Medicine and Health Sciences Commons^™

Detection Of Genes Influencing Chronic And Mendelian Disease Via Loss-Of-Function Variation, Alexander H. Li

Dissertations and Theses (Open Access)

A typical human exome harbors dozens of loss-of-function (LOF) variants predicted to severely disrupt or abolish gene function. These variants are enriched at the extremely rare end of the allele frequency spectrum (< 0.1%), suggesting purifying selection against these sites. However, most previous population-based sequencing studies have not included analysis of genotype-phenotype relationships with LOF variants. Thus, the contribution of LOF variation to health and disease within the general population remains largely uncharacterized.

Using whole exome sequence from 8,554 participants in the Atherosclerosis Risk in Communities (ARIC) study, we explored the impact of LOF variation on a broad spectrum of human phenotypes. First, we selected 20 common chronic disease risk factor phenotypes and performed gene-based association tests. Analysis of this sample verified two relationships in well-studied genes (PCSK9 and APOC3) and identified eight new loci. Novel relationships included …

Computational Modeling Of Rna-Small Molecule And Rna-Protein Interactions, Lu Chen

Dissertations and Theses (Open Access)

The past decade has witnessed an era of RNA biology; despite the considerable discoveries nowadays, challenges still remain when one aims to screen RNA-interacting small molecule or RNA-interacting protein. These challenges imply an immediate need for cost-efficient while predictive computational tools capable of generating insightful hypotheses to discover novel RNA-interacting small molecule or RNA-interacting protein. Thus, we implemented novel computational models in this dissertation to predict RNA-ligand interactions (Chapter 1) and RNA-protein interactions (Chapter 2).

Targeting RNA has not garnered comparable interest as protein, and is restricted by lack of computational tools for structure-based drug design. To test the potential …

Secretion Of Heat-Labile Enterotoxin By Porcine-Origin Enterotoxigenic Escherichia Coli And Relation To Virulence, Prageeth Rukshan Wijemanne

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

Heat-labile enterotoxin (LT) is an important virulence factor secreted by some strains of porcine-origin enterotoxigenic Escherichia coli (pETEC). The prototypic human-origin strain H10407 secretes LT via a type II secretion system (T2SS), but its presence or importance in pETEC has not been established. Exposure of pETEC to glucose has been shown to result in different secretion levels of LT. Furthermore, the relationship between the level of LT secreted and the virulence potential of the respective pETEC strain has not been established. To determine the relationship between the capacity to secrete LT and virulence in wild-type (WT) pETEC, 16 strains isolated …

Measuring Single Cell Responses To Lapatinib In A Heterogeneous Population, Preety Priya

Dissertations and Theses (Open Access)

Cancer is notonedisease butasaga of diseases and is the outcome of disturbed homeostasis in the normal cells due to the deregulation of its genetic makeup. With advent of technologies thatallowdetailed molecular characterizationoftumors, targeted therapies have emerged as a more promising and specific mode of treatment. However, a major challenge with targeted therapy is the acquired resistance in the cancer cells to these therapies, quite often very rapidly in the course of a few months. One of the major targets in cancer has been the EGFR/ErbB2 network in breast and other cancer types. Prior work from our lab and others have …

A Hierarchical Graph For Nucleotide Binding Domain 2, Samuel Kakraba

Electronic Theses and Dissertations

One of the most prevalent inherited diseases is cystic fibrosis. This disease is caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is known to function as a chloride channel that regulates the viscosity of mucus that lines the ducts of a number of organs. Generally, most of the prevalent mutations of CFTR are located in one of two nucleotide binding domains, namely, the nucleotide binding domain 1 (NBD1). However, some mutations in nucleotide binding domain 2 (NBD2) can equally cause cystic fibrosis. In this work, a hierarchical graph is built for NBD2. …

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 …

Enabling Real-Time Ultrasound Imaging Of Soft Tissue Mechanical Properties By Simplification Of The Shear Wave Motion Equation, Aaron J. Engel, Gregory R. Bashford

Biomedical Imaging and Biosignal Analysis Laboratory

Ultrasound based shear wave elastography (SWE) is a technique used for non-invasive characterization and imaging of soft tissue mechanical properties. Robust estimation of shear wave propagation speed is essential for imaging of soft tissue mechanical properties. In this study we propose to estimate shear wave speed by inversion of the firstorder wave equation following directional filtering. This approach relies on estimation of first-order derivatives which allows for accurate estimations using smaller smoothing filters than when estimating second-order derivatives. The performance was compared to three current methods used to estimate shear wave propagation speed: direct inversion of the wave equation (DIWE), …

Functional Transcranial Doppler Ultrasound For High Temporal Resolution Measurement Of Lateralization In Visual Memory And Visual Search Cognitive Tasks, B. Hage, M. Alwatban, E. Barney, M. Mills, M. Dodd, E. Truemper, Gregory R. Bashford

Biomedical Imaging and Biosignal Analysis Laboratory

Functional transcranial Doppler ultrasound (fTCD) is a noninvasive sensing modality that measures blood flow velocities in cerebral arteries (CBFV) with high temporal resolution. Few studies have examined the relationship of CBFV change during visual search and visual memory cognitive tasks. Here a protocol to compare lateralization between these two similar tasks using fTCD is demonstrated. Thirteen healthy volunteers were shown visual scenes on a computer and performed visual search and visual memory tasks while CBFV in the bilateral middle cerebral arteries was monitored with fTCD. Each subject completed 40 trials, consisting of baseline, calibration, instruction, and task periods. Lateralization was …

Evaluation Of The System Attributes Of Timeliness And Completeness Of The West Virginia Electronic Disease Surveillance System' Nationaledss Based System, Rebecca Lee Fahey

Walden Dissertations and Doctoral Studies

Despite technological advances in public health informatics, the evaluation of infectious

disease surveillance systems data remains incomplete. In this study, a thorough

evaluation was performed of the West Virginia Electronic Disease Surveillance System

(WVEDSS, 2007-2010) and the West Virginia Electronic Disease Surveillance System NationalEDSS -Based System (WVEDSS-NBS; March 2012 - March 2014) for Category II infectious diseases in West Virginia. The purpose was to identify key areas in the surveillance system process from disease diagnosis to disease prevention that need improvement. Grounded in the diffusion of innovation theory, a quasi-experimental, interrupted, time-series design was used to evaluate the 2 data …

Dysregulation Of Micrornas In Blood As Biomarkers For Diagnosing Prostate Cancer, Rhonda W. Daniel

Theses and Dissertations

Prostate cancer is the most common noncutaneous cancer among men, yet current diagnostic methods are insufficient and more reliable diagnostic markers need to be developed. The answer that can bridge this gap and enable more efficient diagnoses may lie in microRNAs. These small, single stranded RNA molecules impact protein expression at the translational level and regulate important cellular pathways. Dysregulation of these small RNA molecules can have tumorigenic effects on cells and lead to many types of cancers.

Currently the Prostate-Stimulating Antigen (PSA) is used as a diagnostic marker for prostate cancer. However, many factors can elevate PSA levels such …

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 …

Named Entity Recognition In Chinese Clinical Text, Jianbo Lei

Dissertations and Theses (Open Access)

Objective: Named entity recognition (NER) is one of the fundamental tasks in natural language processing (NLP). In the medical domain, there have been a number of studies on NER in English clinical notes; however, very limited NER research has been done on clinical notes written in Chinese. The goal of this study is to develop corpora, methods, and systems for NER in Chinese clinical text.

Materials and methods: To study entities in Chinese clinical text, we started with building annotated clinical corpora in Chinese. We developed an NER annotation guideline in Chinese by extending the one used in the 2010 …

Design And Development Of A Linked Open Data-Based Health Information Representation And Visualization System: Potentials And Preliminary Evaluation, Binyam Tilahun, Tomi Kauppinen, Carsten Keßler, Fleur Fritz

Publications and Research

Background: Healthcare organizations around the world are challenged by pressures to reduce cost, improve coordination and outcome, and provide more with less. This requires effective planning and evidence-based practice by generating important information from available data. Thus, flexible and user-friendly ways to represent, query, and visualize health data becomes increasingly important. International organizations such as the World Health Organization (WHO) regularly publish vital data on priority health topics that can be utilized for public health policy and health service development. However, the data in most portals is displayed in either Excel or PDF formats, which makes information discovery and reuse …

Applying Novel Tree-Based Frameworks To Big Data For Classification Of Heart Failure Patients And Prediction Of Clinical Responses, Yan Zhang, Nicholas Downing, Emily Bucholz, Suganthi Balasubramanian, Shu-Xia Li, Tara Liptak, Harlan Krumholz, Mark Gerstein

Yale Day of Data

Over 5 million Americans suffer from heart failure, a condition with a 5-year survival that eclipses all cancers apart from that of lung cancer. Conventional understanding of heart failure is simplistic: it is viewed as a single syndrome, despite real heterogeneity. In addition, models predicting outcomes focus on dichotomous results, like 30-day readmission. A novel approach to classification of heart failure may improve our ability to target interventions, improve patient experiences, and predict outcomes.

The Healthcare Cost and Utilization Project is a family of administrative claims databases that describes patient demographics, comorbidities, procedures, acute care utilization and outcomes, such as …

Mapping The Human Vasculature By In Vivo Phage Display, Julianna Bronk

Dissertations and Theses (Open Access)

In vivo phage display screenings by intravenous injection of a random phage-displayed peptide library allow for the selection of peptides that localize to specific vascular beds. At the University of Texas MD Anderson Cancer Center, we have had the opportunity to perform phage display screenings in cancer patients in order to select for cancer specific targets directly in humans. These targets serve to define biochemical diversity of endothelial cell surfaces and can be validated and explored towards the design of vascular-targeted pharmacology. In the most recent patient screen, samples were recovered from hepatocellular carcinoma (HCC) as well as 26 additional …

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 …

Genomic Characterization Of Polyps In Familial Adenomatous Polyposis Patients And Identification Of Candidate Chemopreventive Drugs, Francis A. San Lucas

Dissertations and Theses (Open Access)

Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by APC germline mutations and the development of hundreds to thousands of premalignant adenomas in the gastrointestinal tract at a young age. If left untreated, these patients inevitably develop colon cancer (CRC) and small bowel tumors. We performed exome sequencing of samples from 12 FAP patients to characterize adenomas and to identify candidate genes of adenoma development that may serve as potential targets for chemoprevention drug development. From each patient, a blood and at least one polyp were sequenced with a total of 25 polyps analyzed. In some cases, normal …

Integrating Domain Knowledge To Improve Signal Detection From Electronic Health Records For Pharmacovigilance, Ning Shang

Dissertations and Theses (Open Access)

The intent of this dissertation is to make a contribution to the field of pharmacovigilance. Pharmacovigilance, also known as post-marketing drug surveillance, is the process of continued monitoring for adverse drug reactions (ADRs) after drugs are released into the market. An ADR is a harmful or unpleasant reaction related to the use of a medical product. ADRs were reported to be between the fourth and sixth leading cause of death in the United States in 1994, accounting for 3-7% of medical hospital admissions. On account of the practice of pharmacovigilance, Vioxx (Rofecoxib) and Avandia (Rosiglitazone) are examples of high profile …

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 …

Structure Based Prediction Of Drug-Protein Interactions At Allosteric Sites: To Wards Direct Inhibition Of The Ras Oncogene, Harrison Hocker

Dissertations and Theses (Open Access)

Ras is a monomeric G-protein that mediates multiple signaling pathways. When bound to GTP, Ras binds to and activates effectors and when bound to GDP it does not. Somatic mutations occur in ~15% of all human cancers and cause Ras to be predominantly bound to GTP. Recently, several studies revealed that Ras exists in an ensemble of at least two states when bound to GTP. In the state 1 conformation, Ras is unable to properly bind effectors but holds potential for binding ligands. Conversely, at allosteric sites, state 2 conformations readily bind effectors but not ligands.

To incorporate the flexibility …

Integrated Assessment Of Predicted Mhc Binding And Cross-Conservation With Self Reveals Patterns Of Viral Camouflage, Lu He, Anne S. De Groot, Andres H. Gutierrez, William D. Martin, Lenny Moise, Chris Bailey-Kellogg

Dartmouth Scholarship

Immune recognition of foreign proteins by T cells hinges on the formation of a ternary complex sandwiching a constituent peptide of the protein between a major histocompatibility complex (MHC) molecule and a T cell receptor (TCR). Viruses have evolved means of "camouflaging" themselves, avoiding immune recognition by reducing the MHC and/or TCR binding of their constituent peptides. Computer-driven T cell epitope mapping tools have been used to evaluate the degree to which articular viruses have used this means of avoiding immune response, but most such analyses focus on MHC-facing ‘agretopes'. Here we set out a new means of evaluating the …

Computational Model For Survey And Trend Analysis Of Patients With Endometriosis : A Decision Aid Tool For Ebm, Salvo Reina, Vito Reina, Franco Ameglio, Mauro Costa, Alessandro Fasciani

COBRA Preprint Series

Endometriosis is increasingly collecting worldwide attention due to its medical complexity and social impact. The European community has identified this as a “social disease”. A large amount of information comes from scientists, yet several aspects of this pathology and staging criteria need to be clearly defined on a suitable number of individuals. In fact, available studies on endometriosis are not easily comparable due to a lack of standardized criteria to collect patients’ informations and scarce definitions of symptoms. Currently, only retrospective surgical stadiation is used to measure pathology intensity, while the Evidence Based Medicine (EBM) requires shareable methods and correct …

Evolutionary Approaches For Feature Selection In Biological Data, Vinh Q. Dang

Theses: Doctorates and Masters

Data mining techniques have been used widely in many areas such as business, science, engineering and medicine. The techniques allow a vast amount of data to be explored in order to extract useful information from the data. One of the foci in the health area is finding interesting biomarkers from biomedical data. Mass throughput data generated from microarrays and mass spectrometry from biological samples are high dimensional and is small in sample size. Examples include DNA microarray datasets with up to 500,000 genes and mass spectrometry data with 300,000 m/z values. While the availability of such datasets can aid in …

Space-Time Statistical Analysis Of Malaria Morbidity Incidence Cases In Ghana: A Geostatistical Modelling Approach, Simon K. Appiah

Theses: Doctorates and Masters

Malaria is one of the most prevalent and devastating health problems worldwide. It is a highly endemic disease in Ghana, which poses a major challenge to both the public health and socio-economic development of the country. Major factors accounting for this situation include variability in environmental conditions and lack of prevention services coupled with host of other socio-economic factors. Ghana’s National Malaria Control Programme (NMCP) risk assessment measures have been largely based on household surveys which provided inadequate data for accurate prediction of new incidence cases coupled with frequent incomplete monthly case reports. These raise concerns about annual estimates on …

Art Or Science?, Allison Marsh

Section 3: Imaging the Fast Moving

No abstract provided.

Examination Of The Snsag Surface Antigen Gene Family In Sarcocystis Neurona, Ablesh Gautam

Theses and Dissertations--Veterinary Science

Sarcocystis neurona is a protozoan parasite that causes the serious neurologic disease equine protozoal myeloencephalitis (EPM). The life cycle of S. neurona progresses through multiple developmental stages that differ morphologically and molecularly. The S. neurona merozoite surface is covered by multiple related proteins, which are orthologous to the surface antigen (SAG) gene family of Toxoplasma gondii. The SAG surface antigens in T. gondii and another related parasite Neospora caninum are life cycle stage-specific and seem necessary for parasite transmission and persistence of infection. The present research was conducted to explore the gene family of SnSAGs in S. …

Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet

Undergraduate Research Posters

The World Health Organization has described the rise of antibiotic use as a “global heath security emergency” (who.int). With the growing concern about antibiotic resistant bacteria, there has been an increased interest in bacteriophages. Bacteriophages are high-specific viruses that only infect bacteria. The use of bacteriophages medicinally to treat bacteria is called phage therapy. Research in phage therapy gained momentum until the introduction of antibiotics. While the USA and other Western countries accepted antibiotics, the Soviet Union and their satellite nations still continued to research phages. Since the funding for research was supplied by the Soviet military, the results of …

Finding Them Before They Find Us: Informatics, Parasites, And Environments In Accelerating Climate Change, Daniel R. Brooks, Eric P. Hoberg, Walter A. Boeger, Scott Lyell Gardner, Kurt E. Galbreath, David Herczeg, Hugo H. Mejía-Madrid, S. Elizabeth Rácz, Altangerel Tsogtsaikhan Dursahinhan

Harold W. Manter Laboratory of Parasitology: Faculty Publications

Parasites are agents of disease in humans, livestock, crops, and wildlife and are powerful representations of the ecological and historical context of the diseases they cause. Recognizing a nexus of professional opportunities and global public need, we gathered at the Cedar Point Biological Station of the University of Nebraska in September 2012 to formulate a cooperative and broad platform for providing essential information about the evolution, ecology, and epidemiology of parasites across host groups, parasite groups, geographical regions, and ecosystem types. A general protocol, documentation–assessment–monitoring–action (DAMA), suggests an integrated proposal to build a proactive capacity to understand, anticipate, and respond …

Isolation And Characterization Of Multipotent Lung Stem Cells From P53 Mutant Mice Models, Venkat Sundar Gadepalli

Theses and Dissertations

Recent advances in understanding lung biology have shown evidence for the existence of resident lung stem cells. Independent studies in identifying and characterizing these somatic lung stem cells have shown the potential role of these cells in lung repair and regeneration. Understanding the functional characteristics of these tissue resident stem/progenitor cells has gained much importance with increasing evidence of cancer stem cells, cells in a tumor tissue with stem cell characteristics. Lung cancer is most commonly characterized by loss of p53 function which results in uncontrolled cell divisions. Incidence of p53 point mutations is highest in lung cancer, with a …

Attributing Meaning To Online Social Network Analysis For Tailored Socio-Behavioral Support Systems, Sahiti Myneni

Dissertations and Theses (Open Access)

Ubiquitous online social networks provide us with a unique opportunity to deliver scalable interventions for the support of lifestyle modifications in order to change behaviors that predispose toward cancer and other diseases. At the same time these networks act as rich data sources to inform our understanding of end-user needs. Traditionally, social network analysis is based on communication frequency among members. In this work, I introduce communication content as a complementary frame for studying these networks.

QuitNet, an online social network developed to provide smoking cessation support is considered for analysis. Qualitative coding, automated content analysis, and network analysis were …