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.

Methods for integrating machine learning and constrained optimization

In the framework of industrial problems, the application of Constrained Optimization is known to have overall very good modeling capability and performance and stands as one of the most powerful, explored, and exploited tool to address prescriptive tasks. The number of applications is huge, ranging from logistics to transportation, packing, production, telecommunication, scheduling, and much more. The main reason behind this success is to be found in the remarkable effort put in the last decades by the OR community to develop realistic models and devise exact or approximate methods to solve the largest variety of constrained or combinatorial optimization problems, together with the spread of computational power and easily accessible OR software and resources. On the other hand, the technological advancements lead to a data wealth never seen before and increasingly push towards methods able to extract useful knowledge from them; among the data-driven methods, Machine Learning techniques appear to be one of the most promising, thanks to its successes in domains like Image Recognition, Natural Language Processes and playing games, but also the amount of research involved. The purpose of the present research is to study how Machine Learning and Constrained Optimization can be used together to achieve systems able to leverage the strengths of both methods: this would open the way to exploiting decades of research on resolution techniques for COPs and constructing models able to adapt and learn from available data. In the first part of this work, we survey the existing techniques and classify them according to the type, method, or scope of the integration; subsequently, we introduce a novel and general algorithm devised to inject knowledge into learning models through constraints, Moving Target. In the last part of the thesis, two applications stemming from real-world projects and done in collaboration with Optit will be presented.

A machine learning based method to detect genomic imbalances exploiting X chromosome exome reads

Whole Exome Sequencing (WES) is rapidly becoming the first-tier test in clinics, both thanks to its declining costs and the development of new platforms that help clinicians in the analysis and interpretation of SNV and InDels. However, we still know very little on how CNV detection could increase WES diagnostic yield. A plethora of exome CNV callers have been published over the years, all showing good performances towards specific CNV classes and sizes, suggesting that the combination of multiple tools is needed to obtain an overall good detection performance. Here we present TrainX, a ML-based method for calling heterozygous CNVs in WES data using EXCAVATOR2 Normalized Read Counts. We select males and females’ non pseudo-autosomal chromosome X alignments to construct our dataset and train our model, make predictions on autosomes target regions and use HMM to call CNVs. We compared TrainX against a set of CNV tools differing for the detection method (GATK4 gCNV, ExomeDepth, DECoN, CNVkit and EXCAVATOR2) and found that our algorithm outperformed them in terms of stability, as we identified both deletions and duplications with good scores (0.87 and 0.82 F1-scores respectively) and for sizes reaching the minimum resolution of 2 target regions. We also evaluated the method robustness using a set of WES and SNP array data (n=251), part of the Italian cohort of Epi25 collaborative, and were able to retrieve all clinical CNVs previously identified by the SNP array. TrainX showed good accuracy in detecting heterozygous CNVs of different sizes, making it a promising tool to use in a diagnostic setting.

The three-dimensional single-bin-size bin packing problem: combining metaheuristic and machine learning approaches

The Three-Dimensional Single-Bin-Size Bin Packing Problem is one of the most studied problem in the Cutting & Packing category. From a strictly mathematical point of view, it consists of packing a finite set of strongly heterogeneous “small” boxes, called items, into a finite set of identical “large” rectangles, called bins, minimizing the unused volume and requiring that the items are packed without overlapping. The great interest is mainly due to the number of real-world applications in which it arises, such as pallet and container loading, cutting objects out of a piece of material and packaging design. Depending on these real-world applications, more objective functions and more practical constraints could be needed. After a brief discussion about the real-world applications of the problem and a exhaustive literature review, the design of a two-stage algorithm to solve the aforementioned problem is presented. The algorithm must be able to provide the spatial coordinates of the placed boxes vertices and also the optimal boxes input sequence, while guaranteeing geometric, stability, fragility constraints and a reduced computational time. Due to NP-hard complexity of this type of combinatorial problems, a fusion of metaheuristic and machine learning techniques is adopted. In particular, a hybrid genetic algorithm coupled with a feedforward neural network is used. In the first stage, a rich dataset is created starting from a set of real input instances provided by an industrial company and the feedforward neural network is trained on it. After its training, given a new input instance, the hybrid genetic algorithm is able to run using the neural network output as input parameter vector, providing as output the optimal solution. The effectiveness of the proposed works is confirmed via several experimental tests.

Machine learning as a service for high energy physics (MLaaS4HEP): a service for ML-based data analyses

With the CERN LHC program underway, there has been an acceleration of data growth in the High Energy Physics (HEP) field and the usage of Machine Learning (ML) in HEP will be critical during the HL-LHC program when the data that will be produced will reach the exascale. ML techniques have been successfully used in many areas of HEP nevertheless, the development of a ML project and its implementation for production use is a highly time-consuming task and requires specific skills. Complicating this scenario is the fact that HEP data is stored in ROOT data format, which is mostly unknown outside of the HEP community. The work presented in this thesis is focused on the development of a ML as a Service (MLaaS) solution for HEP, aiming to provide a cloud service that allows HEP users to run ML pipelines via HTTP calls. These pipelines are executed by using the MLaaS4HEP framework, which allows reading data, processing data, and training ML models directly using ROOT files of arbitrary size from local or distributed data sources. Such a solution provides HEP users non-expert in ML with a tool that allows them to apply ML techniques in their analyses in a streamlined manner. Over the years the MLaaS4HEP framework has been developed, validated, and tested and new features have been added. A first MLaaS solution has been developed by automatizing the deployment of a platform equipped with the MLaaS4HEP framework. Then, a service with APIs has been developed, so that a user after being authenticated and authorized can submit MLaaS4HEP workflows producing trained ML models ready for the inference phase. A working prototype of this service is currently running on a virtual machine of INFN-Cloud and is compliant to be added to the INFN Cloud portfolio of services.

Design and testing of innovative, artificial intelligence-based techniques to model and control the combustion process and to reduce the Co2 emissions in modern, high-performance, gasoline direct injection engines

This work deals with the development of calibration procedures and control systems to improve the performance and efficiency of modern spark ignition turbocharged engines. The algorithms developed are used to optimize and manage the spark advance and the air-to-fuel ratio to control the knock and the exhaust gas temperature at the turbine inlet. The described work falls within the activity that the research group started in the previous years with the industrial partner Ferrari S.p.a. . The first chapter deals with the development of a control-oriented engine simulator based on a neural network approach, with which the main combustion indexes can be simulated. The second chapter deals with the development of a procedure to calibrate offline the spark advance and the air-to-fuel ratio to run the engine under knock-limited conditions and with the maximum admissible exhaust gas temperature at the turbine inlet. This procedure is then converted into a model-based control system and validated with a Software in the Loop approach using the engine simulator developed in the first chapter. Finally, it is implemented in a rapid control prototyping hardware to manage the combustion in steady-state and transient operating conditions at the test bench. The third chapter deals with the study of an innovative and cheap sensor for the in-cylinder pressure measurement, which is a piezoelectric washer that can be installed between the spark plug and the engine head. The signal generated by this kind of sensor is studied, developing a specific algorithm to adjust the value of the knock index in real-time. Finally, with the engine simulator developed in the first chapter, it is demonstrated that the innovative sensor can be coupled with the control system described in the second chapter and that the performance obtained could be the same reachable with the standard in-cylinder pressure sensors.

Development of machine learning methods for multi-modal biomarkers detection and integration

In medicine, innovation depends on a better knowledge of the human body mechanism, which represents a complex system of multi-scale constituents. Unraveling the complexity underneath diseases proves to be challenging. A deep understanding of the inner workings comes with dealing with many heterogeneous information. Exploring the molecular status and the organization of genes, proteins, metabolites provides insights on what is driving a disease, from aggressiveness to curability. Molecular constituents, however, are only the building blocks of the human body and cannot currently tell the whole story of diseases. This is why nowadays attention is growing towards the contemporary exploitation of multi-scale information. Holistic methods are then drawing interest to address the problem of integrating heterogeneous data. The heterogeneity may derive from the diversity across data types and from the diversity within diseases. Here, four studies conducted data integration using customly designed workflows that implement novel methods and views to tackle the heterogeneous characterization of diseases. The first study devoted to determine shared gene regulatory signatures for onco-hematology and it showed partial co-regulation across blood-related diseases. The second study focused on Acute Myeloid Leukemia and refined the unsupervised integration of genomic alterations, which turned out to better resemble clinical practice. In the third study, network integration for artherosclerosis demonstrated, as a proof of concept, the impact of network intelligibility when it comes to model heterogeneous data, which showed to accelerate the identification of new potential pharmaceutical targets. Lastly, the fourth study introduced a new method to integrate multiple data types in a unique latent heterogeneous-representation that facilitated the selection of important data types to predict the tumour stage of invasive ductal carcinoma. The results of these four studies laid the groundwork to ease the detection of new biomarkers ultimately beneficial to medical practice and to the ever-growing field of Personalized Medicine.

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.

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).

Supporting Scientific Research Through Machine and Deep Learning: Fluorescence Microscopy and Operational Intelligence Use Cases

Although the debate of what data science is has a long history and has not reached a complete consensus yet, Data Science can be summarized as the process of learning from data. Guided by the above vision, this thesis presents two independent data science projects developed in the scope of multidisciplinary applied research. The first part analyzes fluorescence microscopy images typically produced in life science experiments, where the objective is to count how many marked neuronal cells are present in each image. Aiming to automate the task for supporting research in the area, we propose a neural network architecture tuned specifically for this use case, cell ResUnet (c-ResUnet), and discuss the impact of alternative training strategies in overcoming particular challenges of our data. The approach provides good results in terms of both detection and counting, showing performance comparable to the interpretation of human operators. As a meaningful addition, we release the pre-trained model and the Fluorescent Neuronal Cells dataset collecting pixel-level annotations of where neuronal cells are located. In this way, we hope to help future research in the area and foster innovative methodologies for tackling similar problems. The second part deals with the problem of distributed data management in the context of LHC experiments, with a focus on supporting ATLAS operations concerning data transfer failures. In particular, we analyze error messages produced by failed transfers and propose a Machine Learning pipeline that leverages the word2vec language model and K-means clustering. This provides groups of similar errors that are presented to human operators as suggestions of potential issues to investigate. The approach is demonstrated on one full day of data, showing promising ability in understanding the message content and providing meaningful groupings, in line with previously reported incidents by human operators.

Continual learning for computer vision applications

One of the most visionary goals of Artificial Intelligence is to create a system able to mimic and eventually surpass the intelligence observed in biological systems including, ambitiously, the one observed in humans. The main distinctive strength of humans is their ability to build a deep understanding of the world by learning continuously and drawing from their experiences. This ability, which is found in various degrees in all intelligent biological beings, allows them to adapt and properly react to changes by incrementally expanding and refining their knowledge. Arguably, achieving this ability is one of the main goals of Artificial Intelligence and a cornerstone towards the creation of intelligent artificial agents. Modern Deep Learning approaches allowed researchers and industries to achieve great advancements towards the resolution of many long-standing problems in areas like Computer Vision and Natural Language Processing. However, while this current age of renewed interest in AI allowed for the creation of extremely useful applications, a concerningly limited effort is being directed towards the design of systems able to learn continuously. The biggest problem that hinders an AI system from learning incrementally is the catastrophic forgetting phenomenon. This phenomenon, which was discovered in the 90s, naturally occurs in Deep Learning architectures where classic learning paradigms are applied when learning incrementally from a stream of experiences. This dissertation revolves around the Continual Learning field, a sub-field of Machine Learning research that has recently made a comeback following the renewed interest in Deep Learning approaches. This work will focus on a comprehensive view of continual learning by considering algorithmic, benchmarking, and applicative aspects of this field. This dissertation will also touch on community aspects such as the design and creation of research tools aimed at supporting Continual Learning research, and the theoretical and practical aspects concerning public competitions in this field.

Development of unsupervised learning methods with applications to life sciences data

Machine Learning makes computers capable of performing tasks typically requiring human intelligence. A domain where it is having a considerable impact is the life sciences, allowing to devise new biological analysis protocols, develop patients’ treatments efficiently and faster, and reduce healthcare costs. This Thesis work presents new Machine Learning methods and pipelines for the life sciences focusing on the unsupervised field. At a methodological level, two methods are presented. The first is an “Ab Initio Local Principal Path” and it is a revised and improved version of a pre-existing algorithm in the manifold learning realm. The second contribution is an improvement over the Import Vector Domain Description (one-class learning) through the Kullback-Leibler divergence. It hybridizes kernel methods to Deep Learning obtaining a scalable solution, an improved probabilistic model, and state-of-the-art performances. Both methods are tested through several experiments, with a central focus on their relevance in life sciences. Results show that they improve the performances achieved by their previous versions. At the applicative level, two pipelines are presented. The first one is for the analysis of RNA-Seq datasets, both transcriptomic and single-cell data, and is aimed at identifying genes that may be involved in biological processes (e.g., the transition of tissues from normal to cancer). In this project, an R package is released on CRAN to make the pipeline accessible to the bioinformatic Community through high-level APIs. The second pipeline is in the drug discovery domain and is useful for identifying druggable pockets, namely regions of a protein with a high probability of accepting a small molecule (a drug). Both these pipelines achieve remarkable results. Lastly, a detour application is developed to identify the strengths/limitations of the “Principal Path” algorithm by analyzing Convolutional Neural Networks induced vector spaces. This application is conducted in the music and visual arts domains.

Ethical Perspectives on Big Data in Agri-food: Ownership and Governance for Safety

Big data are reshaping the way we interact with technology, thus fostering new applications to increase the safety-assessment of foods. An extraordinary amount of information is analysed using machine learning approaches aimed at detecting the existence or predicting the likelihood of future risks. Food business operators have to share the results of these analyses when applying to place on the market regulated products, whereas agri-food safety agencies (including the European Food Safety Authority) are exploring new avenues to increase the accuracy of their evaluations by processing Big data. Such an informational endowment brings with it opportunities and risks correlated to the extraction of meaningful inferences from data. However, conflicting interests and tensions among the involved entities - the industry, food safety agencies, and consumers - hinder the finding of shared methods to steer the processing of Big data in a sound, transparent and trustworthy way. A recent reform in the EU sectoral legislation, the lack of trust and the presence of a considerable number of stakeholders highlight the need of ethical contributions aimed at steering the development and the deployment of Big data applications. Moreover, Artificial Intelligence guidelines and charters published by European Union institutions and Member States have to be discussed in light of applied contexts, including the one at stake. This thesis aims to contribute to these goals by discussing what principles should be put forward when processing Big data in the context of agri-food safety-risk assessment. The research focuses on two interviewed topics - data ownership and data governance - by evaluating how the regulatory framework addresses the challenges raised by Big data analysis in these domains. The outcome of the project is a tentative Roadmap aimed to identify the principles to be observed when processing Big data in this domain and their possible implementations.

Robotic Sensing and Manipulation of Deformable Linear Objects with Learning-based methods

Nowadays robotic applications are widespread and most of the manipulation tasks are efficiently solved. However, Deformable-Objects (DOs) still represent a huge limitation for robots. The main difficulty in DOs manipulation is dealing with the shape and dynamics uncertainties, which prevents the use of model-based approaches (since they are excessively computationally complex) and makes sensory data difficult to interpret. This thesis reports the research activities aimed to address some applications in robotic manipulation and sensing of Deformable-Linear-Objects (DLOs), with particular focus to electric wires. In all the works, a significant effort was made in the study of an effective strategy for analyzing sensory signals with various machine learning algorithms. In the former part of the document, the main focus concerns the wire terminals, i.e. detection, grasping, and insertion. First, a pipeline that integrates vision and tactile sensing is developed, then further improvements are proposed for each module. A novel procedure is proposed to gather and label massive amounts of training images for object detection with minimal human intervention. Together with this strategy, we extend a generic object detector based on Convolutional-Neural-Networks for orientation prediction. The insertion task is also extended by developing a closed-loop control capable to guide the insertion of a longer and curved segment of wire through a hole, where the contact forces are estimated by means of a Recurrent-Neural-Network. In the latter part of the thesis, the interest shifts to the DLO shape. Robotic reshaping of a DLO is addressed by means of a sequence of pick-and-place primitives, while a decision making process driven by visual data learns the optimal grasping locations exploiting Deep Q-learning and finds the best releasing point. The success of the solution leverages on a reliable interpretation of the DLO shape. For this reason, further developments are made on the visual segmentation.

On the role of Computational Logic in Data Science: representing, learning, reasoning, and explaining knowledge

In this thesis we discuss in what ways computational logic (CL) and data science (DS) can jointly contribute to the management of knowledge within the scope of modern and future artificial intelligence (AI), and how technically-sound software technologies can be realised along the path. An agent-oriented mindset permeates the whole discussion, by stressing pivotal role of autonomous agents in exploiting both means to reach higher degrees of intelligence. Accordingly, the goals of this thesis are manifold. First, we elicit the analogies and differences among CL and DS, hence looking for possible synergies and complementarities along 4 major knowledge-related dimensions, namely representation, acquisition (a.k.a. learning), inference (a.k.a. reasoning), and explanation. In this regard, we propose a conceptual framework through which bridges these disciplines can be described and designed. We then survey the current state of the art of AI technologies, w.r.t. their capability to support bridging CL and DS in practice. After detecting lacks and opportunities, we propose the notion of logic ecosystem as the new conceptual, architectural, and technological solution supporting the incremental integration of symbolic and sub-symbolic AI. Finally, we discuss how our notion of logic ecosys- tem can be reified into actual software technology and extended towards many DS-related directions.