Bioinformatics

This book is divided into different research areas relevant in Bioinformatics such as biological networks, next generation sequencing, high performance computing, molecular modeling, structural bioinformatics, molecular modeling and intelligent data analysis. Each book section introduces the basic concepts and then explains its application to problems of great relevance, so both novice and expert readers can benefit from the information and research works presented here

Using machine learning to predict gene expression and discover sequence motifs

Recently, large amounts of experimental data for complex biological systems have become available. We use tools and algorithms from machine learning to build data-driven predictive models. We first present a novel algorithm to discover gene sequence motifs associated with temporal expression patterns of genes. Our algorithm, which is based on partial least squares (PLS) regression, is able to directly model the flow of information, from gene sequence to gene expression, to learn cis regulatory motifs and characterize associated gene expression patterns. Our algorithm outperforms traditional computational methods e.g. clustering in motif discovery. We then present a study of extending a machine learning model for transcriptional regulation predictive of genetic regulatory response to Caenorhabditis elegans. We show meaningful results both in terms of prediction accuracy on the test experiments and biological information extracted from the regulatory program. The model discovers DNA binding sites ab intio. We also present a case study where we detect a signal of lineage-specific regulation. Finally we present a comparative study on learning predictive models for motif discovery, based on different boosting algorithms: Adaptive Boosting (AdaBoost), Linear Programming Boosting (LPBoost) and Totally Corrective Boosting (TotalBoost). We evaluate and compare the performance of the three boosting algorithms via both statistical and biological validation, for hypoxia response in Saccharomyces cerevisiae

Exploration of regression models for cancer noncoding mutation recurrence

An important impact of the genome technology revolution will be the elucidation of mechanisms of cancer pathogenesis, leading to improvements in the diagnosis of cancer and the selection of cancer treatment. Integrated with current well-studied massive knowledge and findings about the role of protein-coding mutations in cancer, demystifying the functional role of human "junk" DNA (non-protein-coding DNA) mutations for cancer development and progression is one of the most popular and promising approaches these days to improve our understanding of the complicated cellular mechanisms in cancer. In light of one recent finding that non-protein-coding driver mutations tend to be highly recurrent, in this thesis we explore three different kinds of regression models for predicting non-protein-coding mutation recurrence: generalized linear models, conventional machine learning approaches and deep neural network learning models. We compare the regression model results and find the most accurate model for non-protein-coding mutation recurrence prediction so that we can prioritize somatic mutations based on their predicted recurrence and provide insights for further biological validation and eventually improved cancer therapy.Keywords: Recurrence, Regression, Cancer, Noncoding Mutatio

Learning the Regulatory Code of Gene Expression

Data-driven machine learning is the method of choice for predicting molecular phenotypes from nucleotide sequence, modeling gene expression events including protein-DNA binding, chromatin states as well as mRNA and protein levels. Deep neural networks automatically learn informative sequence representations and interpreting them enables us to improve our understanding of the regulatory code governing gene expression. Here, we review the latest developments that apply shallow or deep learning to quantify molecular phenotypes and decode the cis-regulatory grammar from prokaryotic and eukaryotic sequencing data. Our approach is to build from the ground up, first focusing on the initiating protein-DNA interactions, then specific coding and non-coding regions, and finally on advances that combine multiple parts of the gene and mRNA regulatory structures, achieving unprecedented performance. We thus provide a quantitative view of gene expression regulation from nucleotide sequence, concluding with an information-centric overview of the central dogma of molecular biology

Computational Methods for the Analysis of Genomic Data and Biological Processes

In recent decades, new technologies have made remarkable progress in helping to understand biological systems. Rapid advances in genomic profiling techniques such as microarrays or high-performance sequencing have brought new opportunities and challenges in the fields of computational biology and bioinformatics. Such genetic sequencing techniques allow large amounts of data to be produced, whose analysis and cross-integration could provide a complete view of organisms. As a result, it is necessary to develop new techniques and algorithms that carry out an analysis of these data with reliability and efficiency. This Special Issue collected the latest advances in the field of computational methods for the analysis of gene expression data, and, in particular, the modeling of biological processes. Here we present eleven works selected to be published in this Special Issue due to their interest, quality, and originality

Ordinal HyperPlane Loss

This research presents the development of a new framework for analyzing ordered class data, commonly called “ordinal class” data. The focus of the work is the development of classifiers (predictive models) that predict classes from available data. Ratings scales, medical classification scales, socio-economic scales, meaningful groupings of continuous data, facial emotional intensity and facial age estimation are examples of ordinal data for which data scientists may be asked to develop predictive classifiers. It is possible to treat ordinal classification like any other classification problem that has more than two classes. Specifying a model with this strategy does not fully utilize the ordering information of classes. Alternatively, the researcher may choose to treat the ordered classes as though they are continuous values. This strategy imposes a strong assumption that the real “distance” between two adjacent classes is equal to the distance between two other adjacent classes (e.g., a rating of ‘0’ versus ‘1,’ on an 11-point scale is the same distance as a ‘9’ versus a ‘10’). For Deep Neural Networks (DNNs), the problem of predicting k ordinal classes is typically addressed by performing k-1 binary classifications. These models may be estimated within a single DNN and require an evaluation strategy to determine the class prediction. Another common option is to treat ordinal classes as continuous values for regression and then adjust the cutoff points that represent class boundaries that differentiate one class from another. This research reviews a novel loss function called Ordinal Hyperplane Loss (OHPL) that is particularly designed for data with ordinal classes. OHPLnet has been demonstrated to be a significant advancement in predicting ordinal classes for industry standard structured datasets. The loss function also enables deep learning techniques to be applied to the ordinal classification problem of unstructured data. By minimizing OHPL, a deep neural network learns to map data to an optimal space in which the distance between points and their class centroids are minimized while a nontrivial ordering relationship among classes are maintained. The research reported in this document advances OHPL loss, from a minimally viable loss function, to a more complete deep learning methodology. New analysis strategies were developed and tested that improve model performance as well as algorithm consistency in developing classification models. In the applications chapters, a new algorithm variant is introduced that enables OHPLall to be used when large data records cause a severe limitation on batch size when developing a related Deep Neural Network