Biostatistics Commons^™

Bayesian Analytical Approaches For Metabolomics : A Novel Method For Molecular Structure-Informed Metabolite Interaction Modeling, A Novel Diagnostic Model For Differentiating Myocardial Infarction Type, And Approaches For Compound Identification Given Mass Spectrometry Data., Patrick J. Trainor

Electronic Theses and Dissertations

Metabolomics, the study of small molecules in biological systems, has enjoyed great success in enabling researchers to examine disease-associated metabolic dysregulation and has been utilized for the discovery biomarkers of disease and phenotypic states. In spite of recent technological advances in the analytical platforms utilized in metabolomics and the proliferation of tools for the analysis of metabolomics data, significant challenges in metabolomics data analyses remain. In this dissertation, we present three of these challenges and Bayesian methodological solutions for each. In the first part we develop a new methodology to serve a basis for making higher order inferences in metabolomics, …

Systematic Review And Meta-Analysis: Tuberculosis, Tnfα Inhibitors, And Crohn's Disease, Brent L. Cao

Honors Undergraduate Theses

Inflammation is often a protective reaction against harmful foreign agents. However, in many disease conditions, the mechanisms behind the inflammatory response are poorly understood. Often times, the inflammation causes adverse effects, such as joint pain, abdominal pain, fever, fatigue, and loss of appetite. Thus, many treatments aim to inhibit the inflammatory response in order to control adverse symptoms. Such treatments include TNFα inhibitors. However, a major risk associated with drugs inhibiting tumor necrosis factor alpha (TNFα) is serious infection, including tuberculosis (TB).

Anti-TNFα therapy is used to treat patients with Crohn’s disease, for which the risk of tuberculosis may be …

Functional Data Analysis Methods For Predicting Disease Status., Sarah Kendrick

Electronic Theses and Dissertations

Introduction: Differential scanning calorimetry (DSC) is used to determine thermally-induced conformational changes of biomolecules within a blood plasma sample. Recent research has indicated that DSC curves (or thermograms) may have different characteristics based on disease status and, thus, may be useful as a monitoring and diagnostic tool for some diseases. Since thermograms are curves measured over a range of temperature values, they are often considered as functional data. In this dissertation we propose and apply functional data analysis (FDA) techniques to analyze DSC data from the Lupus Family Registry and Repository (LFRR). The aim is to develop FDA methods to …

Testing The Independence Hypothesis Of Accepted Mutations For Pairs Of Adjacent Amino Acids In Protein Sequences, Jyotsna Ramanan, Peter Revesz

School of Computing: Faculty Publications

Evolutionary studies usually assume that the genetic mutations are independent of each other. However, that does not imply that the observed mutations are independent of each other because it is possible that when a nucleotide is mutated, then it may be biologically beneficial if an adjacent nucleotide mutates too. With a number of decoded genes currently available in various genome libraries and online databases, it is now possible to have a large-scale computer-based study to test whether the independence assumption holds for pairs of adjacent amino acids. Hence the independence question also arises for pairs of adjacent amino acids within …

Statistical Methods For Two Problems In Cancer Research: Analysis Of Rna-Seq Data From Archival Samples And Characterization Of Onset Of Multiple Primary Cancers, Jialu Li

Dissertations and Theses (Open Access)

My dissertation is focused on quantitative methodology development and application for two important topics in translational and clinical cancer research.

The first topic was motivated by the challenge of applying transcriptome sequencing (RNA-seq) to formalin-fixation and paraffin-embedding (FFPE) tumor samples for reliable diagnostic development. We designed a biospecimen study to directly compare gene expression results from different protocols to prepare libraries for RNA-seq from human breast cancer tissues, with randomization to fresh-frozen (FF) or FFPE conditions. To comprehensively evaluate the FFPE RNA-seq data quality for expression profiling, we developed multiple computational methods for assessment, such as the uniformity and continuity …

Network Exploration Of Correlated Multivariate Protein Data For Alzheimer's Disease Association, Matthew J. Lane

Theses

Alzheimer Disease (AD) is difficult to diagnose by using genetic testing or other traditional methods. Unlike diseases with simple genetic risk components, there exists no single marker determining as to whether someone will develop AD. Furthermore, AD is highly heterogeneous and different subgroups of individuals develop the disease due to differing factors. Traditional diagnostic methods using perceivable cognitive deficiencies are often too little too late due to the brain having suffered damage from decades of disease progression. In order to observe AD at early stages prior to the observation of cognitive deficiencies, biomarkers with greater accuracy are required. By using …

A Functional Data Analytic Approach For Region Level Differential Dna Methylation Detection, Mohamed Salem F. Milad

Doctoral Dissertations

"DNA methylation is an epigenetic modification that can alter gene expression without a DNA sequence change. The role of DNA methylation in biological processes and human health is important to understand, with many studies identifying associations between specific methylation patterns and diseases such as cancer. In mammals, DNA methylation almost always occurs when a methyl group attaches to a cytosine followed by a guanine (i.e. CpG dinucleotides) on the DNA sequence. Many statistical methods have been developed to test for a difference in DNA methylation levels between groups (e.g. healthy vs disease) at individual cytosines. Site level testing is often …

Homeolog Specific Expression Bias, Ronald D. Smith

Biology and Medicine Through Mathematics Conference

No abstract provided.

Hpcnmf: A High-Performance Toolbox For Non-Negative Matrix Factorization, Karthik Devarajan, Guoli Wang

COBRA Preprint Series

Non-negative matrix factorization (NMF) is a widely used machine learning algorithm for dimension reduction of large-scale data. It has found successful applications in a variety of fields such as computational biology, neuroscience, natural language processing, information retrieval, image processing and speech recognition. In bioinformatics, for example, it has been used to extract patterns and profiles from genomic and text-mining data as well as in protein sequence and structure analysis. While the scientific performance of NMF is very promising in dealing with high dimensional data sets and complex data structures, its computational cost is high and sometimes could be critical for …

Models For Hsv Shedding Must Account For Two Levels Of Overdispersion, Amalia Magaret

UW Biostatistics Working Paper Series

We have frequently implemented crossover studies to evaluate new therapeutic interventions for genital herpes simplex virus infection. The outcome measured to assess the efficacy of interventions on herpes disease severity is the viral shedding rate, defined as the frequency of detection of HSV on the genital skin and mucosa. We performed a simulation study to ascertain whether our standard model, which we have used previously, was appropriately considering all the necessary features of the shedding data to provide correct inference. We simulated shedding data under our standard, validated assumptions and assessed the ability of 5 different models to reproduce the …

Germline Mutation Detection In Next Generation Sequencing Data And Tp53 Mutation Carrier Probability Estimation For Li-Fraumeni Syndrome, Gang Peng

Dissertations and Theses (Open Access)

Next generation sequencing technology has been widely used in genomic analysis, but its application has been compromised by the missing true variants, especially when these variants are rare. We proposed a family-based variant calling method, FamSeq, integrating Mendelian transmission information with de novo mutation and sequencing data to improve the variant calling accuracy. We investigated the factors impacting the improvement of family-based variant calling in simulation data and validated it in real sequencing data. In both simulation and real data, FamSeq works better than the single individual based method.

In FamSeq, we implemented four different methods for the Mendelian genetic …

Fast, Accurate, And Reliable Molecular Docking With Quickvina 2, Amr Alhossary, Stephanus Daniel Handoko, Yuguang Mu, Chee-Keong Kwoh

Research Collection School Of Computing and Information Systems

Motivation: The need for efficient molecular docking tools for high-throughput screening is growing alongside the rapid growth of drug-fragment databases. AutoDock Vina ('Vina') is a widely used docking tool with parallelization for speed. QuickVina ('QVina 1') then further enhanced the speed via a heuristics, requiring high exhaustiveness. With low exhaustiveness, its accuracy was compromised. We present in this article the latest version of QuickVina ('QVina 2') that inherits both the speed of QVina 1 and the reliability of the original Vina.Results: We tested the efficacy of QVina 2 on the core set of PDBbind 2014. With the default exhaustiveness level …

Optcluster : An R Package For Determining The Optimal Clustering Algorithm And Optimal Number Of Clusters., Michael N. Sekula

Electronic Theses and Dissertations

Determining the best clustering algorithm and ideal number of clusters for a particular dataset is a fundamental difficulty in unsupervised clustering analysis. In biological research, data generated from Next Generation Sequencing technology and microarray gene expression data are becoming more and more common, so new tools and resources are needed to group such high dimensional data using clustering analysis. Different clustering algorithms can group data very differently. Therefore, there is a need to determine the best groupings in a given dataset using the most suitable clustering algorithm for that data. This paper presents the R package optCluster as an efficient …

Summary Of Survival Analysis With Sas Procedures., Derek Duane Childers 1990-

Electronic Theses and Dissertations

The research conducted for this thesis was performed to summarize some of the most commonly used survival analysis techniques as well as to create one macro that will provide the solutions for these techniques. Some of the techniques that this thesis focuses on are survival and hazard functions, mean and median survival times, life table, log rank test, proportional hazards/model building, and competing risk. To further analyze these survival analysis techniques I will use the Bone Marrow Transplantation for Leukemia dataset. This trial consists of either acute myelocytic leukemia (AML 99 patients) or acute lymphoblastic leukemia (ALL 38 patients). There …

Zero-Inflated Models To Identify Transcription Factor Binding Sites In Chip-Seq Experiments, Sameera Dhananjaya Viswakula

Mathematics & Statistics Theses & Dissertations

It is essential to determine the protein-DNA binding sites to understand many biological processes. A transcription factor is a particular type of protein that binds to DNA and controls gene regulation in living organisms. Chromatin immunoprecipitation followed by highthroughput sequencing (ChIP-seq) is considered the gold standard in locating these binding sites and programs use to identify DNA-transcription factor binding sites are known as peak-callers. ChIP-seq data are known to exhibit considerable background noise and other biases. In this study, we propose a negative binomial model (NB), a zero-inflated Poisson model (ZIP) and a zero-inflated negative binomial model (ZINB) for peak-calling. …

Spectral Gene Set Enrichment (Sgse), H Robert Frost, Zhigang Li, Jason H. Moore

Dartmouth Scholarship

Gene set testing is typically performed in a supervised context to quantify the association between groups of genes and a clinical phenotype. In many cases, however, a gene set-based interpretation of genomic data is desired in the absence of a phenotype variable. Although methods exist for unsupervised gene set testing, they predominantly compute enrichment relative to clusters of the genomic variables with performance strongly dependent on the clustering algorithm and number of clusters. We propose a novel method, spectral gene set enrichment (SGSE), for unsupervised competitive testing of the association between gene sets and empirical data sources. SGSE first computes …

Meta-Analysis Of Gene Expression Studies, Umaporn Siangphoe

Theses and Dissertations

Combining effect sizes from individual studies using random-effects models are commonly applied in high-dimensional gene expression data. However, unknown study heterogeneity can arise from inconsistency of sample qualities and experimental conditions. High heterogeneity of effect sizes can reduce statistical power of the models. We proposed two new methods for random effects estimation and measurements for model variation and strength of the study heterogeneity. We then developed a statistical technique to test for significance of random effects and identify heterogeneous genes. We also proposed another meta-analytic approach that incorporates informative weights in the random effects meta-analysis models. We compared the proposed …

Genetic Predictors Of Metabolic Side Effects Of Diuretic Therapy, Jorge L. Del Aguila

Dissertations and Theses (Open Access)

Thiazide diuretics are a recommended first-line monotherapy for hypertension (i.e.SBP>140 mmHg or DBP>90 mmHg). Even so, diuretics are associated with adverse metabolic side effects, such as hyperlipidemia, hyperglycemia and hypokalemia which increase the risk of developing type II diabetes. This thesis used three analytical strategies to identify and quantify genetic factors that contribute to the development of adverse metabolic effects due to thiazide diuretic treatment. I performed a genome-wide association study (GWAS) and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses …

Statistical Methods For Assessing Treatment Effects For Observational Studies., Kristopher C. Gardner 1984-

Electronic Theses and Dissertations

Though randomized clinical (RCTs) trials are the gold standard for comparing treatments, they are often infeasible or exclude clinically important subjects, or generally represent an idealized medical setting rather than real practice. Observational data provide an opportunity to study practice-based evidence, but also present challenges for analysis. Traditional statistical methods which are suitable for RCTs may be inadequate for the observational studies. In this project, four of the most popular statistical methods for observational studies: ANCOVA, propensity score matching, regression with the propensity score as a covariate, and instrumental variables (IV) are investigated through application to MarketScan insurance claims data. …

The Association Between The Il-1 Pathway, Isaac C. Wun

Dissertations and Theses (Open Access)

Cutaneous malignant melanoma (CMM) is a potentially lethal malignancy that warrants attention and further research, as it is known to that there is an increasing rate of incidence in theUnited States, and it is also known that exposure to UV light is its most crucial risk factor, and family history of melanoma is also an important risk factor. Melanoma is an aggressive and lethal cancer in humans. There are an estimated new 132,000 melanoma cases annually worldwide, and the trend has doubled in the past 20 years. However, attempts to treat melanoma have encountered considerable resistance and remained ineffective. The …

Methods For Integrative Analysis Of Genomic Data, Paul Manser

Theses and Dissertations

In recent years, the development of new genomic technologies has allowed for the investigation of many regulatory epigenetic marks besides expression levels, on a genome-wide scale. As the price for these technologies continues to decrease, study sizes will not only increase, but several different assays are beginning to be used for the same samples. It is therefore desirable to develop statistical methods to integrate multiple data types that can handle the increased computational burden of incorporating large data sets. Furthermore, it is important to develop sound quality control and normalization methods as technical errors can compound when integrating multiple genomic …

Estimation Of Variation For High-Throughput Molecular Biological Experiments With Small Sample Size, Danni Yu

Open Access Dissertations

Motivation: In the quantification of molecular components, a large variation can affect and even potentially mislead the biological conclusions. Meanwhile, the high-throughput experiments often involve a small number of samples due to the limitation of cost and time. In such cases, the stochastic information may dominate the outcome of an experiment because there may not be enough samples to present the true biological information. It is challenging to distinguish the changes in phenotype from the stochastic variation.

Methods: Since the biological molecules have been quantified with different technologies, different statistical methods are required. Focusing on three types of important high-throughput …

Compound Identification Using Penalized Linear Regression., Ruiqi Liu

Electronic Theses and Dissertations

In this study, we propose a new method for compound identification using penalized linear regression. Compound identification is often achieved by matching the experimental mass spectra to the mass spectra stored in a reference library based on mass spectral similarity. In the context of the linear regression, the response variable is an experimental mass spectrum (i.e., query) and all the compounds in the reference library are the independent variables. However, the number of compounds in the reference library is much larger than the range of m/z values so that the data become high dimensional data with suffering from singularity. For …

Development Of Novel Methods To Minimize The Impact Of Sequencing Errors In The Next-Generation Sequencing Data Analysis, Xiaofeng Zheng

Dissertations and Theses (Open Access)

Next-generation sequencing (NGS) technology has become a prominent tool in biological and biomedical research. However, NGS data analysis, such as de novo assembly, mapping and variants detection is far from maturity, and the high sequencing error-rate is one of the major problems. .

To minimize the impact of sequencing errors, we developed a highly robust and efficient method, MTM, to correct the errors in NGS reads. We demonstrated the effectiveness of MTM on both single-cell data with highly non-uniform coverage and normal data with uniformly high coverage, reflecting that MTM’s performance does not rely on the coverage of the sequencing …

Gulf-Wide Decreases In The Size Of Large Coastal Sharks Documented By Generations Of Fishermen, Sean P. Powers, F. Joel Frodrie, Steven B. Scyphers, J. Marcus Drymon, Robert L. Shipp, Gregory W. Stunz

University Faculty and Staff Publications

Large sharks are top predators in most coastal and marine ecosystems throughout the world, and evidence of their reduced prominence in marine ecosystems has been a serious concern for fisheries and ecosystem management. Unfortunately, quantitative data to document the extent, timing, and consequences of changes in shark populations are scarce, thwarting examination of long-term (decadal, century) trends, and reconstructions based on incomplete data sets have been the subject of debate. Absence of quantitative descriptors of past ecological conditions is a generic problem facing many fields of science but is particularly troublesome for fisheries scientists who must develop specific targets for …

A Study Of Cellular Calcium Dynamics In Culture Using Fluorescence Microscopy – A Statistical And Mathematical Approach, Richard Adekola Idowu

Doctoral Dissertations

Calcium in its ionic form is very dynamic, especially in excitable cells such as muscle and brain cells, moving from the high concentration exterior of the cell to much lower concentrations inside the cell, where calcium is used as a second messenger. In brain cells, and neurons especially, calcium is a key signaling ion involved in memory and learning with excitatory neurotransmitters such as glutamate turning neurons "on." Glutamate excites the neurons in part by causing large and dynamic changes in the intracellular calcium concentration. While these dynamics are essential for normal signaling in the brain, excessive and sustained elevations …

Dna Methylation Arrays As Surrogate Measures Of Cell Mixture Distribution, Eugene Houseman, William P. Accomando, Devin C. Koestler, Brock C. Christensen, Carmen J. Marsit

Dartmouth Scholarship

There has been a long-standing need in biomedical research for a method that quantifies the normally mixed composition of leukocytes beyond what is possible by simple histological or flow cytometric assessments. The latter is restricted by the labile nature of protein epitopes, requirements for cell processing, and timely cell analysis. In a diverse array of diseases and following numerous immune-toxic exposures, leukocyte composition will critically inform the underlying immuno-biology to most chronic medical conditions. Emerging research demonstrates that DNA methylation is responsible for cellular differentiation, and when measured in whole peripheral blood, serves to distinguish cancer cases from controls.

Secondary Structure Prediction Of Long Rna Sequences Based On Inversion Excursions And A Modularized Mapreduce Framework, Daniel Tesfai Yehdego

Open Access Theses & Dissertations

Ribonucleic acid (RNA) molecules and their secondary structures play important roles in many biological processes including gene expression and regulation. The genomes of many viruses are also RNA molecules. Since secondary structures are crucial for RNA functionality, computational predictions of the RNA secondary structures have been widely studied. However, the tremendous demands on computer memory and computing time for complex secondary structures limit the capability of existing thermodynamically based algorithms for structure predictions to handling only short RNA sequences with a few hundred bases. One approach to overcome this limitation is by first cutting long RNA sequences into shorter, non-overlapping …

Analysis Of Differential Gene Expression And Alternative Splicing In The Liver And Gastrointestinal Tract In The Lactating Rat, Antony Thomas Athippozhy

University of Kentucky Doctoral Dissertations

Rat exon microarrays were utilized to detect changes in mRNA expression and alternative splicing in the liver, duodenum, jejunum, and ileum of the lactating rat when compared to age-matched virgin controls. Analysis of data at the level of gene expression revealed differential expression of genes involved in cholesterol biosynthesis in each tissue examined, suggesting increased Sterol Response Element Binding Protein activity. We also detected decreased mRNA from components of the T-cell signaling pathway in the jejunum and ileum. We characterized expression of solute carrier and adenosine triphosphate binding cassette proteins. In addition to characterizing genes by pathway, we have also …

Minimum Description Length Measures Of Evidence For Enrichment, Zhenyu Yang, David R. Bickel

COBRA Preprint Series

In order to functionally interpret differentially expressed genes or other discovered features, researchers seek to detect enrichment in the form of overrepresentation of discovered features associated with a biological process. Most enrichment methods treat the p-value as the measure of evidence using a statistical test such as the binomial test, Fisher's exact test or the hypergeometric test. However, the p-value is not interpretable as a measure of evidence apart from adjustments in light of the sample size. As a measure of evidence supporting one hypothesis over the other, the Bayes factor (BF) overcomes this drawback of the p-value but lacks …