Improving Cancer Classification Accuracy Using Gene Pairs

Recent studies suggest that the deregulation of pathways, rather than individual genes, may be critical in triggering carcinogenesis. The pathway deregulation is often caused by the simultaneous deregulation of more than one gene in the pathway. This suggests that robust gene pair combinations may exploit the underlying bio-molecular reactions that are relevant to the pathway deregulation and thus they could provide better biomarkers for cancer, as compared to individual genes. In order to validate this hypothesis, in this paper, we used gene pair combinations, called doublets, as input to the cancer classification algorithms, instead of the original expression values, and we showed that the classification accuracy was consistently improved across different datasets and classification algorithms. We validated the proposed approach using nine cancer datasets and five classification algorithms including Prediction Analysis for Microarrays (PAM), C4.5 Decision Trees (DT), Naive Bayesian (NB), Support Vector Machine (SVM), and k-Nearest Neighbor (k-NN)

A Comparative Analysis of Ensemble Classifiers: Case Studies in Genomics

The combination of multiple classifiers using ensemble methods is increasingly important for making progress in a variety of difficult prediction problems. We present a comparative analysis of several ensemble methods through two case studies in genomics, namely the prediction of genetic interactions and protein functions, to demonstrate their efficacy on real-world datasets and draw useful conclusions about their behavior. These methods include simple aggregation, meta-learning, cluster-based meta-learning, and ensemble selection using heterogeneous classifiers trained on resampled data to improve the diversity of their predictions. We present a detailed analysis of these methods across 4 genomics datasets and find the best of these methods offer statistically significant improvements over the state of the art in their respective domains. In addition, we establish a novel connection between ensemble selection and meta-learning, demonstrating how both of these disparate methods establish a balance between ensemble diversity and performance.Comment: 10 pages, 3 figures, 8 tables, to appear in Proceedings of the 2013 International Conference on Data Minin

Classification across gene expression microarray studies

<p>Abstract</p> <p>Background</p> <p>The increasing number of gene expression microarray studies represents an important resource in biomedical research. As a result, gene expression based diagnosis has entered clinical practice for patient stratification in breast cancer. However, the integration and combined analysis of microarray studies remains still a challenge. We assessed the potential benefit of data integration on the classification accuracy and systematically evaluated the generalization performance of selected methods on four breast cancer studies comprising almost 1000 independent samples. To this end, we introduced an evaluation framework which aims to establish good statistical practice and a graphical way to monitor differences. The classification goal was to correctly predict estrogen receptor status (negative/positive) and histological grade (low/high) of each tumor sample in an independent study which was not used for the training. For the classification we chose support vector machines (SVM), predictive analysis of microarrays (PAM), random forest (RF) and k-top scoring pairs (kTSP). Guided by considerations relevant for classification across studies we developed a generalization of kTSP which we evaluated in addition. Our derived version (DV) aims to improve the robustness of the intrinsic invariance of kTSP with respect to technologies and preprocessing.</p> <p>Results</p> <p>For each individual study the generalization error was benchmarked via complete cross-validation and was found to be similar for all classification methods. The misclassification rates were substantially higher in classification across studies, when each single study was used as an independent test set while all remaining studies were combined for the training of the classifier. However, with increasing number of independent microarray studies used in the training, the overall classification performance improved. DV performed better than the average and showed slightly less variance. In particular, the better predictive results of DV in across platform classification indicate higher robustness of the classifier when trained on single channel data and applied to gene expression ratios.</p> <p>Conclusions</p> <p>We present a systematic evaluation of strategies for the integration of independent microarray studies in a classification task. Our findings in across studies classification may guide further research aiming on the construction of more robust and reliable methods for stratification and diagnosis in clinical practice.</p

Feature selection when there are many influential features

Recent discussion of the success of feature selection methods has argued that focusing on a relatively small number of features has been counterproductive. Instead, it is suggested, the number of significant features can be in the thousands or tens of thousands, rather than (as is commonly supposed at present) approximately in the range from five to fifty. This change, in orders of magnitude, in the number of influential features, necessitates alterations to the way in which we choose features and to the manner in which the success of feature selection is assessed. In this paper, we suggest a general approach that is suited to cases where the number of relevant features is very large, and we consider particular versions of the approach in detail. We propose ways of measuring performance, and we study both theoretical and numerical properties of the proposed methodology.Comment: Published in at http://dx.doi.org/10.3150/13-BEJ536 the Bernoulli (http://isi.cbs.nl/bernoulli/) by the International Statistical Institute/Bernoulli Society (http://isi.cbs.nl/BS/bshome.htm

Finding minimum gene subsets with heuristic breadth-first search algorithm for robust tumor classification

Background: Previous studies on tumor classification based on gene expression profiles suggest that gene selection plays a key role in improving the classification performance. Moreover, finding important tumor-related genes with the highest accuracy is a very important task because these genes might serve as tumor biomarkers, which is of great benefit to not only tumor molecular diagnosis but also drug development. Results: This paper proposes a novel gene selection method with rich biomedical meaning based on Heuristic Breadth-first Search Algorithm (HBSA) to find as many optimal gene subsets as possible. Due to the curse of dimensionality, this type of method could suffer from over-fitting and selection bias problems. To address these potential problems, a HBSA-based ensemble classifier is constructed using majority voting strategy from individual classifiers constructed by the selected gene subsets, and a novel HBSA-based gene ranking method is designed to find important tumor-related genes by measuring the significance of genes using their occurrence frequencies in the selected gene subsets. The experimental results on nine tumor datasets including three pairs of cross-platform datasets indicate that the proposed method can not only obtain better generalization performance but also find many important tumor-related genes. Conclusions: It is found that the frequencies of the selected genes follow a power-law distribution, indicating that only a few top-ranked genes can be used as potential diagnosis biomarkers. Moreover, the top-ranked genes leading to very high prediction accuracy are closely related to specific tumor subtype and even hub genes. Compared with other related methods, the proposed method can achieve higher prediction accuracy with fewer genes. Moreover, they are further justified by analyzing the top-ranked genes in the context of individual gene function, biological pathway, and protein-protein interaction network. Keywords: Gene expression profiles; Gene selection; Tumor classification; Heuristic breadth-first search; Power-law distributio

Finding minimum gene subsets with heuristic breadth-first search algorithm for robust tumor classification

Background: Previous studies on tumor classification based on gene expression profiles suggest that gene selection plays a key role in improving the classification performance. Moreover, finding important tumor-related genes with the highest accuracy is a very important task because these genes might serve as tumor biomarkers, which is of great benefit to not only tumor molecular diagnosis but also drug development. Results: This paper proposes a novel gene selection method with rich biomedical meaning based on Heuristic Breadth-first Search Algorithm (HBSA) to find as many optimal gene subsets as possible. Due to the curse of dimensionality, this type of method could suffer from over-fitting and selection bias problems. To address these potential problems, a HBSA-based ensemble classifier is constructed using majority voting strategy from individual classifiers constructed by the selected gene subsets, and a novel HBSA-based gene ranking method is designed to find important tumor-related genes by measuring the significance of genes using their occurrence frequencies in the selected gene subsets. The experimental results on nine tumor datasets including three pairs of cross-platform datasets indicate that the proposed method can not only obtain better generalization performance but also find many important tumor-related genes. Conclusions: It is found that the frequencies of the selected genes follow a power-law distribution, indicating that only a few top-ranked genes can be used as potential diagnosis biomarkers. Moreover, the top-ranked genes leading to very high prediction accuracy are closely related to specific tumor subtype and even hub genes. Compared with other related methods, the proposed method can achieve higher prediction accuracy with fewer genes. Moreover, they are further justified by analyzing the top-ranked genes in the context of individual gene function, biological pathway, and protein-protein interaction network. Keywords: Gene expression profiles; Gene selection; Tumor classification; Heuristic breadth-first search; Power-law distributio

Cross-platform analysis of cancer microarray data improves gene expression based classification of phenotypes

BACKGROUND: The extensive use of DNA microarray technology in the characterization of the cell transcriptome is leading to an ever increasing amount of microarray data from cancer studies. Although similar questions for the same type of cancer are addressed in these different studies, a comparative analysis of their results is hampered by the use of heterogeneous microarray platforms and analysis methods. RESULTS: In contrast to a meta-analysis approach where results of different studies are combined on an interpretative level, we investigate here how to directly integrate raw microarray data from different studies for the purpose of supervised classification analysis. We use median rank scores and quantile discretization to derive numerically comparable measures of gene expression from different platforms. These transformed data are then used for training of classifiers based on support vector machines. We apply this approach to six publicly available cancer microarray gene expression data sets, which consist of three pairs of studies, each examining the same type of cancer, i.e. breast cancer, prostate cancer or acute myeloid leukemia. For each pair, one study was performed by means of cDNA microarrays and the other by means of oligonucleotide microarrays. In each pair, high classification accuracies (> 85%) were achieved with training and testing on data instances randomly chosen from both data sets in a cross-validation analysis. To exemplify the potential of this cross-platform classification analysis, we use two leukemia microarray data sets to show that important genes with regard to the biology of leukemia are selected in an integrated analysis, which are missed in either single-set analysis. CONCLUSION: Cross-platform classification of multiple cancer microarray data sets yields discriminative gene expression signatures that are found and validated on a large number of microarray samples, generated by different laboratories and microarray technologies. Predictive models generated by this approach are better validated than those generated on a single data set, while showing high predictive power and improved generalization performance

Protein sequences classification by means of feature extraction with substitution matrices

<p>Abstract</p> <p>Background</p> <p>This paper deals with the preprocessing of protein sequences for supervised classification. Motif extraction is one way to address that task. It has been largely used to encode biological sequences into feature vectors to enable using well-known machine-learning classifiers which require this format. However, designing a suitable feature space, for a set of proteins, is not a trivial task. For this purpose, we propose a novel encoding method that uses amino-acid substitution matrices to define similarity between motifs during the extraction step.</p> <p>Results</p> <p>In order to demonstrate the efficiency of such approach, we compare several encoding methods using some machine learning classifiers. The experimental results showed that our encoding method outperforms other ones in terms of classification accuracy and number of generated attributes. We also compared the classifiers in term of accuracy. Results indicated that SVM generally outperforms the other classifiers with any encoding method. We showed that SVM, coupled with our encoding method, can be an efficient protein classification system. In addition, we studied the effect of the substitution matrices variation on the quality of our method and hence on the classification quality. We noticed that our method enables good classification accuracies with all the substitution matrices and that the variances of the obtained accuracies using various substitution matrices are slight. However, the number of generated features varies from a substitution matrix to another. Furthermore, the use of already published datasets allowed us to carry out a comparison with several related works.</p> <p>Conclusions</p> <p>The outcomes of our comparative experiments confirm the efficiency of our encoding method to represent protein sequences in classification tasks.</p

Multilevel mixed-type data analysis for validating partitions of scrapie isolates

The dissertation arises from a joint study with the Department of Food Safety and Veterinary Public Health of the Istituto Superiore di Sanità. The aim is to investigate and validate the existence of distinct strains of the scrapie disease taking into account the availability of a priori benchmark partition formulated by researchers. Scrapie of small ruminants is caused by prions, which are unconventional infectious agents of proteinaceous nature a ecting humans and animals. Due to the absence of nucleic acids, which precludes direct analysis of strain variation by molecular methods, the presence of di erent sheep scrapie strains is usually investigated by bioassay in laboratory rodents. Data are collected by an experimental study on scrapie conducted at the Istituto Superiore di Sanità by experimental transmission of scrapie isolates to bank voles. We aim to discuss the validation of a given partition in a statistical classification framework using a multi-step procedure. Firstly, we use unsupervised classification to see how alternative clustering results match researchers’ understanding of the heterogeneity of the isolates. We discuss whether and how clustering results can be eventually exploited to extend the preliminary partition elicited by researchers. Then we motivate the subsequent partition validation based on the predictive performance of several supervised classifiers. Our data-driven approach contains two main methodological original contributions. We advocate the use of partition validation measures to investigate a given benchmark partition: firstly we discuss the issue of how the data can be used to evaluate a preliminary benchmark partition and eventually modify it with statistical results to find a conclusive partition that could be used as a “gold standard” in future studies. Moreover, collected data have a multilevel structure and for each lower-level unit, mixed-type data are available. Each step in the procedure is then adapted to deal with multilevel mixed-type data. We extend distance-based clustering algorithms to deal with multilevel mixed-type data. Whereas in supervised classification we propose a two-step approach to classify the higher-level units starting from the lower-level observations. In this framework, we also need to define an ad-hoc cross validation algorithm

Designing single guide RNAs for CRISPR/Cas9

Researchers have been working towards development of tools to facilitate regular use genome engineering techniques. In recent years, the focus of these efforts has been the Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)/CRISPR associated(Cas) systems. These systems, while found naturally in bacteria and archaea as an immunity mechanism, can be used for genome engineering in eukaryotes. There are three major computational challenges associated with the use of CRISPR/Cas9 in genome engineering for mammals - identification of CRISPR arrays, single guide RNA design and minimizing off-target effects. This project attempts to solve the problem of single guide RNA design using a novel approach. Researchers have been trying to solve the problem by using different machine learning classification algorithms. The algorithms have been trained to use the sequential and structural properties of single guide RNAs (sgRNAs). This project explores the use of a neural network based approach to solve the sgRNA design problem. A form of the Recurrent Neural Network (RNN) called the Long Short Term Memory (LSTM) model can be used as feature-less classification model to differentiate between functional and non-functional single guide RNAs. The project covers different experiments conducted using Support Vector Machine and Random Forest classifiers using sequential and structural features to identify the most potent sgRNAs in a given set of input sgRNAs. It also summarizes the implementation of the LSTM model and its results, along with the cross-validation results for each of these models. Through these results, it has been observed that LSTMs perform better than existing models such as Random Forest Classifiers and Support Vector Machines and give results comparable to existing tools