied the Maximum Likelihood Expectation Maximization (MLEM) iterative method to study dosimetry tomography. As well, two methods based on morphological filtering and deep learning techniques with Convolutional Neural Networks (CNN), respectively, were studied for tumor monitoring. Furthermore, clinical aspects such as the dependence on the boron concentration ratio in image reconstruction and the stretching effect along the detector position axis were analyzed. A simulated spherical gamma source was studied in several conditions (different detector distances and boron concentration ratios) using MLEM. This approach proved the possibility of monitoring the boron dose. Tumor monitoring using the CNN method shows promising results that could be enhanced by increasing the training dataset.

Short-term anti-remodeling effects of gliflozins in diabetic patients with heart failure and reduced ejection fraction: an explainable artificial intelligence approach.

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), gliflozins, play an emerging role for the treatment of heart failure with reduced left ventricular ejection fraction (HFrEF). Nevertheless, the effects of SGLT2i on ventricular remodeling and function have not been completely understood yet. Explainable artificial intelligence represents an unprecedented explorative option to clinical research in this field. Based on echocardiographic evaluations, we identified some key clinical responses to gliflozins by employing a machine learning approach. Methods: Seventy-eight consecutive diabetic outpatients followed for HFrEF were enrolled in the study. Using a random forests classification, a single subject analysis was performed to define the profile of patients treated with gliflozins. An explainability analysis using Shapley values was used to outline clinical parameters that mostly improved after gliflozin therapy and machine learning runs highlighted specific variables predictive of gliflozin response. Results: The five-fold cross-validation analyses showed that gliflozins patients can be identified with a 0.70 ± 0.03% accuracy. The most relevant parameters distinguishing gliflozins patients were Right Ventricular S'-Velocity, Left Ventricular End Systolic Diameter and E/e' ratio. In addition, low Tricuspid Annular Plane Systolic Excursion values along with high Left Ventricular End Systolic Diameter and End Diastolic Volume values were associated to lower gliflozin efficacy in terms of anti-remodeling effects. Discussion: In conclusion, a machine learning analysis on a population of diabetic patients with HFrEF showed that SGLT2i treatment improved left ventricular remodeling, left ventricular diastolic and biventricular systolic function. This cardiovascular response may be predicted by routine echocardiographic parameters, with an explainable artificial intelligence approach, suggesting a lower efficacy in case of advanced stages of cardiac remodeling.

Microbiome Preterm Birth DREAM Challenge: Crowdsourcing Machine Learning Approaches to Advance Preterm Birth Research.

Globally, every year about 11% of infants are born preterm, defined as a birth prior to 37 weeks of gestation, with significant and lingering health consequences. Multiple studies have related the vaginal microbiome to preterm birth. We present a crowdsourcing approach to predict: (a) preterm or (b) early preterm birth from 9 publicly available vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from raw sequences via an open-source tool, MaLiAmPi. We validated the crowdsourced models on novel datasets representing 331 samples from 148 pregnant individuals. From 318 DREAM challenge participants we received 148 and 121 submissions for our two separate prediction sub-challenges with top-ranking submissions achieving bootstrapped AUROC scores of 0.69 and 0.87, respectively. Alpha diversity, VALENCIA community state types, and composition (via phylotype relative abundance) were important features in the top performing models, most of which were tree based methods. This work serves as the foundation for subsequent efforts to translate predictive tests into clinical practice, and to better understand and prevent preterm birth.

Functional connectivity alterations in traumatic brain injury patients with late seizures.

PTE is a neurological disorder characterized by recurrent and spontaneous epileptic seizures. PTE is a major public health problem occurring in 2-50% of TBI patients. Identifying PTE biomarkers is crucial for the development of effective treatments. Functional neuroimaging studies in patients with epilepsy and in epileptic rodents have observed that abnormal functional brain activity plays a role in the development of epilepsy. Network representations of complex systems ease quantitative analysis of heterogeneous interactions within a unified mathematical framework. In this work, graph theory was used to study resting state functional magnetic resonance imaging (rs-fMRI) and reveal functional connectivity abnormalities that are associated with seizure development in traumatic brain injury (TBI) patients. We examined rs-fMRI of 75 TBI patients from Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) which aims to identify validated Post-traumatic epilepsy (PTE) biomarkers and antiepileptogenic therapies using multimodal and longitudinal data acquired from 14 international sites. The dataset includes 28 subjects who had at least one late seizure after TBI and 47 subjects who had no seizures within 2 years post-injury. Each subject's neural functional network was investigated by computing the correlation between the low frequency time series of 116 regions of interest (ROIs). Each subject's functional organization was represented as a network consisting of nodes, brain regions, and edges that show the relationship between the nodes. Then, several graph measures concerning the integration and the segregation of the functional brain networks were extracted in order to highlight changes in functional connectivity between the two TBI groups. Results showed that the late seizure-affected group had a compromised balance between integration and segregation and presents functional networks that are hyperconnected, hyperintegrated but at the same time hyposegregated compared with seizure-free patients. Moreover, TBI subjects who developed late seizures had more low betweenness hubs.

Analyzing breast cancer invasive disease event classification through explainable artificial intelligence.

Introduction: Recently, accurate machine learning and deep learning approaches have been dedicated to the investigation of breast cancer invasive disease events (IDEs), such as recurrence, contralateral and second cancers. However, such approaches are poorly interpretable. Methods: Thus, we designed an Explainable Artificial Intelligence (XAI) framework to investigate IDEs within a cohort of 486 breast cancer patients enrolled at IRCCS Istituto Tumori "Giovanni Paolo II" in Bari, Italy. Using Shapley values, we determined the IDE driving features according to two periods, often adopted in clinical practice, of 5 and 10 years from the first tumor diagnosis. Results: Age, tumor diameter, surgery type, and multiplicity are predominant within the 5-year frame, while therapy-related features, including hormone, chemotherapy schemes and lymphovascular invasion, dominate the 10-year IDE prediction. Estrogen Receptor (ER), proliferation marker Ki67 and metastatic lymph nodes affect both frames. Discussion: Thus, our framework aims at shortening the distance between AI and clinical practice.

Detecting the socio-economic drivers of confidence in government with eXplainable Artificial Intelligence.

The European Quality of Government Index (EQI) measures the perceived level of government quality by European Union citizens, combining surveys on corruption, impartiality and quality of provided services. It is, thus, an index based on individual subjective evaluations. Understanding the most relevant objective factors affecting the EQI outcomes is important for both evaluators and policy makers, especially in view of the fact that perception of government integrity contributes to determine the level of civic engagement. In our research, we employ methods of Artificial Intelligence and complex systems physics to measure the impact on the perceived government quality of multifaceted variables, describing territorial development and citizen well-being, from an economic, social and environmental viewpoint. Our study, focused on a set of regions in European Union at a subnational scale, leads to identifying the territorial and demographic drivers of citizens' confidence in government institutions. In particular, we find that the 2021 EQI values are significantly related to two indicators: the first one is the difference between female and male labour participation rates, and the second one is a proxy of wealth and welfare such as the average number of rooms per inhabitant. This result corroborates the idea of a central role played by labour gender equity and housing policies in government confidence building. In particular, the relevance of the former indicator in EQI prediction results from a combination of positive conditions such as equal job opportunities, vital labour market, welfare and availability of income sources, while the role of the latter is possibly amplified by the lockdown policies related to the COVID-19 pandemics. The analysis is based on combining regression, to predict EQI from a set of publicly available indicators, with the eXplainable Artificial Intelligence approach, that quantifies the impact of each indicator on the prediction. Such a procedure does not require any ad-hoc hypotheses on the functional dependence of EQI on the indicators used to predict it. Finally, using network science methods concerning community detection, we investigate how the impact of relevant indicators on EQI prediction changes throughout European regions. Thus, the proposed approach enables to identify the objective factors at the basis of government quality perception by citizens in different territorial contexts, providing the methodological basis for the development of a quantitative tool for policy design.

The spatial association between environmental pollution and long-term cancer mortality in Italy.

Tumours are nowadays the second world­leading cause of death after cardiovascular diseases. During the last decades of cancer research, lifestyle and random/genetic factors have been blamed for cancer mortality, with obesity, sedentary habits, alcoholism, and smoking contributing as supposed major causes. However, there is an emerging consensus that environmental pollution should be considered one of the main triggers. Unfortunately, all this preliminary scientific evidence has not always been followed by governments and institutions, which still fail to pursue research on cancer's environmental connections. In this unprecedented national-scale detailed study, we analyzed the links between cancer mortality, socio-economic factors, and sources of environmental pollution in Italy, both at wider regional and finer provincial scales, with an artificial intelligence approach. Overall, we found that cancer mortality does not have a random or spatial distribution and exceeds the national average mainly when environmental pollution is also higher, despite healthier lifestyle habits. Our machine learning analysis of 35 environmental sources of pollution showed that air quality ranks first for importance concerning the average cancer mortality rate, followed by sites to be reclaimed, urban areas, and motor vehicle density. Moreover, other environmental sources of pollution proved to be relevant for the mortality of some specific cancer types. Given these alarming results, we call for a rearrangement of the priority of cancer research and care that sees the reduction and prevention of environmental contamination as a priority action to put in place in the tough struggle against cancer.

TIRESIA: An eXplainable Artificial Intelligence Platform for Predicting Developmental Toxicity.

Herein, a robust and reproducible eXplainable Artificial Intelligence (XAI) approach is presented, which allows prediction of developmental toxicity, a challenging human-health endpoint in toxicology. The application of XAI as an alternative method is of the utmost importance with developmental toxicity being one of the most animal-intensive areas of regulatory toxicology. In this work, the established CAESAR (Computer Assisted Evaluation of industrial chemical Substances According to Regulations) training set made of 234 chemicals for model learning is employed. Two test sets, including as a whole 585 chemicals, were instead used for validation and generalization purposes. The proposed framework favorably compares with the state-of-the-art approaches in terms of accuracy, sensitivity, and specificity, thus resulting in a reliable support system for developmental toxicity ensuring informativeness, uncertainty estimation, generalization, and transparency. Based on the eXtreme Gradient Boosting (XGB) algorithm, our predictive model provides easy interpretative keys based on specific molecular descriptors and structural alerts enabling one to distinguish toxic and nontoxic chemicals. Inspired by the Organisation for Economic Co-operation and Development (OECD) principles for the validation of Quantitative Structure-Activity Relationships (QSARs) for regulatory purposes, the results are summarized in a standard report in portable document format, enclosing also details concerned with a density-based model applicability domain and SHAP (SHapley Additive exPlanations) explainability, the latter particularly useful to better understand the effective roles played by molecular features. Notably, our model has been implemented in TIRESIA (Toxicology Intelligence and Regulatory Evaluations for Scientific and Industry Applications), a free of charge web platform available at http://tiresia.uniba.it.