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.

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.

Satellite data and machine learning reveal a significant correlation between NO2 and COVID-19 mortality.

The Coronavirus disease 2019 (COVID-19) pandemic has officially spread all over the world since the beginning of 2020. Although huge efforts are addressed by scientists to shed light over the several questions raised by the novel SARS-CoV-2 virus, many aspects need to be clarified, yet. In particular, several studies have pointed out significant variations between countries in per-capita mortality. In this work, we investigated the association between COVID-19 mortality with climate variables and air pollution throughout European countries using the satellite remote sensing images provided by the Sentinel-5p mission. We analyzed data collected for two years of observations and extracted the concentrations of several pollutants; we used these measurements to feed a Random Forest regression. We performed a cross-validation analysis to assess the robustness of the model and compared several regression strategies. Our findings reveal a significant statistical association between air pollution (NO2) and COVID-19 mortality and a significant role played by the socio-demographic features, like the number of nurses or the hospital beds and the gross domestic product per capita.

Predicting brain age with complex networks: From adolescence to adulthood.

In recent years, several studies have demonstrated that machine learning and deep learning systems can be very useful to accurately predict brain age. In this work, we propose a novel approach based on complex networks using 1016 T1-weighted MRI brain scans (in the age range 7-64years). We introduce a structural connectivity model of the human brain: MRI scans are divided in rectangular boxes and Pearson's correlation is measured among them in order to obtain a complex network model. Brain connectivity is then characterized through few and easy-to-interpret centrality measures; finally, brain age is predicted by feeding a compact deep neural network. The proposed approach is accurate, robust and computationally efficient, despite the large and heterogeneous dataset used. Age prediction accuracy, in terms of correlation between predicted and actual age r=0.89and Mean Absolute Error MAE =2.19years, compares favorably with results from state-of-the-art approaches. On an independent test set including 262 subjects, whose scans were acquired with different scanners and protocols we found MAE =2.52. The only imaging analysis steps required in the proposed framework are brain extraction and linear registration, hence robust results are obtained with a low computational cost. In addition, the network model provides a novel insight on aging patterns within the brain and specific information about anatomical districts displaying relevant changes with aging.

Modelling cognitive loads in schizophrenia by means of new functional dynamic indexes.

Functional connectivity analysis techniques have broadly applied to capture phenomenological aspects of the brain, e.g., by identifying characteristic network topologies for healthy and disease-affected populations, by highlighting several areas important for the global efficiency of the brain during some cognitive processing and at rest. However, most of the known methods for quantifying functional coupling between fMRI time series are focused on linear correlation metrics. In this work, we propose a multidimensional framework to extract multiple descriptors of the dynamic interaction among BOLD signals in their phase space. A set of metrics is extracted from the cross recurrence plots of each couple of signals to form a multilayer connectivity matrix in which each layer is related to a specific complex dynamic phenomenon. The proposed framework is used to characterize functional abnormalities during a working memory task in patients with schizophrenia. Some topological descriptors are then extracted from both multilayer connectivity matrices and the most used Pearson-based connectivity networks to perform a binary classification task of normal controls and patients. The results show that the proposed connectivity model outperforms the statistical correlation-based connectivity in accuracy, sensitivity and specificity. Moreover, the statistical analysis of the selected features highlights that several dynamic metrics could better identify disease-related dynamic states in brain activity than the statistical correlation among physiological signals.

Communicability Characterization of Structural DWI Subcortical Networks in Alzheimer's Disease.

In this paper, we investigate the connectivity alterations of the subcortical brain network due to Alzheimer's disease (AD). Mostly, the literature investigated AD connectivity abnormalities at the whole brain level or at the cortex level, while very few studies focused on the sub-network composed only by the subcortical regions, especially using diffusion-weighted imaging (DWI) data. In this work, we examine a mixed cohort including 46 healthy controls (HC) and 40 AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. We reconstruct the brain connectome through the use of state of the art tractography algorithms and we propose a method based on graph communicability to enhance the information content of subcortical brain regions in discriminating AD. We develop a classification framework, achieving 77% of area under the receiver operating characteristic (ROC) curve in the binary discrimination AD vs. HC only using a 12 × 12 subcortical features matrix. We find some interesting AD-related connectivity patterns highlighting that subcortical regions tend to increase their communicability through cortical regions to compensate the physical connectivity reduction between them due to AD. This study also suggests that AD connectivity alterations mostly regard the inter-connectivity between subcortical and cortical regions rather than the intra-subcortical connectivity.

Alzheimer's disease diagnosis based on the Hippocampal Unified Multi-Atlas Network (HUMAN) algorithm.

BACKGROUND: Hippocampal atrophy is a supportive feature for the diagnosis of probable Alzheimer's disease (AD). However, even for an expert neuroradiologist, tracing the hippocampus and measuring its volume is a time consuming and extremely challenging task. Accordingly, the development of reliable fully-automated segmentation algorithms is of paramount importance. MATERIALS AND METHODS: The present study evaluates (i) the precision and the robustness of the novel Hippocampal Unified Multi-Atlas Network (HUMAN) segmentation algorithm and (ii) its clinical reliability for AD diagnosis. For these purposes, we used a mixed cohort of 456 subjects and their T1 weighted magnetic resonance imaging (MRI) brain scans. The cohort included 145 controls (CTRL), 217 mild cognitive impairment (MCI) subjects and 94 AD patients from Alzheimer's Disease Neuroimaging Initiative (ADNI). For each subject the baseline, repeat, 12 and 24 month follow-up scans were available. RESULTS: HUMAN provides hippocampal volumes with a 3% precision; volume measurements effectively reveal AD, with an area under the curve (AUC) AUC1 = 0.08 ± 0.02. Segmented volumes can also reveal the subtler effects present in MCI subjects, AUC2 = 0.76 ± 0.05. The algorithm is stable and reproducible over time, even for 24 month follow-up scans. CONCLUSIONS: The experimental results demonstrate HUMAN is a precise segmentation algorithm, besides hippocampal volumes, provided by HUMAN, can effectively support the diagnosis of Alzheimer's disease and become a useful tool for other neuroimaging applications.

MSA-PAD: DNA multiple sequence alignment framework based on PFAM accessed domain information.

Here we present the MSA-PAD application, a DNA multiple sequence alignment framework that uses PFAM protein domain information to align DNA sequences encoding either single or multiple protein domains. MSA-PAD has two alignment options: gene and genome mode.

BioMaS: a modular pipeline for Bioinformatic analysis of Metagenomic AmpliconS.

BACKGROUND: Substantial advances in microbiology, molecular evolution and biodiversity have been carried out in recent years thanks to Metagenomics, which allows to unveil the composition and functions of mixed microbial communities in any environmental niche. If the investigation is aimed only at the microbiome taxonomic structure, a target-based metagenomic approach, here also referred as Meta-barcoding, is generally applied. This approach commonly involves the selective amplification of a species-specific genetic marker (DNA meta-barcode) in the whole taxonomic range of interest and the exploration of its taxon-related variants through High-Throughput Sequencing (HTS) technologies. The accessibility to proper computational systems for the large-scale bioinformatic analysis of HTS data represents, currently, one of the major challenges in advanced Meta-barcoding projects. RESULTS: BioMaS (Bioinformatic analysis of Metagenomic AmpliconS) is a new bioinformatic pipeline designed to support biomolecular researchers involved in taxonomic studies of environmental microbial communities by a completely automated workflow, comprehensive of all the fundamental steps, from raw sequence data upload and cleaning to final taxonomic identification, that are absolutely required in an appropriately designed Meta-barcoding HTS-based experiment. In its current version, BioMaS allows the analysis of both bacterial and fungal environments starting directly from the raw sequencing data from either Roche 454 or Illumina HTS platforms, following two alternative paths, respectively. BioMaS is implemented into a public web service available at https://recasgateway.ba.infn.it/ and is also available in Galaxy at http://galaxy.cloud.ba.infn.it:8080 (only for Illumina data). CONCLUSION: BioMaS is a friendly pipeline for Meta-barcoding HTS data analysis specifically designed for users without particular computing skills. A comparative benchmark, carried out by using a simulated dataset suitably designed to broadly represent the currently known bacterial and fungal world, showed that BioMaS outperforms QIIME and MOTHUR in terms of extent and accuracy of deep taxonomic sequence assignments.

Air pollution and mortality for cancer of the respiratory system in Italy: an explainable artificial intelligence approach.

Respiratory system cancer, encompassing lung, trachea and bronchus cancer, constitute a substantial and evolving public health challenge. Since pollution plays a prominent cause in the development of this disease, identifying which substances are most harmful is fundamental for implementing policies aimed at reducing exposure to these substances. We propose an approach based on explainable artificial intelligence (XAI) based on remote sensing data to identify the factors that most influence the prediction of the standard mortality ratio (SMR) for respiratory system cancer in the Italian provinces using environment and socio-economic data. First of all, we identified 10 clusters of provinces through the study of the SMR variogram. Then, a Random Forest regressor is used for learning a compact representation of data. Finally, we used XAI to identify which features were most important in predicting SMR values. Our machine learning analysis shows that NO, income and O3 are the first three relevant features for the mortality of this type of cancer, and provides a guideline on intervention priorities in reducing risk factors.

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.

Insights from Explainable Artificial Intelligence of Pollution and Socioeconomic Influences for Respiratory Cancer Mortality in Italy.

Respiratory malignancies, encompassing cancers affecting the lungs, the trachea, and the bronchi, pose a significant and dynamic public health challenge. Given that air pollution stands as a significant contributor to the onset of these ailments, discerning the most detrimental agents becomes imperative for crafting policies aimed at mitigating exposure. This study advocates for the utilization of explainable artificial intelligence (XAI) methodologies, leveraging remote sensing data, to ascertain the primary influencers on the prediction of standard mortality rates (SMRs) attributable to respiratory cancer across Italian provinces, utilizing both environmental and socioeconomic data. By scrutinizing thirteen distinct machine learning algorithms, we endeavor to pinpoint the most accurate model for categorizing Italian provinces as either above or below the national average SMR value for respiratory cancer. Furthermore, employing XAI techniques, we delineate the salient factors crucial in predicting the two classes of SMR. Through our machine learning scrutiny, we illuminate the environmental and socioeconomic factors pertinent to mortality in this disease category, thereby offering a roadmap for prioritizing interventions aimed at mitigating risk factors.

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.

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.

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.

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.

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.

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.