Medicine and Health Sciences Commons^™

Machine Learning Framework For Real-World Electronic Health Records Regarding Missingness, Interpretability, And Fairness, Jing Lucas Liu

Theses and Dissertations--Computer Science

Machine learning (ML) and deep learning (DL) techniques have shown promising results in healthcare applications using Electronic Health Records (EHRs) data. However, their adoption in real-world healthcare settings is hindered by three major challenges. Firstly, real-world EHR data typically contains numerous missing values. Secondly, traditional ML/DL models are typically considered black-boxes, whereas interpretability is required for real-world healthcare applications. Finally, differences in data distributions may lead to unfairness and performance disparities, particularly in subpopulations.

This dissertation proposes methods to address missing data, interpretability, and fairness issues. The first work proposes an ensemble prediction framework for EHR data with large missing …

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 …

Application Of Mass Spectrometry For The Characterization Of Synthetic Oligomers And Natural Lignin, Poorya Kamali

Theses and Dissertations--Chemistry

As part of the ongoing effort to substitute finite fuel and chemical resources with renewable ones, biomass is emerging as one of the most promising sources. Biomass consists of three main components of cellulose, hemicellulose, and lignin. Traditionally, cellulose has been used extensively in pulping industry, while lignin has been considered waste and is burned to generate heat. Lignin, a complex aromatic polymer component of biomass, has the potential to be used as a source of aromatic chemicals and pharmaceutical synthons. The recalcitrant nature of lignin, the lack of effective lignin breakdown methods and analytical techniques to analyze it are …

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. …

Investigating The Uncertainties In Ct Non-Small Cell Lung Cancer Radiomics, Gary Ge

Theses and Dissertations--Radiation Medicine

Radiomics is a technique that extracts quantitative features, termed radiomic features, from medical images using data-characterization algorithms. These radiomic features can be used to identify tissue characteristics and radiologic phenotyping that are not observable by clinicians in a non-invasive, low-cost manner, potentially generating image biomarkers for clinical decision. To date, there are still many uncertainties involved in radiomics which limit its clinical implementation. Herein, we propose to explore the impact of each component in the radiomics pipeline on predicting clinical outcomes. In Chapter II, we conduct a thorough review of CT lung cancer radiomics studies to examine the typical feature …

Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Investigating The Physical Stability Of Amorphous Pharmaceutical Formulations, Travis W. Jarrells

Theses and Dissertations--Pharmacy

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in …

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 …

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 …

A Study Of The Analysis Of Hemp-Derived Oil Products: Development Of A Method For The Analysis Of Phytocannabinoids In Medicinal Products, Erin Johnson

Theses and Dissertations--Pharmacology and Nutritional Sciences

Human interactions with cannabis have a history spanning millennia as a source of fiber, food, and medicine. The plant came across Asia, Europe, and Africa with the movements of people and travelers eventually coming to the Americas with European explorers. In colonizing North America, cannabis fiber was key to the production of canvas and ropes for ships. Although fiber was the driver for cannabis production in the United States, medicinal uses were prevalent and propelled the eventual regulations. The Pure Food and Drug Act of 1906 mandated accurate labeling on drugs such as cannabis followed by the Marihuana Tax Act …

Investigations Into The Genetics Of Mixed Pathologies In Dementia, Adam Dugan

Theses and Dissertations--Epidemiology and Biostatistics

Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that leads to a loss of memory and thinking skills. While tremendous progress has been made in our understanding of the genetics underlying AD, currently known genetic variants explain only approximately 30% of the heritable risk of developing AD. One hurdle to AD research is that it can only be definitively diagnosed at autopsy, making cruder, clinic-based diagnoses more common. In recent years, several brain pathologies that mimic AD’s clinical presentation have been identified including brain arteriolosclerosis, hippocampal sclerosis (HS), and, most recently, limbic-predominant age-related TDP-43 encephalopathy (LATE). It has become …

Maternal Proximity To Mountaintop Removal Mining And Birth Defects In Appalachian Kentucky, 1997-2003, Daniel B. Cooper

Theses and Dissertations--Public Health (M.P.H. & Dr.P.H.)

Background: Extraction of coal through mountaintop removal mining (MTR) alters many dimensions of the landscape, and explosive blasts, exposed rock, and coal washing have the potential to pollute air and water with substances known to increase risk of developmental and birth anomalies. Previous research suggests that infants born to mothers living in MTR coal mining counties have higher prevalence of most types of birth defects.

Objectives: This study seeks to examine further the relationship between MTR activity and birth defects by employing individual level exposure estimation through precise satellite data of MTR activity in the Appalachian region and maternal residence …

Sexual Behaviors Associated With Online Partner-Seeking Among Men Who Have Sex With Men From Small/Midsized Towns Or Rural Areas In Kentucky, Vira Pravosud

Theses and Dissertations--Epidemiology and Biostatistics

The HIV epidemic remains one of the most significant public health issues in the United States, particularly among men who have sex with men (MSM). New avenues for partner-seeking have emerged over the past three decades, including through the Internet, social media, and geosocial networking applications. Consisting of three cross-sectional studies, this dissertation research aimed to determine associations between the use of various online tools for partner-seeking (hereafter collectively referred to as “apps”) and HIV-related sexual behaviors among 252 young adult MSM residing in small/midsized towns or rural areas in Central Kentucky, a group that has been under-represented in the …

Evaluating The Incidence Of Melanoma And Lung Cancer Of Current And Former Active-Duty U.S. Military Who Were Deployed In Support Of Operation Enduring Freedom And Operation Iraqi Freedom, Brian Kovacic

Theses and Dissertations--Epidemiology and Biostatistics

The incidence of melanoma and lung cancer has been gradually increasing in the United States over the past three decades with the reputed causes due to etiological and environmental exposures, and tobacco usage. There has been concern that melanoma and lung cancer incidence among military personnel may be associated with deployment to environments with intense sun exposure and increased smoking rates due to post-traumatic stress disorder. The aim of this study was to examine associations between deployment in support of Operation Enduring Freedom (OEF) or Operation Iraqi Freedom (OIF), from 2001 through 2015, with subsequent melanoma and lung cancer incidence. …

Design, Synthesis, And Anticancer Properties Of Ru(Ii) Complexes With Organometallic, “Expanded” Bipyridine, And O,O’-Chelating Ligands, Raphael Ryan

Theses and Dissertations--Chemistry

Cancer is a worldwide public health crisis that requires new and improved drugs to be developed to extend survival rates and improve quality of life for the patient. Platinum-based drugs are used in approximately 50% of cancer treatment regimens. These drugs are highly effective in many kinds of cancer; however, cancers can develop platinum resistance and these drugs have troubling side effects that reduced their use and efficacy. To overcome these disadvantages, many other metals have been studied for their anticancer properties. Notably, the anticancer properties of ruthenium-based agents have drawn considerable attention with multiple ruthenium complexes entering clinical trials. …

Multi-Modal Medical Imaging Analysis With Modern Neural Networks, Gongbo Liang

Theses and Dissertations--Computer Science

Medical imaging is an important non-invasive tool for diagnostic and treatment purposes in medical practice. However, interpreting medical images is a time consuming and challenging task. Computer-aided diagnosis (CAD) tools have been used in clinical practice to assist medical practitioners in medical imaging analysis since the 1990s. Most of the current generation of CADs are built on conventional computer vision techniques, such as manually defined feature descriptors. Deep convolutional neural networks (CNNs) provide robust end-to-end methods that can automatically learn feature representations. CNNs are a promising building block of next-generation CADs. However, applying CNNs to medical imaging analysis tasks is …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Development Of A Robust Treatment Delivery Framework For Stereotactic Body Radiotherapy (Sbrt) Of Synchronous Multiple Lung Lesions, Lana Catherine Critchfield

Theses and Dissertations--Radiation Medicine

Stereotactic body radiation therapy (SBRT) of lung tumors uses high doses of radiation to deliver high biological effective doses (BED) in very few fractions (1-5). With the use of highly conformal fields to cover the tumor without depositing large doses to non-cancerous structures, this technique has proven time and again to be successful at achieving high local control. However, frequently patients receiving SBRT are elderly with multiple medical comorbidities who may not tolerate long treatment times. Furthermore, many patients present with oligometastatic or multiple primary lung tumors. The success of SBRT on oligometastatic lung disease relies on physician experience with …

Evaluating The Impacts Of Antidepressant Use On The Risk Of Dementia, Ran Duan

Theses and Dissertations--Epidemiology and Biostatistics

Dementia is a clinical syndrome caused by neurodegeneration or cerebrovascular injury. Patients with dementia suffer from deterioration in memory, thinking, behavior and the ability to perform everyday activities. Since there are no cures or disease-modifying therapies for dementia, there is much interest in identifying modifiable risk factors that may help prevent or slow the progression of cognitive decline. Medications are a common focus of this type of research.

Importantly, according to a report from the Centers for Disease Control and Prevention (CDC), 19.1% of the population aged 60 and over report taking antidepressants during 2011-2014, and this number tends to …

Evaluating The Impact Of Fine Particulate Matter Pollution Standards On Mortality Rates In The Southeastern United States, Lauren Wice

MPA/MPP/MPFM Capstone Projects

The Environmental Protection Agency (EPA) continuously monitors six criteria pollutants that are known to have impacts on public health and welfare. One of these pollutants, fine particulate matter, or PM_2.5 (which includes particles that are smaller than 2.5 micrometers in diameter), is easily inhalable and can enter the lining of the lungs and the bloodstream, posing a great risk to human health. Standards for allowable concentrations of PM_2.5 were amended in 1997, 2006, and again in 2012, becoming increasingly stringent each time. According to the EPA, health organizations, and other research studies, these particles can specifically contribute to …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Aggressive Diuresis And Severity-Adjusted Length Of Hospital Stay In Acute Congestive Heart Failure Patients, Muhammad U. Butt

Theses and Dissertations--Clinical Research Design

To see if aggressive diuresis in first twenty four hours is associated with a comparable number of total days in the hospital as compared to non-aggressive diuresis. In this retrospective cohort study, we compared the length of hospital stay of consecutive patients admitted in one year based on their diuresis during the first twenty-four hours of hospitalization: aggressive diuresis (group 1) i.e. > 2400mL versus non-aggressive diuresis (group 2) i.e. ≤ 2400mL urine output. Patients were excluded if in cardiogenic shock, had creatinine level above 3 mg/dL on admission, or on dialysis. A total of 194 patients were enrolled (29 in …

Investigating The Role Of Prescription Drug Monitoring Programs In Reducing Rates Of Opioid-Related Poisonings, Nathan James Pauly

Theses and Dissertations--Pharmacy

The United States is in the midst of an opioid epidemic. In addition to other system level interventions, almost all states have responded to the crisis by implementing prescription drug monitoring programs (PDMPs). PDMPs are state-level interventions that track the dispensing of Controlled Substances. Data generated at the time of medication dispensing is uploaded to a central data server that may be used to assist in identifying drug diversion, medication misuse, or potentially aberrant prescribing practices.

Prior studies assessing the impact of PDMPs on trends in opioid-related morbidity have often failed to take into account the wide heterogeneity of program …

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 …

Using The Qbest Equation To Evaluate Ellagic Acid Safety Data: Generating A Qnoael With Confidence Levels From Disparate Literature, Cynthia Rose Dickerson

Theses and Dissertations--Pharmacy

QBEST, a novel statistical method, can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL or QNOAEL) of a New Molecular Entity (NME) in order to anticipate a safe starting dose for beginning clinical trials. The NOAEL from QBEST (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from the lab. The QNOAEL is similar in some ways to the Benchmark Dose Method (BMD) used widely in toxicological research, but is superior to the BMD in some ways. The QNOAEL simulation generates an intuitive curve that is comparable to the …

Using Prescription Drug Monitoring Data To Inform Population Level Analysis Of Opioid Analgesic Utilization, Huong T. T. Luu

Theses and Dissertations--Epidemiology and Biostatistics

Increased opioid analgesic (OA) prescribing has been associated with increased risk of prescription opioid diversion, misuse, and abuse. States established prescription drug monitoring programs (PDMPs) to collect and analyze electronic records for dispensed controlled substances to reduce prescription drug abuse and diversion. PDMP data can be used by prescribers for tracking patient’s history of controlled substance prescribing to inform clinical decisions.

The studies in this dissertation are focused on the less utilized potential of the PDMP data to enhance public health surveillance to monitor OA prescribing and co-prescribing and association with opioid overdose mortality and morbidity. Longitudinal analysis of OA …

An Exploratory Statistical Method For Finding Interactions In A Large Dataset With An Application Toward Periodontal Diseases, Joshua Lambert

Theses and Dissertations--Epidemiology and Biostatistics

It is estimated that Periodontal Diseases effects up to 90% of the adult population. Given the complexity of the host environment, many factors contribute to expression of the disease. Age, Gender, Socioeconomic Status, Smoking Status, and Race/Ethnicity are all known risk factors, as well as a handful of known comorbidities. Certain vitamins and minerals have been shown to be protective for the disease, while some toxins and chemicals have been associated with an increased prevalence. The role of toxins, chemicals, vitamins, and minerals in relation to disease is believed to be complex and potentially modified by known risk factors. A …

Development Of Diverse Size And Shape Rna Nanoparticles And Investigation Of Their Physicochemical Properties For Optimized Drug Delivery, Daniel L. Jasinski

Theses and Dissertations--Pharmacy

RNA nanotechnology is an emerging field that holds great promise for advancing drug delivery and materials science. Recently, RNA nanoparticles have seen increased use as an in vivo delivery system. RNA was once thought to have little potential for in vivo use due to biological and thermodynamic stability issues. However, these issues have been solved by: (1) Finding of a thermodynamically stable three-way junction (3WJ) motif; (2) Chemical modifications to RNA confer enzymatic stability in vivo; and (3) the finding that RNA nanoparticles exhibit low immunogenicity in vivo.

In vivo biodistribution and pharmacokinetics are affected by the physicochemical …

Statistical Analyses To Detect And Refine Genetic Associations With Neurodegenerative Diseases, Yuriko Katsumata

Theses and Dissertations--Epidemiology and Biostatistics

Dementia is a clinical state caused by neurodegeneration and characterized by a loss of function in cognitive domains and behavior. Alzheimer’s disease (AD) is the most common form of dementia. Although the amyloid β (Aβ) protein and hyperphosphorylated tau aggregates in the brain are considered to be the key pathological hallmarks of AD, the exact cause of AD is yet to be identified. In addition, clinical diagnoses of AD can be error prone. Many previous studies have compared the clinical diagnosis of AD against the gold standard of autopsy confirmation and shown substantial AD misdiagnosis Hippocampal sclerosis of aging (HS-Aging) …