Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

Machine Learning Approaches for Improving Prediction Performance of Structure-Activity Relationship Models

In silico bioactivity prediction studies are designed to complement in vivo and in vitro efforts to assess the activity and properties of small molecules. In silico methods such as Quantitative Structure-Activity/Property Relationship (QSAR) are used to correlate the structure of a molecule to its biological property in drug design and toxicological studies. In this body of work, I started with two in-depth reviews into the application of machine learning based approaches and feature reduction methods to QSAR, and then investigated solutions to three common challenges faced in machine learning based QSAR studies. First, to improve the prediction accuracy of learning from imbalanced data, Synthetic Minority Over-sampling Technique (SMOTE) and Edited Nearest Neighbor (ENN) algorithms combined with bagging as an ensemble strategy was evaluated. The Friedman’s aligned ranks test and the subsequent Bergmann-Hommel post hoc test showed that this method significantly outperformed other conventional methods. SMOTEENN with bagging became less effective when IR exceeded a certain threshold (e.g., \u3e40). The ability to separate the few active compounds from the vast amounts of inactive ones is of great importance in computational toxicology. Deep neural networks (DNN) and random forest (RF), representing deep and shallow learning algorithms, respectively, were chosen to carry out structure-activity relationship-based chemical toxicity prediction. Results suggest that DNN significantly outperformed RF (p \u3c 0.001, ANOVA) by 22-27% for four metrics (precision, recall, F-measure, and AUPRC) and by 11% for another (AUROC). Lastly, current features used for QSAR based machine learning are often very sparse and limited by the logic and mathematical processes used to compute them. Transformer embedding features (TEF) were developed as new continuous vector descriptors/features using the latent space embedding from a multi-head self-attention. The significance of TEF as new descriptors was evaluated by applying them to tasks such as predictive modeling, clustering, and similarity search. An accuracy of 84% on the Ames mutagenicity test indicates that these new features has a correlation to biological activity. Overall, the findings in this study can be applied to improve the performance of machine learning based Quantitative Structure-Activity/Property Relationship (QSAR) efforts for enhanced drug discovery and toxicology assessments

Coupling different methods for overcoming the class imbalance problem

Many classification problems must deal with imbalanced datasets where one class \u2013 the majority class \u2013 outnumbers the other classes. Standard classification methods do not provide accurate predictions in this setting since classification is generally biased towards the majority class. The minority classes are oftentimes the ones of interest (e.g., when they are associated with pathological conditions in patients), so methods for handling imbalanced datasets are critical. Using several different datasets, this paper evaluates the performance of state-of-the-art classification methods for handling the imbalance problem in both binary and multi-class datasets. Different strategies are considered, including the one-class and dimension reduction approaches, as well as their fusions. Moreover, some ensembles of classifiers are tested, in addition to stand-alone classifiers, to assess the effectiveness of ensembles in the presence of imbalance. Finally, a novel ensemble of ensembles is designed specifically to tackle the problem of class imbalance: the proposed ensemble does not need to be tuned separately for each dataset and outperforms all the other tested approaches. To validate our classifiers we resort to the KEEL-dataset repository, whose data partitions (training/test) are publicly available and have already been used in the open literature: as a consequence, it is possible to report a fair comparison among different approaches in the literature. Our best approach (MATLAB code and datasets not easily accessible elsewhere) will be available at https://www.dei.unipd.it/node/2357

Stability and Accuracy of Feature Selection Methods on Datasets of Varying Data Complexity

Postprin

Ensemble feature learning of genomic data using support vector machine

© 2016 Anaissi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The identification of a subset of genes having the ability to capture the necessary information to distinguish classes of patients is crucial in bioinformatics applications. Ensemble and bagging methods have been shown to work effectively in the process of gene selection and classification. Testament to that is random forest which combines random decision trees with bagging to improve overall feature selection and classification accuracy. Surprisingly, the adoption of these methods in support vector machines has only recently received attention but mostly on classification not gene selection. This paper introduces an ensemble SVM-Recursive Feature Elimination (ESVM-RFE) for gene selection that follows the concepts of ensemble and bagging used in random forest but adopts the backward elimination strategy which is the rationale of RFE algorithm. The rationale behind this is, building ensemble SVM models using randomly drawn bootstrap samples from the training set, will produce different feature rankings which will be subsequently aggregated as one feature ranking. As a result, the decision for elimination of features is based upon the ranking of multiple SVM models instead of choosing one particular model. Moreover, this approach will address the problem of imbalanced datasets by constructing a nearly balanced bootstrap sample. Our experiments show that ESVM-RFE for gene selection substantially increased the classification performance on five microarray datasets compared to state-of-the-art methods. Experiments on the childhood leukaemia dataset show that an average 9% better accuracy is achieved by ESVM-RFE over SVM-RFE, and 5% over random forest based approach. The selected genes by the ESVM-RFE algorithm were further explored with Singular Value Decomposition (SVD) which reveals significant clusters with the selected data

SMOTE for Learning from Imbalanced Data: Progress and Challenges, Marking the 15-year Anniversary

The Synthetic Minority Oversampling Technique (SMOTE) preprocessing algorithm is considered \de facto" standard in the framework of learning from imbalanced data. This is due to its simplicity in the design of the procedure, as well as its robustness when applied to di erent type of problems. Since its publication in 2002, SMOTE has proven successful in a variety of applications from several di erent domains. SMOTE has also inspired several approaches to counter the issue of class imbalance, and has also signi cantly contributed to new supervised learning paradigms, including multilabel classi cation, incremental learning, semi-supervised learning, multi-instance learning, among others. It is standard benchmark for learning from imbalanced data. It is also featured in a number of di erent software packages | from open source to commercial. In this paper, marking the fteen year anniversary of SMOTE, we re ect on the SMOTE journey, discuss the current state of a airs with SMOTE, its applications, and also identify the next set of challenges to extend SMOTE for Big Data problems.This work have been partially supported by the Spanish Ministry of Science and Technology under projects TIN2014-57251-P, TIN2015-68454-R and TIN2017-89517-P; the Project 887 BigDaP-TOOLS - Ayudas Fundaci on BBVA a Equipos de Investigaci on Cient ca 2016; and the National Science Foundation (NSF) Grant IIS-1447795

Otimização multi-objetivo em aprendizado de máquina

Orientador: Fernando José Von ZubenTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de ComputaçãoResumo: Regressão logística multinomial regularizada, classificação multi-rótulo e aprendizado multi-tarefa são exemplos de problemas de aprendizado de máquina em que objetivos conflitantes, como funções de perda e penalidades que promovem regularização, devem ser simultaneamente minimizadas. Portanto, a perspectiva simplista de procurar o modelo de aprendizado com o melhor desempenho deve ser substituída pela proposição e subsequente exploração de múltiplos modelos de aprendizado eficientes, cada um caracterizado por um compromisso (trade-off) distinto entre os objetivos conflitantes. Comitês de máquinas e preferências a posteriori do tomador de decisão podem ser implementadas visando explorar adequadamente este conjunto diverso de modelos de aprendizado eficientes, em busca de melhoria de desempenho. A estrutura conceitual multi-objetivo para aprendizado de máquina é suportada por três etapas: (1) Modelagem multi-objetivo de cada problema de aprendizado, destacando explicitamente os objetivos conflitantes envolvidos; (2) Dada a formulação multi-objetivo do problema de aprendizado, por exemplo, considerando funções de perda e termos de penalização como objetivos conflitantes, soluções eficientes e bem distribuídas ao longo da fronteira de Pareto são obtidas por um solver determinístico e exato denominado NISE (do inglês Non-Inferior Set Estimation); (3) Esses modelos de aprendizado eficientes são então submetidos a um processo de seleção de modelos que opera com preferências a posteriori, ou a filtragem e agregação para a síntese de ensembles. Como o NISE é restrito a problemas de dois objetivos, uma extensão do NISE capaz de lidar com mais de dois objetivos, denominada MONISE (do inglês Many-Objective NISE), também é proposta aqui, sendo uma contribuição adicional que expande a aplicabilidade da estrutura conceitual proposta. Para atestar adequadamente o mérito da nossa abordagem multi-objetivo, foram realizadas investigações mais específicas, restritas à aprendizagem de modelos lineares regularizados: (1) Qual é o mérito relativo da seleção a posteriori de um único modelo de aprendizado, entre os produzidos pela nossa proposta, quando comparado com outras abordagens de modelo único na literatura? (2) O nível de diversidade dos modelos de aprendizado produzidos pela nossa proposta é superior àquele alcançado por abordagens alternativas dedicadas à geração de múltiplos modelos de aprendizado? (3) E quanto à qualidade de predição da filtragem e agregação dos modelos de aprendizado produzidos pela nossa proposta quando aplicados a: (i) classificação multi-classe, (ii) classificação desbalanceada, (iii) classificação multi-rótulo, (iv) aprendizado multi-tarefa, (v) aprendizado com multiplos conjuntos de atributos? A natureza determinística de NISE e MONISE, sua capacidade de lidar adequadamente com a forma da fronteira de Pareto em cada problema de aprendizado, e a garantia de sempre obter modelos de aprendizado eficientes são aqui pleiteados como responsáveis pelos resultados promissores alcançados em todas essas três frentes de investigação específicasAbstract: Regularized multinomial logistic regression, multi-label classification, and multi-task learning are examples of machine learning problems in which conflicting objectives, such as losses and regularization penalties, should be simultaneously minimized. Therefore, the narrow perspective of looking for the learning model with the best performance should be replaced by the proposition and further exploration of multiple efficient learning models, each one characterized by a distinct trade-off among the conflicting objectives. Committee machines and a posteriori preferences of the decision-maker may be implemented to properly explore this diverse set of efficient learning models toward performance improvement. The whole multi-objective framework for machine learning is supported by three stages: (1) The multi-objective modelling of each learning problem, explicitly highlighting the conflicting objectives involved; (2) Given the multi-objective formulation of the learning problem, for instance, considering loss functions and penalty terms as conflicting objective functions, efficient solutions well-distributed along the Pareto front are obtained by a deterministic and exact solver named NISE (Non-Inferior Set Estimation); (3) Those efficient learning models are then subject to a posteriori model selection, or to ensemble filtering and aggregation. Given that NISE is restricted to two objective functions, an extension for many objectives, named MONISE (Many Objective NISE), is also proposed here, being an additional contribution and expanding the applicability of the proposed framework. To properly access the merit of our multi-objective approach, more specific investigations were conducted, restricted to regularized linear learning models: (1) What is the relative merit of the a posteriori selection of a single learning model, among the ones produced by our proposal, when compared with other single-model approaches in the literature? (2) Is the diversity level of the learning models produced by our proposal higher than the diversity level achieved by alternative approaches devoted to generating multiple learning models? (3) What about the prediction quality of ensemble filtering and aggregation of the learning models produced by our proposal on: (i) multi-class classification, (ii) unbalanced classification, (iii) multi-label classification, (iv) multi-task learning, (v) multi-view learning? The deterministic nature of NISE and MONISE, their ability to properly deal with the shape of the Pareto front in each learning problem, and the guarantee of always obtaining efficient learning models are advocated here as being responsible for the promising results achieved in all those three specific investigationsDoutoradoEngenharia de ComputaçãoDoutor em Engenharia Elétrica2014/13533-0FAPES

Can machine learning methods contribute as a decision support system in sequential oligometastatic radioablation therapy?

Dissertation presented as the partial requirement for obtaining a Master's degree in Data Science and Advanced AnalyticsCancer treatment is among the major medical challenges of this century. Sequential oligometastatic radio-ablation (SOMA) is a novel treatment method that aims at ablating reoccurring metastasis in a single session with a targeted high dose of radiation. To know if SOMA is the best possible treatment method for a patient, the benefits of each available therapy need to be understood and evaluated. The ability to model complex systems, such as cancer treatment, is the strength of machine learning techniques. These techniques have improved the understanding of numerous medical therapies already. In some cases, they can serve as medical support systems if they deliver reliable results that doctors can trust and understand. The results obtained from applying numerous machine learning techniques to the data of SOMA-treated patients show that there are favorable techniques in some cases. It was observed that the Random Forest algorithm proved superior at different classification tasks. Additionally, regression problems opposed a great challenge, as the amount of data is very limited. Finally, SHAP values - a novel machine learning interpretation technique – provided valuable insights into understanding the rationale of each algorithm. They proved that the machine learning algorithms could learn patterns aligned with the human intuition in the problems presented. SHAP values show great potential in bridging the gap between complex machine learning algorithms and their interpretability. They display how an algorithm learns from the data and derives results. This opens up exciting possibilities for applying machine learning algorithms in the real world