Genetics Commons^™

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.

A Unifying Approach For Haplotype Analysis Of Quantitative Traits In Family-Based Association Studies: Testing And Estimating Gene-Environment Interactions With Complex Exposure Variables, Stijn Vansteelandt, Christoph Lange

COBRA Preprint Series

We propose robust and e±cient tests and estimators for gene-environment/gene-drug interactions in family-based association studies. The methodology is designed for studies in which haplotypes, quantitative pheno- types and complex exposure/treatment variables are analyzed. Using causal inference methodology, we derive family-based association tests and estimators for the genetic main effects and the interactions. The tests and estimators are robust against population admixture and strati¯cation without requiring adjustment for confounding variables. We illustrate the practical relevance of our approach by an application to a COPD study. The data analysis suggests a gene-environment interaction between a SNP in the Serpine gene and smok- …

Structural Inference In Transition Measurement Error Models For Longitudinal Data, Wenqin Pan, Xihong Lin, Donglin Zeng

Harvard University Biostatistics Working Paper Series

No abstract provided.

Nonparametric Regression Using Local Kernel Estimating Equations For Correlated Failure Time Data, Zhangsheng Yu, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

Causal Inference In Hybrid Intervention Trials Involving Treatment Choice, Qi Long, Rod Little, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

A Comparison Of Methods For Estimating The Causal Effect Of A Treatment In Randomized Clinical Trials Subject To Noncompliance, Rod Little, Qi Long, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

A Faster Circular Binary Segmentation Algorithm For The Analysis Of Array Cgh Data, E S. Venkatraman, Adam Olshen

Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series

Motivation: Array CGH technologies enable the simultaneous measurement of DNA copy number for thousands of sites on a genome. We developed the circular binary segmentation (CBS) algorithm to divide the genome into regions of equal copy number (Olshen {\it et~al}, 2004). The algorithm tests for change-points using a maximal $t$-statistic with a permutation reference distribution to obtain the corresponding $p$-value. The number of computations required for the maximal test statistic is $O(N^2),$ where $N$ is the number of markers. This makes the full permutation approach computationally prohibitive for the newer arrays that contain tens of thousands markers and highlights the …

Poor Performance Of Bootstrap Confidence Intervals For The Location Of A Quantitative Trait Loucs, Ani Manichaikul, Josee Dupuis, Saunak Sen, Karl W. Broman

Johns Hopkins University, Dept. of Biostatistics Working Papers

The aim of many genetic studies is to locate the genomic regions (called quantitative trait loci, QTLs) that contribute to variation in a quantitative trait (such as body weight). Confidence intervals for the locations of QTLs are particularly important for the design of further experiments to identify the gene or genes responsible for the effect. Likelihood support intervals are the most widely used method to obtain confidence intervals for QTL location, but the non-parametric bootstrap has also been recommended. Through extensive computer simulation, we show that bootstrap confidence intervals are poorly behaved and so should not be used in this …

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 …

The Role Of An Explicit Causal Framework In Affected Sib Pair Designs With Covariates , Constantine E. Frangakis, Fan Li, Betty Q. Doan

Johns Hopkins University, Dept. of Biostatistics Working Papers

The affected sib/relative pair (ASP/ARP) design is often used with covariates to find genes that can cause a disease in pathways other than through those covariates. However, such "covariates" can themselves have genetic determinants, and the validity of existing methods has so far only been argued under implicit assumptions. We propose an explicit causal formulation of the problem using potential outcomes and principal stratification. The general role of this formulation is to identify and separate the meaning of the different assumptions that can provide valid causal inference in linkage analysis. This separation helps to (a) develop better methods under explicit …

Feature-Specific Penalized Latent Class Analysis For Genomic Data, E. Andres Houseman, Brent A. Coull, Rebecca A. Betensky

Harvard University Biostatistics Working Paper Series

No abstract provided.

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 …

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 …

Searching For Differentially Expressed Gene Combinations, Marcel Dettling, Edward Gabrielson, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

Background: Comparison of mRNA expression levels across biological samples is a widely used approach in genomics. Available data-analytic tools for deriving comprehensive lists of differentially expressed genes rely on data summaries formed using each gene in isolation from others. These approaches ignore biological relationships among genes and may miss important biological insight provided by genomics data.

Methods: We propose a fast, easily interpretable and scalable approach for identifying pairs of genes that are differentially expressed across phenotypes or experimental conditions. These are defined as pairs for which there is detectable phenotype discrimination using the joint distribution, but not from either …

The Clustering Of Regression Models Method With Applications In Gene Expression Data, Li-Xuan Qin, Steven G. Self

UW Biostatistics Working Paper Series

Identification of differentially expressed genes and clustering of genes are two important and complementary objectives addressed with gene expression data. For the differential expression question, many "per-gene" analytic methods have been proposed. These methods can generally be characterized as using a regression function to independently model the observations for each gene; various adjustments for multiplicity are then used to interpret the statistical significance of these per-gene regression models over the collection of genes analyzed. Motivated by this common structure of per-gene models, we propose a new model-based clustering method -- the clustering of regression models method, which groups genes that …

Cluster Analysis Of Genomic Data With Applications In R, Katherine S. Pollard, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

In this paper, we provide an overview of existing partitioning and hierarchical clustering algorithms in R. We discuss statistical issues and methods in choosing the number of clusters, the choice of clustering algorithm, and the choice of dissimilarity matrix. In particular, we illustrate how the bootstrap can be employed as a statistical method in cluster analysis to establish the reproducibility of the clusters and the overall variability of the followed procedure. We also show how to visualize a clustering result by plotting ordered dissimilarity matrices in R. We present a new R package, hopach, which implements the hybrid clustering method, …

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 …

Effect Of Misreported Family History On Mendelian Mutation Prediction Models, Hormuzd A. Katki

Johns Hopkins University, Dept. of Biostatistics Working Papers

People with familial history of disease often consult with genetic counselors about their chance of carrying mutations that increase disease risk. To aid them, genetic counselors use Mendelian models that predict whether the person carries deleterious mutations based on their reported family history. Such models rely on accurate reporting of each member's diagnosis and age of diagnosis, but this information may be inaccurate. Commonly encountered errors in family history can significantly distort predictions, and thus can alter the clinical management of people undergoing counseling, screening, or genetic testing. We derive general results about the distortion in the carrier probability estimate …

Significance Analysis Of Time Course Microarray Experiments, John D. Storey, Wenzhong Xiao, Jeffrey T. Leek, Ronald G. Tompkins, Ron W. Davis

UW Biostatistics Working Paper Series

Characterizing the genome-wide dynamic regulation of gene expression is important and will be of much interest in the future. However, there is currently no established method for identifying differentially expressed genes in a time course study. Here we propose a significance method for analyzing time course microarray studies that can be applied to the typical types of comparisons and sampling schemes. This method is applied to two studies on humans. In one study, genes are identified that show differential expression over time in response to in vivo endotoxin administration. Using our method 7409 genes are called significant at a 1% …

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 …

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 …

Accuracy Of Msi Testing In Predicting Germline Mutations Of Msh2 And Mlh1: A Case Study In Bayesian Meta-Analysis Of Diagnostic Tests Without A Gold Standard, Sining Chen, Patrice Watson, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

Microsatellite instability (MSI) testing is a common screening procedure used to identify families that may harbor mutations of a mismatch repair gene and therefore may be at high risk for hereditary colorectal cancer. A reliable estimate of sensitivity and specificity of MSI for detecting germline mutations of mismatch repair genes is critical in genetic counseling and colorectal cancer prevention. Several studies published results of both MSI and mutation analysis on the same subjects. In this article we perform a meta-analysis of these studies and obtain estimates that can be directly used in counseling and screening. In particular we estimate the …

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 …