Integrated mining of feature spaces for bioinformatics domain discovery

One of the major challenges in the field of bioinformatics is the elucidation of protein folding for the functional annotation of proteins. The factors that govern protein folding include the chemical, physical, and environmental conditions of the protein\u27s surroundings, which can be measured and exploited for computational discovery purposes. These conditions enable the protein to transform from a sequence of amino acids to a globular three-dimensional structure. Information concerning the folded state of a protein has significant potential to explain biochemical pathways and their involvement in disorders and diseases. This information impacts the ways in which genetic diseases are characterized and cured and in which designer drugs are created. With the exponential growth of protein databases and the limitations of experimental protein structure determination, sophisticated computational methods have been developed and applied to search for, detect, and compare protein homology. Most computational tools developed for protein structure prediction are primarily based on sequence similarity searches. These approaches have improved the prediction accuracy of high sequence similarity proteins but have failed to perform well with proteins of low sequence similarity. Data mining offers unique algorithmic computational approaches that have been used widely in the development of automatic protein structure classification and prediction. In this dissertation, we present a novel approach for the integration of physico-chemical properties and effective feature extraction techniques for the classification of proteins. Our approaches overcome one of the major obstacles of data mining in protein databases, the encapsulation of different hydrophobicity residue properties into a much reduced feature space that possess high degrees of specificity and sensitivity in protein structure classification. We have developed three unique computational algorithms for coherent feature extraction on selected scale properties of the protein sequence. When plagued by the problem of the unequal cardinality of proteins, our proposed integration scheme effectively handles the varied sizes of proteins and scales well with increasing dimensionality of these sequences. We also detail a two-fold methodology for protein functional annotation. First, we exhibit our success in creating an algorithm that provides a means to integrate multiple physico-chemical properties in the form of a multi-layered abstract feature space, with each layer corresponding to a physico-chemical property. Second, we discuss a wavelet-based segmentation approach that efficiently detects regions of property conservation across all layers of the created feature space. Finally, we present a unique graph-theory based algorithmic framework for the identification of conserved hydrophobic residue interaction patterns using identified scales of hydrophobicity. We report that these discriminatory features are specific to a family of proteins, which consist of conserved hydrophobic residues that are then used for structural classification. We also present our rigorously tested validation schemes, which report significant degrees of accuracy to show that homologous proteins exhibit the conservation of physico-chemical properties along the protein backbone. We conclude our discussion by summarizing our results and contributions and by listing our goals for future research

Highly Accurate Fragment Library for Protein Fold Recognition

Proteins play a crucial role in living organisms as they perform many vital tasks in every living cell. Knowledge of protein folding has a deep impact on understanding the heterogeneity and molecular functions of proteins. Such information leads to crucial advances in drug design and disease understanding. Fold recognition is a key step in the protein structure discovery process, especially when traditional computational methods fail to yield convincing structural homologies. In this work, we present a new protein fold recognition approach using machine learning and data mining methodologies. First, we identify a protein structural fragment library (Frag-K) composed of a set of backbone fragments ranging from 4 to 20 residues as the structural “keywords” that can effectively distinguish between major protein folds. We firstly apply randomized spectral clustering and random forest algorithms to construct representative and sensitive protein fragment libraries from a large-scale of high-quality, non-homologous protein structures available in PDB. We analyze the impacts of clustering cut-offs on the performance of the fragment libraries. Then, the Frag-K fragments are employed as structural features to classify protein structures in major protein folds defined by SCOP (Structural Classification of Proteins). Our results show that a structural dictionary with ~400 4- to 20-residue Frag-K fragments is capable of classifying major SCOP folds with high accuracy. Then, based on Frag-k, we design a novel deep learning architecture, so-called DeepFrag-k, which identifies fold discriminative features to improve the accuracy of protein fold recognition. DeepFrag-k is composed of two stages: the first stage employs a multimodal Deep Belief Network (DBN) to predict the potential structural fragments given a sequence, represented as a fragment vector, and then the second stage uses a deep convolution neural network (CNN) to classify the fragment vectors into the corresponding folds. Our results show that DeepFrag-k yields 92.98% accuracy in predicting the top-100 most popular fragments, which can be used to generate discriminative fragment feature vectors to improve protein fold recognition

Associative Pattern Recognition for Biological Regulation Data

In the last decade, bioinformatics data has been accumulated at an unprecedented rate, thanks to the advancement in sequencing technologies. Such rapid development poses both challenges and promising research topics. In this dissertation, we propose a series of associative pattern recognition algorithms in biological regulation studies. In particular, we emphasize efficiently recognizing associative patterns between genes, transcription factors, histone modifications and functional labels using heterogeneous data sources (numeric, sequences, time series data and textual labels). In protein-DNA associative pattern recognition, we introduce an efficient algorithm for affinity test by searching for over-represented DNA sequences using a hash function and modulo addition calculation. This substantially improves the efficiency of \textit{next generation sequencing} data analysis. In gene regulatory network inference, we propose a framework for refining weak networks based on transcription factor binding sites, thus improved the precision of predicted edges by up to 52%. In histone modification code analysis, we propose an approach to genome-wide combinatorial pattern recognition for histone code to function associative pattern recognition, and achieved improvement by up to $38.1\%$. We also propose a novel shape based modification pattern analysis approach, using this to successfully predict sub-classes of genes in flowering-time category. We also propose a combination to combination associative pattern recognition, and achieved better performance compared against multi-label classification and bidirectional associative memory methods. Our proposed approaches recognize associative patterns from different types of data efficiently, and provides a useful toolbox for biological regulation analysis. This dissertation presents a road-map to associative patterns recognition at genome wide level

Molecular Science for Drug Development and Biomedicine

With the avalanche of biological sequences generated in the postgenomic age, molecular science is facing an unprecedented challenge, i.e., how to timely utilize the huge amount of data to benefit human beings. Stimulated by such a challenge, a rapid development has taken place in molecular science, particularly in the areas associated with drug development and biomedicine, both experimental and theoretical. The current thematic issue was launched with the focus on the topic of “Molecular Science for Drug Development and Biomedicine”, in hopes to further stimulate more useful techniques and findings from various approaches of molecular science for drug development and biomedicine

Network and multi-scale signal analysis for the integration of large omic datasets: applications in \u3ci\u3ePopulus trichocarpa\u3c/i\u3e

Poplar species are promising sources of cellulosic biomass for biofuels because of their fast growth rate, high cellulose content and moderate lignin content. There is an increasing movement on integrating multiple layers of ’omics data in a systems biology approach to understand gene-phenotype relationships and assist in plant breeding programs. This dissertation involves the use of network and signal processing techniques for the combined analysis of these various data types, for the goals of (1) increasing fundamental knowledge of P. trichocarpa and (2) facilitating the generation of hypotheses about target genes and phenotypes of interest. A data integration “Lines of Evidence” method is presented for the identification and prioritization of target genes involved in functions of interest. A new post-GWAS method, Pleiotropy Decomposition, is presented, which extracts pleiotropic relationships between genes and phenotypes from GWAS results, allowing for identification of genes with signatures favorable to genome editing. Continuous wavelet transform signal processing analysis is applied in the characterization of genome distributions of various features (including variant density, gene density, and methylation profiles) in order to identify chromosome structures such as the centromere. This resulted in the approximate centromere locations on all P. trichocarpa chromosomes, which had previously not been adequately reported in the scientific literature. Discrete wavelet transform signal processing followed by correlation analysis was applied to genomic features from various data types including transposable element density, methylation density, SNP density, gene density, centromere position and putative ancestral centromere position. Subsequent correlation analysis of the resulting wavelet coefficients identified scale-specific relationships between these genomic features, and provide insights into the evolution of the genome structure of P. trichocarpa. These methods have provided strategies to both increase fundamental knowledge about the P. trichocarpa system, as well as to identify new target genes related to biofuels targets. We intend that these approaches will ultimately be used in the designing of better plants for more efficient and sustainable production of bioenergy

Protein interface prediction using graph convolutional networks

2017 Fall.Includes bibliographical references.Proteins play a critical role in processes both within and between cells, through their interactions with each other and other molecules. Proteins interact via an interface forming a protein complex, which is difficult, expensive, and time consuming to determine experimentally, giving rise to computational approaches. These computational approaches utilize known electrochemical properties of protein amino acid residues in order to predict if they are a part of an interface or not. Prediction can occur in a partner independent fashion, where amino acid residues are considered independently of their neighbor, or in a partner specific fashion, where pairs of potentially interacting residues are considered together. Ultimately, prediction of protein interfaces can help illuminate cellular biology, improve our understanding of diseases, and aide pharmaceutical research. Interface prediction has historically been performed with a variety of methods, to include docking, template matching, and more recently, machine learning approaches. The field of machine learning has undergone a revolution of sorts with the emergence of convolutional neural networks as the leading method of choice for a wide swath of tasks. Enabled by large quantities of data and the increasing power and availability of computing resources, convolutional neural networks efficiently detect patterns in grid structured data and generate hierarchical representations that prove useful for many types of problems. This success has motivated the work presented in this thesis, which seeks to improve upon state of the art interface prediction methods by incorporating concepts from convolutional neural networks. Proteins are inherently irregular, so they don't easily conform to a grid structure, whereas a graph representation is much more natural. Various convolution operations have been proposed for graph data, each geared towards a particular application. We adapted these convolutions for use in interface prediction, and proposed two new variants. Neural networks were trained on the Docking Benchmark Dataset version 4.0 complexes and tested on the new complexes added in version 5.0. Results were compared against the state of the art method partner specific method, PAIRpred [1]. Results show that multiple variants of graph convolution outperform PAIRpred, with no method emerging as the clear winner. In the future, additional training data may be incorporated from other sources, unsupervised pretraining such as autoencoding may be employed, and a generalization of convolution to simplicial complexes may also be explored. In addition, the various graph convolution approaches may be applied to other applications with graph structured data, such as Quantitative Structure Activity Relationship (QSAR) learning, and knowledge base inference

Applicability domains of neural networks for toxicity prediction

In this paper, the term "applicability domain" refers to the range of chemical compounds for which the statistical quantitative structure-activity relationship (QSAR) model can accurately predict their toxicity. This is a crucial concept in the development and practical use of these models. First, a multidisciplinary review is provided regarding the theory and practice of applicability domains in the context of toxicity problems using the classical QSAR model. Then, the advantages and improved performance of neural networks (NNs), which are the most promising machine learning algorithms, are reviewed. Within the domain of medicinal chemistry, nine different methods using NNs for toxicity prediction were compared utilizing 29 alternative artificial intelligence (AI) techniques. Similarly, seven NN-based toxicity prediction methodologies were compared to six other AI techniques within the realm of food safety, 11 NN-based methodologies were compared to 16 different AI approaches in the environmental sciences category and four specific NN-based toxicity prediction methodologies were compared to nine alternative AI techniques in the field of industrial hygiene. Within the reviewed approaches, given known toxic compound descriptors and behaviors, we observed a difficulty in being able to extrapolate and predict the effects with untested chemical compounds. Different methods can be used for unsupervised clustering, such as distance-based approaches and consensus-based decision methods. Additionally, the importance of model validation has been highlighted within a regulatory context according to the Organization for Economic Co-operation and Development (OECD) principles, to predict the toxicity of potential new drugs in medicinal chemistry, to determine the limits of detection for harmful substances in food to predict the toxicity limits of chemicals in the environment, and to predict the exposure limits to harmful substances in the workplace. Despite its importance, a thorough application of toxicity models is still restricted in the field of medicinal chemistry and is virtually overlooked in other scientific domains. Consequently, only a small proportion of the toxicity studies conducted in medicinal chemistry consider the applicability domain in their mathematical models, thereby limiting their predictive power to untested drugs. Conversely, the applicability of these models is crucial; however, this has not been sufficiently assessed in toxicity prediction or in other related areas such as food science, environmental science, and industrial hygiene. Thus, this review sheds light on the prevalent use of Neural Networks in toxicity prediction, thereby serving as a valuable resource for researchers and practitioners across these multifaceted domains that could be extended to other fields in future research

Genetic Algorithms for Feature Selection and Classification of Complex Chromatographic and Spectroscopic Data

A basic methodology for analyzing large multivariate chemical data sets based on feature selection is proposed. Each chromatogram or spectrum is represented as a point in a high dimensional measurement space. A genetic algorithm for feature selection and classification is applied to the data to identify features that optimize the separation of the classes in a plot of the two or three largest principal components of the data. A good principal component plot can only be generated using features whose variance or information is primarily about differences between classes in the data. Hence, feature subsets that maximize the ratio of between-class to within-class variance are selected by the pattern recognition genetic algorithm. Furthermore, the structure of the data set can be explored, for example, new classes can be discovered by simply tuning various parameters of the fitness function of the pattern recognition genetic algorithm. The proposed method has been validated on a wide range of data. A two-step procedure for pattern recognition analysis of spectral data has been developed. First, wavelets are used to denoise and deconvolute spectral bands by decomposing each spectrum into wavelet coefficients, which represent the samples constituent frequencies. Second, the pattern recognition genetic algorithm is used to identify wavelet coefficients characteristic of the class. In several studies involving spectral library searching, this method was employed. In one study, a search pre-filter to detect the presence of carboxylic acids from vapor phase infrared spectra which has previously eluted prominent researchers has been successfully formulated and validated. In another study, this same approach has been used to develop a pattern recognition assisted infrared library searching technique to determine the model, manufacturer, and year of the vehicle from which a clear coat paint smear originated. The pattern recognition genetic algorithm has also been used to develop a potential method to identify molds in indoor environments using volatile organic compounds. A distinct profile indicative of microbial volatile organic compounds was developed from air sampling data that could be readily differentiated from the blank for both high mold count and moderate mold count exposure samples. The utility of the pattern recognition genetic algorithm for discovery of biomarker candidates from genomic and proteomic data sets has also been shown.Chemistry Departmen