Medical Genetics Commons^™

Detecting Overlapping Gene Regions Using The U-Net Attention Mechanism, Samuel Lemma

All Graduate Theses, Dissertations, and Other Capstone Projects

The current issue of locating, diagnosing, and treating cancer and other diseases linked to specific target genes necessitates the creation of a reliable system for precisely identifying target genes that are initially extracted from a human chromosome. Current methodologies often suffer from overlapping gene regions in the target gene that occurs during the analysis process, which can have a substantial impact on the accuracy of the results. Our recommended approach, which was the appropriate model to apply for this particular problem, is set to enhance the analytical process by utilizing neural networks' U-Net with an attention mechanism. We were able …

The Ratio Method: Addressing Complex Tort Liability In The Fourth Industrial Revolution, Harrison C. Margolin, Grant H. Frazier

St. Mary's Law Journal

Emerging technologies of the Fourth Industrial Revolution show fundamental promise for improving productivity and quality of life, though their misuse may also cause significant social disruption. For example, while artificial intelligence will be used to accelerate society’s processes, it may also displace millions of workers and arm cybercriminals with increasingly powerful hacking capabilities. Similarly, human gene editing shows promise for curing numerous diseases, but also raises significant concerns about adverse health consequences related to the corruption of human and pathogenic genomes.

In most instances, only specialists understand the growing intricacies of these novel technologies. As the complexity and speed of …

Epigenome-Wide Association Study Of Kidney Function Identifies Trans-Ethnic And Ethnic-Specific Loci, Charles E. Breeze, Anna Batorsky, Mi Kyeong Lee, Mindy D. Szeto, Xiaoguang Xu, Daniel L. Mccartney, Rong Jiang, Amit Patki, Holly J. Kramer, James M. Eales, Laura Raffield, Leslie Lange, Ethan Lange, Peter Durda, Yongmei Liu, Russ P. Tracy, David Van Den Berg, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Mesa Multi-Omics Working Group, Kathryn L. Evans, William E. Kraus, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear …

Understanding The Effect Of Adaptive Mutations On The Three-Dimensional Structure Of Rna, Justin Cook

Undergraduate Research and Scholarship Symposium

Single-nucleotide polymorphisms (SNPs) are variations in the genome where one base pair can differ between individuals.¹ SNPs occur throughout the genome and can correlate to a disease-state if they occur in a functional region of DNA.¹According to the central dogma of molecular biology, any variation in the DNA sequence will have a direct effect on the RNA sequence and will potentially alter the identity or conformation of a protein product. A single RNA molecule, due to intramolecular base pairing, can acquire a plethora of 3-D conformations that are described by its structural ensemble. One SNP, rs12477830, which …

Subject Level Clustering Using A Negative Binomial Model For Small Transcriptomic Studies., Qian Li, Janelle R. Noel-Macdonnell, Devin C. Koestler, Ellen L. Goode, Brooke L. Fridley

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Unsupervised clustering represents one of the most widely applied methods in analysis of high-throughput 'omics data. A variety of unsupervised model-based or parametric clustering methods and non-parametric clustering methods have been proposed for RNA-seq count data, most of which perform well for large samples, e.g. N ≥ 500. A common issue when analyzing limited samples of RNA-seq count data is that the data follows an over-dispersed distribution, and thus a Negative Binomial likelihood model is often used. Thus, we have developed a Negative Binomial model-based (NBMB) clustering approach for application to RNA-seq studies.

RESULTS: We have developed a Negative …

Penalized Mixed-Effects Ordinal Response Models For High-Dimensional Genomic Data In Twins And Families, Amanda E. Gentry

Theses and Dissertations

The Brisbane Longitudinal Twin Study (BLTS) was being conducted in Australia and was funded by the US National Institute on Drug Abuse (NIDA). Adolescent twins were sampled as a part of this study and surveyed about their substance use as part of the Pathways to Cannabis Use, Abuse and Dependence project. The methods developed in this dissertation were designed for the purpose of analyzing a subset of the Pathways data that includes demographics, cannabis use metrics, personality measures, and imputed genotypes (SNPs) for 493 complete twin pairs (986 subjects.) The primary goal was to determine what combination of SNPs and …

The Battle Against Malaria: A Teachable Moment, Randy K. Schwartz

Journal of Humanistic Mathematics

Malaria has been humanity’s worst public health problem throughout recorded history. Mathematical methods are needed to understand which factors are relevant to the disease and to develop counter-measures against it. This article and the accompanying exercises provide examples of those methods for use in lower- or upper-level courses dealing with probability, statistics, or population modeling. These can be used to illustrate such concepts as correlation, causation, conditional probability, and independence. The article explains how the apparent link between sickle cell trait and resistance to malaria was first verified in Uganda using the chi-squared probability distribution. It goes on to explain …

User-Centered Design Of Multi-Gene Sequencing Panel Reports For Clinicians., Elizabeth Cutting, Meghan Banchero, Amber L. Beitelshees, James J. Cimino, Guilherme Del Fiol, Ayse P. Gurses, Mark A. Hoffman, Linda Jo Bone Jeng, Kensaku Kawamoto, Mark Kelemen, Harold Alan Pincus, Alan R. Shuldiner, Marc S. Williams, Toni I. Pollin, Casey Lynnette Overby

Manuscripts, Articles, Book Chapters and Other Papers

The objective of this study was to develop a high-fidelity prototype for delivering multi-gene sequencing panel (GS) reports to clinicians that simulates the user experience of a final application. The delivery and use of GS reports can occur within complex and high-paced healthcare environments. We employ a user-centered software design approach in a focus group setting in order to facilitate gathering rich contextual information from a diverse group of stakeholders potentially impacted by the delivery of GS reports relevant to two precision medicine programs at the University of Maryland Medical Center. Responses from focus group sessions were transcribed, coded and …

Functional Linear Models Extensions Uncover Pleiotropic Effects Of Chronic Pain Phenotypes, Dmitri V. Zaykin, L. Qing, G. D. Slade, R. Dubner, R. B. Fillingim, J. D. Greenspan, R. Ohrbach, W. Maixner, L. B. Diatchenko, Olga A. Vsevolozhskaya

Biostatistics Presentations

Growing scientific evidence suggests that intricate interactions of genetic risk factors with environmental exposures play a major role in the development of chronic pain conditions. In studies of relative contribution of an individual’s genetic composition to the perception of pain, the general characteristics of pain sensitivity are typically measured by a wide range of different, yet possibly etiologically related pain phenotypes. Testing each of these pain-perception traits individually is subject to problems of multiple testing and low statistical power. Furthermore, pain-related traits may share common etiology and comprise binary, categorical, and quantitative measurements. In the current study, we propose a …

Genetics Of Obesity In Starr County, Texas Mexican Americans, Heather M. Highland

Dissertations & Theses (Open Access)

Currently, over two-thirds of Americans are classified as over-weight or obese. Obesity increases risk for many other diseases including type 2 diabetes, heart disease, stroke, and cancer, making obesity the largest public health problem in America and most other Westernized nations. Hispanics have a higher rate of both obesity and type 2 diabetes, making them a particularly interesting population in which to study obesity. For the last 33 years, the Starr County Health Studies has collected an array of phenotypes and biological samples from residents of Starr County, along Texas-Mexico border. This study includes 825 subjects who were not known …

Data Mining The Functional Characterizations Of Proteins To Predict Their Cancer-Relatedness, Peter Revesz, Christopher Assi

School of Computing: Faculty Publications

This paper considers two types of protein data. First, data about protein function described in a number of ways, such as, GO terms and PFAM families. Second, data about whether individual proteins are experimentally associated with cancer by an anomalous elevation or lowering of their expressions within cancerous cells. We combine these two types of protein data and test whether the first type of data, that is, the functional descriptors, can predict the second type of data, that is, cancer-relatedness. By using data mining and machine learning, we derive a classifier algorithm that using only GO term and PFAM family …

Piscine Myocarditis Virus (Pmcv) In Wild Atlantic Salmon Salmo Salar, Torstein Tengs Dr.

Dr. Torstein Tengs

Cardiomyopathy syndrome (CMS) is a severe cardiac disease of sea-farmed Atlantic salmon Salmo salar L., but CMS-like lesions have also been found in wild Atlantic salmon. In 2010 a double-stranded RNA virus of the Totiviridae family, provisionally named piscine myocarditis virus (PMCV), was described as the causative agent of CMS. In the present paper we report the first detection of PMCV in wild Atlantic salmon. The study is based on screening of 797 wild Atlantic salmon by real-time RT-PCR. The samples were collected from 35 different rivers along the coast of Norway, and all individuals included in the study were …

Prevalence Of Tick Borne Encephalitis Virus In Tick Nymphs In Relation To Climatic Factors On The Southern Coast Of Norway, Torstein Tengs Dr.

Dr. Torstein Tengs

BACKGROUND

Tick-borne encephalitis (TBE) is among the most important vector borne diseases of humans in Europe and is currently identified as a major health problem in many countries. TBE endemic zones have expanded over the past two decades, as well as the number of reported cases within endemic areas. Multiple factors are ascribed for the increased incidence of TBE, including climatic change. The number of TBE cases has also increased in Norway over the past decade, and the human cases cluster along the southern coast of Norway. In Norway the distribution and prevalence of TBE virus (TBEV) in tick populations …

A Strain Of Piscine Myocarditis Virus (Pmcv) Infecting Argentina Silus (Ascanius), Torstein Tengs Dr.

Dr. Torstein Tengs

No abstract.

Quantification Of Piscine Reovirus (Prv) At Different Stages Of Atlantic Salmon Salmo Salar Production, Torstein Tengs Dr.

Dr. Torstein Tengs

The newly described piscine reovirus (PRV) appears to be associated with the development of heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon Salmo salar L. PRV seems to be ubiquitous among fish in Norwegian salmon farms, but high viral loads and tissue distribution support a causal relationship between virus and disease. In order to improve understanding of the distribution of PRV in the salmon production line, we quantified PRV by using real-time PCR on heart samples collected at different points in the life cycle from pre-smolts to fish ready for slaughter. PRV positive pre-smolts were found in about …

Genetic Studies Of Complex Human Diseases: Characterizing Snp-Disease Associations Using Bayesian Networks, Bing Han, Xue-Wen Chen, Zohreh Talebizadeh, Hua Xu

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Detecting epistatic interactions plays a significant role in improving pathogenesis, prevention, diagnosis, and treatment of complex human diseases. Applying machine learning or statistical methods to epistatic interaction detection will encounter some common problems, e.g., very limited number of samples, an extremely high search space, a large number of false positives, and ways to measure the association between disease markers and the phenotype.

Results

To address the problems of computational methods in epistatic interaction detection, we propose a score-based Bayesian network structure learning method, EpiBN, to detect epistatic interactions. We apply the proposed method to both simulated datasets and …

Down-Weighting Overlapping Genes Improves Gene Set Analysis, Adi Tarca, Sorin Draghici, Gaurav Bhatti, Roberto Romero

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The identification of gene sets that are significantly impacted in a given condition based on microarray data is a crucial step in current life science research. Most gene set analysis methods treat genes equally, regardless how specific they are to a given gene set.

Results

In this work we propose a new gene set analysis method that computes a gene set score as the mean of absolute values of weighted moderated gene t-scores. The gene weights are designed to emphasize the genes appearing in few gene sets, versus genes that appear in many gene sets. We demonstrate the …

James-Stein Estimation And The Benjamini-Hochberg Procedure, Debashis Ghosh

Debashis Ghosh

For the problem of multiple testing, the Benjamini-Hochberg (B-H) procedure has become a very popular method in applications. Based on a spacings theory representation of the B-H procedure, we are able to motivate the use of shrinkage estimators for modifying the B-H procedure. Several generalizations in the paper are discussed, and the methodology is applied to real and simulated datasets.

Shrinkage In Adaptive Procedures For False Discovery Rate Estimation In Multiple Testing: Structure And Synthesis, Debashis Ghosh

Debashis Ghosh

There has been much interest in the study of adaptive estimation procedures for controlling the false discovery rate (FDR). In this article, we take the direct approach to estimation of FDR of Storey (2002) and show how it can reexpressed as a particular type of shrinkage estimator. This representation leads to natural conditions on finite-sample FDR control for a general class of shrinkage estimators. In addition, many previous proposals from the literature can be unified under this framework for which finite-sample FDR results can be developed. Some asymptotic results are also provided.

Structural Properties Of Thermoresponsive Poly(N-Isopropylacrylamide)-Poly(Ethyleneglycol) Microgels, J. Clara-Rahola, A. Fernandez-Nieves, B. Sierra-Martin, A. B. South, L. Andrew Lyon, J. Kohlbrecher, A. F. Barbero

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The application of RNA interference to treat disease is an important yet challenging concept in modern medicine. In particular, small interfering RNA (siRNA) have shown tremendous promise in the treatment of cancer. However, siRNA show poor pharmacological properties, which presents a major hurdle for effective disease treatment especially through intravenous delivery routes. In response to these shortcomings, a variety of nanoparticle carriers have emerged, which are designed to encapsulate, protect, and transport siRNA into diseased cells. To be effective as carrier vehicles, nanoparticles must overcome a series of biological hurdles throughout the course of delivery. As a result, one promising …

Gene By Bmi Interactions Influencing C-Reactive Protein Levels In European-Americans, Sarah Tudor

Dissertations & Theses (Open Access)

C-Reactive Protein (CRP) is a biomarker indicating tissue damage, inflammation, and infection. High-sensitivity CRP (hsCRP) is an emerging biomarker often used to estimate an individual’s risk for future coronary heart disease (CHD). hsCRP levels falling below 1.00 mg/l indicate a low risk for developing CHD, levels ranging between 1.00 mg/l and 3.00 mg/l indicate an elevated risk, and levels exceeding 3.00 mg/l indicate high risk. Multiple Genome-Wide Association Studies (GWAS) have identified a number of genetic polymorphisms which influence CRP levels. SNPs implicated in such studies have been found in or near genes of interest including: CRP, APOE, APOC, IL-6, …

A Supermatrix Analysis Of Genomic, Morphological, And Paleontological Data From Crown Cetacea, Jonathan H. Geisler, Michael R. Mcgowen, Guang Yang, John Gatesy

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Cetacea (dolphins, porpoises, and whales) is a clade of aquatic species that includes the most massive, deepest diving, and largest brained mammals. Understanding the temporal pattern of diversification in the group as well as the evolution of cetacean anatomy and behavior requires a robust and well-resolved phylogenetic hypothesis. Although a large body of molecular data has accumulated over the past 20 years, DNA sequences of cetaceans have not been directly integrated with the rich, cetacean fossil record to reconcile discrepancies among molecular and morphological characters.

Results

We combined new nuclear DNA sequences, including segments of six genes (~2800 …

Bio::Phylo-Phyloinformatic Analysis Using Perl, Rutger A. Vos, Jason Caravas, Klaas Hartmann, Mark A. Jensen, Chase Miller

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Phyloinformatic analyses involve large amounts of data and metadata of complex structure. Collecting, processing, analyzing, visualizing and summarizing these data and metadata should be done in steps that can be automated and reproduced. This requires flexible, modular toolkits that can represent, manipulate and persist phylogenetic data and metadata as objects with programmable interfaces.

Results

This paper presents Bio::Phylo, a Perl5 toolkit for phyloinformatic analysis. It implements classes and methods that are compatible with the well-known BioPerl toolkit, but is independent from it (making it easy to install) and features a richer API and a data model that is …

Prevalence Of Piscine Myocarditis Virus (Pmcv) In Marine Fish Species, Torstein Tengs Dr.

Dr. Torstein Tengs

No abstract.

Generalized Benjamini-Hochberg Procedures Using Spacings, Debashis Ghosh

Debashis Ghosh

For the problem of multiple testing, the Benjamini-Hochberg (B-H) procedure has become a very popular method in applications. We show how the B-H procedure can be interpreted as a test based on the spacings corresponding to the p-value distributions. Using this equivalence, we develop a class of generalized B-H procedures that maintain control of the false discovery rate in finite-samples. We also consider the effect of correlation on the procedure; simulation studies are used to illustrate the methodology.

A Causal Framework For Surrogate Endpoints With Semi-Competing Risks Data, Debashis Ghosh

Debashis Ghosh

In this note, we address the problem of surrogacy using a causal modelling framework that differs substantially from the potential outcomes model that pervades the biostatistical literature. The framework comes from econometrics and conceptualizes direct effects of the surrogate endpoint on the true endpoint. While this framework can incorporate the so-called semi-competing risks data structure, we also derive a fundamental non-identifiability result. Relationships to existing causal modelling frameworks are also discussed.

Propensity Score Modelling In Observational Studies Using Dimension Reduction Methods, Debashis Ghosh

Debashis Ghosh

Conditional independence assumptions are very important in causal inference modelling as well as in dimension reduction methodologies. These are two very strikingly different statistical literatures, and we study links between the two in this article. The concept of covariate sufficiency plays an important role, and we provide theoretical justication when dimension reduction and partial least squares methods will allow for valid causal inference to be performed. The methods are illustrated with application to a medical study and to simulated data.

A Novel Totivirus And Piscine Reovirus (Prv) In Atlantic Salmon (Salmo Salar) With Cardiomyopathy Syndrome (Cms), Torstein Tengs

Dr. Torstein Tengs

BACKGROUNDCardiomyopathy syndrome (CMS) is a severe disease affecting large farmed Atlantic salmon. Mortality often appears without prior clinical signs, typically shortly prior to slaughter. We recently reported the finding and the complete genomic sequence of a novel piscine reovirus (PRV), which is associated with another cardiac disease in Atlantic salmon; heart and skeletal muscle inflammation (HSMI). In the present work we have studied whether PRV or other infectious agents may be involved in the etiology of CMS.RESULTSUsing high throughput sequencing on heart samples from natural outbreaks of CMS and from fish experimentally challenged with material from fish diagnosed with CMS …

Heart And Skeletal Muscle Inflammation Of Farmed Salmon Is Associated With Infection With A Novel Reovirus, Torstein Tengs

Dr. Torstein Tengs

Atlantic salmon (Salmo salar L.) mariculture has been associated with epidemics of infectious diseases that threaten not only local production, but also wild fish coming into close proximity to marine pens and fish escaping from them. Heart and skeletal muscle inflammation (HSMI) is a frequently fatal disease of farmed Atlantic salmon. First recognized in one farm in Norway in 1999, HSMI was subsequently implicated in outbreaks in other farms in Norway and the United Kingdom. Although pathology and disease transmission studies indicated an infectious basis, efforts to identify an agent were unsuccessful. Here we provide evidence that HSMI is associated …

Non-Prejudiced Detection And Characterization Of Genetic Modifications, Torstein Tengs

Dr. Torstein Tengs

The application of gene technology is becoming widespread much thanks to the rapid increase in technology, resource, and knowledge availability. Consequently, the diversity and number of genetically modified organisms (GMOs) that may find their way into the food chain or the environment, intended or unintended, is rapidly growing. From a safety point of view the ability to detect and characterize in detail any GMO, independent of publicly available information, is fundamental. Pre-release risk assessments of GMOs are required in most jurisdictions and are usually based on application of technologies with limited ability to detect unexpected rearrangements and insertions. We present …