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32942.Pdf (3.33 MP RJ Vaitinadin – PhD Epidemiology Dissertation A Study of Cardiometabolic Traits and their Progression, over a Decade, in a Croatian Island Population A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Division of Epidemiology of the Department of Environmental Health of the College of Medicine by Nataraja Sarma Vaitinadin M.B.B.S. - Jawaharlal Institute of Post-Graduate Medical Education and Research M.P.H. - University of Cincinnati March, 2019 Committee Chair: Ranjan Deka, Ph.D. 1 MP RJ Vaitinadin – PhD Epidemiology Dissertation Abstract The growth of computation and big data have allowed us to ask more and more complex questions about healthcare. One of the key questions being asked is about using data to predict outcomes. With the alarming rise in cardiometabolic diseases, and associated healthcare costs, it is about time to focus energy and resources on developing methodologies to predict disease status in the future. We have implemented a productive workflow that takes data from epidemiologic field studies, to develop prediction models to determine disease status a decade into the future. The models were tested for accuracy and were used to develop a diagnostic test. The test was validated using an ROC (Receiver Operating Characteristic) curve. Further, the model was cross validated on untrained data. The robustness of the approach was demonstrated across four different disease outcomes – high blood pressure, coronary heart disease, diabetes and gout. We further examined changes in biomarker measurements at the population level, over time and with sex. Both these approaches target two important aspects of public health – precision medicine and population health. To that extent, the study is a successful demonstration of utilizing field data to develop and test contrasting research questions – at the individual level and at the population level, simultaneously. 2 MP RJ Vaitinadin – PhD Epidemiology Dissertation 3 MP RJ Vaitinadin – PhD Epidemiology Dissertation Acknowledgements At the outset, I would like to record my gratitude to the faculty and staff at the Department of Environmental Health for the wonderful experiences during the graduate program. I will always be in debt to Dr Ranjan Deka, my advisor and mentor, and to Dr Aimin Chen, for their kindness, steadfast guidance and financial support throughout the program. Dr Deka and Dr Chen have taught me the art and the science of epidemiologic research – that unique blend of skills where methodologic rigor happily co-exists with inspiring moments of discovery. I would like to thank Dr Marepalli Rao for spending long hours putting up with my ignorance of statistics and for inspiring my interest in the field. I would like to thank my qualifying committee – Dr Aimin Chen, Dr Marepalli Rao and Dr Eric Hall, for their guidance and support in understanding the research process. I am grateful to my dissertation committee – Dr Ranjan Deka (Chair), Dr Aimin Chen, Dr Roman Jandarov and Dr Jane C, Khoury – for all their precious time spent in trying to work through my inadequacies, even while encouraging and supporting me at every turn of this arduous journey. I would also like to thank Dr Mary-Beth Genter, Angela Riall, Amy Itescu and Kathy McCann for their patience and support through the administrative minefield. I would like to thank all my teachers, friends and colleagues – past and present – for all the experiences that have moulded my life. I am grateful for the steadfast support, sacrifices and understanding of Aparna Sreeshankaren, Mrs and Mr Sreeshankaren, and Chandramouli Shankaren. Manasvini and Anirudh … you inspire me every day! I have no illusions about how insignificant I am in the grand scheme of things … and yet, through all of life’s challenges, there seems to be the invisible hand … guiding … protecting … thank you, Mahaperiyava! How can I forget my late grandparents? Their love and encouragement played no small part in helping me accomplish everything I have done so far. I will always be in debt to my parents, Mrs (Late) and Mr Vaitinadin. Mom … I miss you, this one is for you, up there! Nataraja Sarma Vaitinadin, March 27, 2019 4 MP RJ Vaitinadin – PhD Epidemiology Dissertation Table of Contents Chapter 1: Cardiometabolic traits Study – Introduction, Hypothesis and Specific Aims 09 Introduction to Cardiometabolic Traits and Disease 10 Hypothesis and Specific Aims 11 Chapter 2: Background, Significance and Public Health Importance 12 Background 13 Significance and Public Health Importance 13 Chapter 3: Methods 15 Description of Study Population 16 Laboratory and Other Data Collection Methods 17 Cardiometabolic Disease and Trait Characterization 19 Statistical Methods and Specific Aims 19 Predictive Modeling 22 Diagnostic Test and Receiver Operating Characteristic 22 Rigor and Transparency 22 Chapter 4: The High Blood Pressure (HBP) Cohort – Results & Discussion 23 Descriptive Statistics 24 Exploratory Data Analysis 25 Epidemiologic Association Measures 26 Predictive Modeling for HBP 27 Diagnostic Test for HBP status 28 Repeated Cross Validation 30 5 MP RJ Vaitinadin – PhD Epidemiology Dissertation Chapter 5: The Coronary Heart Disease Cohort (CHD) – Results & Discussion 32 Descriptive Statistics 33 Exploratory Data Analysis 34 Epidemiologic Association Measures 35 Predictive Modeling for CHD 36 Diagnostic Test for CHD status 37 Repeated Cross Validation 38 Chapter 6: The Diabetes Cohort – Results & Discussion 40 Descriptive Statistics 41 Exploratory Data Analysis 42 Epidemiologic Association Measures 43 Predictive Modeling for Diabetes 44 Diagnostic Test for Diabetes Status 45 Repeated Cross Validation 47 Chapter 7: The Gout Cohort – Results & Discussion 49 Descriptive Statistics 50 Exploratory Data Analysis 51 Epidemiologic Association measures 52 Predictive Modeling for Gout 53 Diagnostic Test for Gout Status 54 Repeated Cross Validation 56 6 MP RJ Vaitinadin – PhD Epidemiology Dissertation Chapter 8: Study of Population Means of Fibrinogen - Results and Discussion 58 Descriptive Statistics and Paired t-Test 59 Does time influence the population mean of fibrinogen? 60 Is there an interaction between time and sex that affects the population mean of fibrinogen? 61 Chapter 9: Study of Population Means of Uric Acid - Results and Discussion 62 Descriptive Statistics and Paired t-Test 63 Does time influence the population mean of uric acid? 64 Is there an interaction between time and sex that affects the population mean of uric acid? 65 Chapter 10: Conclusion 66 Major Conclusions 67 Strengths and Limitations 68 Future Research 69 References 70 Appendix 77 Key Terms 103 7 MP RJ Vaitinadin – PhD Epidemiology Dissertation A Study of Cardiometabolic Traits and their Progression, over a Decade, in a Croatian Island Population 8 MP RJ Vaitinadin – PhD Epidemiology Dissertation Chapter 1: Cardiometabolic Traits Study – Introduction, Hypothesis and Specific Aims 09 Introduction to Cardiometabolic Traits and Disease 10 Hypothesis and Specific Aims 11 9 MP RJ Vaitinadin – PhD Epidemiology Dissertation Chapter 1: Cardiometabolic Traits Study - Introduction, Hypothesis and Specific Aims 1.1 Introduction to Cardiometabolic Traits and Disease Cardiometabolic diseases are complex diseases that arise due to complicated interactions between genetic, lifestyle, and environmental factors, and this makes it difficult to understand, let alone manage, these medical conditions (Lander & Schork 1994; Kibertsis & Roberts 2002). The cardiometabolic conditions that we focus on in this study are – high blood pressure, coronary heart disease, diabetes and gout. High Blood pressure refers to increased vascular resistance to blood flow. Typically, normal blood pressure is around 120 mm Hg systolic and 80 mm Hg diastolic. Systolic at or above 140 mm Hg is high blood pressure, similarly, diastolic at or above 90 mm Hg is considered high blood pressure. This can manifest as breathlessness, reduced blood supply to organs, added pressure on the heart, and a higher risk of rupture and bleeding from blood vessels in the brain (Merai, 2016; Mozzafarian, 2015; Heidenreich, 2011; Palar, 2009). Coronary heart disease refers to the development of atherosclerotic plaques that progress to diminish blood supply to cardiac tissue, impairing cardiac function. This can manifest as reduced exercise tolerance, breathlessness, chest pains and eventually, a cardiac arrest, also known as heart attack (ACCF/AHA/ACP/AATS/PCNA/SCAI/STS, 2012; Diamond, 1982). Diabetes, and in our context type 2, refers to the development of the inability to maintain normal levels of blood glucose due to insulin resistance, the inability of secreted insulin to act effectively in reducing blood sugar levels (Beckman, 2002). This results in 10 MP RJ Vaitinadin – PhD Epidemiology Dissertation higher levels of insulin, higher levels of blood glucose, and over a period, higher HbA1c (glycosylated hemoglobin levels) – this is a measure of the average blood sugar level over the previous 120 days. This manifests as reduced healing capability, increases hunger, increases urination and thirst (Beckman, 2002; Combettes, 2006). Gout is a metabolic condition, characterized by the deposition of monosodium urate crystals in joint spaces and eventually, even in the kidneys, due to prolonged elevated levels of uric acid in the blood, caused by derangements in the mechanisms involved in metabolizing uric acid. This results in
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