Statistical Models Commons^™

Mechanistic Home Range Models And Resource Selection Analysis: A Reconciliation And Unification, Paul R. Moorcroft, Alex Barnett

Dartmouth Scholarship

In the three decades since its introduction, resource selection analysis (RSA) has become a widespread method for analyzing spatial patterns of animal relocations obtained from telemetry studies. Recently, mechanistic home range models have been proposed as an alternative framework for studying patterns of animal space-use. In contrast to RSA models, mechanistic home range models are derived from underlying mechanistic descriptions of individual movement behavior and yield spatially explicit predictions for patterns of animal space-use. In addition, their mechanistic underpinning means that, unlike RSA, mechanistic home range models can also be used to predict changes in space-use following perturbation. In this …

Assessing Population Level Genetic Instability Via Moving Average, Samuel Mcdaniel, Rebecca Betensky, Tianxi Cai

Harvard University Biostatistics Working Paper Series

No abstract provided.

The Time Invariance Principle, Ecological (Non)Chaos, And A Fundamental Pitfall Of Discrete Modeling, Bo Deng

Department of Mathematics: Faculty Publications

This paper is to show that most discrete models used for population dynamics in ecology are inherently pathological that their predications cannot be independently verified by experiments because they violate a fundamental principle of physics. The result is used to tackle an on-going controversy regarding ecological chaos. Another implication of the result is that all continuous dynamical systems must be modeled by differential equations. As a result it suggests that researches based on discrete modeling must be closely scrutinized and the teaching of calculus and differential equations must be emphasized for students of biology.

Semiparametric Regression Of Multi-Dimensional Genetic Pathway Data: Least Squares Kernel Machines And Linear Mixed Models, Dawei Liu, Xihong Lin, Debashis Ghosh

Harvard University Biostatistics Working Paper Series

No abstract provided.

Multiple Tests Of Association With Biological Annotation Metadata, Sandrine Dudoit, Sunduz Keles, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a general and formal statistical framework for the multiple tests of associations between known fixed features of a genome and unknown parameters of the distribution of variable features of this genome in a population of interest. The known fixed gene-annotation profiles, corresponding to the fixed features of the genome, may concern Gene Ontology (GO) annotation, pathway membership, regulation by particular transcription factors, nucleotide sequences, or protein sequences. The unknown gene-parameter profiles, corresponding to the variable features of the genome, may be, for example, regression coefficients relating genome-wide transcript levels or DNA copy numbers to possibly censored biological and …

A Pseudolikelihood Approach For Simultaneous Analysis Of Array Comparative Genomic Hybridizations (Acgh), David A. Engler, Gayatry Mohapatra, David N. Louis, Rebecca Betensky

Harvard University Biostatistics Working Paper Series

DNA sequence copy number has been shown to be associated with cancer development and progression. Array-based Comparative Genomic Hybridization (aCGH) is a recent development that seeks to identify the copy number ratio at large numbers of markers across the genome. Due to experimental and biological variations across chromosomes and across hybridizations, current methods are limited to analyses of single chromosomes. We propose a more powerful approach that borrows strength across chromosomes and across hybridizations. We assume a Gaussian mixture model, with a hidden Markov dependence structure, and with random effects to allow for intertumoral variation, as well as intratumoral clonal …

Application Of A Multiple Testing Procedure Controlling The Proportion Of False Positives To Protein And Bacterial Data, Merrill D. Birkner, Alan E. Hubbard, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Simultaneously testing multiple hypotheses is important in high-dimensional biological studies. In these situations, one is often interested in controlling the Type-I error rate, such as the proportion of false positives to total rejections (TPPFP) at a specific level, alpha. This article will present an application of the E-Bayes/Bootstrap TPPFP procedure, presented in van der Laan et al. (2005), which controls the tail probability of the proportion of false positives (TPPFP), on two biological datasets. The two data applications include firstly, the application to a mass-spectrometry dataset of two leukemia subtypes, AML and ALL. The protein data measurements include intensity and …

Test Statistics Null Distributions In Multiple Testing: Simulation Studies And Applications To Genomics, Katherine S. Pollard, Merrill D. Birkner, Mark J. Van Der Laan, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

Multiple hypothesis testing problems arise frequently in biomedical and genomic research, for instance, when identifying differentially expressed or co-expressed genes in microarray experiments. We have developed generally applicable resampling-based single-step and stepwise multiple testing procedures (MTP) for control of a broad class of Type I error rates, defined as tail probabilities and expected values for arbitrary functions of the numbers of false positives and rejected hypotheses (Dudoit and van der Laan, 2005; Dudoit et al., 2004a,b; Pollard and van der Laan, 2004; van der Laan et al., 2005, 2004a,b). As argued in the early article of Pollard and van der …

New Statistical Paradigms Leading To Web-Based Tools For Clinical/Translational Science, Knut M. Wittkowski

COBRA Preprint Series

As the field of functional genetics and genomics is beginning to mature, we become confronted with new challenges. The constant drop in price for sequencing and gene expression profiling as well as the increasing number of genetic and genomic variables that can be measured makes it feasible to address more complex questions. The success with rare diseases caused by single loci or genes has provided us with a proof-of-concept that new therapies can be developed based on functional genomics and genetics.

Common diseases, however, typically involve genetic epistasis, genomic pathways, and proteomic pattern. Moreover, to better understand the underlying biologi-cal …

A Bayesian Method For Finding Interactions In Genomic Studies, Wei Chen, Debashis Ghosh, Trivellore E. Raghuanthan, Sharon Kardia

The University of Michigan Department of Biostatistics Working Paper Series

An important step in building a multiple regression model is the selection of predictors. In genomic and epidemiologic studies, datasets with a small sample size and a large number of predictors are common. In such settings, most standard methods for identifying a good subset of predictors are unstable. Furthermore, there is an increasing emphasis towards identification of interactions, which has not been studied much in the statistical literature. We propose a method, called BSI (Bayesian Selection of Interactions), for selecting predictors in a regression setting when the number of predictors is considerably larger than the sample size with a focus …

Finding Cancer Subtypes In Microarray Data Using Random Projections, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

One of the benefits of profiling of cancer samples using microarrays is the generation of molecular fingerprints that will define subtypes of disease. Such subgroups have typically been found in microarray data using hierarchical clustering. A major problem in interpretation of the output is determining the number of clusters. We approach the problem of determining disease subtypes using mixture models. A novel estimation procedure of the parameters in the mixture model is developed based on a combination of random projections and the expectation-maximization algorithm. Because the approach is probabilistic, our approach provides a measure for the number of true clusters …

Semiparametric Quantitative-Trait-Locus Mapping: I. On Functional Growth Curves, Ying Qing Chen, Rongling Wu

U.C. Berkeley Division of Biostatistics Working Paper Series

The genetic study of certain quantitative traits in growth curves as a function of time has recently been of major scientific interest to explore the developmental evolution processes of biological subjects. Various parametric approaches in the statistical literature have been proposed to study the quantitative-trait-loci (QTL) mapping of the growth curves as multivariate outcomes. In this article, we view the growth curves as functional quantitative traits and propose some semiparametric models to relax the strong parametric assumptions which may not be always practical in reality. Appropriate inference procedures are developed to estimate the parameters of interest which characterise the possible …

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 …

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 …

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 …

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 …

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 …