Exploring matrix factorization techniques for significant genes identification of Alzheimer’s disease microarray gene expression data

<p>Abstract</p> <p>Background</p> <p>The wide use of high-throughput DNA microarray technology provide an increasingly detailed view of human transcriptome from hundreds to thousands of genes. Although biomedical researchers typically design microarray experiments to explore specific biological contexts, the relationships between genes are hard to identified because they are complex and noisy high-dimensional data and are often hindered by low statistical power. The main challenge now is to extract valuable biological information from the colossal amount of data to gain insight into biological processes and the mechanisms of human disease. To overcome the challenge requires mathematical and computational methods that are versatile enough to capture the underlying biological features and simple enough to be applied efficiently to large datasets.</p> <p>Methods</p> <p>Unsupervised machine learning approaches provide new and efficient analysis of gene expression profiles. In our study, two unsupervised knowledge-based matrix factorization methods, independent component analysis (ICA) and nonnegative matrix factorization (NMF) are integrated to identify significant genes and related pathways in microarray gene expression dataset of Alzheimer’s disease. The advantage of these two approaches is they can be performed as a biclustering method by which genes and conditions can be clustered simultaneously. Furthermore, they can group genes into different categories for identifying related diagnostic pathways and regulatory networks. The difference between these two method lies in ICA assume statistical independence of the expression modes, while NMF need positivity constrains to generate localized gene expression profiles.</p> <p>Results</p> <p>In our work, we performed FastICA and non-smooth NMF methods on DNA microarray gene expression data of Alzheimer’s disease respectively. The simulation results shows that both of the methods can clearly classify severe AD samples from control samples, and the biological analysis of the identified significant genes and their related pathways demonstrated that these genes play a prominent role in AD and relate the activation patterns to AD phenotypes. It is validated that the combination of these two methods is efficient.</p> <p>Conclusions</p> <p>Unsupervised matrix factorization methods provide efficient tools to analyze high-throughput microarray dataset. According to the facts that different unsupervised approaches explore correlations in the high-dimensional data space and identify relevant subspace base on different hypotheses, integrating these methods to explore the underlying biological information from microarray dataset is an efficient approach. By combining the significant genes identified by both ICA and NMF, the biological analysis shows great efficient for elucidating the molecular taxonomy of Alzheimer’s disease and enable better experimental design to further identify potential pathways and therapeutic targets of AD.</p

Simplivariate Models: Ideas and First Examples

One of the new expanding areas in functional genomics is metabolomics: measuring the metabolome of an organism. Data being generated in metabolomics studies are very diverse in nature depending on the design underlying the experiment. Traditionally, variation in measurements is conceptually broken down in systematic variation and noise where the latter contains, e.g. technical variation. There is increasing evidence that this distinction does not hold (or is too simple) for metabolomics data. A more useful distinction is in terms of informative and non-informative variation where informative relates to the problem being studied. In most common methods for analyzing metabolomics (or any other high-dimensional x-omics) data this distinction is ignored thereby severely hampering the results of the analysis. This leads to poorly interpretable models and may even obscure the relevant biological information. We developed a framework from first data analysis principles by explicitly formulating the problem of analyzing metabolomics data in terms of informative and non-informative parts. This framework allows for flexible interactions with the biologists involved in formulating prior knowledge of underlying structures. The basic idea is that the informative parts of the complex metabolomics data are approximated by simple components with a biological meaning, e.g. in terms of metabolic pathways or their regulation. Hence, we termed the framework ‘simplivariate models’ which constitutes a new way of looking at metabolomics data. The framework is given in its full generality and exemplified with two methods, IDR analysis and plaid modeling, that fit into the framework. Using this strategy of ‘divide and conquer’, we show that meaningful simplivariate models can be obtained using a real-life microbial metabolomics data set. For instance, one of the simple components contained all the measured intermediates of the Krebs cycle of E. coli. Moreover, these simplivariate models were able to uncover regulatory mechanisms present in the phenylalanine biosynthesis route of E. coli

FABIA: factor analysis for bicluster acquisition

Motivation: Biclustering of transcriptomic data groups genes and samples simultaneously. It is emerging as a standard tool for extracting knowledge from gene expression measurements. We propose a novel generative approach for biclustering called ‘FABIA: Factor Analysis for Bicluster Acquisition’. FABIA is based on a multiplicative model, which accounts for linear dependencies between gene expression and conditions, and also captures heavy-tailed distributions as observed in real-world transcriptomic data. The generative framework allows to utilize well-founded model selection methods and to apply Bayesian techniques

Simplivariate Models: Uncovering the Underlying Biology in Functional Genomics Data

One of the first steps in analyzing high-dimensional functional genomics data is an exploratory analysis of such data. Cluster Analysis and Principal Component Analysis are then usually the method of choice. Despite their versatility they also have a severe drawback: they do not always generate simple and interpretable solutions. On the basis of the observation that functional genomics data often contain both informative and non-informative variation, we propose a method that finds sets of variables containing informative variation. This informative variation is subsequently expressed in easily interpretable simplivariate components

Nonparametric Bayesian Bi-Clustering for Next Generation Sequencing Count Data

Histone modifications (HMs) play important roles in transcription through post-translational modifications. Combinations of HMs, known as chromatin signatures, encode specific messages for gene regulation. We therefore expect that inference on possible clustering of HMs and an annotation of genomic locations on the basis of such clustering can contribute new insights about the functions of regulatory elements and their relationships to combinations of HMs. We propose a nonparametric Bayesian local clustering Poisson model (NoB-LCP) to facilitate posterior inference on two-dimensional clustering of HMs and genomic locations. The NoB-LCP clusters HMs into HM sets and lets each HM set define its own clustering of genomic locations. Furthermore, it probabilistically excludes HMs and genomic locations that are irrelevant to clustering. By doing so, the proposed model effectively identifies important sets of HMs and groups regulatory elements with similar functionality based on HM patterns.NIH R01 CA132897NCI 5 K25 CA123344Mathematic

Kupffer cells are protective in alcoholic steatosis

Massive accumulation of lipids is a characteristic of alcoholic liver disease. Excess of hepatic fat activates Kupffer cells (KCs), which affect disease progression. Yet, KCs contribute to the resolution and advancement of liver injury. Aim of the present study was to evaluate the effect of KC depletion on markers of liver injury and the hepatic lipidome in liver steatosis (Lieber-DeCarli diet, LDC, female mice, mixed C57BL/6J and DBA/2J background). LDC increased the number of dead hepatocytes without changing the mRNA levels of inflammatory cytokines in the liver. Animals fed LDC accumulated elevated levels of almost all lipid classes. KC ablation normalized phosphatidylcholine and phosphatidylinositol levels in LDC livers, but had no effect in the controls. A modest decline of trigylceride and diglyceride levels upon KC loss was observed in both groups. Serum aminotransferases and hepatic ceramide were elevated in all animals upon KC depletion, and in particular, cytotoxic very long-chain ceramides increased in the LDC livers. Meta-biclustering revealed that eight lipid species occurred in more than 40% of the biclusters, and four of them were very long-chain ceramides. KC loss was further associated with excess free cholesterol levels in LDC livers. Expression of inflammatory cytokines did, however, not increase in parallel. In summary, the current study described a function of KCs in hepatic ceramide and cholesterol metabolism in an animal model of LDC liver steatosis. High abundance of cytotoxic ceramides and free cholesterol predispose the liver to disease progression suggesting a protective role of KCs in alcoholic liver diseases

Biclustering: Methods, Software and Application

Over the past 10 years, biclustering has become popular not only in the field of biological data analysis but also in other applications with high-dimensional two way datasets. This technique clusters both rows and columns simultaneously, as opposed to clustering only rows or only columns. Biclustering retrieves subgroups of objects that are similar in one subgroup of variables and different in the remaining variables. This dissertation focuses on improving and advancing biclustering methods. Since most existing methods are extremely sensitive to variations in parameters and data, we developed an ensemble method to overcome these limitations. It is possible to retrieve more stable and reliable bicluster in two ways: either by running algorithms with different parameter settings or by running them on sub- or bootstrap samples of the data and combining the results. To this end, we designed a software package containing a collection of bicluster algorithms for different clustering tasks and data scales, developed several new ways of visualizing bicluster solutions, and adapted traditional cluster validation indices (e.g. Jaccard index) for validating the bicluster framework. Finally, we applied biclustering to marketing data. Well-established algorithms were adjusted to slightly different data situations, and a new method specially adapted to ordinal data was developed. In order to test this method on artificial data, we generated correlated original random values. This dissertation introduces two methods for generating such values given a probability vector and a correlation structure. All the methods outlined in this dissertation are freely available in the R packages biclust and orddata. Numerous examples in this work illustrate how to use the methods and software.In den letzten 10 Jahren wurde das Biclustern vor allem auf dem Gebiet der biologischen Datenanalyse, jedoch auch in allen Bereichen mit hochdimensionalen Daten immer populärer. Unter Biclustering versteht man das simultane Clustern von 2-Wege-Daten, um Teilmengen von Objekten zu finden, die sich zu Teilmengen von Variablen ähnlich verhalten. Diese Arbeit beschäftigt sich mit der Weiterentwicklung und Optimierung von Biclusterverfahren. Neben der Entwicklung eines Softwarepaketes zur Berechnung, Aufarbeitung und graphischen Darstellung von Bicluster Ergebnissen wurde eine Ensemble Methode für Bicluster Algorithmen entwickelt. Da die meisten Algorithmen sehr anfällig auf kleine Veränderungen der Startparameter sind, können so robustere Ergebnisse erzielt werden. Die neue Methode schließt auch das Zusammenfügen von Bicluster Ergebnissen auf Subsample- und Bootstrap-Stichproben mit ein. Zur Validierung der Ergebnisse wurden auch bestehende Maße des traditionellen Clusterings (z.B. Jaccard Index) für das Biclustering adaptiert und neue graphische Mittel für die Interpretation der Ergebnisse entwickelt. Ein weiterer Teil der Arbeit beschäftigt sich mit der Anwendung von Bicluster Algorithmen auf Daten aus dem Marketing Bereich. Dazu mussten bestehende Algorithmen verändert und auch ein neuer Algorithmus speziell für ordinale Daten entwickelt werden. Um das Testen dieser Methoden auf künstlichen Daten zu ermöglichen, beinhaltet die Arbeit auch die Ausarbeitung eines Verfahrens zur Ziehung ordinaler Zufallszahlen mit vorgegebenen Wahrscheinlichkeiten und Korrelationsstruktur. Die in der Arbeit vorgestellten Methoden stehen durch die beiden R Pakete biclust und orddata allgemein zur Verfügung. Die Nutzbarkeit wird in der Arbeit durch zahlreiche Beispiele aufgezeigt

Improved biclustering of microarray data demonstrated through systematic performance tests

A new algorithm is presented for fitting the plaid model, a biclustering method developed for clustering gene expression data. The approach is based on speedy individual differences clustering and uses binary least squares to update the cluster membership parameters, making use of the binary constraints on these parameters and simplifying the other parameter updates. The performance of both algorithms is tested on simulated data sets designed to imitate (normalised) gene expression data, covering a range of biclustering configurations. Empirical distributions for the components of these data sets, including non-systematic error, are derived from a real set of microarray data. A set of two-way quality measures is proposed, based on one-way measures commonly used in information retrieval, to evaluate the quality of a retrieved bicluster with respect to a target bicluster in terms of both genes and samples. By defining a one-to-one correspondence between target biclusters and retrieved biclusters, the performance of each algorithm can be assessed. The results show that, using appropriately selected starting criteria, the proposed algorithm out-performs the original plaid model algorithm across a range of data sets. Furthermore, through the rigorous assessment of the plaid model a benchmark for future evaluation of biclustering methods is established