Developing a radiomic based machine learning model to identify patients with resected non-small-cell lung cancer at high risk of relapse

Background There is a wide variation of recurrence risk of Non-small-cell lung cancer (NSCLC) within the same Tumor Node Metastasis (TNM) stage, suggesting that other parameters are involved in determining this probability. Radiomics allows extraction of quantitative information from images that can be used for clinical purposes. The primary objective of this study is to develop a radiomic prognostic model that predicts a 3 year disease free-survival (DFS) of resected Early Stage (ES) NSCLC patients. Material and Methods 56 pre-surgery non contrast Computed Tomography (CT) scans were retrieved from the PACS of our institution and anonymized. Then they were automatically segmented with an open access deep learning pipeline and reviewed by an experienced radiologist to obtain 3D masks of the NSCLC. Images and masks underwent to resampling normalization and discretization. From the masks hundreds Radiomic Features (RF) were extracted using Py-Radiomics. Hence, RF were reduced to select the most representative features. The remaining RF were used in combination with Clinical parameters to build a DFS prediction model using Leave-one-out cross-validation (LOOCV) with Random Forest. Results and Conclusion A poor agreement between the radiologist and the automatic segmentation algorithm (DICE score of 0.37) was found. Therefore, another experienced radiologist manually segmented the lesions and only stable and reproducible RF were kept. 50 RF demonstrated a high correlation with the DFS but only one was confirmed when clinicopathological covariates were added: Busyness a Neighbouring Gray Tone Difference Matrix (HR 9.610). 16 clinical variables (which comprised TNM) were used to build the LOOCV model demonstrating a higher Area Under the Curve (AUC) when RF were included in the analysis (0.67 vs 0.60) but the difference was not statistically significant (p=0,5147).

Topics in Local Economic Development

This thesis contributes to the current debate in literature about local economic development by considering two different topics: quality of institutions, and the role of clusters in innovation and productivity growth. The research is built upon three papers. The first paper deals with the analysis of the effect of administrative continuity on administrative efficiency. The analysis underlines the importance of different typologies of social capital. Findings reveal a positive impact on administrative efficiency (AE) by administrative continuity (AC) when it is coupled by bridging and linking social capital. On the contrary, bonding social capital influences negatively the effect by AC on AE. The second paper investigates the spatial interaction in levels of quality of government (QoG) among European regions. Notwithstanding the largely recognised role by institutions in the design of regional policies, no study has been conducted about the mechanisms of interaction and diffusion of QoG at regional level. This research wants to overcome this knowledge gap in literature. Findings reveal a heterogeneity in spatial interaction among groups of regions, i.e. ‘leader regions’ (Northern regions) and ‘lagging regions’ (Southern regions), when considering different mechanisms of interaction (learning / imitating competition and pure competition). Moreover, the effect of wealth on the levels of QoG is nonlinear. Finally, the third paper analyses the relation among specialization and productivity within the agricultural sector. In literature, the study of clusters dynamics has long neglected agriculture. The analysis describes the changes in sectorial specialization for eight main crop groups in Italian regions (NUTS 3), assessing the existence of spatial autocorrelations by using an exploratory data analysis. Furthermore, the effect of specialization on productivity is analysed within the main crop groups using a spatial panel data model. Findings reveal a marked tendency to specialization in the Italian agriculture, and a heterogeneous effect by specialization on productivity.

Development and characterization of deep learning techniques for neuroimaging data

Deep learning methods are extremely promising machine learning tools to analyze neuroimaging data. However, their potential use in clinical settings is limited because of the existing challenges of applying these methods to neuroimaging data. In this study, first a data leakage type caused by slice-level data split that is introduced during training and validation of a 2D CNN is surveyed and a quantitative assessment of the model’s performance overestimation is presented. Second, an interpretable, leakage-fee deep learning software written in a python language with a wide range of options has been developed to conduct both classification and regression analysis. The software was applied to the study of mild cognitive impairment (MCI) in patients with small vessel disease (SVD) using multi-parametric MRI data where the cognitive performance of 58 patients measured by five neuropsychological tests is predicted using a multi-input CNN model taking brain image and demographic data. Each of the cognitive test scores was predicted using different MRI-derived features. As MCI due to SVD has been hypothesized to be the effect of white matter damage, DTI-derived features MD and FA produced the best prediction outcome of the TMT-A score which is consistent with the existing literature. In a second study, an interpretable deep learning system aimed at 1) classifying Alzheimer disease and healthy subjects 2) examining the neural correlates of the disease that causes a cognitive decline in AD patients using CNN visualization tools and 3) highlighting the potential of interpretability techniques to capture a biased deep learning model is developed. Structural magnetic resonance imaging (MRI) data of 200 subjects was used by the proposed CNN model which was trained using a transfer learning-based approach producing a balanced accuracy of 71.6%. Brain regions in the frontal and parietal lobe showing the cerebral cortex atrophy were highlighted by the visualization tools.

Network analysis and machine learning assist drug repurposing and safety assessment in neurological diseases

In recent decades, two prominent trends have influenced the data modeling field, namely network analysis and machine learning. This thesis explores the practical applications of these techniques within the domain of drug research, unveiling their multifaceted potential for advancing our comprehension of complex biological systems. The research undertaken during this PhD program is situated at the intersection of network theory, computational methods, and drug research. Across six projects presented herein, there is a gradual increase in model complexity. These projects traverse a diverse range of topics, with a specific emphasis on drug repurposing and safety in the context of neurological diseases. The aim of these projects is to leverage existing biomedical knowledge to develop innovative approaches that bolster drug research. The investigations have produced practical solutions, not only providing insights into the intricacies of biological systems, but also allowing the creation of valuable tools for their analysis. In short, the achievements are: • A novel computational algorithm to identify adverse events specific to fixed-dose drug combinations. • A web application that tracks the clinical drug research response to SARS-CoV-2. • A Python package for differential gene expression analysis and the identification of key regulatory "switch genes". • The identification of pivotal events causing drug-induced impulse control disorders linked to specific medications. • An automated pipeline for discovering potential drug repurposing opportunities. • The creation of a comprehensive knowledge graph and development of a graph machine learning model for predictions. Collectively, these projects illustrate diverse applications of data science and network-based methodologies, highlighting the profound impact they can have in supporting drug research activities.

Deep learning and spatial transcriptomics to investigate thyroid tumors

There are many diseases that affect the thyroid gland, and among them are carcinoma. Thyroid cancer is the most common endocrine neoplasm and the second most frequent cancer in the 0-49 age group. This thesis deals with two studies I conducted during my PhD. The first concerns the development of a Deep Learning model to be able to assist the pathologist in screening of thyroid cytology smears. This tool created in collaboration with Prof. Diciotti, affiliated with the DEI-UNIBO "Guglielmo Marconi" Department of Electrical Energy and Information Engineering, has an important clinical implication in that it allows patients to be stratified between those who should undergo surgery and those who should not. The second concerns the application of spatial transcriptomics on well-differentiated thyroid carcinomas to better understand their invasion mechanisms and thus to better comprehend which genes may be involved in the proliferation of these tumors. This project specifically was made possible through a fruitful collaboration with the Gustave Roussy Institute in Paris. Studying thyroid carcinoma deeply is essential to improve patient care, increase survival rates, and enhance the overall understanding of this prevalent cancer. It can lead to more effective prevention, early detection, and treatment strategies that benefit both patients and the healthcare system.

Tensor-Train decomposition for image classification problems

In these last years a great effort has been put in the development of new techniques for automatic object classification, also due to the consequences in many applications such as medical imaging or driverless cars. To this end, several mathematical models have been developed from logistic regression to neural networks. A crucial aspect of these so called classification algorithms is the use of algebraic tools to represent and approximate the input data. In this thesis, we examine two different models for image classification based on a particular tensor decomposition named Tensor-Train (TT) decomposition. The use of tensor approaches preserves the multidimensional structure of the data and the neighboring relations among pixels. Furthermore the Tensor-Train, differently from other tensor decompositions, does not suffer from the curse of dimensionality making it an extremely powerful strategy when dealing with high-dimensional data. It also allows data compression when combined with truncation strategies that reduce memory requirements without spoiling classification performance. The first model we propose is based on a direct decomposition of the database by means of the TT decomposition to find basis vectors used to classify a new object. The second model is a tensor dictionary learning model, based on the TT decomposition where the terms of the decomposition are estimated using a proximal alternating linearized minimization algorithm with a spectral stepsize.

Computational methods applied to undeciphered scripts from the Aegean and Cyprus: Linear A and Cypro-Minoan

The study of ancient, undeciphered scripts presents unique challenges, that depend both on the nature of the problem and on the peculiarities of each writing system. In this thesis, I present two computational approaches that are tailored to two different tasks and writing systems. The first of these methods is aimed at the decipherment of the Linear A afraction signs, in order to discover their numerical values. This is achieved with a combination of constraint programming, ad-hoc metrics and paleographic considerations. The second main contribution of this thesis regards the creation of an unsupervised deep learning model which uses drawings of signs from ancient writing system to learn to distinguish different graphemes in the vector space. This system, which is based on techniques used in the field of computer vision, is adapted to the study of ancient writing systems by incorporating information about sequences in the model, mirroring what is often done in natural language processing. In order to develop this model, the Cypriot Greek Syllabary is used as a target, since this is a deciphered writing system. Finally, this unsupervised model is adapted to the undeciphered Cypro-Minoan and it is used to answer open questions about this script. In particular, by reconstructing multiple allographs that are not agreed upon by paleographers, it supports the idea that Cypro-Minoan is a single script and not a collection of three script like it was proposed in the literature. These results on two different tasks shows that computational methods can be applied to undeciphered scripts, despite the relatively low amount of available data, paving the way for further advancement in paleography using these methods.

Addressing challenges in heterogeneous embedded systems programming: security and performance

Embedded systems are increasingly integral to daily life, improving and facilitating the efficiency of modern Cyber-Physical Systems which provide access to sensor data, and actuators. As modern architectures become increasingly complex and heterogeneous, their optimization becomes a challenging task. Additionally, ensuring platform security is important to avoid harm to individuals and assets. This study primarily addresses challenges in contemporary Embedded Systems, focusing on platform optimization and security enforcement. The initial section of this study delves into the application of machine learning methods to efficiently determine the optimal number of cores for a parallel RISC-V cluster to minimize energy consumption using static source code analysis. Results demonstrate that automated platform configuration is not only viable but also that there is a moderate performance trade-off when relying solely on static features. The second part focuses on addressing the problem of heterogeneous device mapping, which involves assigning tasks to the most suitable computational device in a heterogeneous platform for optimal runtime. The contribution of this section lies in the introduction of novel pre-processing techniques, along with a training framework called Siamese Networks, that enhances the classification performance of DeepLLVM, an advanced approach for task mapping. Importantly, these proposed approaches are independent from the specific deep-learning model used. Finally, this research work focuses on addressing issues concerning the binary exploitation of software running in modern Embedded Systems. It proposes an architecture to implement Control-Flow Integrity in embedded platforms with a Root-of-Trust, aiming to enhance security guarantees with limited hardware modifications. The approach involves enhancing the architecture of a modern RISC-V platform for autonomous vehicles by implementing a side-channel communication mechanism that relays control-flow changes executed by the process running on the host core to the Root-of-Trust. This approach has limited impact on performance and it is effective in enhancing the security of embedded platforms.

A take on complexity: bio-molecules and human metabolism interaction modelling for health and nutrition with machine learning

The advent of omic data production has opened many new perspectives in the quest for modelling complexity in biophysical systems. With the capability of characterizing a complex organism through the patterns of its molecular states, observed at different levels through various omics, a new paradigm of investigation is arising. In this thesis, we investigate the links between perturbations of the human organism, described as the ensemble of crosstalk of its molecular states, and health. Machine learning plays a key role within this picture, both in omic data analysis and model building. We propose and discuss different frameworks developed by the author using machine learning for data reduction, integration, projection on latent features, pattern analysis, classification and clustering of omic data, with a focus on 1H NMR metabolomic spectral data. The aim is to link different levels of omic observations of molecular states, from nanoscale to macroscale, to study perturbations such as diseases and diet interpreted as changes in molecular patterns. The first part of this work focuses on the fingerprinting of diseases, linking cellular and systemic metabolomics with genomic to asses and predict the downstream of perturbations all the way down to the enzymatic network. The second part is a set of frameworks and models, developed with 1H NMR metabolomic at its core, to study the exposure of the human organism to diet and food intake in its full complexity, from epidemiological data analysis to molecular characterization of food structure.

Formazione, apprendimento e nuove prospettive e-learning. Lo sviluppo delle nuove tecnologie didattiche e la creazione di sistemi di apprendimento lungo l’intero arco della vita

The thesis of this paper is based on the assumption that the socio-economic system in which we are living is characterised by three great trends: growing attention to the promotion of human capital; extremely rapid technological progress, based above all on the information and communication technologies (ICT); the establishment of new production and organizational set-ups. These transformation processes pose a concrete challenge to the training sector, which is called to satisfy the demand for new skills that need to be developed and disseminated. Hence the growing interest that the various training sub-systems devote to the issues of lifelong learning and distance learning. In such a context, the so-called e-learning acquires a central role. The first chapter proposes a reference theoretical framework for the transformations that are shaping post-industrial society. It analyzes some key issues such as: how work is changing, the evolution of organizational set-ups and the introduction of learning organization, the advent of the knowledge society and of knowledge companies, the innovation of training processes, and the key role of ICT in the new training and learning systems. The second chapter focuses on the topic of e-learning as an effective training model in response to the need for constant learning that is emerging in the knowledge society. This chapter starts with a reflection on the importance of lifelong learning and introduces the key arguments of this thesis, i.e. distance learning (DL) and the didactic methodology called e-learning. It goes on with an analysis of the various theoretic and technical aspects of e-learning. In particular, it delves into the theme of e-learning as an integrated and constant training environment, characterized by customized programmes and collaborative learning, didactic assistance and constant monitoring of the results. Thus, all the aspects of e-learning are taken into exam: the actors and the new professionals, the virtual communities as learning subjects, the organization of contents in learning objects, the conformity to international standards, the integrated platforms and so on. The third chapter, which concludes the theoretic-interpretative part, starts with a short presentation of the state-of-the-art e-learning international market that aims to understand its peculiarities and its current trends. Finally, we focus on some important regulation aspects related to the strong impulse given by the European Commission first, and by the Italian governments secondly, to the development and diffusion of e-learning. The second part of the thesis (chapters 4, 5 and 6) focus on field research, which aims to define the Italian scenario for e-learning. In particular, we have examined some key topics such as: the challenges of training and the instruments to face such challenges; the new didactic methods and technologies for lifelong learning; the level of diffusion of e-learning in Italy; the relation between classroom training and online training; the main factors of success as well as the most critical aspects of the introduction of e-learning in the various learning environments. As far as the methodological aspects are concerned, we have favoured a qualitative and quantitative analysis. A background analysis has been done to collect the statistical data available on this topic, as well as the research previously carried out in this area. The main source of data is constituted by the results of the Observatory on e-learning of Aitech-Assinform, which covers the 2000s and four areas of implementation (firms, public administration, universities, school): the thesis has reviewed the results of the last three available surveys, offering a comparative interpretation of them. We have then carried out an in-depth empirical examination of two case studies, which have been selected by virtue of the excellence they have achieved and can therefore be considered advanced and emblematic experiences (a large firm and a Graduate School).