Medicine and Health Sciences Commons^™

An Evaluation Of The Use Of A Clinical Research Data Warehouse And I2b2 Infrastructure To Facilitate Replication Of Research, Bret Gardner

Theses & Dissertations

Replication of clinical research is requisite for forming effective clinical decisions and guidelines. While rerunning a clinical trial may be unethical and prohibitively expensive, the adoption of EHRs and the infrastructure for distributed research networks provide access to clinical data for observational and retrospective studies. Herein I demonstrate a means of using these tools to validate existing results and extend the findings to novel populations. I describe the process of evaluating published risk models as well as local data and infrastructure to assess the replicability of the study. I use an example of a risk model unable to be replicated …

Comparing Attributional And Relational Similarity As A Means To Identify Clinically Relevant Drug-Gene Relationships, Safa Fathiamini

Dissertations and Theses (Open Access)

In emerging domains, such as precision oncology, knowledge extracted from explicit assertions may be insufficient to identify relationships of interest. One solution to this problem involves drawing inference on the basis of similarity. Computational methods have been developed to estimate the semantic similarity and relatedness between terms and relationships that are distributed across corpora of literature such as Medline abstracts and other forms of human readable text. Most research on distributional similarity has focused on the notion of attributional similarity, which estimates the similarity between entities based on the contexts in which they occur across a large corpus. A relatively …

Ontology-Based Clinical Information Extraction Using Snomed Ct, Jun Li

Dissertations and Theses (Open Access)

Extracting and encoding clinical information captured in unstructured clinical documents with standard medical terminologies is vital to enable secondary use of clinical data from practice. SNOMED CT is the most comprehensive medical ontology with broad types of concepts and detailed relationships and it has been widely used for many clinical applications. However, few studies have investigated the use of SNOMED CT in clinical information extraction.

In this dissertation research, we developed a fine-grained information model based on the SNOMED CT and built novel information extraction systems to recognize clinical entities and identify their relations, as well as to encode them …

Green Tea Polyphenol Epigallocatechin-3-Gallate-Stearate Inhibits The Growth Of Streptococcus Mutans: A Promising New Approach In Caries Prevention, Amy Lynn Melok, Lee Lee, Siti Ayuni Mohamed Yussof, Tinchun Chu

Department of Biology Faculty Scholarship and Creative Works

Streptococcus mutans (S. mutans) is the main etiological bacteria present in the oral cavity that leads to dental caries. All of the S. mutans in the oral cavity form biofilms that adhere to the surfaces of teeth. Dental caries are infections facilitated by the development of biofilm. An esterified derivative of epigallocatechin-3-gallate (EGCG), epigallocatechin-3-gallate-stearate (EGCG-S), was used in this study to assess its ability to inhibit the growth and biofilm formation of S. mutans. The effect of EGCG-S on bacterial growth was evaluated with colony forming units (CFU) and log reduction; biofilm formation was qualitatively determined by Congo red assay, …

Genomic Approaches To Identify Important Traits In Avian Species, Bhuwan Khatri

Graduate Theses and Dissertations

This dissertation focusses on identifying different molecular markers that have impact on overall poultry production. Chapter one reviews microRNA (miRNA), copy number variation (CNV) and single nucleotide polymorphism (SNP) as markers suggested in different avian species by various studies. It reviews modern genomic approaches that are employed for next generation sequencing data analysis and verification.

Chapter two seeks to identify and validate the muscle specific miRNAs in the breast muscle of modern broilers and its foundational chicken line. Small RNA sequencing was performed to identify differentially expressed mature miRNAs in the breast muscles of these two chicken lines. Results showed …

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, …

Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle

Electronic Theses and Dissertations

Background: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-coenzyme A (acetyl-CoA) in the absence of an arylamine substrate. NAT1 expression varies inter-individually and is elevated in several cancers including estrogen receptor positive (ER+) breast cancers. Additionally, multiple studies have shown the knockdown of NAT1, by both small molecule inhibition and siRNA methods, in breast cancer cells leads to decreased invasive ability and proliferation and decreased anchorage-independent colony formation. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Additionally, consequences …

Genomic And Transcriptomic Landscape Of Colorectal Premalignancy, Kyle Chang

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among men and women in the United States, with 3 to 5 percent of the cases diagnosed in the background of a hereditary form of the disease. Biologically, CRC is divided into two groups: microsatellite instable (MSI) and chromosomally unstable (CIN). Genomic and transcriptomic characterization of CRC has emerged from large-scale studies in recent years due to the advancement of next-generation sequencing technologies. These studies have identified key genes and pathways altered in CRC and provided insights to the discovery of therapeutic targets. Despite the wealth of knowledge acquired in …

Omics Approaches To Uncover Germline And Somatic Variation Underlying Inherited Sarcomagenesis, Justin Wong

Dissertations and Theses (Open Access)

Sarcomas are rare mesenchymal tumors, making up 15% of all childhood and 1% of all adult tumors. They account for a disproportionate share of mortality in young adults, and if left untreated, are highly likely to metastasize. However, sarcoma etiology is poorly understood, and having numerous histological subtypes has complicated elucidation. To better understand factors underlying sarcomagenesis, we leveraged two rare inherited cancer predisposition syndromes, Li-Fraumeni Syndrome (LFS), and LFS-like (LFSL), both with a high incidence of sarcomas. LFS is caused by mutations in the tumor suppressor gene TP53 (p53), but has variable and incomplete penetrance, suggesting additional acquired …

Transcriptomics Of Learning, Pablo Iturralde

Theses

Learning is a basic and important component of behavior yet we have very little empirical information about the interaction between mechanisms of learning and evolution. In our work, we are testing hypotheses about the neurogenetic mechanisms through which animal learning abilities evolve. We are able to test this directly by using experimentally evolved populations of flies, which differ in learning ability. These populations were previously evolved within the lab by creating worlds with different patterns of change following theoretically predicted effects on which enhanced learning will evolve. How has evolution acted to modulate genes and gene expression in the brain …

Polygenic Scores For Metabolic Traits And Related Drug Prescriptions In The Michigan Genomics Initiative, Samuel K. Handelman, Xiaomeng Du, Yanhua H. Chen, Elizabeth K. Speliotes

Biology and Medicine Through Mathematics Conference

No abstract provided.

Schistosomiasis In The Wild: A Transcriptomics Perspective On Field-Derived Biomphalaria Pfeifferi And Schistosoma Mansoni, And Their Interactions, Sarah K. Buddenborg

Biology ETDs

Schistosomiasis, caused by trematodes in the genus Schistosoma, is a widespread neglected tropical disease with the species S. mansoni infecting over 100 million people. We aimed to better understand the snail host and parasite responses during intramolluscan stages of infection by performing dual RNA-Seq on field-collected snails with natural infections from western Kenya. We collected uninfected Biomphalaria pfeifferi, B. pfeifferi with a patent cercariae-producing S. mansoni infection, and B. pfeifferi exposed to field-collected S. mansoni at 1 and 3d (days post infection).

We first created a high-quality B. pfeifferi transcriptome to identify the snail response to S. mansoni infection. …

Evolution Of Bordetella Pertussis Genome May Play A Role In The Increased Rate Of Whooping Cough Cases In The United States, Kevin Loftus

Senior Honors Projects, 2010-2019

Bordetella pertussis is the bacterium responsible for pertussis, a disease commonly referred to as whooping cough. Recently, pertussis has made a resurgence in the U.S. despite high-vaccination coverage. Possible causes of the increased number of pertussis cases include genetic evolution of B. pertussis, increased awareness of the disease, better laboratory diagnostics, and the switch from a whole-cellular (wP) vaccine to an acellular vaccine (aP) in the 1990s. Fortunately, just as B. pertussis is evolving, so is the arsenal of technologies used to understand and combat this pathogenic bacterium. Whole genome sequencing is one technology that helps researchers better understand …

Functional Signature Ontology-Based Identification And Validation Of Novel Therapeutic Targets And Natural Products For The Treatment Of Cancer, Beth Neilsen

Theses & Dissertations

Multiple studies have revealed that Ras-driven tumors acquire vulnerabilities by adapting cellular mechanisms that promote uncontrolled proliferation and suppress apoptosis. Kinase Suppressor of Ras 1 (KSR1) modulates ERK activation downstream of oncogenic Ras, and knockdown of KSR1 selectively kills malignant, Ras-driven cancer cells, but does not kill immortalized, non-transformed human colon epithelial cells (HCECs). KSR1^-/- mice are fertile and phenotypically normal, but resistant to Ras-driven tumor formation suggesting KSR1 represents a vulnerability in cancer cells.

To identify additional vulnerabilities in cancer, a screening approach termed Functional Signature Ontology (FUSION) was used to screen 14,355 genes and 1,200 natural product …

Modeling And Analyzing An Optogenetic System For Photoactivatable Protein Dissociation, Anvin Thomas, James Schaff

Honors Scholar Theses

Computational modeling of cell-cell interactions can grant clues and can answer questions about an experiment, especially for observations about binding interactions and kinetics. This approach was used to investigate an interaction between a light-oxygen-voltage (LOV) domain and an engineered protein called Zdark (Zdk). The LOV domain is membrane-bound while Zdk is cytosolic. The LOV domain and Zdk bind strongly in dark (K_d 26.2 nM), and weakly upon exposure to blue light (K_d > 4 μM). Total internal reflection fluorescence (TIRF) images are acquired of Zdk, the fluorescent species bound to a mCherry tag, and the loss of fluorescence is …

Investigating The Impact Of Intragenic Dna Methylation On Gene Expression, And The Clinical Implications On Tumor Cells And Associated Stroma, Michael Mcguire

Dissertations and Theses (Open Access)

Investigations into the function of non-promoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated non-promoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we uncovered an enrichment of DNA methylation sites within the gene body and 3’UTR in which DNA methylation is strongly positively correlated with gene expression. We examined 32 tumor types and identified 57 …

Computational Insights Into The Generation Of Chromosomal Copy Number Changes, Yihua Liu

Dissertations and Theses (Open Access)

Deviations from a diploid configuration of the human genome, spanning single genes or entire chromosomes, can have wide-ranging impacts on the variation of human phenotypes, including Mendelian and complex forms of diseases. These chromosomal alterations — such as duplications, deletions or copy-neutral loss-of-heterozygosity — are thus important forms of genetic variation for phenotyping populations of individuals as well as populations of cells. Indeed, copy number variants (CNVs) serve as hallmarks of critical changes in the development of particular diseases such as cancer and thus may be used as biomarkers. These CNVs may be either inherited (transmitted by germ cells, originating …

Similarity Based Classification Of Adhd Using Singular Value Decomposition, Taban Eslami, Fahad Saeed

Parallel Computing and Data Science Lab Technical Reports

Attention deficit hyperactivity disorder (ADHD) is one of the most common brain disorders among children. This disorder is considered as a big threat for public health and causes attention, focus and organizing difficulties for children and even adults. Since the cause of ADHD is not known yet, data mining algorithms are being used to help discover patterns which discriminate healthy from ADHD subjects. Numerous efforts are underway with the goal of developing classification tools for ADHD diagnosis based on functional and structural magnetic resonance imaging data of the brain. In this paper, we used Eros, which is a technique for …

The Pharmacogene Variation (Pharmvar) Consortium: Incorporation Of The Human Cytochrome P450 (Cyp) Allele Nomenclature Database, Andrea Gaedigk, Magnus Ingelman-Sundberg, Neil A. Miller, J Steven Leeder, Michelle Whirl-Carrillo, Teri E. Klein

Manuscripts, Articles, Book Chapters and Other Papers

The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource to the pharmacogenetics and genomics communities, will be transitioning to the Pharmacogene Variation (PharmVar) Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature.

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 …

Using The Literature To Identify Confounders, Scott Malec

Dissertations and Theses (Open Access)

Prior work in causal modeling has focused primarily on learning graph structures and parameters to model data generating processes from observational or experimental data, while the focus of the literature-based discovery paradigm was to identify novel therapeutic hypotheses in publicly available knowledge. The critical contribution of this dissertation is to refashion the literature-based discovery paradigm as a means to populate causal models with relevant covariates to abet causal inference. In particular, this dissertation describes a generalizable framework for mapping from causal propositions in the literature to subgraphs populated by instantiated variables that reflect observational data. The observational data are those …

Scalable Feature Selection And Extraction With Applications In Kinase Polypharmacology, Derek Jones

Theses and Dissertations--Computer Science

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in …

Does The Foundational Model Of Anatomy Ontology Provide A Knowledge Base For Learning And Assessment In Anatomy Education?, Melissa D. Clarkson, Mark E. Whipple

Institute for Biomedical Informatics Faculty Publications

Throughout the development of the Foundational Model of Anatomy (FMA) ontology, one of the use cases put forth has been anatomy education. In this work, we examine which types of knowledge taught to anatomy students can be supported by the FMA knowledge base. We first categorize types of anatomical knowledge, then express these patterns in the form “Given ____, state ____”. Each of the 33 patterns was evaluated for whether this type of knowledge is compatible with the modeling and scope of the FMA.

Developing Graphic Libraries To Accompany The Craniofacial Human Ontology, Melissa D. Clarkson

Institute for Biomedical Informatics Faculty Publications

I describe the development of two graphic libraries to accompany parts of the Craniofacial Human Ontology. One library depicts phenotypes of cleft lip. The other represents development of the human head between 4 and 8 weeks of gestation.

A Frame-Based Nlp System For Cancer-Related Information Extraction, Yuqi Si, Kirk Roberts

Faculty, Staff and Student Publications

We propose a frame-based natural language processing (NLP) method that extracts cancer-related information from clinical narratives. We focus on three frames: cancer diagnosis, cancer therapeutic procedure, and tumor description. We utilize a deep learning-based approach, bidirectional Long Short-term Memory (LSTM) Conditional Random Field (CRF), which uses both character and word embeddings. The system consists of two constituent sequence classifiers: a frame identification (lexical unit) classifier and a frame element classifier. The classifier achieves an F

Understanding Huntington's Disease Using Machine Learning Approaches, Sonali Lokhande

KGI Theses and Dissertations

Huntington’s disease (HD) is a debilitating neurodegenerative disorder with a complex pathophysiology. Despite extensive studies to study the disease, the sequence of events through which mutant Huntingtin (mHtt) protein executes its action still remains elusive. The phenotype of HD is an outcome of numerous processes initiated by the mHtt protein along with other proteins that act as either suppressors or enhancers of the effects of mHtt protein and PolyQ aggregates. Utilizing an integrative systems biology approach, I construct and analyze a Huntington’s disease integrome using human orthologs of protein interactors of wild type and mHtt protein. Analysis of this integrome …

Identification Of Prognostic Cancer Biomarkers Through The Application Of Rna-Seq Technologies And Bioinformatics, Nathan Wong

McKelvey School of Engineering Graduate Student Theses & Dissertations

MicroRNAs (miRNAs) are short single-stranded RNAs that function as the guide sequence of the post-transcriptional regulatory process known as the RNA-induced silencing complex (RISC), which targets mRNA sequences for degradation through complementary binding to the guide miRNA. Changes in miRNA expression have been reported as correlated with numerous biological processes, including embryonic development, cellular differentiation, and disease manifestation. In the latter case, dysregulation has been observed in response to infection by human papillomavirus (HPV), which has also been established as both oncogenic in cervical cancers and oropharyngeal cancers and favorable for overall patient survival after tumor formation. The identification of …

Impact Of Terminology Mapping On Population Health Cohorts Impact, Barbara A. Berkovich

Dissertations and Theses (Open Access)

Background and Objectives: The population health care delivery model uses phenotype algorithms in the electronic health record (EHR) system to identify patient cohorts targeted for clinical interventions such as laboratory tests, and procedures. The standard terminology used to identify disease cohorts may contribute to significant variation in error rates for patient inclusion or exclusion. The United States requires EHR systems to support two diagnosis terminologies, the International Classification of Disease (ICD) and the Systematized Nomenclature of Medicine (SNOMED). Terminology mapping enables the retrieval of diagnosis data using either terminology. There are no standards of practice by which to evaluate and …

Computational Identification Of Noncoding Driver Mutations Based On Impact On Rna Processing, Kevin Zhu

Dissertations and Theses (Open Access)

Despite the prevalence of mutations in the noncoding regions of the DNA, their effects on cancer development remain largely uninvestigated. This is especially evident when compared to coding mutations, which have been relatively well-studied and, in certain cases, been identified as driver mutations for cancer. Recent studies, however, have identified noncoding mutations that frequently appear in certain types of cancer, which may be evidence that those mutations are important to cancer development. Nonetheless, the role of noncoding mutations in cancer remains unclear. A potential vector for understanding this mechanism is through observing the relation between noncoding mutations and functional RNA …

Integrative Cancer Immunogenomic Analysis Of Serial Melanoma Biopsies Reveals Correlates Of Response And Resistance To Sequential Ctla-4 And Pd-1 Blockade Treatment, Whijae Roh

Dissertations and Theses (Open Access)

Melanoma is the most malignant form of skin cancer. The five-year survival rate for metastatic melanoma is 19.9%. Although targeted therapy of BRAF and MEK inhibitors were developed for melanoma, resistance to therapy is inevitable. Immune checkpoint blockade, which reverses the suppression of the immune system, on the other hand, has shown a durable response in 20-30% of patients with metastatic melanoma. However, more predictive and robust biomarkers of response to this therapy are still needed, and resistance mechanisms remain incompletely understood. To address this, we examined a cohort of metastatic melanoma patients treated with sequential checkpoint blockade against cytotoxic …