Genetics and Genomics Commons^™

Differential Expression With The Bioconductor Project, Anja Von Heydebreck, Wolfgang Huber, Robert Gentleman

Bioconductor Project Working Papers

A basic, yet challenging task in the analysis of microarray gene expression data is the identification of changes in gene expression that are associated with particular biological conditions. We discuss different approaches to this task and illustrate how they can be applied using software from the Bioconductor Project. A central problem is the high dimensionality of gene expression space, which prohibits a comprehensive statistical analysis without focusing on particular aspects of the joint distribution of the genes expression levels. Possible strategies are to do univariate gene-by-gene analysis, and to perform data-driven nonspecific filtering of genes before the actual statistical analysis. …

Nonparametric Methods For Analyzing Replication Origins In Genomewide Data, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

Due to the advent of high-throughput genomic technology, it has become possible to globally monitor cellular activities on a genomewide basis. With these new methods, scientists can begin to address important biological questions. One such question involves the identification of replication origins, which are regions in chromosomes where DNA replication is initiated. In addition, one hypothesis regarding replication origins is that their locations are non-random throughout the genome. In this article, we develop methods for identification of and cluster inference regarding replication origins involving genomewide expression data. We compare several nonparametric regression methods for the identification of replication origin locations. …

Semiparametric Methods For Identification Of Tumor Progression Genes From Microarray Data, Debashis Ghosh, Arul Chinnaiyan

The University of Michigan Department of Biostatistics Working Paper Series

The use of microarray data has become quite commonplace in medical and scientific experiments. We focus here on microarray data generated from cancer studies. It is potentially important for the discovery of biomarkers to identify genes whose expression levels correlate with tumor progression. In this article, we develop statistical procedures for the identification of such genes, which we term tumor progression genes. Two methods are considered in this paper. The first is use of a proportional odds procedure, combined with false discovery rate estimation techniques to adjust for the multiple testing problem. The second method is based on order-restricted estimation …

The False Discovery Rate: A Variable Selection Perspective, Debashis Ghosh, Wei Chen, Trivellore E. Raghuanthan

The University of Michigan Department of Biostatistics Working Paper Series

In many scientific and medical settings, large-scale experiments are generating large quantities of data that lead to inferential problems involving multiple hypotheses. This has led to recent tremendous interest in statistical methods regarding the false discovery rate (FDR). Several authors have studied the properties involving FDR in a univariate mixture model setting. In this article, we turn the problem on its side; in this manuscript, we show that FDR is a by-product of Bayesian analysis of variable selection problem for a hierarchical linear regression model. This equivalence gives many Bayesian insights as to why FDR is a natural quantity to …

A Graph Theoretic Approach To Testing Associations Between Disparate Sources Of Functional Genomic Data, Raji Balasubramanian, Thomas Laframboise, Denise Scholtens, Robert Gentleman

Bioconductor Project Working Papers

The last few years have seen the advent of high-throughput technologies to analyze various properties of the transcriptome and proteome of several organisms. The congruency of these different data sources, or lack thereof, can shed light on the mechanisms that govern cellular function. A central challenge for bioinformatics research is to develop a unified framework for combining the multiple sources of functional genomics information and testing associations between them, thus obtaining a robust and integrated view of the underlying biology.

We present a graph theoretic approach to test the significance of the association between multiple disparate sources of functional genomics …

Statistical Analyses And Reproducible Research, Robert Gentleman, Duncan Temple Lang

Bioconductor Project Working Papers

For various reasons, it is important, if not essential, to integrate the computations and code used in data analyses, methodological descriptions, simulations, etc. with the documents that describe and rely on them. This integration allows readers to both verify and adapt the statements in the documents. Authors can easily reproduce them in the future, and they can present the document's contents in a different medium, e.g. with interactive controls. This paper describes a software framework for authoring and distributing these integrated, dynamic documents that contain text, code, data, and any auxiliary content needed to recreate the computations. The documents are …

A Model Based Background Adjustment For Oligonucleotide Expression Arrays, Zhijin Wu, Rafael A. Irizarry, Robert Gentleman, Francisco Martinez Murillo, Forrest Spencer

Johns Hopkins University, Dept. of Biostatistics Working Papers

High density oligonucleotide expression arrays are widely used in many areas of biomedical research. Affymetrix GeneChip arrays are the most popular. In the Affymetrix system, a fair amount of further pre-processing and data reduction occurs following the image processing step. Statistical procedures developed by academic groups have been successful at improving the default algorithms provided by the Affymetrix system. In this paper we present a solution to one of the pre-processing steps, background adjustment, based on a formal statistical framework. Our solution greatly improves the performance of the technology in various practical applications.

Affymetrix GeneChip arrays use short oligonucleotides to …

Classification Using Generalized Partial Least Squares, Beiying Ding, Robert Gentleman

Bioconductor Project Working Papers

The advances in computational biology have made simultaneous monitoring of thousands of features possible. The high throughput technologies not only bring about a much richer information context in which to study various aspects of gene functions but they also present challenge of analyzing data with large number of covariates and few samples. As an integral part of machine learning, classification of samples into two or more categories is almost always of interest to scientists. In this paper, we address the question of classification in this setting by extending partial least squares (PLS), a popular dimension reduction tool in chemometrics, in …

Mixture Models For Assessing Differential Expression In Complex Tissues Using Microarray Data, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

The use of DNA microarrays has become quite popular in many scientific and medical disciplines, such as in cancer research. One common goal of these studies is to determine which genes are differentially expressed between cancer and healthy tissue, or more generally, between two experimental conditions. A major complication in the molecular profiling of tumors using gene expression data is that the data represent a combination of tumor and normal cells. Much of the methodology developed for assessing differential expression with microarray data has assumed that tissue samples are homogeneous. In this article, we outline a general framework for determining …

Optimal Sample Size For Multiple Testing: The Case Of Gene Expression Microarrays, Peter Muller, Giovanni Parmigiani, Christian Robert, Judith Rousseau

Johns Hopkins University, Dept. of Biostatistics Working Papers

We consider the choice of an optimal sample size for multiple comparison problems. The motivating application is the choice of the number of microarray experiments to be carried out when learning about differential gene expression. However, the approach is valid in any application that involves multiple comparisons in a large number of hypothesis tests. We discuss two decision problems in the context of this setup: the sample size selection and the decision about the multiple comparisons. We adopt a decision theoretic approach,using loss functions that combine the competing goals of discovering as many ifferentially expressed genes as possible, while keeping …

Calibrating Observed Differential Gene Expression For The Multiplicity Of Genes On The Array, Yingye Zheng, Margaret S. Pepe

UW Biostatistics Working Paper Series

In a gene expression array study, the expression levels of thousands of genes are monitored simultaneously across various biological conditions on a small set of subjects. One goal of such studies is to explore a large pool of genes in order to select a subset of genes that appear to be differently expressed for further investigation. Of particular interest here is how to select the top k genes once genes are ranked based on their evidence for differential expression in two tissue types. We consider statistical methods that provide a more rigorous and intuitively appealing selection process for k. We …

Bioconductor: Open Software Development For Computational Biology And Bioinformatics, Robert C. Gentleman, Vincent J. Carey, Douglas J. Bates, Benjamin M. Bolstad, Marcel Dettling, Sandrine Dudoit, Byron Ellis, Laurent Gautier, Yongchao Ge, Jeff Gentry, Kurt Hornik, Torsten Hothorn, Wolfgang Huber, Stefano Iacus, Rafael Irizarry, Friedrich Leisch, Cheng Li, Martin Maechler, Anthony J. Rossini, Guenther Sawitzki, Colin Smith, Gordon K. Smyth, Luke Tierney, Yee Hwa Yang, Jianhua Zhang

Bioconductor Project Working Papers

The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. We detail some of the design decisions, software paradigms and operational strategies that have allowed a small number of researchers to provide a wide variety of innovative, extensible, software solutions in a relatively short time. The use of an object oriented programming paradigm, the adoption and development of a software package system, designing by contract, distributed development and collaboration with other projects are elements of this project's success. Individually, each of these concepts are useful and important but when combined they have …

Smart Sequence Similarity Search (S⁴) System, Zhuo Chen

Theses Digitization Project

Sequence similarity searching is commonly used to help clarify the biochemical and physiological features of newly discovered genes or proteins. An efficient similarity search relies on the choice of tools and their associated subprograms and numerous parameter settings. To assist researchers in selecting optimal programs and parameter settings for efficient sequence similarity searches, the web-based expert system, Smart Sequence Similarity Search (S4) was developed.

Computational Protein Biomarker Prediction: A Case Study For Prostate Cancer, Michael Wagner, Dayanand N. Naik, Alex Pothen, Srinivas Kasukurti, Raghu Ram Devineni, Bao-Ling Adam, O. John Semmes, George L. Wright Jr.

Mathematics & Statistics Faculty Publications

Background: Recent technological advances in mass spectrometry pose challenges in computational mathematics and statistics to process the mass spectral data into predictive models with clinical and biological significance. We discuss several classification-based approaches to finding protein biomarker candidates using protein profiles obtained via mass spectrometry, and we assess their statistical significance. Our overall goal is to implicate peaks that have a high likelihood of being biologically linked to a given disease state, and thus to narrow the search for biomarker candidates.

Results: Thorough cross-validation studies and randomization tests are performed on a prostate cancer dataset with over 300 patients, obtained …

Loss-Based Estimation With Cross-Validation: Applications To Microarray Data Analysis And Motif Finding, Sandrine Dudoit, Mark J. Van Der Laan, Sunduz Keles, Annette M. Molinaro, Sandra E. Sinisi, Siew Leng Teng

U.C. Berkeley Division of Biostatistics Working Paper Series

Current statistical inference problems in genomic data analysis involve parameter estimation for high-dimensional multivariate distributions, with typically unknown and intricate correlation patterns among variables. Addressing these inference questions satisfactorily requires: (i) an intensive and thorough search of the parameter space to generate good candidate estimators, (ii) an approach for selecting an optimal estimator among these candidates, and (iii) a method for reliably assessing the performance of the resulting estimator. We propose a unified loss-based methodology for estimator construction, selection, and performance assessment with cross-validation. In this approach, the parameter of interest is defined as the risk minimizer for a suitable …

Unification Of Variance Components And Haseman-Elston Regression For Quantitative Trait Linkage Analysis, Wei-Min Chen, Karl W. Broman, Kung-Yee Liang

Johns Hopkins University, Dept. of Biostatistics Working Papers

Two of the major approaches for linkage analysis with quantitative traits in humans include variance components and Haseman-Elston regression. Previously, these have been viewed as quite separate methods. We describe a general model, fit by use of generalized estimating equations (GEE), for which the variance components and Haseman-Elston methods (including many of the extensions to the original Haseman-Elston method) are special cases, corresponding to different choices for a working covariance matrix. We also show that the regression-based test of Sham et al.(2002) is equivalent to a robust score statistic derived from our GEE approach. These results have several important implications. …

A Nested Unsupervised Approach To Identifying Novel Molecular Subtypes, Elizabeth Garrett, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

In classification problems arising in genomics research it is common to study populations for which a broad class assignment is known (say, normal versus diseased) and one seeks to find undiscovered subclasses within one or both of the known classes. Formally, this problem can be thought of as an unsupervised analysis nested within a supervised one. Here we take the view that the nested unsupervised analysis can successfully utilize information from the entire data set for constructing and/or selecting useful predictors. Specifically, we propose a mixture model approach to the nested unsupervised problem, where the supervised information is used to …

Tree-Based Multivariate Regression And Density Estimation With Right-Censored Data , Annette M. Molinaro, Sandrine Dudoit, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a unified strategy for estimator construction, selection, and performance assessment in the presence of censoring. This approach is entirely driven by the choice of a loss function for the full (uncensored) data structure and can be stated in terms of the following three main steps. (1) Define the parameter of interest as the minimizer of the expected loss, or risk, for a full data loss function chosen to represent the desired measure of performance. Map the full data loss function into an observed (censored) data loss function having the same expected value and leading to an efficient estimator …

Sheep Updates 2003 - Wool, Richard Coole, Stephen Gherardi, Chris Oldham, K. Curtis, J. Stanton, Johan Greeff, Chris Oldham, Mike Hyder, Beth Pagamoni, Andrew Thompson, Tom Plaisted, Kazue Tanaka, Mike Ferguson, Darren Gordon, Andrew Peterson, Peter Sommerville

Sheep Updates

This session covers six papers from different authors:1.‘Pastures from space’ - an opportunity to increase the profitability of sheep production Richard Coole Farmer Kojonup W.A. Stephen Gherardi Chris Oldham Department of Agriculture Western Australia 2. K. Curtis Department of Agriculture WA J. Stanton Department of Agriculture WA and Curtin University 3. Is selection of ewe hogget replacement on measurement profitable? Johan Greeff Department of Agriculture of Western Australia 4. Optimising the nutrition/grazing management of ewe flocks Chris Oldham Mike Hyder Beth Paganoni Department of Agriculture of Western Australia Andrew Thompson Department of Primary Industries, Hamilton, Victoria Tom Plaisted Kazue Tanaka …

Cluster Stability Scores For Microarray Data In Cancer Studies, Mark Smolkin, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

A potential benefit of profiling of tissue samples using microarrays is the generation of molecular fingerprints that will define subtypes of disease. Hierarchical clustering has been the primary analytical tool used to define disease subtypes from microarray experiments in cancer settings. Assessing cluster reliability poses a major complication in analyzing output from these procedures. While much work has been done on assessing the global question of number of clusters in a dataset, relatively little research exists on assessing stability of individual clusters. A potential benefit of profiling of tissue samples using microarrays is the generation of molecular fingerprints that will …

Supervised Detection Of Regulatory Motifs In Dna Sequences, Sunduz Keles, Mark J. Van Der Laan, Sandrine Dudoit, Biao Xing, Michael B. Eisen

U.C. Berkeley Division of Biostatistics Working Paper Series

Identification of transcription factor binding sites (regulatory motifs) is a major interest in contemporary biology. We propose a new likelihood based method, COMODE, for identifying structural motifs in DNA sequences. Commonly used methods (e.g. MEME, Gibbs sampler) model binding sites as families of sequences described by a position weight matrix (PWM) and identify PWMs that maximize the likelihood of observed sequence data under a simple multinomial mixture model. This model assumes that the positions of the PWM correspond to independent multinomial distributions with four cell probabilities. We address supervising the search for DNA binding sites using the information derived from …

Simple Parallel Statistical Computing In R, Anthony Rossini, Luke Tierney, Na Li

UW Biostatistics Working Paper Series

Theoretically, many modern statistical procedures are trivial to parallelize. However, practical deployment of a parallelized implementation which is robust and reliably runs on different computational cluster configurations and environments is far from trivial. We present a framework for the R statistical computing language that provides a simple yet powerful programming interface to a computational cluster. This interface allows the development of R functions that distribute independent computations across the nodes of the computational cluster. The resulting framework allows statisticians to obtain significant speed-ups for some computations at little additional development cost. The particular implementation can be deployed in heterogeneous computing …

Literate Statistical Practice, Anthony Rossini, Friedrich Leisch

UW Biostatistics Working Paper Series

Literate Statistical Practice (LSP, Rossini, 2001) describes an approach for creating self-documenting statistical results. It applies literate programming (Knuth, 1992) and related techniques in a natural fashion to the practice of statistics. In particular, documentation, specification, and descriptions of results are written concurrently with writing and evaluation of statistical programs. We discuss how and where LSP can be integrated into practice and illustrate this with an example derived from an actual statistical consulting project. The approach is simplified through the use of a comprehensive, open source toolset incorporating Noweb, Emacs Speaks Statistics (ESS), Sweave (Ramsey, 1994; Rossini, et al, 2002; …

Ibd Configuration Transition Matrices And Linkage Score Tests For Unilineal Relative Pairs, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

Properties of transition matrices between IBD configurations are derived for four general classes of unilineal relative pairs obtained from the grand-parent/ grand-child, half-sib, avuncular, and cousin relationships. In this setting, IBD configurations are defined as orbits of groups acting on a set of inheritance vectors. Properties of the transition matrix between IBD configurations at two linked loci are derived by relating its infinitesimal generator to the adjacency matrix of a quotient graph. The second largest eigenvalue of the infinitesimal generator and its multiplicity are key in determining the form of the transition matrix and of likelihood-based linkage tests such as …

Selecting Differentially Expressed Genes From Microarray Experiments, Margaret S. Pepe, Gary M. Longton, Garnet L. Anderson, Michel Schummer

UW Biostatistics Working Paper Series

High throughput technologies, such as gene expression arrays and protein mass spectrometry, allow one to simultaneously evaluate thousands of potential biomarkers that distinguish different tissue types. Of particular interest here is cancer versus normal organ tissues. We consider statistical methods to rank genes (or proteins) in regards to differential expression between tissues. Various statistical measures are considered and we argue that two measures related to the Receiver Operating Characteristic Curve are particularly suitable for this purpose. We also propose that sampling variability in the gene rankings be quantified and suggest using the “selection probability function”, the probability distribution of rankings …

Conservation And Restoration Of Pine Forest Genetic Resources In México, C. Sáenz-Romero, Amy E. Snively, R. Lindig-Cisneros

Student Published Works

Deforestation rates in México are about 670,000 ha/year. This threatens the richness of forest genetic resources in México, causing the disappearance of locally adapted populations and rare and endangered pine species. México is one of the six megadiverse countries in the world, with half of the world’s Pinus species. Pinus is one of the most economically and ecologically important forest genera in México. We suggest that delineation of seed zones and the establishment of a network of Forest Genetic Resource Conservation Units (FGRCUs), linked with forest management and ecological restoration programs will protect this valuable resource. We estimate that FGRCUs …

Phylogenomic Identification Of Five New Human Homologs Of The Dna Repair Enzyme Alkb, Michal A. Kurowski, Ashok S. Bhagwat, Grzegorz Papaj, Janusz M. Bujnicki

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Combination of biochemical and bioinformatic analyses led to the discovery of oxidative demethylation – a novel DNA repair mechanism catalyzed by the Escherichia coli AlkB protein and its two human homologs, hABH2 and hABH3. This discovery was based on the prediction made by Aravind and Koonin that AlkB is a member of the 2OG-Fe²⁺ oxygenase superfamily.

Results

In this article, we report identification and sequence analysis of five human members of the (2OG-Fe²⁺) oxygenase superfamily designated here as hABH4 through hABH8. These experimentally uncharacterized and poorly annotated genes were not associated with the AlkB family …

Ordering Genetic Algorithm Genomes With Reconstructability Analysis, Stephen Shervais, Martin Zwick

Complex Systems Faculty Publications and Presentations

The building block hypothesis implies that genetic algorithm effectiveness is influenced by the relative location of epistatic genes on the chromosome. We find that this influence exists, but depends on the generation in which it is measured. Early in the search process it may be more effective to have epistatic genes widely separated. Late in the search process, effectiveness is improved when they are close together. The early search effect is weak but still statistically significant; the late search effect is much stronger and plainly visible. We demonstrate both effects with a set of simple problems, and show that infonnation-theoretic …

A Neural Network Method For Protein Classification, Arie D. Jones

All-Inclusive List of Electronic Theses and Dissertations

The investigation detailed in this paper attempts to utilize a Leaming Vector Quantization network in order to classify a set of mitochondrial proteins based upon their amino acid sequence. The Learning Vector Quantization network uses a nearest neighbor approach to classification. Input vectors are fed into the network, which produces output vectors. Those output vectors are then matched by means of a distance bias to a corresponding classification vector. The learning and test sets consisted of thirteen similar mitochodrial proteins from seventy-two different species. This provided a pool of over nine hundred proteins to use. Half of the species were …

Mining Of Correlated Rules In Genome Sequences, L. Lin, L. Wong, Tze-Yun Leong, P. S. Lai

Research Collection School Of Computing and Information Systems

With the huge amount of data collected by scientists in the molecular genetics community in recent years, there exists a need to develop some novel algorithms based on existing data mining techniques to discover useful information from genome databases. We propose an algorithm that integrates the statistical method, association rule mining, and classification rule mining in the discovery of allelic combinations of genes that are peculiar to certain phenotypes of diseased patients.