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1.  Independent Principal Component Analysis for biologically meaningful dimension reduction of large biological data sets 
BMC Bioinformatics  2012;13:24.
Background
A key question when analyzing high throughput data is whether the information provided by the measured biological entities (gene, metabolite expression for example) is related to the experimental conditions, or, rather, to some interfering signals, such as experimental bias or artefacts. Visualization tools are therefore useful to better understand the underlying structure of the data in a 'blind' (unsupervised) way. A well-established technique to do so is Principal Component Analysis (PCA). PCA is particularly powerful if the biological question is related to the highest variance. Independent Component Analysis (ICA) has been proposed as an alternative to PCA as it optimizes an independence condition to give more meaningful components. However, neither PCA nor ICA can overcome both the high dimensionality and noisy characteristics of biological data.
Results
We propose Independent Principal Component Analysis (IPCA) that combines the advantages of both PCA and ICA. It uses ICA as a denoising process of the loading vectors produced by PCA to better highlight the important biological entities and reveal insightful patterns in the data. The result is a better clustering of the biological samples on graphical representations. In addition, a sparse version is proposed that performs an internal variable selection to identify biologically relevant features (sIPCA).
Conclusions
On simulation studies and real data sets, we showed that IPCA offers a better visualization of the data than ICA and with a smaller number of components than PCA. Furthermore, a preliminary investigation of the list of genes selected with sIPCA demonstrate that the approach is well able to highlight relevant genes in the data with respect to the biological experiment.
IPCA and sIPCA are both implemented in the R package mixomics dedicated to the analysis and exploration of high dimensional biological data sets, and on mixomics' web-interface.
doi:10.1186/1471-2105-13-24
PMCID: PMC3298499  PMID: 22305354
2.  Clustering and principal-components approach based on heritability for mapping multiple gene expressions 
BMC Proceedings  2007;1(Suppl 1):S121.
When the number of phenotypes in a genetic study is on the scale of thousands, such as in studies concerning thousands of gene expression levels, the single-trait analysis is computationally intensive, and heavy adjustment of multiple comparisons is required. Traditional multivariate genetic linkage analysis for quantitative traits focuses on mapping only a few phenotypes and is not feasible for a large number of traits. To cope with high-dimensional phenotype data, clustering analysis and principal-component analysis (PCA) are proposed to reduce the data dimensionality and to map shared genetic contributions for multiple traits. However, standard clustering analysis and PCA are applicable for independent observations. In most genetic studies, where family data are collected, these standard analyses can only be applied to founders and can lead to the loss of information. Here, we proposed a clustering method that can exploit family structure information and applied the method to 29 gene expression levels mapped to a reported hot spot on chromosome 14. We then used a PCA approach based on heritability applicable to small number of traits to combine phenotypes in the clusters. Lastly, we used a penalized PCA approach based on heritability applicable to arbitrary number of traits to combine 150 gene expression levels with the highest heritability. Genome-wide multipoint linkage analysis was carried out on the individual traits and on the combined traits. Two previously reported peaks on chromosomes 14 and 20 were identified. Linkage evidence was stronger for traits derived from methods that incorporate family structure information.
PMCID: PMC2367519  PMID: 18466463
3.  Independent component analysis of Alzheimer's DNA microarray gene expression data 
Background
Gene microarray technology is an effective tool to investigate the simultaneous activity of multiple cellular pathways from hundreds to thousands of genes. However, because data in the colossal amounts generated by DNA microarray technology are usually complex, noisy, high-dimensional, and often hindered by low statistical power, their exploitation is difficult. To overcome these problems, two kinds of unsupervised analysis methods for microarray data: principal component analysis (PCA) and independent component analysis (ICA) have been developed to accomplish the task. PCA projects the data into a new space spanned by the principal components that are mutually orthonormal to each other. The constraint of mutual orthogonality and second-order statistics technique within PCA algorithms, however, may not be applied to the biological systems studied. Extracting and characterizing the most informative features of the biological signals, however, require higher-order statistics.
Results
ICA is one of the unsupervised algorithms that can extract higher-order statistical structures from data and has been applied to DNA microarray gene expression data analysis. We performed FastICA method on DNA microarray gene expression data from Alzheimer's disease (AD) hippocampal tissue samples and consequential gene clustering. Experimental results showed that the ICA method can improve the clustering results of AD samples and identify significant genes. More than 50 significant genes with high expression levels in severe AD were extracted, representing immunity-related protein, metal-related protein, membrane protein, lipoprotein, neuropeptide, cytoskeleton protein, cellular binding protein, and ribosomal protein. Within the aforementioned categories, our method also found 37 significant genes with low expression levels. Moreover, it is worth noting that some oncogenes and phosphorylation-related proteins are expressed in low levels. In comparison to the PCA and support vector machine recursive feature elimination (SVM-RFE) methods, which are widely used in microarray data analysis, ICA can identify more AD-related genes. Furthermore, we have validated and identified many genes that are associated with AD pathogenesis.
Conclusion
We demonstrated that ICA exploits higher-order statistics to identify gene expression profiles as linear combinations of elementary expression patterns that lead to the construction of potential AD-related pathogenic pathways. Our computing results also validated that the ICA model outperformed PCA and the SVM-RFE method. This report shows that ICA as a microarray data analysis tool can help us to elucidate the molecular taxonomy of AD and other multifactorial and polygenic complex diseases.
doi:10.1186/1750-1326-4-5
PMCID: PMC2646728  PMID: 19173745
4.  A Pure L1-norm Principal Component Analysis 
The L1 norm has been applied in numerous variations of principal component analysis (PCA). L1-norm PCA is an attractive alternative to traditional L2-based PCA because it can impart robustness in the presence of outliers and is indicated for models where standard Gaussian assumptions about the noise may not apply. Of all the previously-proposed PCA schemes that recast PCA as an optimization problem involving the L1 norm, none provide globally optimal solutions in polynomial time. This paper proposes an L1-norm PCA procedure based on the efficient calculation of the optimal solution of the L1-norm best-fit hyperplane problem. We present a procedure called L1-PCA* based on the application of this idea that fits data to subspaces of successively smaller dimension. The procedure is implemented and tested on a diverse problem suite. Our tests show that L1-PCA* is the indicated procedure in the presence of unbalanced outlier contamination.
doi:10.1016/j.csda.2012.11.007
PMCID: PMC3746759  PMID: 23976807
principal component analysis; linear programming; L1 regression
5.  Supervised principal component analysis for gene set enrichment of microarray data with continuous or survival outcomes 
Bioinformatics  2008;24(21):2474-2481.
Motivation: Gene set analysis allows formal testing of subtle but coordinated changes in a group of genes, such as those defined by Gene Ontology (GO) or KEGG Pathway databases. We propose a new method for gene set analysis that is based on principal component analysis (PCA) of genes expression values in the gene set. PCA is an effective method for reducing high dimensionality and capture variations in gene expression values. However, one limitation with PCA is that the latent variable identified by the first PC may be unrelated to outcome.
Results: In the proposed supervised PCA (SPCA) model for gene set analysis, the PCs are estimated from a selected subset of genes that are associated with outcome. As outcome information is used in the gene selection step, this method is supervised, thus called the Supervised PCA model. Because of the gene selection step, test statistic in SPCA model can no longer be approximated well using t-distribution. We propose a two-component mixture distribution based on Gumbel exteme value distributions to account for the gene selection step. We show the proposed method compares favorably to currently available gene set analysis methods using simulated and real microarray data.
Software: The R code for the analysis used in this article are available upon request, we are currently working on implementing the proposed method in an R package.
Contact: chenx3@ccf.org.
doi:10.1093/bioinformatics/btn458
PMCID: PMC2732277  PMID: 18753155
6.  A novel data mining method to identify assay-specific signatures in functional genomic studies 
BMC Bioinformatics  2006;7:377.
Background:
The highly dimensional data produced by functional genomic (FG) studies makes it difficult to visualize relationships between gene products and experimental conditions (i.e., assays). Although dimensionality reduction methods such as principal component analysis (PCA) have been very useful, their application to identify assay-specific signatures has been limited by the lack of appropriate methodologies. This article proposes a new and powerful PCA-based method for the identification of assay-specific gene signatures in FG studies.
Results:
The proposed method (PM) is unique for several reasons. First, it is the only one, to our knowledge, that uses gene contribution, a product of the loading and expression level, to obtain assay signatures. The PM develops and exploits two types of assay-specific contribution plots, which are new to the application of PCA in the FG area. The first type plots the assay-specific gene contribution against the given order of the genes and reveals variations in distribution between assay-specific gene signatures as well as outliers within assay groups indicating the degree of importance of the most dominant genes. The second type plots the contribution of each gene in ascending or descending order against a constantly increasing index. This type of plots reveals assay-specific gene signatures defined by the inflection points in the curve. In addition, sharp regions within the signature define the genes that contribute the most to the signature. We proposed and used the curvature as an appropriate metric to characterize these sharp regions, thus identifying the subset of genes contributing the most to the signature. Finally, the PM uses the full dataset to determine the final gene signature, thus eliminating the chance of gene exclusion by poor screening in earlier steps. The strengths of the PM are demonstrated using a simulation study, and two studies of real DNA microarray data – a study of classification of human tissue samples and a study of E. coli cultures with different medium formulations.
Conclusion
We have developed a PCA-based method that effectively identifies assay-specific signatures in ranked groups of genes from the full data set in a more efficient and simplistic procedure than current approaches. Although this work demonstrates the ability of the PM to identify assay-specific signatures in DNA microarray experiments, this approach could be useful in areas such as proteomics and metabolomics.
doi:10.1186/1471-2105-7-377
PMCID: PMC1599756  PMID: 16907975
7.  PRINCIPAL COMPONENTS ANALYSIS TO SUMMARIZE MICROARRAY EXPERIMENTS: APPLICATION TO SPORULATION TIME SERIES 
A series of microarray experiments produces observations of differential expression for thousands of genes across multiple conditions. It is often not clear whether a set of experiments are measuring fundamentally different gene expression states or are measuring similar states created through different mechanisms. It is useful, therefore, to define a core set of independent features for the expression states that allow them to be compared directly. Principal components analysis (PCA) is a statistical technique for determining the key variables in a multidimensional data set that explain the differences in the observations, and can be used to simplify the analysis and visualization of multidimensional data sets. We show that application of PCA to expression data (where the experimental conditions are the variables, and the gene expression measurements are the observations) allows us to summarize the ways in which gene responses vary under different conditions. Examination of the components also provides insight into the underlying factors that are measured in the experiments. We applied PCA to the publicly released yeast sporulation data set (Chu et al. 1998). In that work, 7 different measurements of gene expression were made over time. PCA on the time-points suggests that much of the observed variability in the experiment can be summarized in just 2 components—i.e. 2 variables capture most of the information. These components appear to represent (1) overall induction level and (2) change in induction level over time. We also examined the clusters proposed in the original paper, and show how they are manifested in principal component space. Our results are available on the internet at http://www.smi.stanford.edu/projects/helix/PCArray.
PMCID: PMC2669932  PMID: 10902193
8.  Detecting evolution of bioinformatics with a content and co-authorship analysis 
SpringerPlus  2013;2:186.
Bioinformatics is an interdisciplinary research field that applies advanced computational techniques to biological data. Bibliometrics analysis has recently been adopted to understand the knowledge structure of a research field by citation pattern. In this paper, we explore the knowledge structure of Bioinformatics from the perspective of a core open access Bioinformatics journal, BMC Bioinformatics with trend analysis, the content and co-authorship network similarity, and principal component analysis. Publications in four core journals including Bioinformatics – Oxford Journal and four conferences in Bioinformatics were harvested from DBLP. After converting publications into TF-IDF term vectors, we calculate the content similarity, and we also calculate the social network similarity based on the co-authorship network by utilizing the overlap measure between two co-authorship networks. Key terms is extracted and analyzed with PCA, visualization of the co-authorship network is conducted. The experimental results show that Bioinformatics is fast-growing, dynamic and diversified. The content analysis shows that there is an increasing overlap among Bioinformatics journals in terms of topics and more research groups participate in researching Bioinformatics according to the co-authorship network similarity.
doi:10.1186/2193-1801-2-186
PMCID: PMC3661075  PMID: 23710427
9.  SPARSE LOGISTIC PRINCIPAL COMPONENTS ANALYSIS FOR BINARY DATA 
The annals of applied statistics  2010;4(3):1579-1601.
We develop a new principal components analysis (PCA) type dimension reduction method for binary data. Different from the standard PCA which is defined on the observed data, the proposed PCA is defined on the logit transform of the success probabilities of the binary observations. Sparsity is introduced to the principal component (PC) loading vectors for enhanced interpretability and more stable extraction of the principal components. Our sparse PCA is formulated as solving an optimization problem with a criterion function motivated from penalized Bernoulli likelihood. A Majorization-Minimization algorithm is developed to efficiently solve the optimization problem. The effectiveness of the proposed sparse logistic PCA method is illustrated by application to a single nucleotide polymorphism data set and a simulation study.
doi:10.1214/10-AOAS327SUPP
PMCID: PMC2992445  PMID: 21116451
Binary data; Dimension reduction; MM algorithm; LASSO; PCA; Regularization; Sparsity
10.  Nonlinear PCA: characterizing interactions between modes of brain activity. 
This paper presents a nonlinear principal component analysis (PCA) that identifies underlying sources causing the expression of spatial modes or patterns of activity in neuroimaging time-series. The critical aspect of this technique is that, in relation to conventional PCA, the sources can interact to produce (second-order) spatial modes that represent the modulation of one (first-order) spatial mode by another. This nonlinear PCA uses a simple neural network architecture that embodies a specific form for the nonlinear mixing of sources that cause observed data. This form is motivated by a second-order approximation to any general nonlinear mixing and emphasizes interactions among pairs of sources. By introducing these nonlinearities principal components obtain with a unique rotation and scaling that does not depend on the biologically implausible constraints adopted by conventional PCA. The technique is illustrated by application to functional (positron emission tomography and functional magnetic resonance imaging) imaging data where the ensuing first- and second-order modes can be interpreted in terms of distributed brain systems. The interactions among sources render the expression of any one mode context-sensitive, where that context is established by the expression of other modes. The examples considered include interactions between cognitive states and time (i.e. adaptation or plasticity in PET data) and among functionally specialized brain systems (using a fMRI study of colour and motion processing).
PMCID: PMC1692722  PMID: 10703049
11.  Super-sparse principal component analyses for high-throughput genomic data 
BMC Bioinformatics  2010;11:296.
Background
Principal component analysis (PCA) has gained popularity as a method for the analysis of high-dimensional genomic data. However, it is often difficult to interpret the results because the principal components are linear combinations of all variables, and the coefficients (loadings) are typically nonzero. These nonzero values also reflect poor estimation of the true vector loadings; for example, for gene expression data, biologically we expect only a portion of the genes to be expressed in any tissue, and an even smaller fraction to be involved in a particular process. Sparse PCA methods have recently been introduced for reducing the number of nonzero coefficients, but these existing methods are not satisfactory for high-dimensional data applications because they still give too many nonzero coefficients.
Results
Here we propose a new PCA method that uses two innovations to produce an extremely sparse loading vector: (i) a random-effect model on the loadings that leads to an unbounded penalty at the origin and (ii) shrinkage of the singular values obtained from the singular value decomposition of the data matrix. We develop a stable computing algorithm by modifying nonlinear iterative partial least square (NIPALS) algorithm, and illustrate the method with an analysis of the NCI cancer dataset that contains 21,225 genes.
Conclusions
The new method has better performance than several existing methods, particularly in the estimation of the loading vectors.
doi:10.1186/1471-2105-11-296
PMCID: PMC2902448  PMID: 20525176
12.  GeoPCA: a new tool for multivariate analysis of dihedral angles based on principal component geodesics 
Nucleic Acids Research  2011;40(3):e25.
The GeoPCA package is the first tool developed for multivariate analysis of dihedral angles based on principal component geodesics. Principal component geodesic analysis provides a natural generalization of principal component analysis for data distributed in non-Euclidean space, as in the case of angular data. GeoPCA presents projection of angular data on a sphere composed of the first two principal component geodesics, allowing clustering based on dihedral angles as opposed to Cartesian coordinates. It also provides a measure of the similarity between input structures based on only dihedral angles, in analogy to the root-mean-square deviation of atoms based on Cartesian coordinates. The principal component geodesic approach is shown herein to reproduce clusters of nucleotides observed in an η–θ plot. GeoPCA can be accessed via http://pca.limlab.ibms.sinica.edu.tw.
doi:10.1093/nar/gkr1069
PMCID: PMC3273787  PMID: 22139913
13.  An approach to incorporate linkage disequilibrium structure into genomic association analysis 
In this study, we propose to use the principal component analysis (PCA) and regression model to incorporate linkage disequilibrium (LD) in genomic association data analysis. To accommodate LD in genomic data and reduce multiple testing, we suggest performing PCA and extracting the PCA score to capture the variation of genomic data, after which regression analysis is used to assess the association of the disease with the principal component score. An empirical analysis result shows that both genotype-based correlation matrix and haplotype-based LD matrix can produce similar results for PCA. Principal component score seems to be more powerful in detecting genetic association because the principal component score is quantitatively measured and may be able to capture the effect of multiple loci.
doi:10.1016/S1673-8527(08)60055-7
PMCID: PMC2746675  PMID: 18571127
genetic association analysis; principal component analysis; linkage disequilibrium
14.  Comparative study of unsupervised dimension reduction techniques for the visualization of microarray gene expression data 
BMC Bioinformatics  2010;11:567.
Background
Visualization of DNA microarray data in two or three dimensional spaces is an important exploratory analysis step in order to detect quality issues or to generate new hypotheses. Principal Component Analysis (PCA) is a widely used linear method to define the mapping between the high-dimensional data and its low-dimensional representation. During the last decade, many new nonlinear methods for dimension reduction have been proposed, but it is still unclear how well these methods capture the underlying structure of microarray gene expression data. In this study, we assessed the performance of the PCA approach and of six nonlinear dimension reduction methods, namely Kernel PCA, Locally Linear Embedding, Isomap, Diffusion Maps, Laplacian Eigenmaps and Maximum Variance Unfolding, in terms of visualization of microarray data.
Results
A systematic benchmark, consisting of Support Vector Machine classification, cluster validation and noise evaluations was applied to ten microarray and several simulated datasets. Significant differences between PCA and most of the nonlinear methods were observed in two and three dimensional target spaces. With an increasing number of dimensions and an increasing number of differentially expressed genes, all methods showed similar performance. PCA and Diffusion Maps responded less sensitive to noise than the other nonlinear methods.
Conclusions
Locally Linear Embedding and Isomap showed a superior performance on all datasets. In very low-dimensional representations and with few differentially expressed genes, these two methods preserve more of the underlying structure of the data than PCA, and thus are favorable alternatives for the visualization of microarray data.
doi:10.1186/1471-2105-11-567
PMCID: PMC2998530  PMID: 21087509
15.  On Consistency and Sparsity for Principal Components Analysis in High Dimensions 
Principal components analysis (PCA) is a classic method for the reduction of dimensionality of data in the form of n observations (or cases) of a vector with p variables. Contemporary datasets often have p comparable with or even much larger than n. Our main assertions, in such settings, are (a) that some initial reduction in dimensionality is desirable before applying any PCA-type search for principal modes, and (b) the initial reduction in dimensionality is best achieved by working in a basis in which the signals have a sparse representation. We describe a simple asymptotic model in which the estimate of the leading principal component vector via standard PCA is consistent if and only if p(n)/n→0. We provide a simple algorithm for selecting a subset of coordinates with largest sample variances, and show that if PCA is done on the selected subset, then consistency is recovered, even if p(n) ⪢ n.
doi:10.1198/jasa.2009.0121
PMCID: PMC2898454  PMID: 20617121
Eigenvector estimation; Reduction of dimension; Regularization, Thresholding; Variable selection
16.  A Statistical Texture Model of the Liver Based on Generalized N-Dimensional Principal Component Analysis (GND-PCA) and 3D Shape Normalization 
We present a method based on generalized N-dimensional principal component analysis (GND-PCA) and a 3D shape normalization technique for statistical texture modeling of the liver. The 3D shape normalization technique is used for normalizing liver shapes in order to remove the liver shape variability and capture pure texture variations. The GND-PCA is used to overcome overfitting problems when the training samples are too much fewer than the dimension of the data. The preliminary results of leave-one-out experiments show that the statistical texture model of the liver built by our method can represent an untrained liver volume well, even though the mode is trained by fewer samples. We also demonstrate its potential application to classification of normal and abnormal (with tumors) livers.
doi:10.1155/2011/601672
PMCID: PMC3195762  PMID: 22013432
17.  A New Method Combining LDA and PLS for Dimension Reduction 
PLoS ONE  2014;9(5):e96944.
Linear discriminant analysis (LDA) is a classical statistical approach for dimensionality reduction and classification. In many cases, the projection direction of the classical and extended LDA methods is not considered optimal for special applications. Herein we combine the Partial Least Squares (PLS) method with LDA algorithm, and then propose two improved methods, named LDA-PLS and ex-LDA-PLS, respectively. The LDA-PLS amends the projection direction of LDA by using the information of PLS, while ex-LDA-PLS is an extension of LDA-PLS by combining the result of LDA-PLS and LDA, making the result closer to the optimal direction by an adjusting parameter. Comparative studies are provided between the proposed methods and other traditional dimension reduction methods such as Principal component analysis (PCA), LDA and PLS-LDA on two data sets. Experimental results show that the proposed method can achieve better classification performance.
doi:10.1371/journal.pone.0096944
PMCID: PMC4018361  PMID: 24820185
18.  ROC-supervised principal component analysis in connection with the diagnosis of diseases 
Principal component analysis (PCA) is a data analysis method that can deal with large volumes of data. Owing to the complexity and volume of the data generated by today's advanced technologies in genomics, proteomics, and metabolomics, PCA has become predominant in the medical sciences. Despite its popularity, PCA leaves much to be desired in terms of accuracy and may not be suitable for certain medical applications, such as diagnostics, where accuracy is paramount. In this study, we introduced a new PCA method, one that is carefully supervised by receiver operating characteristic (ROC) curve analysis. In order to assess its performance with respect to its ability to render an accurate differential diagnosis, and to compare its performance with that of standard PCA, we studied the striatal metabolomic profile of R6/2 Huntington disease (HD) transgenic mice, as well as that of wild type (WT) mice, using high field in vivo proton nuclear magnetic resonance (NMR) spectroscopy (9.4-Tesla). We tested both the standard PCA and our ROC-supervised PCA (using in each case both the covariance and the correlation matrix), 1) with the original R6/2 HD mice and WT mice, 2) with unknown mice, whose status had been determined via genotyping, and 3) with the ability to separate the original R6/2 mice into the two age subgroups (8 and 12 wks old). Only our ROC-supervised PCA (both with the covariance and the correlation matrix) passed all tests with a total accuracy of 100%; thus, providing evidence that it may be used for diagnostic purposes.
PMCID: PMC3056564  PMID: 21416060
Diagnostic methods; principal component analysis; receiver operating characteristic (ROC) curve analysis; metabolomics; nuclear magnetic resonance spectroscopy; huntington disease
19.  An extended data mining method for identifying differentially expressed assay-specific signatures in functional genomic studies 
BioData Mining  2010;3:11.
Background
Microarray data sets provide relative expression levels for thousands of genes for a small number, in comparison, of different experimental conditions called assays. Data mining techniques are used to extract specific information of genes as they relate to the assays. The multivariate statistical technique of principal component analysis (PCA) has proven useful in providing effective data mining methods. This article extends the PCA approach of Rollins et al. to the development of ranking genes of microarray data sets that express most differently between two biologically different grouping of assays. This method is evaluated on real and simulated data and compared to a current approach on the basis of false discovery rate (FDR) and statistical power (SP) which is the ability to correctly identify important genes.
Results
This work developed and evaluated two new test statistics based on PCA and compared them to a popular method that is not PCA based. Both test statistics were found to be effective as evaluated in three case studies: (i) exposing E. coli cells to two different ethanol levels; (ii) application of myostatin to two groups of mice; and (iii) a simulated data study derived from the properties of (ii). The proposed method (PM) effectively identified critical genes in these studies based on comparison with the current method (CM). The simulation study supports higher identification accuracy for PM over CM for both proposed test statistics when the gene variance is constant and for one of the test statistics when the gene variance is non-constant.
Conclusions
PM compares quite favorably to CM in terms of lower FDR and much higher SP. Thus, PM can be quite effective in producing accurate signatures from large microarray data sets for differential expression between assays groups identified in a preliminary step of the PCA procedure and is, therefore, recommended for use in these applications.
doi:10.1186/1756-0381-3-11
PMCID: PMC3017041  PMID: 21162755
20.  pcaGoPromoter - An R Package for Biological and Regulatory Interpretation of Principal Components in Genome-Wide Gene Expression Data 
PLoS ONE  2012;7(2):e32394.
Analyzing data obtained from genome-wide gene expression experiments is challenging due to the quantity of variables, the need for multivariate analyses, and the demands of managing large amounts of data. Here we present the R package pcaGoPromoter, which facilitates the interpretation of genome-wide expression data and overcomes the aforementioned problems. In the first step, principal component analysis (PCA) is applied to survey any differences between experiments and possible groupings. The next step is the interpretation of the principal components with respect to both biological function and regulation by predicted transcription factor binding sites. The robustness of the results is evaluated using cross-validation, and illustrative plots of PCA scores and gene ontology terms are available. pcaGoPromoter works with any platform that uses gene symbols or Entrez IDs as probe identifiers. In addition, support for several popular Affymetrix GeneChip platforms is provided. To illustrate the features of the pcaGoPromoter package a serum stimulation experiment was performed and the genome-wide gene expression in the resulting samples was profiled using the Affymetrix Human Genome U133 Plus 2.0 chip. Array data were analyzed using pcaGoPromoter package tools, resulting in a clear separation of the experiments into three groups: controls, serum only and serum with inhibitor. Functional annotation of the axes in the PCA score plot showed the expected serum-promoted biological processes, e.g., cell cycle progression and the predicted involvement of expected transcription factors, including E2F. In addition, unexpected results, e.g., cholesterol synthesis in serum-depleted cells and NF-κB activation in inhibitor treated cells, were noted. In summary, the pcaGoPromoter R package provides a collection of tools for analyzing gene expression data. These tools give an overview of the input data via PCA, functional interpretation by gene ontology terms (biological processes), and an indication of the involvement of possible transcription factors.
doi:10.1371/journal.pone.0032394
PMCID: PMC3288097  PMID: 22384239
21.  Probabilistic Principal Component Analysis with Expectation Maximization (PPCA-EM) Facilitates Volume Classification and Estimates the Missing Data 
Journal of Structural Biology  2010;171(1):18-30.
We have developed a new method for classifying 3D reconstructions with missing data obtained by electron microscopy techniques. The method is based on principal component analysis (PCA) combined with expectation maximization. The missing data, together with the principal components, are treated as hidden variables that are estimated by maximizing a likelihood function. PCA in 3D is similar to PCA for 2D image analysis. A lower dimensional subspace of significant features is selected, into which the data are projected, and if desired, subsequently classified. In addition, our new algorithm estimates the missing data for each individual volume within the lower dimensional subspace. Application to both a large model data set and cryo-electron microscopy experimental data demonstrates the good performance of the algorithm and illustrates its potential for studying macromolecular assemblies with continuous conformational variations.
doi:10.1016/j.jsb.2010.04.002
PMCID: PMC3353830  PMID: 20385241
image processing; Electron Microscopy; single particle reconstruction; missing cone/missing wedge; Multivariate Statistical Analysis; Principal Component Analysis; Expectation Maximization
22.  Combining least absolute shrinkage and selection operator (LASSO) and principal-components analysis for detection of gene-gene interactions in genome-wide association studies 
BMC Proceedings  2009;3(Suppl 7):S62.
Variable selection in genome-wide association studies can be a daunting task and statistically challenging because there are more variables than subjects. We propose an approach that uses principal-component analysis (PCA) and least absolute shrinkage and selection operator (LASSO) to identify gene-gene interaction in genome-wide association studies. A PCA was used to first reduce the dimension of the single-nucleotide polymorphisms (SNPs) within each gene. The interaction of the gene PCA scores were placed into LASSO to determine whether any gene-gene signals exist. We have extended the PCA-LASSO approach using the bootstrap to estimate the standard errors and confidence intervals of the LASSO coefficient estimates. This method was compared to placing the raw SNP values into the LASSO and the logistic model with individual gene-gene interaction. We demonstrated these methods with the Genetic Analysis Workshop 16 rheumatoid arthritis genome-wide association study data and our results identified a few gene-gene signals. Based on our results, the PCA-LASSO method shows promise in identifying gene-gene interactions, and, at this time we suggest using it with other conventional approaches, such as generalized linear models, to narrow down genetic signals.
PMCID: PMC2795963  PMID: 20018056
23.  Investigating the Efficacy of Nonlinear Dimensionality Reduction Schemes in Classifying Gene- and Protein-Expression Studies 
The recent explosion in procurement and availability of high-dimensional gene- and protein-expression profile datasets for cancer diagnostics has necessitated the development of sophisticated machine learning tools with which to analyze them. While some investigators are focused on identifying informative genes and proteins that play a role in specific diseases, other researchers have attempted instead to use patients based on their expression profiles to prognosticate disease status. A major limitation in the ability to accurate classify these high-dimensional datasets stems from the ‘curse of dimensionality’, occurring in situations where the number of genes or peptides significantly exceeds the total number of patient samples. Previous attempts at dealing with this issue have mostly centered on the use of a dimensionality reduction (DR) scheme, Principal Component Analysis (PCA), to obtain a low-dimensional projection of the high-dimensional data. However, linear PCA and other linear DR methods, which rely on Euclidean distances to estimate object similarity, do not account for the inherent underlying nonlinear structure associated with most biomedical data. While some researchers have begun to explore nonlinear DR methods for computer vision problems such as face detection and recognition, to the best of our knowledge, few such attempts have been made for classification and visualization of high-dimensional biomedical data. The motivation behind this work is to identify the appropriate DR methods for analysis of high-dimensional gene- and protein-expression studies. Towards this end, we empirically and rigorously compare three nonlinear (Isomap, Locally Linear Embedding, Laplacian Eigenmaps) and three linear DR schemes (PCA, Linear Discriminant Analysis, Multidimensional Scaling) with the intent of determining a reduced subspace representation in which the individual object classes are more easily discriminable. Owing to the to the inherent nonlinear structure of gene- and protein-expression studies, our claim is that the nonlinear DR methods provide a more truthful low-dimensional representation of the data compared to the linear DR schemes. Evaluation of the DR schemes was done by (i) assessing the discriminability of two supervised classifiers (Support Vector Machine and C4.5 Decision Trees) in the different low-dimensional data embeddings and (ii) 5 cluster validity measures to evaluate the size, distance and tightness of object aggregates in the low-dimensional space. For each of the 7 evaluation measures considered, statistically significant improvement in the quality of the embeddings across 10 cancer datasets via the use of 3 nonlinear DR schemes over 3 linear DR techniques was observed. Similar trends were observed when linear and nonlinear DR was applied to the high-dimensional data following feature pruning to isolate the most informative features. Qualitative evaluation of the low-dimensional data embedding obtained via the 6 DR methods further suggests that the nonlinear schemes are better able to identify potential novel classes (e.g. cancer subtypes) within the data.
doi:10.1109/TCBB.2008.36
PMCID: PMC2562675  PMID: 18670041
Dimensionality reduction; bioinformatics; data clustering; data visualization; machine learning; manifold learning; nonlinear dimensionality reduction; gene expression; proteomics; prostate cancer; lung cancer; ovarian cancer; principal component analysis; linear discriminant analysis; multidimensional scaling; Isomap; locally linear embedding; laplacian eigenmaps; classification; support vector machine; decision trees; LLE; PCA
24.  An application of principal component analysis to the clavicle and clavicle fixation devices 
Background
Principal component analysis (PCA) enables the building of statistical shape models of bones and joints. This has been used in conjunction with computer assisted surgery in the past. However, PCA of the clavicle has not been performed. Using PCA, we present a novel method that examines the major modes of size and three-dimensional shape variation in male and female clavicles and suggests a method of grouping the clavicle into size and shape categories.
Materials and methods
Twenty-one high-resolution computerized tomography scans of the clavicle were reconstructed and analyzed using a specifically developed statistical software package. After performing statistical shape analysis, PCA was applied to study the factors that account for anatomical variation.
Results
The first principal component representing size accounted for 70.5 percent of anatomical variation. The addition of a further three principal components accounted for almost 87 percent. Using statistical shape analysis, clavicles in males have a greater lateral depth and are longer, wider and thicker than in females. However, the sternal angle in females is larger than in males. PCA confirmed these differences between genders but also noted that men exhibit greater variance and classified clavicles into five morphological groups.
Discussion And Conclusions
This unique approach is the first that standardizes a clavicular orientation. It provides information that is useful to both, the biomedical engineer and clinician. Other applications include implant design with regard to modifying current or designing future clavicle fixation devices. Our findings support the need for further development of clavicle fixation devices and the questioning of whether gender-specific devices are necessary.
doi:10.1186/1749-799X-5-21
PMCID: PMC3003245  PMID: 20346123
25.  Dimension Reduction of Microarray Data in the Presence of a Censored Survival Response: a Simulation Study 
An important aspect of microarray studies involves the prediction of patient survival based on their gene expression levels. To cope with the high dimensionality of the microarray gene expression data, it is customary to first reduce the dimension of the gene expression data via dimension reduction methods, and then use the Cox proportional hazards model to predict patient survival. In this paper, we propose a variant of Partial Least Squares, denoted as Rank-based Modified Partial Least Squares (RMPLS), that is insensitive to outlying values of both the response and the gene expressions. We assess the performance of RMPLS and several dimension reduction methods using a simulation model for gene expression data with a censored response. In particular, Principal Component Analysis (PCA), modified Partial Least Squares (MPLS), RMPLS, Sliced Inverse Regression (SIR), Correlation Principal Component Regression (CPCR), Supervised Principal Component Regression (SPCR) and Univariate Selection (UNIV) are compared in terms of mean squared error of the estimated survival function and the estimated coefficients of the covariates, and in terms of the bias of the estimated survival function. It turns out that RMPLS outperforms all other methods in terms of the mean squared error and the bias of the survival function in the presence of outliers in the response. In addition, RMPLS is comparable to MPLS in the absence of outliers. In this setting, both RMPLS and MPLS outperform all other methods considered in this study in terms of mean squared error and bias of the estimated survival function.
doi:10.2202/1544-6115.1395
PMCID: PMC2756975  PMID: 19222387
censored response; Cox proportional hazards model; outliers; mean squared error; bias

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