Mapping Novel Pathways in Cardiovascular Disease Using eQTL Data: The Past, Present, and Future of Gene Expression Analysis

Genome-wide association studies (GWAS) have identified genetic variants associated with numerous cardiovascular and metabolic diseases. Newly identified polymorphisms associated with myocardial infarction, dyslipidemia, hypertension, diabetes, and insulin resistance suggest novel mechanistic pathways that underlie these and other complex diseases. Working out the connections between the polymorphisms identified in GWAS and their biological mechanisms has been especially challenging given the number of non-coding variants identified thus far. In this review, we discuss the utility of expression quantitative trait locus (eQTL) databases in the study of non-coding variants with respect to cardiovascular and metabolic phenotypes. Recent successes in using eQTL data to link variants with functional candidate genes will be reviewed, and the shortcomings of this approach will be outlined. Finally, we discuss the emerging next generation of eQTL studies that take advantage of the ability to generate induced pluripotent stem cell lines from population cohorts

Master of Science

thesisFor more than twenty years, the introduction of reliability-based analysis into roadway geometric design has been investigated. This type of probabilistic geometric design analysis is well suited to explicitly address the level of variability and randomness associated with design inputs when compared to a more deterministic design approach. In this study, reliability analysis was used to estimate the probability distribution of operational performance that might result from basic number of lanes decisions made to achieve a design level of service on a freeway. The concept is demonstrated using data from Interstate 15 and Interstate 80 in Utah. The basic traffic count data used for analysis were obtained from Utah Department of Transportation (UDOT). To account for the uncertainty in the design inputs, statistical distributions were developed and reliability analysis was carried out using Monte Carlo simulation. A statistical software Minitab was used to develop statistical distributions of design inputs involving variability from the traffic count data. Minitab was also used to run Monte Carlo simulation by generating random samples of the design inputs. The outcome of this probabilistic analysis is a distribution of vehicle density for a given number of lanes during the design hour. The main benefit of reliability analysis is that it enables designers to explicitly consider uncertainties in their decision-making and to illustrate specific values of the distributions that correspond their target level of service (e.g., the 65th through 85th percentile density corresponds to the design level of service). The results demonstrate how uncertainty in estimates of K (i.e., the percent of daily traffic in the design hour), directional distribution, percent heavy-vehicles, and free-flow speed significantly contribute to the variation in the vehicle density on a freeway

Modeling and Analysis of GaN/InGaN Light Emitting Diodes

GaN based optoelectronic devices have had significant impact in solid state lighting. Developing efficient light emitting diodes has been of great research interest in recent years. Electrical modeling of light emitting diodes is now gaining its importance with the development of TCAD tools to have a better understanding of the device structure and to have cost reduction associated with the material and labor.;In this thesis a TCAD model for our device has been developed with the finite element analysis TCAD tool sentaurus from synopsys. The developed model has been validated to the experimental results. The electrical characteristics of the device have been analyzed with the use of band diagrams, current distribution, radiative recombination rate and IV plots.;Different layers of the device have been studied and analyzed and certain design changes to achieve an enhancement in the efficiencies are proposed. The problem of current crowding in LEDs has been widely reported in the literature. In this study passive modeling of the LED structure with PSPICE has been carried out to understand the impact of the conductivities of different layers on the problem of current crowding. With the feedback from the PSPICE model an analytical relation has been determined between the p-GaN layer and n-GaN layer to have uniform current spreading. However, establishing the analytical relation between these layers is experimentally challenging. An alternate design change utilizing transparent conducting AZO contact to p-GaN has been designed and analyzed

Doctor of Philosophy

dissertationObservational studies are a frequently used "tool" in the field of road safety research because random assignments of safety treatments are not feasible or ethical. Data and modeling issues and challenges often plague observational road safety studies, and impact study results. The objective of this research was to explore a selected number of current data and modeling limitations in observational road safety studies and identify possible solutions. Three limitations were addressed in this research: (1) a majority of statistical road safety models use average annual daily traffic (AADT) to represent traffic volume and do not explicitly capture differences in traffic volume patterns throughout the day, even though crash risk is known to change by time of day, (2) statistical road safety models that use AADT on the "right-hand side" of the model equation do not explicitly account for the fact that these values for AADT are estimates with estimation errors, leading to potential bias in model estimation results, and (3) the current state-of-the-practice in road safety research often involves "starting over" with each study, choosing a model functional form based on the data fit, and letting the estimation results drive interpretations, without fully utilizing previous study results. These limitations were addressed by: (1) estimating the daily traffic patterns (by time of day) using geo-spatial interpolation methods, (2) accounting for measurement error in AADT estimates using measurement error models of expected crash frequency, and (3) incorporating prior knowledge on the safety effects of explanatory variables into regression models of expected crash frequency through informative priors in a Bayesian methodological framework. These alternative approaches to address the selected observational road safety study limitations were evaluated using data from rural, two-lane highways in the states of Utah and Washington. The datasets consisted of horizontal curve segments, for which crash data, roadway geometric features, operational characteristics, roadside features, and weather data were obtained. The results show that the methodological approaches developed in this research will allow road safety researchers and practitioners to accurately evaluate the expected road safety effects. These methods can further be used to increase the accuracy and repeatability of study results, and ultimately expand the current practice of evaluating regression models of expected crash frequency in observational road safety studies

Genome‐Wide Family‐Based Linkage Analysis of Exome Chip Variants and Cardiometabolic Risk

Linkage analysis of complex traits has had limited success in identifying trait‐influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African‐American ( n = 596) and 90 Hispanic ( n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two‐point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB ( P ‐value = 4 × 10 −19 ) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P ‐value <4.6 × 10 −12 ), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106817/1/gepi21801.pd

Sharing Hope Together

The primary purpose was to raise donations and aid those in need. Establishing a resource center to serve as an information center and library for farmers to gain the most up-to-date knowledge on climate change is a realistic aim and a solid sign of a successful fundraising event. It seemed like a great opportunity to engage with key contributors and supporters, so the team went ahead with it. Indeed, it may provide an opportunity to show thanks for their cooperation and provide an update on critical activities. Furthermore, it may provide an excellent opportunity to invite influencers and notable corporate leaders who are not currently involved with the charity and use it to gain new support. Knowing that a small number of people have made nearly all the campaign goal\u27s progress can inspire more giving than learning that many people have made all the goal\u27s progress. The MVC framework 7 in Dot Net Core was chosen by our team to create the website\u27s back-end, while HTML5, CSS3, Bootstrap, JavaScript, and Ajax were chosen to create the front end. Data was stored in MS-SQL. Users, Donors, and Administrators all use the fund-raising mechanism. The application is managed by the administrator. The campaigns can be posted by people as needed. Donors can sponsor campaigns or reserve events

Clinical efficacy and safety of statins in managing cardiovascular risk

Since their introduction in the 1980s, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as the one of the best-selling medication classes to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular outcomes. As our understanding of low-density lipoprotein cholesterol (LDL-C) and atherosclerosis continues to grow, the concept of ‘lower is better’ has corresponded with a ‘more is better’ approach to statin-based therapy. This review provides a detailed understanding of the clinical efficacy and safety of statins with a particular emphasis on the third generation drug, rosuvastatin

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Examining the presence of cyclical behavior in Cattle prices

The determination of cattle cyclic behavior in prices is significant to the cattle producers and for the consumers. This study focused on the cyclical, Seasonal, time series prices of cattle or cows was examined from 1983-2023. We used Harmonic regression model to determine the cycle pressure ranging from 5-to 25 years. Results indicated that there is a significant cyclical behavior in 12- and 25-year price cycle with MAPE (18.87and 12.64) and Akaike Information Criterion (AIC) (5 and 4.6). The result can assist producers in making short- and long-term pricing estimates. Keywords: - Cattle price cycle, Cyclic and seasonal length, Harmonic regression model, Time serie