Personalized Medicine Support System for Chronic Myeloid Leukemia Patients

Personalized medicine offers the most effective treatment protocols to the individual Chronic Myeloid Leukemia (CML) patients. Understanding the molecular biology that causes CML assists in providing efficient treatment. After the identification of an activated tyrosine kinase BCR-ABL1 as the causative lesion in CML, the first-generation Tyrosine Kinase inhibitors (TKI) imatinib (Glivec®), were developed to inhibit BCR-ABL1 activity and approved as a treatment for CML. Despite the remarkable increase in the survival rate of CML patients treated with imatinib, some patients discontinued imatinib therapy due to intolerance, resistance or progression. These patients may benefit from the use of secondgeneration TKIs, such as nilotinib (Tasigna®) and dasatinib (Sprycel®). All three of these TKIs are currently approved for use as frontline treatments. Prognostic scores and molecularbased predictive assays are used to personalize the care of CML patients by allocating risk groups and predicting responses to therapy. Although prognostic scores remain in use today, they are often inadequate for three main reasons. Firstly, since each prognostic score may generate conflicting prognoses for the risk index and it can be difficult to know how to treat patients with conflicting prognoses. Secondly, since prognostic score systems are developed over time, patients can benefit from newly developed systems and information. Finally, the earlier scores use mostly clinically oriented factors instead of those directly related to genetic or molecular indicators. As the current CML treatment guidelines recommend the use of TKI therapy, a new tool that combines the well-known, molecular-based predictive assays to predict molecular response to TKI has not been considered in previous research. Therefore, the main goal of this research is to improve the ability to manage CML disease in individual CML patients and support CML physicians in TKI therapy treatment selection by correctly allocating patients to risk groups and predicting their molecular response to the selected treatment. To achieve this objective, the research detailed here focuses on developing a prognostic model and a predictive model for use as a personalized medicine support system. The system will be considered a knowledge-based clinical decision support system that includes two models embedded in a decision tree. The main idea is to classify patients into risk groups using the prognostic model, while the patients identified as part of the high-risk group should be considered for more aggressive imatinib therapy or switched to secondgeneration TKI with close monitoring. For patients assigned to the low-risk group to imatinib should be predicted using the predictive model. The outcomes should be evaluated by comparing the results of these models with the actual responses to imatinib in patients from a previous medical trial and from patients admitted to hospitals. Validating such a predictive system could greatly assist clinicians in clinical decision-making geared toward individualized medicine. Our findings suggest that the system provides treatment recommendations that could help improve overall healthcare for CML patients. Study limitations included the impact of diversity on human expertise, changing predictive factors, population and prediction endpoints, the impact of time and patient personal issues. Further intensive research activities based on the development of a new predictive model and the method for selecting predictive factors and validation can be expanded to other health organizations and the development of models to predict responses to other TKIs.Thesis (Ph.D.) -- University of Adelaide, School of Computer Science, 201

System-Level Modeling of Endothelial Permeability Pathway and High-throughput Data Analysis for Disease Biomarker Selection

Ph.DDOCTOR OF PHILOSOPH

Pattern Recognition

Pattern recognition is a very wide research field. It involves factors as diverse as sensors, feature extraction, pattern classification, decision fusion, applications and others. The signals processed are commonly one, two or three dimensional, the processing is done in real- time or takes hours and days, some systems look for one narrow object class, others search huge databases for entries with at least a small amount of similarity. No single person can claim expertise across the whole field, which develops rapidly, updates its paradigms and comprehends several philosophical approaches. This book reflects this diversity by presenting a selection of recent developments within the area of pattern recognition and related fields. It covers theoretical advances in classification and feature extraction as well as application-oriented works. Authors of these 25 works present and advocate recent achievements of their research related to the field of pattern recognition

Generalized multi-stream hidden Markov models.

For complex classification systems, data is usually gathered from multiple sources of information that have varying degree of reliability. In fact, assuming that the different sources have the same relevance in describing all the data might lead to an erroneous behavior. The classification error accumulates and can be more severe for temporal data where each sample is represented by a sequence of observations. Thus, there is compelling evidence that learning algorithms should include a relevance weight for each source of information (stream) as a parameter that needs to be learned. In this dissertation, we assumed that the multi-stream temporal data is generated by independent and synchronous streams. Using this assumption, we develop, implement, and test multi- stream continuous and discrete hidden Markov model (HMM) algorithms. For the discrete case, we propose two new approaches to generalize the baseline discrete HMM. The first one combines unsupervised learning, feature discrimination, standard discrete HMMs and weighted distances to learn the codebook with feature-dependent weights for each symbol. The second approach consists of modifying the HMM structure to include stream relevance weights, generalizing the standard discrete Baum-Welch learning algorithm, and deriving the necessary conditions to optimize all model parameters simultaneously. We also generalize the minimum classification error (MCE) discriminative training algorithm to include stream relevance weights. For the continuous HMM, we introduce a. new approach that integrates the stream relevance weights in the objective function. Our approach is based on the linearization of the probability density function. Two variations are proposed: the mixture and state level variations. As in the discrete case, we generalize the continuous Baum-Welch learning algorithm to accommodate these changes, and we derive the necessary conditions for updating the model parameters. We also generalize the MCE learning algorithm to derive the necessary conditions for the model parameters\u27 update. The proposed discrete and continuous HMM are tested on synthetic data sets. They are also validated on various applications including Australian Sign Language, audio classification, face classification, and more extensively on the problem of landmine detection using ground penetrating radar data. For all applications, we show that considerable improvement can be achieved compared to the baseline HMM and the existing multi-stream HMM algorithms

Robust learning to rank models and their biomedical applications

There exist many real-world applications such as recommendation systems, document retrieval, and computational biology where the correct ordering of instances is of equal or greater importance than predicting the exact value of some discrete or continuous outcome. Learning-to-Rank (LTR) refers to a group of algorithms that apply machine learning techniques to tackle these ranking problems. Despite their empirical success, most existing LTR models are not built to be robust to errors in labeling or annotation, distributional data shift, or adversarial data perturbations. To fill this gap, we develop four LTR frameworks that are robust to various types of perturbations. First, Pairwise Elastic Net Regression Ranking (PENRR) is an elastic-net-based regression method for drug sensitivity prediction. PENRR infers robust predictors of drug responses from patient genomic information. The special design of this model (comparing each drug with other drugs in the same cell line and comparing that drug with itself in other cell lines) significantly enhances the accuracy of the drug prediction model under limited data. This approach is also able to solve the problem of fitting on the insensitive drugs that is commonly encountered in regression-based models. Second, Regression-based Ranking by Pairwise Cluster Comparisons (RRPCC) is a ridge-regression-based method for ranking clusters of similar protein complex conformations generated by an underlying docking program (i.e., ClusPro). Rather than using regression to predict scores, which would equally penalize deviations for either low-quality and high-quality clusters, we seek to predict the difference of scores for any pair of clusters corresponding to the same complex. RRPCC combines these pairwise assessments to form a ranked list of clusters, from higher to lower quality. We apply RRPCC to clusters produced by the automated docking server ClusPro and, depending on the training/validation strategy, we show. improvement by 24%–100% in ranking acceptable or better quality clusters first, and by 15%–100% in ranking medium or better quality clusters first. Third, Distributionally Robust Multi-Output Regression Ranking (DRMRR) is a listwise LTR model that induces robustness into LTR problems using the Distributionally Robust Optimization framework. Contrasting to existing methods, the scoring function of DRMRR was designed as a multivariate mapping from a feature vector to a vector of deviation scores, which captures local context information and cross-document interactions. DRMRR employs ranking metrics (i.e., NDCG) in its output. Particularly, we used the notion of position deviation to define a vector of relevance score instead of a scalar one. We then adopted the DRO framework to minimize a worst-case expected multi-output loss function over a probabilistic ambiguity set that is defined by the Wasserstein metric. We also presented an equivalent convex reformulation of the DRO problem, which is shown to be tighter than the ones proposed by the previous studies. Fourth, Inversion Transformer-based Neural Ranking (ITNR) is a Transformer-based model to predict drug responses using RNAseq gene expression profiles, drug descriptors, and drug fingerprints. It utilizes a Context-Aware-Transformer architecture as its scoring function that ensures the modeling of inter-item dependencies. We also introduced a new loss function using the concept of Inversion and approximate permutation matrices. The accuracy and robustness of these LTR models are verified through three medical applications, namely cluster ranking in protein-protein docking, medical document retrieval, and drug response prediction

Tracking the Temporal-Evolution of Supernova Bubbles in Numerical Simulations

The study of low-dimensional, noisy manifolds embedded in a higher dimensional space has been extremely useful in many applications, from the chemical analysis of multi-phase flows to simulations of galactic mergers. Building a probabilistic model of the manifolds has helped in describing their essential properties and how they vary in space. However, when the manifold is evolving through time, a joint spatio-temporal modelling is needed, in order to fully comprehend its nature. We propose a first-order Markovian process that propagates the spatial probabilistic model of a manifold at fixed time, to its adjacent temporal stages. The proposed methodology is demonstrated using a particle simulation of an interacting dwarf galaxy to describe the evolution of a cavity generated by a Supernov

Knowledge derivation and data mining strategies for probabilistic functional integrated networks

PhDOne of the fundamental goals of systems biology is the experimental verification of the interactome: the entire complement of molecular interactions occurring in the cell. Vast amounts of high-throughput data have been produced to aid this effort. However these data are incomplete and contain high levels of both false positives and false negatives. In order to combat these limitations in data quality, computational techniques have been developed to evaluate the datasets and integrate them in a systematic fashion using graph theory. The result is an integrated network which can be analysed using a variety of network analysis techniques to draw new inferences about biological questions and to guide laboratory experiments. Individual research groups are interested in specific biological problems and, consequently, network analyses are normally performed with regard to a specific question. However, the majority of existing data integration techniques are global and do not focus on specific areas of biology. Currently this issue is addressed by using known annotation data (such as that from the Gene Ontology) to produce process-specific subnetworks. However, this approach discards useful information and is of limited use in poorly annotated areas of the interactome. Therefore, there is a need for network integration techniques that produce process-specific networks without loss of data. The work described here addresses this requirement by extending one of the most powerful integration techniques, probabilistic functional integrated networks (PFINs), to incorporate a concept of biological relevance. Initially, the available functional data for the baker’s yeast Saccharomyces cerevisiae was evaluated to identify areas of bias and specificity which could be exploited during network integration. This information was used to develop an integration technique which emphasises interactions relevant to specific biological questions, using yeast ageing as an exemplar. The integration method improves performance during network-based protein functional prediction in relation to this process. Further, the process-relevant networks complement classical network integration techniques and significantly improve network analysis in a wide range of biological processes. The method developed has been used to produce novel predictions for 505 Gene Ontology biological processes. Of these predictions 41,610 are consistent with existing computational annotations, and 906 are consistent with known expert-curated annotations. The approach significantly reduces the hypothesis space for experimental validation of genes hypothesised to be involved in the oxidative stress response. Therefore, incorporation of biological relevance into network integration can significantly improve network analysis with regard to individual biological questions

Pattern Recognition

A wealth of advanced pattern recognition algorithms are emerging from the interdiscipline between technologies of effective visual features and the human-brain cognition process. Effective visual features are made possible through the rapid developments in appropriate sensor equipments, novel filter designs, and viable information processing architectures. While the understanding of human-brain cognition process broadens the way in which the computer can perform pattern recognition tasks. The present book is intended to collect representative researches around the globe focusing on low-level vision, filter design, features and image descriptors, data mining and analysis, and biologically inspired algorithms. The 27 chapters coved in this book disclose recent advances and new ideas in promoting the techniques, technology and applications of pattern recognition

Women in Artificial intelligence (AI)

This Special Issue, entitled "Women in Artificial Intelligence" includes 17 papers from leading women scientists. The papers cover a broad scope of research areas within Artificial Intelligence, including machine learning, perception, reasoning or planning, among others. The papers have applications to relevant fields, such as human health, finance, or education. It is worth noting that the Issue includes three papers that deal with different aspects of gender bias in Artificial Intelligence. All the papers have a woman as the first author. We can proudly say that these women are from countries worldwide, such as France, Czech Republic, United Kingdom, Australia, Bangladesh, Yemen, Romania, India, Cuba, Bangladesh and Spain. In conclusion, apart from its intrinsic scientific value as a Special Issue, combining interesting research works, this Special Issue intends to increase the invisibility of women in AI, showing where they are, what they do, and how they contribute to developments in Artificial Intelligence from their different places, positions, research branches and application fields. We planned to issue this book on the on Ada Lovelace Day (11/10/2022), a date internationally dedicated to the first computer programmer, a woman who had to fight the gender difficulties of her times, in the XIX century. We also thank the publisher for making this possible, thus allowing for this book to become a part of the international activities dedicated to celebrating the value of women in ICT all over the world. With this book, we want to pay homage to all the women that contributed over the years to the field of AI