Elephant Search with Deep Learning for Microarray Data Analysis

Even though there is a plethora of research in Microarray gene expression data analysis, still, it poses challenges for researchers to effectively and efficiently analyze the large yet complex expression of genes. The feature (gene) selection method is of paramount importance for understanding the differences in biological and non-biological variation between samples. In order to address this problem, a novel elephant search (ES) based optimization is proposed to select best gene expressions from the large volume of microarray data. Further, a promising machine learning method is envisioned to leverage such high dimensional and complex microarray dataset for extracting hidden patterns inside to make a meaningful prediction and most accurate classification. In particular, stochastic gradient descent based Deep learning (DL) with softmax activation function is then used on the reduced features (genes) for better classification of different samples according to their gene expression levels. The experiments are carried out on nine most popular Cancer microarray gene selection datasets, obtained from UCI machine learning repository. The empirical results obtained by the proposed elephant search based deep learning (ESDL) approach are compared with most recent published article for its suitability in future Bioinformatics research.Comment: 12 pages, 5 Tabl

Robustness of Random Forest-based gene selection methods

Gene selection is an important part of microarray data analysis because it provides information that can lead to a better mechanistic understanding of an investigated phenomenon. At the same time, gene selection is very difficult because of the noisy nature of microarray data. As a consequence, gene selection is often performed with machine learning methods. The Random Forest method is particularly well suited for this purpose. In this work, four state-of-the-art Random Forest-based feature selection methods were compared in a gene selection context. The analysis focused on the stability of selection because, although it is necessary for determining the significance of results, it is often ignored in similar studies. The comparison of post-selection accuracy in the validation of Random Forest classifiers revealed that all investigated methods were equivalent in this context. However, the methods substantially differed with respect to the number of selected genes and the stability of selection. Of the analysed methods, the Boruta algorithm predicted the most genes as potentially important. The post-selection classifier error rate, which is a frequently used measure, was found to be a potentially deceptive measure of gene selection quality. When the number of consistently selected genes was considered, the Boruta algorithm was clearly the best. Although it was also the most computationally intensive method, the Boruta algorithm's computational demands could be reduced to levels comparable to those of other algorithms by replacing the Random Forest importance with a comparable measure from Random Ferns (a similar but simplified classifier). Despite their design assumptions, the minimal optimal selection methods, were found to select a high fraction of false positives

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants

An Improved Parallelized mRMR for Gene Subset Selection in Cancer Classification

DNA microarray technique has become a more attractive tool for cancer classification in the scientific and industrial fields. Based on the previous researchers, the conventional approach for cancer classification is primarily based on morphological appearance of the tumor. The limitations of this approach are bias in identify the tumors by expert and faced the difficulty in differentiate the cancer subtypes due to most cancers being highly related to the specific biological insight.  Thus, this study propose an improved parallelized Minimum Redundancy Maximum Relevance (mRMR), which is a particularly fast feature selection method for finding a set of both relevant and complementary features. The mRMR can identify genes more relevance to biological context that leads to richer biological interpretations. The proposed method is expected to achieve accurate classification performance using small number of predictive genes when tested using two datasets from Cancer Genome Project and compared to previous methods

Building a robust clinical diagnosis support system for childhood cancer using data mining methods

University of Technology Sydney. Faculty of Engineering and Information Technology.Progress in understanding core pathways and processes of cancer requires thorough analysis of many coding and noncoding regions of the genome. Data mining and knowledge discovery have been applied to datasets across many industries, including bioinformatics. However, data mining faces a major challenge in its application to bioinformatics: the diversity and dimensionality of biomedical data. The term ‘big data’ was applied to the clinical domain by Yoo et al. (2014), specifically referring to single nucleotide polymorphism (SNP) and gene expression data. This research thesis focuses on three different types of data: gene-annotations, gene expression and single nucleotide polymorphisms. Genetic association studies have led to the discovery of single genetic variants associated with common diseases. However, complex diseases are not caused by a single gene acting alone but are the result of complex linear and non-linear interactions among different types of microarray data. In this scenario, a single gene can have a small effect on disease but cannot be the major cause of the disease. For this reason there is a critical need to implement new approaches which take into account linear and non-linear gene-gene and patient-patient interactions that can eventually help in diagnosis and prognosis of complex diseases. Several computational methods have been developed to deal with gene annotations, gene expressions and SNP data of complex diseases. However, analysis of every gene expression and SNP profile, and finding gene-to-gene relationships, is computationally infeasible because of the high-dimensionality of data. In addition, many computational methods have problems with scaling to large datasets, and with overfitting. Therefore, there is growing interest in applying data mining and machine learning approaches to understand different types of microarray data. Cancer is the disease that kills the most children in Australia (Torre et al., 2015). Within this thesis, the focus is on childhood Acute Lymphoblastic Leukaemia. Acute Lymphoblastic Leukaemia is the most common childhood malignancy with 24% of all new cancers occurring in children within Australia (Coates et al., 2001). According to the American Cancer Society (2016), a total of 6,590 cases of ALL have been diagnosed across all age groups in USA and the expected deaths are 1,430 in 2016. The project uses different data mining and visualisation methods applied on different types of biological data: gene annotations, gene expression and SNPs. This thesis focuses on three main issues in genomic and transcriptomic data studies: (i) Proposing, implementing and evaluating a novel framework to find functional relationships between genes from gene-annotation data. (ii) Identifying an optimal dimensionality reduction method to classify between relapsed and non-relapsed ALL patients using gene expression. (iii) Proposing, implementing and evaluating a novel feature selection approach to identify related metabolic pathways in ALL This thesis proposes, implements and validates an efficient framework to find functional relationships between genes based on gene-annotation data. The framework is built on a binary matrix and a proximity matrix, where the binary matrix contains information related to genes and their functionality, while the proximity matrix shows similarity between different features. The framework retrieves gene functionality information from Gene Ontology (GO), a publicly available database, and visualises the functional related genes using singular value decomposition (SVD). From a simple list of gene-annotations, this thesis retrieves features (i.e Gene Ontology terms) related to each gene and calculates a similarity measure based on the distance between terms in the GO hierarchy. The distance measures are based on hierarchical structure of Gene Ontology and these distance measures are called similarity measures. In this framework, two different similarity measures are applied: (i) A hop-based similarity measure where the distance is calculated based on the number of links between two terms. (ii) An information-content similarity measure where the similarity between terms is based on the probability of GO terms in the gene dataset. This framework also identifies which method performs better among these two similarity measures at identifying functional relationships between genes. Singular value decomposition method is used for visualisation, having the advantage that multiple types of relationships can be visualised simultaneously (gene-to-gene, term-to-term and gene-to-term) In this thesis a novel framework is developed for visualizing patient-to-patient relationships using gene expression values. The framework builds on the random forest feature selection method to filter gene expression values and then applies different linear and non-linear machine learning methods to them. The methods used in this framework are Principal Component Analysis (PCA), Kernel Principal Component Analysis (kPCA), Local Linear Embedding (LLE), Stochastic Neighbour Embedding (SNE) and Diffusion Maps. The framework compares these different machine learning methods by tuning different parameters to find the optimal method among them. Area under the curve (AUC) is used to rank the results and SVM is used to classify between relapsed and non-relapsed patients. The final section of the thesis proposes, implements and validates a framework to find active metabolic pathways in ALL using single nucleotide polymorphism (SNP) profiles. The framework is based on the random forest feature selection method. A collected dataset of ALL patient and healthy controls is constructed and later random forest is applied using different parameters to find highly-ranked SNPs. The credibility of the model is assessed based on the error rate of the confusion matrix and kappa values. Selected high ranked SNPs are used to retrieve metabolic pathways related to ALL from the KEGG metabolic pathways database. The methodologies and approaches presented in this thesis emphasise the critical role that different types of microarray data play in understanding complex diseases like ALL. The availability of flexible frameworks for the task of disease diagnosis and prognosis, as proposed in this thesis, will play an important role in understanding the genetic basis to common complex diseases. This thesis contributes to knowledge in two ways: (i) Providing novel data mining and visualisation frameworks to handle biological data. (ii) Providing novel visualisations for microarray data to increase understanding of disease

Gene selection and classification in autism gene expression data

Autism spectrum disorders (ASD) are neurodevelopmental disorders that are currently diagnosed on the basis of abnormal stereotyped behaviour as well as observable deficits in communication and social functioning. Although a variety of candidate genes have been attributed to the disorder, no single gene is applicable to more than 1–2% of the general ASD population. Despite extensive efforts, definitive genes that contribute to autism susceptibility have yet to be identified. The major problems in dealing with the gene expression dataset of autism include the presence of limited number of samples and large noises due to errors of experimental measurements and natural variation. In this study, a systematic combination of three important filters, namely t-test (TT), Wilcoxon Rank Sum (WRS) and Feature Correlation (COR) are applied along with efficient wrapper algorithm based on geometric binary particle swarm optimization-support vector machine (GBPSO-SVM), aiming at selecting and classifying the most attributed genes of autism. A new approach based on the criterion of median ratio, mean ratio and variance deviations is also applied to reduce the initial dataset prior to its involvement. Results showed that the most discriminative genes that were identified in the first and last selection steps concluded the presence of a repetitive gene (CAPS2), which was assigned as the most ASD risk gene. The fused result of genes subset that were selected by the GBPSO-SVM algorithm increased the classification accuracy to about 92.10%, which is higher than those reported in literature for the same autism dataset. Noticeably, the application of ensemble using random forest (RF) showed better performance compared to that of previous studies. However, the ensemble approach based on the employment of SVM as an integrator of the fused genes from the output branches of GBPSO-SVM outperformed the RF integrator. The overall improvement was ascribed to the selection strategies that were taken to reduce the dataset and the utilization of efficient wrapper based GBPSO-SVM algorithm