Tclass: tumor classification system based on gene expression profile

A method that incorporates feature selection into Fisher's linear discriminant analysis for gene expression based tumor classification and a corresponding program Tclass were developed. The proposed method was applied to a public gene expression data set for colon cancer that consists of 22 normal and 40 tumor colon tissue samples to evaluate its performance for classification. Preliminary results demonstrated that using only a subset of genes ranging from 3 to 10 can achieve high classification accuracy.     

On sparse Fisher discriminant method for microarray data analysis

One of the applications of the discriminant analysis on microarray data is to classify patient and normal samples based on gene expression values. The analysis is especially important in medical trials and diagnosis of cancer subtypes. The main contribution of this paper is to propose a simple Fisher-type discriminant method on gene selection in microarray data. In the new algorithm, we calculate a weight for each gene and use the weight values as an indicator to identify the subsets of relevant genes that categorize patient and normal samples. A l(2) - l(1) norm minimization method is implemented to the discriminant process to automatically compute the weights of all genes in the samples. The experiments on two microarray data sets have shown that the new algorithm can generate classification results as good as other classification methods, and effectively determine relevant genes for classification purpose. In this study, we demonstrate the gene selection's ability and the computational effectiveness of the proposed algorithm. Experimental results are given to illustrate the usefulness of the proposed model.     

Gene expression data classification using consensus independent component analysis

We propose a new method for tumor classification from gene expression data, which mainly contains three steps. Firstly, the original DNA microarray gene expression data are modeled by independent component analysis （ICA）. Secondly, the most discriminant eigenassays extracted by ICA are selected by the sequential floating forward selection technique. Finally, support vector machine is used to classify the modeling data. To show the validity of the proposed method, we applied it to classify three DNA microarray datasets involving various human normal and tumor tissue samples. The experimental results show that the method is efficient and feasible.     

肺鳞状细胞癌发生的早期标志物及肿瘤预测模型

选取癌症基因组图谱数据库的肺鳞状细胞癌(Lung Squamous Cell Carcinoma,LUSC)样本作为数据集,在全基因组的水平上研究肺鳞状细胞癌病人从正常到发病I期基因表达的变化,寻找与LUSC发病密切相关的早期标志物,并建立一种基于早期标志基因的肿瘤预测模型。方法 采用模式识别分类法和基因通路和功能分析相结合的筛选方法,对LUSC的早期标志物进行识别,并运用Fisher判别建立肿瘤预测模型。得到12个LUSC的早期标志物,分别是CLDN18, CD34, ESAM, JAM2, CDH5, F11, F8, CFD, MRC1, MARCO, SFTPA2 和 SFTPA1,机器学习建模后对LUSC早期癌症样本和正常肺组织样本的分类精度达到了98%以上。由基因SFTPA1和ESAM建立的LUSC早期肿瘤预测模型,对正常肺组织和LUSC肿瘤Ⅰ期样本的分类敏感性和特异性分别为99.18%和100%,并且独立验证集的分类准确率也在90%以上。结论 筛选出的12个早期分子标志物有望成为LUSC诊断的标志分子,并且建立的肿瘤预测模型具有极高的准确性,可以为LUSC的发生机理研究以及早期肿瘤预测提供帮助。     

Tissue classification with gene expression profiles.

Constantly improving gene expression profiling technologies are expected to provide understanding and insight into cancer-related cellular processes. Gene expression data is also expected to significantly aid in the development of efficient cancer diagnosis and classification platforms. In this work we examine three sets of gene expression data measured across sets of tumor(s) and normal clinical samples: The first set consists of 2,000 genes, measured in 62 epithelial colon samples (Alon et al., 1999). The second consists of approximately equal to 100,000 clones, measured in 32 ovarian samples (unpublished extension of data set described in Schummer et al. (1999)). The third set consists of approximately equal to 7,100 genes, measured in 72 bone marrow and peripheral blood samples (Golub et al, 1999). We examine the use of scoring methods, measuring separation of tissue type (e.g., tumors from normals) using individual gene expression levels. These are then coupled with high-dimensional classification methods to assess the classification power of complete expression profiles. We present results of performing leave-one-out cross validation (LOOCV) experiments on the three data sets, employing nearest neighbor classifier, SVM (Cortes and Vapnik, 1995), AdaBoost (Freund and Schapire, 1997) and a novel clustering-based classification technique. As tumor samples can differ from normal samples in their cell-type composition, we also perform LOOCV experiments using appropriately modified sets of genes, attempting to eliminate the resulting bias. We demonstrate success rate of at least 90% in tumor versus normal classification, using sets of selected genes, with, as well as without, cellular-contamination-related members. These results are insensitive to the exact selection mechanism, over a certain range.     

Using uncorrelated discriminant analysis for tissue classification with gene expression data

The classification of tissue samples based on gene expression data is an important problem in medical diagnosis of diseases such as cancer. In gene expression data, the number of genes is usually very high (in the thousands) compared to the number of data samples (in the tens or low hundreds); that is, the data dimension is large compared to the number of data points (such data is said to be undersampled). To cope with performance and accuracy problems associated with high dimensionality, it is commonplace to apply a preprocessing step that transforms the data to a space of significantly lower dimension with limited loss of the information present in the original data. Linear discriminant analysis (LDA) is a well-known technique for dimension reduction and feature extraction, but it is not applicable for undersampled data due to singularity problems associated with the matrices in the underlying representation. This paper presents a dimension reduction and feature extraction scheme, called uncorrelated linear discriminant analysis (ULDA), for undersampled problems and illustrates its utility on gene expression data. ULDA employs the generalized singular value decomposition method to handle undersampled data and the features that it produces in the transformed space are uncorrelated, which makes it attractive for gene expression data. The properties of ULDA are established rigorously and extensive experimental results on gene expression data are presented to illustrate its effectiveness in classifying tissue samples. These results provide a comparative study of various state-of-the-art classification methods on well-known gene expression data sets     

Optimal approach for classification of acute leukemia subtypes based on gene expression data

The classification of cancer subtypes, which is critical for successful treatment, has been studied extensively with the use of gene expression profiles from oligonucleotide chips or cDNA microarrays. Various pattern recognition methods have been successfully applied to gene expression data. However, these methods are not optimal, rather they are high-performance classifiers that emphasize only classification accuracy. In this paper, we propose an approach for the construction of the optimal linear classifier using gene expression data. Two linear classification methods, linear discriminant analysis (LDA) and discriminant partial least-squares (DPLS), are applied to distinguish acute leukemia subtypes. These methods are shown to give satisfactory accuracy. Moreover, we determined optimally the number of genes participating in the classification (a remarkably small number compared to previous results) on the basis of the statistical significance test. Thus, the proposed method constructs the optimal classifier that is composed of a small size predictor and provides high accuracy.     

A decomposition model to track gene expression signatures: preview on observer-independent classification of ovarian cancer

MOTIVATION: A number of algorithms and analytical models have been employed to reduce the multidimensional complexity of DNA array data and attempt to extract some meaningful interpretation of the results. These include clustering, principal components analysis, self-organizing maps, and support vector machine analysis. Each method assumes an implicit model for the data, many of which separate genes into distinct clusters defined by similar expression profiles in the samples tested. A point of concern is that many genes may be involved in a number of distinct behaviours, and should therefore be modelled to fit into as many separate clusters as detected in the multidimensional gene expression space. The analysis of gene expression data using a decomposition model that is independent of the observer involved would be highly beneficial to improve standard and reproducible classification of clinical and research samples. RESULTS: We present a variational independent component analysis (ICA) method for reducing high dimensional DNA array data to a smaller set of latent variables, each associated with a gene signature. We present the results of applying the method to data from an ovarian cancer study, revealing a number of tissue type-specific and tissue type-independent gene signatures present in varying amounts among the samples surveyed. The observer independent results of such molecular analysis of biological samples could help identify patients who would benefit from different treatment strategies. We further explore the application of the model to similar high-throughput studies.     

Tumor classification by partial least squares using microarray gene expression data

MOTIVATION: One important application of gene expression microarray data is classification of samples into categories, such as the type of tumor. The use of microarrays allows simultaneous monitoring of thousands of genes expressions per sample. This ability to measure gene expression en masse has resulted in data with the number of variables p(genes) far exceeding the number of samples N. Standard statistical methodologies in classification and prediction do not work well or even at all when N < p. Modification of existing statistical methodologies or development of new methodologies is needed for the analysis of microarray data. RESULTS: We propose a novel analysis procedure for classifying (predicting) human tumor samples based on microarray gene expressions. This procedure involves dimension reduction using Partial Least Squares (PLS) and classification using Logistic Discrimination (LD) and Quadratic Discriminant Analysis (QDA). We compare PLS to the well known dimension reduction method of Principal Components Analysis (PCA). Under many circumstances PLS proves superior; we illustrate a condition when PCA particularly fails to predict well relative to PLS. The proposed methods were applied to five different microarray data sets involving various human tumor samples: (1) normal versus ovarian tumor; (2) Acute Myeloid Leukemia (AML) versus Acute Lymphoblastic Leukemia (ALL); (3) Diffuse Large B-cell Lymphoma (DLBCLL) versus B-cell Chronic Lymphocytic Leukemia (BCLL); (4) normal versus colon tumor; and (5) Non-Small-Cell-Lung-Carcinoma (NSCLC) versus renal samples. Stability of classification results and methods were further assessed by re-randomization studies.     

Gene selection for sample classifications in microarray experiments

DNA microarray technology provides useful tools for profiling global gene expression patterns in different cell/tissue samples. One major challenge is the large number of genes relative to the number of samples. The use of all genes can suppress or reduce the performance of a classification rule due to the noise of nondiscriminatory genes. Selection of an optimal subset from the original gene set becomes an important prestep in sample classification. In this study, we propose a family-wise error (FWE) rate approach to selection of discriminatory genes for two-sample or multiple-sample classification. The FWE approach controls the probability of the number of one or more false positives at a prespecified level. A public colon cancer data set is used to evaluate the performance of the proposed approach for the two classification methods: k nearest neighbors (k-NN) and support vector machine (SVM). The selected gene sets from the proposed procedure appears to perform better than or comparable to several results reported in the literature using the univariate analysis without performing multivariate search. In addition, we apply the FWE approach to a toxicogenomic data set with nine treatments (a control and eight metals, As, Cd, Ni, Cr, Sb, Pb, Cu, and AsV) for a total of 55 samples for a multisample classification. Two gene sets are considered: the gene set omegaF formed by the ANOVA F-test, and a gene set omegaT formed by the union of one-versus-all t-tests. The predicted accuracies are evaluated using the internal and external crossvalidation. Using the SVM classification, the overall accuracies to predict 55 samples into one of the nine treatments are above 80% for internal crossvalidation. OmegaF has slightly higher accuracy rates than omegaT. The overall predicted accuracies are above 70% for the external crossvalidation; the two gene sets omegaT and omegaF performed equally well.     

Gene selection for sample classification based on gene expression data: study of sensitivity to choice of parameters of the GA/KNN method.

MOTIVATION: We recently introduced a multivariate approach that selects a subset of predictive genes jointly for sample classification based on expression data. We tested the algorithm on colon and leukemia data sets. As an extension to our earlier work, we systematically examine the sensitivity, reproducibility and stability of gene selection/sample classification to the choice of parameters of the algorithm. METHODS: Our approach combines a Genetic Algorithm (GA) and the k-Nearest Neighbor (KNN) method to identify genes that can jointly discriminate between different classes of samples (e.g. normal versus tumor). The GA/KNN method is a stochastic supervised pattern recognition method. The genes identified are subsequently used to classify independent test set samples. RESULTS: The GA/KNN method is capable of selecting a subset of predictive genes from a large noisy data set for sample classification. It is a multivariate approach that can capture the correlated structure in the data. We find that for a given data set gene selection is highly repeatable in independent runs using the GA/KNN method. In general, however, gene selection may be less robust than classification. AVAILABILITY: The method is available at http://dir.niehs.nih.gov/microarray/datamining CONTACT: LI3@niehs.nih.gov     

A computational approach to measuring coherence of gene expression in pathways

This study uses a computational approach to analyze coherence of expression of genes in pathways. Microarray data were analyzed with respect to coherent gene expression in a group of genes defined as a pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Our hypothesis is that genes in the same pathway are more likely to be coordinately regulated than a randomly selected gene set. A correlation coefficient for each pair of genes in a pathway was estimated based on gene expression in normal or tumor samples, and statistically significant correlation coefficients were identified. The coherence indicator was defined as the ratio of the number of gene pairs in the pathway whose correlation coefficients are significant, divided by the total number of gene pairs in the pathway. We defined all genes that appeared in the KEGG pathways as a reference gene set. Our analysis indicated that the mean coherence indicator of pathways is significantly larger than the mean coherence indicator of random gene sets drawn from the reference gene set. Thus, the result supports our hypothesis. The significance of each individual pathway of n genes was evaluated by comparing its coherence indicator with coherence indicators of 1000 random permutation sets of n genes chosen from the reference gene set. We analyzed three data sets: two Affymetrix microarrays and one cDNA microarray. For each of the three data sets, statistically significant pathways were identified among all KEGG pathways. Seven of 96 pathways had a significant coherence indicator in normal tissue and 14 of 96 pathways had a significant coherence indicator in tumor tissue in all three data sets. The increase in the number of pathways with significant coherence indicators may reflect the fact that tumor cells have a higher rate of metabolism than normal cells. Five pathways involved in oxidative phosphorylation, ATP synthesis, protein synthesis, or RNA synthesis were coherent in both normal and tumor tissue, demonstrating that these are essential genes, a high level of expression of which is required regardless of cell type.     

A mathematical programming approach for gene selection and tissue classification

MOTIVATION: Extracting useful information from expression levels of thousands of genes generated with microarray technology needs a variety of analytical techniques. Mathematical programming approaches for classification analysis outperform parametric methods when the data depart from assumptions underlying these methods. Therefore, a mathematical programming approach is developed for gene selection and tissue classification using gene expression profiles. RESULTS: A new mixed integer programming model is formulated for this purpose. The mixed integer programming model simultaneously selects genes and constructs a classification model to classify two groups of tissue samples as accurately as possible. Very encouraging results were obtained with two data sets from the literature as examples. These results show that the mathematical programming approach can rival or outperform traditional classification methods.     

Classification using functional data analysis for temporal gene expression data

MOTIVATION: Temporal gene expression profiles provide an important characterization of gene function, as biological systems are predominantly developmental and dynamic. We propose a method of classifying collections of temporal gene expression curves in which individual expression profiles are modeled as independent realizations of a stochastic process. The method uses a recently developed functional logistic regression tool based on functional principal components, aimed at classifying gene expression curves into known gene groups. The number of eigenfunctions in the classifier can be chosen by leave-one-out cross-validation with the aim of minimizing the classification error. RESULTS: We demonstrate that this methodology provides low-error-rate classification for both yeast cell-cycle gene expression profiles and Dictyostelium cell-type specific gene expression patterns. It also works well in simulations. We compare our functional principal components approach with a B-spline implementation of functional discriminant analysis for the yeast cell-cycle data and simulations. This indicates comparative advantages of our approach which uses fewer eigenfunctions/base functions. The proposed methodology is promising for the analysis of temporal gene expression data and beyond. AVAILABILITY: MATLAB programs are available upon request.     

Multiclass Decision Forest--a novel pattern recognition method for multiclass classification in microarray data analysis

The wealth of knowledge imbedded in gene expression data from DNA microarrays portends rapid advances in both research and clinic. Turning the prodigious and noisy data into knowledge is a challenge to the field of bioinformatics, and development of classifiers using supervised learning techniques is the primary methodological approach for clinical application using gene expression data. In this paper, we present a novel classification method, multiclass Decision Forest (DF), that is the direct extension of the two-class DF previously developed in our lab. Central to DF is the synergistic combining of multiple heterogenic but comparable decision trees to reach a more accurate and robust classification model. The computationally inexpensive multiclass DF algorithm integrates gene selection and model development, and thus eliminates the bias of gene preselection in crossvalidation. Importantly, the method provides several statistical means for assessment of prediction accuracy, prediction confidence, and diagnostic capability. We demonstrate the method by application to gene expression data for 83 small round blue-cell tumors (SRBCTs) samples belonging to one of four different classes. Based on 500 runs of 10-fold crossvalidation, tumor prediction accuracy was approximately 97%, sensitivity was approximately 95%, diagnostic sensitivity was approximately 91%, and diagnostic accuracy was approximately 99.5%. Among 25 genes selected to distinguish tumor class, 12 have functional information in the literature implicating their involvement in cancer. The four types of SRBCTs samples are also distinguishable in a clustering analysis based on the expression profiles of these 25 genes. The results demonstrated that the multiclass DF is an effective classification method for analysis of gene expression data for the purpose of molecular diagnostics.     

A TRIZ-inspired bat algorithm for gene selection in cancer classification

Gene expression data are expected to make a great contribution in the producing of efficient cancer diagnosis and prognosis. Gene expression data are coded by large measured genes, and only of a few number of them carry precious information for different classes of samples. Recently, several researchers proposed gene selection methods based on metaheuristic algorithms for analysing and interpreting gene expression data. However, due to large number of selected genes with limited number of patient's samples and complex interaction between genes, many gene selection methods experienced challenges in order to approach the most relevant and reliable genes. Hence, in this paper, a hybrid filter/wrapper, called rMRMR-MBA is proposed for gene selection problem. In this method, robust Minimum Redundancy Maximum Relevancy (rMRMR) as filter to select the most promising genes and an modified bat algorithm (MBA) as search engine in wrapper approach is proposed to identify a small set of informative genes. The performance of the proposed method has been evaluated using ten gene expression datasets. For performance evaluation, MBA is evaluated by studying the convergence behaviour of MBA with and without TRIZ optimisation operators. For comparative evaluation, the results of the proposed rMRMR-MBA were compared against ten state-of-arts methods using the same datasets. The comparative study demonstrates that the proposed method produced better results in terms of classification accuracy and number of selected genes in two out of ten datasets and competitive results on the remaining datasets. In a nutshell, the proposed method is able to produce very promising results with high classification accuracy which can be considered a promising contribution for gene selection domain.     

Interval-valued analysis for discriminative gene selection and tissue sample classification using microarray data

An important application of gene expression data is to classify samples in a variety of diagnostic fields. However, high dimensionality and a small number of noisy samples pose significant challenges to existing classification methods. Focused on the problems of overfitting and sensitivity to noise of the dataset in the classification of microarray data, we propose an interval-valued analysis method based on a rough set technique to select discriminative genes and to use these genes to classify tissue samples of microarray data. We first select a small subset of genes based on interval-valued rough set by considering the preference-ordered domains of the gene expression data, and then classify test samples into certain classes with a term of similar degree. Experiments show that the proposed method is able to reach high prediction accuracies with a small number of selected genes and its performance is robust to noise.     

Regularization network-based gene selection for microarray data analysis

Microarray data contains a large number of genes (usually more than 1000) and a relatively small number of samples (usually fewer than 100). This presents problems to discriminant analysis of microarray data. One way to alleviate the problem is to reduce dimensionality of data by selecting important genes to the discriminant problem. Gene selection can be cast as a feature selection problem in the context of pattern classification. Feature selection approaches are broadly grouped into filter methods and wrapper methods. The wrapper method outperforms the filter method but at the cost of more intensive computation. In the present study, we proposed a wrapper-like gene selection algorithm based on the Regularization Network. Compared with classical wrapper method, the computational costs in our gene selection algorithm is significantly reduced, because the evaluation criterion we proposed does not demand repeated training in the leave-one-out procedure.