Physical Sciences and Mathematics Commons^™

The Performance Of Marginal Modeling Methods For Rare Events With Application To Opioid Overdose Mortality And Morbidity, Shawn Nigam

Theses and Dissertations--Epidemiology and Biostatistics

Opioid misuse is a nationwide epidemic, with Kentucky having one of the highest opioid overdose-related fatality rates across all US states. These rates have increased significantly over the past decade, with particularly large increases during the COVID-19 pandemic. This dissertation aims to study the behavior of these increases and the methods for the marginal modeling of count outcomes related to opioid overdose.

Opioid overdose-related fatality rates in Kentucky increased significantly during the COVID-19 pandemic. In this chapter, we characterize the changes in opioid overdose fatality rates in Kentucky and identify associations between potential factors and fatality rates. County-level opioid overdose …

Striving For Appropriate Antibiotic Use: A Biomarker Initiative, And Outcomes Associated With Azithromycin Exposure, Amanda Gusovsky

Theses and Dissertations--Pharmacy

The introduction of antibiotics into clinical practice is considered the greatest medical breakthrough of the 20^thcentury. However, the use of antibiotics can contribute to the development of resistance. In the United States (U.S.), approximately 2.8 million people are infected with antibiotic-resistant bacteria each year, and more than 35,000 people die as a result. Moreover, some antibiotics are known to cause cardiac side effects including QT prolongation, hypotension, and ventricular arrythmias. The U.S. Centers for Disease Control and Prevention (CDC) defines appropriate antibiotic use as the effort to use “the right antibiotic, at the right dose, for the right …

Potential Alzheimer's Disease Plasma Biomarkers, Taylor Estepp

Theses and Dissertations--Epidemiology and Biostatistics

In this series of studies, we examined the potential of a variety of blood-based plasma biomarkers for the identification of Alzheimer's disease (AD) progression and cognitive decline. With the end goal of studying these biomarkers via mixture modeling, we began with a literature review of the methodology. An examination of the biomarkers with demographics and other health factors found evidence of minimal risk of confounding along the causal pathway from biomarkers to cognitive performance. Further study examined the usefulness of linear combinations of biomarkers, achieved via partial least squares (PLS) analysis, as predictors of various cognitive assessment scores and clinical …

High Dimensional Data Analysis: Variable Screening And Inference, Lei Fang

Theses and Dissertations--Statistics

This dissertation focuses on the problem of high dimensional data analysis, which arises in many fields including genomics, finance, and social sciences. In such settings, the number of features or variables is much larger than the number of observations, posing significant challenges to traditional statistical methods.

To address these challenges, this dissertation proposes novel methods for variable screening and inference. The first part of the dissertation focuses on variable screening, which aims to identify a subset of important variables that are strongly associated with the response variable. Specifically, we propose a robust nonparametric screening method to effectively select the predictors …

A Novel Nonparametric Test For Heterogeneity Detection And Assessment Of Fluid Removal Among Crrt Patients In Icu, Shaowli Kabir

Theses and Dissertations--Epidemiology and Biostatistics

Over the past decade acute kidney injury (AKI) has been occurring among 20%-50% of patients admitted to the intensive care unit (ICU) in United States. Continuous renal replacement therapy (CRRT) has become a popular treatment method among these critically ill patients. But there are multiple complications in implementing this treatment, including discrepancies in practiced and prescribed fluid removal, possibly related to the heterogeneity among these patients. With mixture modeling there have been several techniques in detecting heterogeneity with their specific limitations. In this dissertation a novel nonparametric ‘d test’ will be used to detect heterogeneity among CRRT patients in ICU. …

Upregulation Of Cd36, A Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis By Increasing Mmp28 And Decreasing E-Cadherin Expression, James Drury, Piotr G. Rychahou, Courtney O. Kelson, Mariah E. Geisen, Yuanyuan Wu, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers, Yekaterina Y. Zaytseva

Surgery Faculty Publications

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation …

Opioid Use Disorder Treatment With Buprenorphine: Analysis Of Treatment Utilization And Associated Outcomes In Kentucky, Feitong Lei

Theses and Dissertations--Epidemiology and Biostatistics

Opioid use disorder (OUD) is chronic opioid use that results in clinically significant suffering, impairment, or even death. The opioid epidemic in the United States has become a public health and economic crisis, affecting patients' well-being and the nation's overall health and welfare. Eastern Kentucky was among the first regions affected by the opioid crisis, and Kentucky has historically ranked among the top five states for age-adjusted drug overdose mortality rate.

There are three medications (buprenorphine, methadone, naltrexone) approved by the U.S. Food and Drug Administration to treat OUD. As a partial opioid agonist, buprenorphine is a safe medication for …

Addressing Ascertainment Bias In The Study Of Cardiovascular Disease Burden In Opioid Use Disorders - Application Of Natural Language Processing Of Electronic Health Records, Jade Huang Singleton

Theses and Dissertations--Epidemiology and Biostatistics

In the United States, the prevalence of long-term exposure to opioid drugs, for both medically and nonmedically indicated purposes, has increased considerably since the mid-1990’s. Concerns have emerged about the potential health effects of opioid use. There is also growing interest in other possible connections with opioid use including cardiovascular disease. Electronic health records (EHR) contain information about patient care in the form of structured codes and unstructured notes. Natural language processing (NLP) provides a tool for processing unstructured textual data in EHR clinical notes and extracts useful information for research with structured formats. The purpose of this dissertation was …

Multivariate Statistical Modeling For Radio-Genomics Study, Tiantian Zeng

Theses and Dissertations--Statistics

Radiogenomics is a new direction in cancer research that focuses on the associations among radiomics, genomics and clinical outcome. Currently, the major challenge for Radiogenomics lies in the effective integration of genomics and imaging data for promising clinical outcome prediction. Herein, we propose a multivariate joint model that can integrate imaging and genomic data for better predicting the clinical outcome. Specifically, we jointly consider two multivariate group lasso models, one regresses imaging features on genomic features, and the other regresses patient’s clinical outcome on genomic features. An L1 penalty term is introduced for each variable, and weight in the penalty …

Statistical Theory For Specialized Linear Regression Adjustment Methods Compared To Multiple Linear Regression In The Presence And Absence Of Interaction Effects, Leon Su

Theses and Dissertations--Statistics

When building models to investigate outcomes and variables of interest, researchers often want to adjust for other variables. There is a variety of ways that these adjustments are performed. In this work, we will consider four approaches to adjustment utilized by researchers in various fields. We will compare the efficacy of these methods to what we call the ”true model method”, fitting a multiple linear regression model in which adjustment variables are model covariates. Our goal is to show that these adjustment methods have inferior performance to the true model method by comparing model parameter estimates, power, type I error, …

Genetic Contributors Of Incident Stroke In 10,700 African Americans With Hypertension: A Meta-Analysis From The Genetics Of Hypertension Associated Treatments And Reasons For Geographic And Racial Differences In Stroke Studies, Nicole D. Armstrong, Vinodh Srinivasasainagendra, Amit Patki, Rikki M. Tanner, Bertha A. Hidalgo, Hemant K. Tiwari, Nita A. Limdi, Ethan M. Lange, Leslie A. Lange, Donna K. Arnett, Marguerite R. Irvin

Epidemiology and Environmental Health Faculty Publications

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals.

Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs …

The Efficacy Of Plant-Based Dietary Program In Patients With Diabetes: A Pilot Study, Reuben Adatorwovor, Nisha Sharma, Dakota Mccoy, Sharon Wasserstrom, Matthew Robinson, Jacquelyn Nyenhuis, Sowmya Suryanarayanan

Biostatistics Faculty Publications

Dietary choices play a key role in insulin sensitivity among diabetes patients. An 8-week pilot study was conducted to evaluate whether a mostly plant-based dietary program will lead to improvement in biochemical markers in adults with diabetes. The dietary program included educational presentations, weekly cooking demonstrations and small group discussions. A sample of thirty-two adults with diabetes (types 1 and 2) were recruited and seventeen (53%) completed the study. Matched-pair tests and Fishers exact tests were used to compare the changes in means and proportion of the participants’ responses. There were changes in HbA1c, lipids, CRP (mg/L), cholesterol (mg/dL), HDL …

Characterizing Long Covid: Deep Phenotype Of A Complex Condition, Rachel R. Deer, Madeline A. Rock, Nicole Vasilevsky, Leigh Carmody, Halie Rando, Alfred J. Anzalone, Marc D. Basson, Tellen D. Bennett, Timothy Bergquist, Eilis A. Boudreau, Carolyn T. Bramante, James Brian Byrd, Tiffany J. Callahan, Lauren E. Chan, Haitao Chu, Christopher G. Chute, Ben D. Coleman, Hannah E. Davis, Joel Gagnier, Casey S. Greene, Ramakanth Kavuluru

Institute for Biomedical Informatics Faculty Publications

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies.

METHODS: The Human Phenotype Ontology …

A 6-Cpg Validated Methylation Risk Score Model For Metabolic Syndrome: The Hypergen And Goldn Studies, Bertha A. Hidalgo, Bre Minniefield, Amit Patki, Rikki Tanner, Minoo Bagheri, Hemant K. Tiwari, Donna K. Arnett, Marguerite Ryan Irvin

Epidemiology and Environmental Health Faculty Publications

There has been great interest in genetic risk prediction using risk scores in recent years, however, the utility of scores developed in European populations and later applied to non-European populations has not been successful. The goal of this study was to create a methylation risk score (MRS) for metabolic syndrome (MetS), demonstrating the utility of MRS across race groups using cross-sectional data from the Hypertension Genetic Epidemiology Network (HyperGEN, N = 614 African Americans (AA)) and the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, N = 995 European Americans (EA)). To demonstrate this, we first selected cytosine-guanine dinucleotides …

Genomics Of Postprandial Lipidomics In The Genetics Of Lipid-Lowering Drugs And Diet Network Study, Marguerite R. Irvin, May E. Montasser, Tobias Kind, Sili Fan, Dinesh K. Barupal, Amit Patki, Rikki M. Tanner, Nicole D. Armstrong, Kathleen A. Ryan, Steven A. Claas, Jeffrey R. O’Connell, Hemant K. Tiwari, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled …

Ovarian Cancer Epidemiology, Healthcare Access And Disparities (Orchid): Methodology For A Population-Based Study Of Black, Hispanic And White Patients With Ovarian Cancer, Tomi Akinyemiju, April Deveaux, Lauren Wilson, Anjali Gupta, Ashwini Joshi, Malcolm Bevel, Chioma Omeogu, Onyinye Ohamadike, Bin Huang, Maria Pisu, Margaret Liang, Molly Mcfatrich, Erin Daniell, Laura Jane Fish, Kevin Ward, Maria Schymura, Andrew Berchuck, Arnold L. Potosky

Biostatistics Faculty Publications

INTRODUCTION: Less than 40% of patients with ovarian cancer (OC) in the USA receive stage-appropriate guideline-adherent surgery and chemotherapy. Black patients with cancer report greater depression, pain and fatigue than white patients. Lack of access to healthcare likely contributes to low treatment rates and racial differences in outcomes. The Ovarian Cancer Epidemiology, Healthcare Access and Disparities study aims to characterise healthcare access (HCA) across five specific dimensions-Availability, Affordability, Accessibility, Accommodation and Acceptability-among black, Hispanic and white patients with OC, evaluate the impact of HCA on quality of treatment, supportive care and survival, and explore biological mechanisms that may contribute to …

The Mediating/Moderating Role Of Cultural Context Factors On Self-Care Practices Among Those Living With Diabetes In Rural Appalachia, Brittany L. Smalls, Adebola Adegboyega, Ellen Combs, Matthew Rutledge, Philip M. Westgate, Md. Tofial Azam, Felipe De La Barra, Lovoria B. Williams, Nancy E. Schoenberg

Family and Community Medicine Faculty Publications

Background

The aim of this study was to examine whether cultural factors, such as religiosity and social support, mediate/moderate the relationship between personal/psychosocial factors and T2DM self-care in a rural Appalachian community.

Methods

Regression models were utilized to assess for mediation and moderation. Multilevel linear mixed effects models and GEE-type logistic regression models were fit for continuous (social support, self-care) and binary (religiosity) outcomes, respectively.

Results

The results indicated that cultural context factors (religiosity and social support) can mediate/moderate the relationship between psychosocial factors and T2DM self-care. Specifically, after adjusting for demographic variables, the findings suggested that social support may …

Analysis Of Genes (Tmem106b, Grn, Abcc9, Kcnmb2, And Apoe) Implicated In Risk For Late-Nc And Hippocampal Sclerosis Provides Pathogenetic Insights: A Retrospective Genetic Association Study, Adam J. Dugan, Peter T. Nelson, Yuriko Katsumata, Lincoln M. P. Shade, Kevin L. Boehme, Merilee A. Teylan, Matthew D. Cykowski, Shubhabrata Mukherjee, John S. K. Kauwe, Timothy J. Hohman, Julie A. Schneider, Alzheimer’S Disease Genetics Consortium, David W. Fardo

Biostatistics Faculty Publications

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer’s Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory …

Hiv Infection And The Risk Of World Health Organization-Defined Sudden Cardiac Death, Matthew S. Freiberg, Meredith S. Duncan, Charles Alcorn, Chung-Chou H. Chang, Suman Kundu, Asri Mumpuni, Emily K. Smith, Sarah Loch, Annie Bedigian, Eric Vittinghoff, Kaku So-Armah, Priscilla Y. Hsue, Amy C. Justice, Zian H. Tseng

Biostatistics Faculty Publications

Background

People living with HIV have higher sudden cardiac death (SCD) rates compared with the general population. Whether HIV infection is an independent SCD risk factor is unclear.

Methods and Results

This study evaluated participants from the Veterans Aging Cohort Study, an observational, longitudinal cohort of veterans with and without HIV infection matched 1:2 on age, sex, race/ethnicity, and clinical site. Baseline for this study was a participant's first clinical visit on or after April 1, 2003. Participants were followed through December 31, 2014. Using Cox proportional hazards regression, we assessed whether HIV infection, CD4 cell counts, and/or HIV viral …

Associations Of Circulating Dimethylarginines With The Metabolic Syndrome In The Framingham Offspring Study, Ibrahim Musa Yola, Carlee Moser, Meredith S. Duncan, Edzard Schwedhelm, Dorothee Atzler, Renke Maas, Juliane Hannemann, Rainer H. Böger, Ramachandran S. Vasan, Vanessa Xanthakis

Biostatistics Faculty Publications

BACKGROUND: Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively.

METHODS: We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study …

A Randomized Controlled Trial To Determine Whether Beta-Hydroxy-Beta-Methylbutyrate And/Or Eicosapentaenoic Acid Improves Diaphragm And Quadriceps Strength In Critically Ill Mechanically Ventilated Patients, Gerald S. Supinski, Paul F. Netzel, Philip M. Westgate, Elizabeth A. Schroder, Lin Wang, Leigh Ann Callahan

Internal Medicine Faculty Publications

BACKGROUND: Intensive care unit acquired weakness is a serious problem, contributing to respiratory failure and reductions in ambulation. Currently, there is no pharmacological therapy for this condition. Studies indicate, however, that both beta-hydroxy-beta-methylbutyrate (HMB) and eicosapentaenoic acid (EPA) increase muscle function in patients with cancer and in older adults. The purpose of this study was to determine whether HMB and/or EPA administration would increase diaphragm and quadriceps strength in mechanically ventilated patients.

METHODS: Studies were performed on 83 mechanically ventilated patients who were recruited from the Medical Intensive Care Units at the University of Kentucky. Diaphragm strength was assessed as …

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids To Predict Carboplatin Resistance, Justin W. Gorski, Zhuwei Zhang, J. Robert Mccorkle, Jodi M. Dejohn, Chi Wang, Rachel W. Miller, Holly H. Gallion, Charles S. Dietrich Iii, Frederick R. Ueland, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC₅₀ values …

Effect Sizes And Intra-Cluster Correlation Coefficients Measured From The Green Dot High School Study For Guiding Sample Size Calculations When Designing Future Violence Prevention Cluster Randomized Trials In School Settings, Md. Tofial Azam, Heather M. Bush, Ann L. Coker, Philip M. Westgate

Biostatistics Faculty Publications

Purpose: Cluster randomized controlled trials (cRCTs) are popular in school-based research designs where schools are randomized to different trial arms. To help guide future study planning, we provide information on anticipated effect sizes and intra-cluster correlation coefficients (ICCs), as well as school sizes, for dating violence (DV) and interpersonal violence outcomes based on data from a cRCT which evaluated the bystander-based violence intervention ‘Green Dot’.

Methods: We utilized data from 25 schools from the Green Dot High School study. Effect size and ICC values corresponding to dating and interpersonal violence outcomes are obtained from linear mixed effect models. We …

Lapatinib And Poziotinib Overcome Abcb1-Mediated Paclitaxel Resistance In Ovarian Cancer, J. Robert Mccorkle, Justin W. Gorski, Jinpeng Liu, Mckayla J. Riggs, Anthony B. Mcdowell Jr., Nan Lin, Chi Wang, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. …

Predictors Of Chronic Opioid Therapy In Medicaid Beneficiaries With Hiv Who Initiated Antiretroviral Therapy, Gyeon Oh, Emily S. Brouwer, Erin L. Abner, David W. Fardo, Patricia R. Freeman, Chris Delcher, Daniela C. Moga

Epidemiology and Environmental Health Faculty Publications

The factors associated with chronic opioid therapy (COT) in patients with HIV is understudied. Using Medicaid data (2002-2009), this retrospective cohort study examines COT in beneficiaries with HIV who initiated standard combination anti-retroviral therapy (cART). We used generalized estimating equations on logistic regression models with backward selection to identify significant predictors of COT initiation. COT was initiated among 1014 out of 9615 beneficiaries with HIV (male: 10.4%; female: 10.7%). Those with older age, any malignancy, Hepatitis C infection, back pain, arthritis, neuropathy pain, substance use disorder, polypharmacy, (use of) benzodiazepines, gabapentinoids, antidepressants, and prior opioid therapies were positively associated with …

Clinical Outcomes Of Molecular Tumor Boards: A Systematic Review, Kara L. Larson, Bin Huang, Heidi L. Weiss, Pamela C. Hull, Philip M. Westgate, Rachel W. Miller, Susanne M. Arnold, Jill M. Kolesar

Markey Cancer Center Faculty Publications

PURPOSE: We conducted this systematic review to evaluate the clinical outcomes associated with molecular tumor board (MTB) review in patients with cancer.

METHODS: A systematic search of PubMed was performed to identify studies reporting clinical outcomes in patients with cancer who were reviewed by an MTB. To be included, studies had to report clinical outcomes, including clinical benefit, response, progression-free survival, or overall survival. Two reviewers independently selected studies and assessed quality with the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group or the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies depending on the type …

Covid-19 And The Impact On Rural And Black Church Congregants: Results Of The C-M-C Project, Lovoria B. Williams, Anita F. Fernander, Tofial Azam, Maria L. Gomez, Junghee Kang, Cassidy L. Moody, Hannah Bowman, Nancy E. Schoenberg

Nursing Faculty Publications

The COVID-19 pandemic has had devastating effects on Black and rural populations with a mortality rate among Blacks three times that of Whites and both rural and Black populations experiencing limited access to COVID-19 resources. The primary purpose of this study was to explore the health, financial, and psychological impact of COVID-19 among rural White Appalachian and Black nonrural central Kentucky church congregants. Secondarily we sought to examine the association between sociodemographics and behaviors, attitudes, and beliefs regarding COVID-19 and intent to vaccinate. We used a cross sectional survey design developed with the constructs of the Health Belief and Theory …

Identification Of Novel And Rare Variants Associated With Handgrip Strength Using Whole Genome Sequence Data From The Nhlbi Trans-Omics In Precision Medicine (Topmed) Program, Chloé Sarnowski, Han Chen, Mary L. Biggs, Sylvia Wassertheil-Smoller, Jan Bressler, Marguerite R. Irvin, Kathleen A. Ryan, David Karasik, Donna K. Arnett, L. Adrienne Cupples, David W. Fardo, Stephanie M. Gogarten, Benjamin D. Heavner, Deepti Jain, Hyun Min Kang, Charles Kooperberg, Arch G. Mainous, Braxton D. Mitchell, Alanna C. Morrison, Jeffrey R. O'Connell

Epidemiology and Environmental Health Faculty Publications

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant …

Analysis Of Genetic Variants Associated With Levels Of Immune Modulating Proteins For Impact On Alzheimer’S Disease Risk Reveal A Potential Role For Siglec14, Benjamin C. Shaw, Yuriko Katsumata, James F. Simpson, David W. Fardo, Steven Estus

Biostatistics Faculty Publications

Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer’s disease (AD), including TREM2 and CD33, frequently passing a stringent false-discovery rate. These genes either encode or signal through immunomodulatory tyrosine-phosphorylated inhibitory motifs (ITIMs) or activation motifs (ITAMs) and govern processes critical to AD pathology, such as inflammation and amyloid phagocytosis. To investigate whether additional ITIM and ITAM-containing family members may contribute to AD risk and be overlooked due to the stringent multiple testing in GWAS, we combined protein quantitative trait loci (pQTL) data from a recent plasma proteomics study with AD associations in a recent …

A Highly Predictive Microrna Panel For Determining Delayed Cerebral Vasospasm Risk Following Aneurysmal Subarachnoid Hemorrhage, Wang-Xia Wang, Joe E. Springer, Kevin Xie, David W. Fardo, Kevin W. Hatton

Sanders-Brown Center on Aging Faculty Publications

Approximately one-third of aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral vasospasm (DCV) 3–10 days after aneurysm rupture resulting in additional, permanent neurologic disability. Currently, no validated biomarker is available to determine the risk of DCV in aSAH patients. MicroRNAs (miRNAs) have been implicated in virtually all human diseases, including aSAH, and are found in extracellular biofluids including plasma and cerebrospinal fluid (CSF). We used a custom designed TaqMan Low Density Array miRNA panel to examine the levels of 47 selected brain and vasculature injury related miRNAs in CSF and plasma specimens collected from 31 patients with or without DCV …