Genetics Commons^™

Semiparametric Quantitative-Trait-Locus Mapping: Ii. On Censored Age-At-Onset, Ying Qing Chen, Chengcheng Hu, Rongling Wu

U.C. Berkeley Division of Biostatistics Working Paper Series

In genetic studies, the variation in genotypes may not only affect different inheritance patterns in qualitative traits, but may also affect the age-at-onset as quantitative trait. In this article, we use standard cross designs, such as backcross or F2, to propose some hazard regression models, namely, the additive hazards model in quantitative trait loci mapping for age-at-onset, although the developed method can be extended to more complex designs. With additive invariance of the additive hazards models in mixture probabilities, we develop flexible semiparametric methodologies in interval regression mapping without heavy computing burden. A recently developed multiple comparison procedures is adapted …

Quantification And Visualization Of Ld Patterns And Identification Of Haplotype Blocks, Yan Wang, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

Classical measures of linkage disequilibrium (LD) between two loci, based only on the joint distribution of alleles at these loci, present noisy patterns. In this paper, we propose a new distance-based LD measure, R, which takes into account multilocus haplotypes around the two loci in order to exploit information from neighboring loci. The LD measure R yields a matrix of pairwise distances between markers, based on the correlation between the lengths of shared haplotypes among chromosomes around these markers. Data analysis demonstrates that visualization of LD patterns through the R matrix reveals more deterministic patterns, with much less noise, than …

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 …

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 …

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 …

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 …

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 …

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 …

Comparative Genomic Hybridization Array Analysis, Annette M. Molinaro, Mark J. Van Der Laan, Dan H. Moore

U.C. Berkeley Division of Biostatistics Working Paper Series

At the present time, there is increasing evidence that cancer may be regulated by the number of copies of genes in tumor cells. Through microarray technology it is now possible to measure the number of copies of thousands of genes and gene segments in samples of chromosomal DNA. Microarray comparative genomic hybridization (array CGH) provides the opportunity to both measure DNA sequence copy number gains and losses and map these aberrations to the genomic sequence. Gains can signify the over-expression of oncogenes, genes which stimulate cell growth and have become hyperactive, while losses can signify under-expression of tumor suppressor genes, …

A New Partitioning Around Medoids Algorithm, Mark J. Van Der Laan, Katherine S. Pollard, Jennifer Bryan

U.C. Berkeley Division of Biostatistics Working Paper Series

Kaufman & Rousseeuw (1990) proposed a clustering algorithm Partitioning Around Medoids (PAM) which maps a distance matrix into a specified number of clusters. A particularly nice property is that PAM allows clustering with respect to any specified distance metric. In addition, the medoids are robust representations of the cluster centers, which is particularly important in the common context that many elements do not belong well to any cluster. Based on our experience in clustering gene expression data, we have noticed that PAM does have problems recognizing relatively small clusters in situations where good partitions around medoids clearly exist. In this …

Identification Of Regulatory Elements Using A Feature Selection Method, Sunduz Keles, Mark J. Van Der Laan, Michael B. Eisen

U.C. Berkeley Division of Biostatistics Working Paper Series

Many methods have been described to identify regulatory motifs in the transcription control regions of genes that exhibit similar patterns of gene expression across a variety of experimental conditions. Here we focus on a single experimental condition, and utilize gene expression data to identify sequence motifs associated with genes that are activated under this experimental condition. We use a linear model with two way interactions to model gene expression as a function of sequence features (words) present in presumptive transcription control regions. The most relevant features are selected by a feature selection method called stepwise selection with monte carlo cross …

Approximation Methods For Singular Diffusions Arising In Genetics, Nacer E. Abrouk

Mathematical Sciences Technical Reports (MSTR)

Stochastic models in population genetics leading to diffusion equations are considered. When the drift and the square of the diffusion coefficients are polynomials, an infinite system of ordinary differential equations for the moments of the diffusion process can be derived using the Martingale property. An example is provided to show how the classical Fokker-Planck Equation approach may not be appropriate for this derivation. A Gauss-Galerkin method for approximating the laws of the diffusion, originally proposed by Dawson (1980), is examined. In the few special cases for which exact solutions are known, comparison shows that the method is accurate and the …