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- All Subjects: Genetics
Description
Serotonin 2A receptor (5-HT2AR) levels are decreased in the brains of schizophrenia patients. This phenomenon is modeled in mice that lack the transcription factor Egr3. The head-twitch response (HTR) is a behavioral assay used to assess the physiological function of 5-HT2ARs. However, current quantification methods are time consuming and prone to inter-rater variability. Here, we demonstrate the validity and reliability of an automated head-twitch system to quantify HTRs of Egr3-/- mice.
ContributorsOzols, Annika Biruta (Author) / Lisenbee, Cayle S. (Thesis director) / Gallitano, Amelia L. (Committee member) / College of Health Solutions (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
This thesis explores the ethical implications of using facial recognition artificial intelligence (AI) technologies in medicine, with a focus on both the opportunities and challenges presented by the use of this technology in the diagnosis and treatment of rare genetic disorders. We highlight the positive outcomes of using AI in medicine, such as accuracy and efficiency in diagnosing rare genetic disorders, while also examining the ethical concerns including bias, misdiagnosis, the issues it may cause within patient-clinician relationships, misuses outside of medicine, and privacy. This paper draws on the opinions of medical providers and other professionals outside of medicine, which finds that while many are excited about the potential of AI to improve medicine, concerns remain about the ethical implications of these technologies. We discuss current legislation controlling the use of AI in healthcare and its ambiguity. Overall, this thesis highlights the need for further research and public discourse to address the ethical implications of using facial recognition and AI technologies in medicine, while also providing recommendations for its future use in medicine.
ContributorsVargas Jordan, Anna (Author) / Kohlenberg, Maiya (Co-author) / Martin, Thomas (Thesis director) / Sellner, Erin (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor)
Created2023-05
Evaluating the Heterogeneity of Logistic Regression Models to Predict Coronary Artery Disease Status
Description
Coronary artery disease (CAD) is one of the most diagnosed heart diseases globally, affecting about 5% of adults over the age of twenty[1]. Lifestyle changes can positively impact risk of developing CAD and are especially important for individuals with high genetic risk [1]. In this study, we sought to predict the likelihood of developing CAD using genetic, demographic, and clinical variables. Leveraging genetic and clinical data from the UK Biobank on over 500,000 individuals, we classified and separated 500 genetically similar individuals to a target individual from another 500 genetically dissimilar individuals. This process was repeated for 10 target individuals as a proof-of-concept. Then, CAD-related variables were used and these include age, relevant clinical factors, and polygenic risk score to train models for predicting CAD status for the 500 genetically similar and 500 genetically dissimilar groups, and determine which group predicts the likelihood of CAD more accurately. To compute genetic similarity to the target individuals we used the Mahalanobis distance. To reduce the heterogeneity between sexes and races, the studies were restricted to British male Caucasians. The models using the more similar individuals demonstrated better predictive performance. The area under the receiver operating characteristic curve (AUC) was found to be significantly higher for the ‘similar’ rather than the ’dissimilar’ groups, indicating better predictive capability (AUC=0.67 vs. 0.65, respectively; p-value<0.05). These findings support the potential of precision prevention strategies, since one should build predictive models of disease for any one target individual from more similar individuals to that target even within an otherwise homogenous group of individuals (e.g., British Caucasians). Although intuitive, such practices are not done routinely. Further validation and exploration of additional predictors are warranted to enhance the predictive accuracy and applicability of the model.
ContributorsPandari, Sadhana (Author) / Ghassamzadeh, Hassan (Thesis director) / Scotch, Matthew (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor)
Created2024-05
Description
Computational and systems biology are rapidly growing fields of academic study, but unfamiliar researchers are impeded by a lack of accessible, programming-optional, modelling tools. To address this gap, I developed BioSSA, a web framework built on JavaScript and D3.js which allows users to explore a small library of curated biophysical models as well as create and simulate their own reaction network. The mathematical foundation of BioSSA is the Stochastic Gillespie Algorithm, which is widely used in mathematical modeling and biology to represent chemical reaction systems. SGA is particularly well-suited as an introductory modelling tool because of its flexibility, broad applicability, and its ability to numerically approximate systems when analytical solutions are not available. BioSSA is freely available to the community and further improvements are planned.
ContributorsRamirez, Daniel (Author) / Ghasemzadeh, Hassan (Thesis director) / Liu, Li (Committee member) / Lu, Mingyang (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor)
Created2023-05
Description
Vitamin D is a nutrient that is obtained through the diet and vitamin D supplementation and created from exposure to Ultraviolet B (UVB) radiation. While there are many factors that determine how much serum 25-hydroxyvitamin D (25(OH)D) concentration is in the body, little is known about how genetic variation in vitamin D-related genes influences serum 25(OH)D concentrations resulting from daily vitamin D intake and exposure to direct sunlight. Previous studies show that common genetic variants rs10741657 (CYP2R1), rs4588 (GC), rs228678 (GC), and rs4516035 (VDR) act as moderators and alter the effect of outdoor time and vitamin D intake on serum 25(OH)D concentrations. The objective of this study is to analyze the associations between serum 25(OH)D concentrations resulting from outdoor time and vitamin D intake, and genetic risk scores (GRS) established from previous studies involving single nucleotide polymorphisms (SNP) located on or near genes involving vitamin D synthesis, transport, activation, and degradation in 102 Hispanic and Non-Hispanic adults in the San Diego County, California. This study is a secondary analysis of data from the Community of Mine study. Global Positioning System (GPS) data collected by the Qstarz GPS device worn by each participant was used to measure outdoor time, a proxy measurement for sun exposure time. Vitamin D intake was assessed using two 24-hour dietary recalls. Blood samples were measured for serum 25(OH)D concentrations. DNA was provided to assess each participant for the various genetic variants. Adjusted analyses of the GRS and serum 25(OH)D concentrations showed that individuals with high GRS (3-4) had lower serum 25(OH)D concentrations than individuals with low GRS (0-2) for both Nissen GRS and Rivera-Paredez GRS.
ContributorsAnderson, Heather Ray (Author) / Sears, Dorothy (Thesis advisor) / Alexon, Christy (Committee member) / Dinu, Valentin (Committee member) / Jankowska, Marta (Committee member) / Arizona State University (Publisher)
Created2022
Description
Obesity and its underlying insulin resistance are caused by environmental and genetic factors. DNA methylation provides a mechanism by which environmental factors can regulate transcriptional activity. The overall goal of the work herein was to (1) identify alterations in DNA methylation in human skeletal muscle with obesity and its underlying insulin resistance, (2) to determine if these changes in methylation can be altered through weight-loss induced by bariatric surgery, and (3) to identify DNA methylation biomarkers in whole blood that can be used as a surrogate for skeletal muscle.
Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.
These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.
Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.
These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.
ContributorsDay, Samantha Elaine (Author) / Coletta, Dawn K. (Thesis advisor) / Katsanos, Christos (Committee member) / Mandarino, Lawrence J. (Committee member) / Shaibi, Gabriel Q. (Committee member) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2017
Description
All biological processes like cell growth, cell differentiation, development, and aging requires a series of steps which are characterized by gene regulation. Studies have shown that gene regulation is the key to various traits and diseases. Various factors affect the gene regulation which includes genetic signals, epigenetic tracks, genetic variants, etc. Deciphering and cataloging these functional genetic elements in the non-coding regions of the genome is one of the biggest challenges in precision medicine and genetic research. This thesis presents two different approaches to identifying these elements: TreeMap and DeepCORE. The first approach involves identifying putative causal genetic variants in cis-eQTL accounting for multisite effects and genetic linkage at a locus. TreeMap performs an organized search for individual and multiple causal variants using a tree guided nested machine learning method. DeepCORE on the other hand explores novel deep learning techniques that models the relationship between genetic, epigenetic and transcriptional patterns across tissues and cell lines and identifies co-operative regulatory elements that affect gene regulation. These two methods are believed to be the link for genotype-phenotype association and a necessary step to explaining various complex diseases and missing heritability.
ContributorsChandrashekar, Pramod Bharadwaj (Author) / Liu, Li (Thesis advisor) / Runger, George C. (Committee member) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2020