Preventing, delaying and managing morbidities is critical to sustain a strong economy and health care system as the proportion of adults over 65 years increases. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Americans. Signs of CVD are apparent in the vasculature before symptoms of clinical disease are present. Subclinical disease can be measured using non-invasive B-mode ultrasound to assess carotid-femoral pulse wave velocity, common carotid artery intima media thickness, adventitial diameter and lumen diameter. Vascular aging is a natural process that can be modified by lifestyle and pharmacologic interventions. The purpose of this dissertation is to evaluate the impact of lifestyle factors on vascular aging. Hormone therapy use in early postmenopausal women was associated with significantly smaller adventitial and lumen diameter than those who did not use hormone therapy after adjustment for traditional CVD risk factors. These results concur with findings from another study in which higher levels of endogenous estrogen was related to smaller adventitial diameters. Together, these results suggest endogenous and exogenous estrogen have similar effects on adventitial diameter. Sedentary, overweight and obese male young adults at low risk of sleep apnea, and non-snorers had better vascular health, reflected in smaller adventitial and lumen diameters, than those at high risk for sleep apnea and snorers in a cross-sectional study. Results were robust after adjustment for age and systolic blood pressure and add to the literature linking CVD with sleep disordered breathing. Sedentary older adults who participated in a 6-month physical activity intervention had a clinically relevant decline in arterial stiffness, but greater increases in adventitial and lumen diameters compared to control participants. These findings support that it is never too late to gain cardiovascular benefit from physical activity. Research is needed to understand the implications of arterial diameter following introduction of physical activity to sedentary older adults. Together these studies support the public health importance of lifestyle factors contribution to subclinical CVD. Each study also provides evidence that measurement of adventitial diameter is critical for a comprehensive understanding of the vascular remodeling processes that accompany these lifestyle changes across the vascular aging continuum.

Head and neck cancer accounted for 3.3% of incident malignancies and 2.0% of cancer-deaths in the US in 2009, the majority of which are squamous in origin. Thus, there is a need for novel biomarkers for early detection and prognosis of squamous cell carcinoma of the head and neck (SCCHN). MicroRNA-137 plays a role in cell cycle control through negative regulation of Cdk6, and has been reported to undergo promoter methylation in oral squamous cell carcinoma. Oral rinse is a non-invasive mode of DNA collection, which may have some utility in detection of promoter methylation. The primary goals of this research were to determine if miR-137 promoter methylation occurs in all SCCHN, including pharyngeal and laryngeal tumors, and whether it is detectable in oral rinse samples; and to assess miR-137 promoter methylation as an etiologic and prognostic biomarker for SCCHN. DNA was extracted from oral rinses from 99 SCCHN patients and 99 cancer-free control subjects and from tumor tissue of 67 SCCHN patients; paired oral rinses and tumor tissue was available for 64 of the SCCHN patients. Promoter methylation status of miR-137 was determined by methylation-specific PCR. We identified a strong association between miR-137 promoter methylation detected in oral rinses and SCCHN (OR = 4.80, 95% CI: 1.23-18.82). There was a strong positive association between female gender and miR-137 promoter methylation in oral rinse from SCCHN patients (OR = 5.30, 95% CI: 1.20-23.44) and an inverse association with body mass index (OR = 0.88, 95% CI: 0.77-0.99). Promoter methylation of miR-137 in tumor tissue was associated with poorer overall survival (HR = 3.68, 95% CI: 1.01-13.38). In spite of its low sensitivity (21.2%), miR-137 methylation detected in oral rinse may have future value in methylation panels for early diagnosis of SCCHN due to its high specificity (97.0%) and occurrence in early stage disease; and its detection in tumor tissue has promise as a prognostic marker. The identification of novel diagnostic and prognostic biomarkers for SCCHN such as miR-137 promoter methylation will significantly impact public health through the reduction of morbidity and mortality that occurs as a result of this disease.

Osteoporosis is a major public health problem in men and women. Low bone mineral density (BMD) is a major risk factor for fracture. Fractures have major implications for morbidity and mortality. This research project evaluated correlates of trabecular and cortical vBMD at the radius and tibia in primarily Caucasian men aged 69 years or older using the Osteoporotic Fractures in Men study (MrOS). The correlation between serum 25-hydroxy vitamin D [25(OH)D] and bone density, content, geometry and strength was also assessed using Caucasian men from MrOS and men of African descent from the Tobago Bone Health Study, aged 65 years and older. We also investigated the longitudinal impact of serum leptin and adiponectin on bone loss and fractures in the Health Aging and Body Composition study (Health ABC) in men and women, aged 70 years and older, of African American and Caucasian descent. Our findings have important public health implications. We have a better understanding of how different factors are correlated with trabecular and cortical and vBMD. Future research can generate hypotheses to evaluate these associations prospectively. Men of African descent had significantly higher 25(OH)D than Caucasians, which has never been reported. Serum 25(OH)D was positively correlated with indices of bone strength in Caucasian men, but not men of African descent. Serum 25(OH)D thresholds were identified at an estimated 20 ng/ml (lower than previous consensus of 30 ng/ml), greater levels of 25(OH)D had minimal effects on bone measures. Significant correlations between 25(OH)D occurred only at cortical regions. Prospective studies that evaluate the impact of 25(OH)D on trabecular and cortical vBMD loss are needed. There was an association between higher adiponectin and greater risk of incident fracture in men only. We also report that adiponectin predicted greater hip areal BMD (aBMD) loss among women, but not men. The impact of leptin on bone loss and incident fractures was largely attenuated by BMI and weight change. This study provides strong evidence that higher levels of adiponectin may increase the risk of bone loss and fracture. Studies are needed to explain these differential associations for adiponectin in women and men.

Prostate cancer is one of the most common malignancy affecting blacks worldwide. Blacks have a higher incidence and prevalence of prostate cancer than Caucasians. Treatment for prostate cancer usually involves androgen deprivation therapy. Even though androgen deprivation therapy has a high efficacy there are many deleterious side effects such as increase in body fat. Consequently, we investigated the association between androgen deprivation therapy for prostate cancer and the rate of change of percent total body fat in a cohort of Afro-Tobagonian men. Case-control analysis of 1691 men in our study indicated that, men with prostate cancer exposed to ADT had higher increases in percent total body fat over time compared to unexposed men. Likewise, obesity and hypertension disproportionately affects individuals of African descent. These complex diseases are multifactorial in origin and are typically controlled by many genes. Consequently, we investigated the association between ADRB2, body composition and blood pressure. We also investigated the association between AR CAG repeats and body composition. Cross-sectional analysis of 2,584 men in our cohort indicated that, men with shorter AR CAG repeats had higher body fat measurements (DEXA). We found that the direction of the association was opposite what we had anticipated, of men with longer AR CAG repeats having higher body fat measurements. 1,965 men were investigated cross-sectionally to determine the association between ADRB2, body composition and blood pressure. We found no association between ADRB2, DEXA measures of body fat and blood pressure. In our cohort of Afro-Tobagonian men AR CAG repeats and ADRB2 did not show an association with our outcome of interest. Even though we had non-significant findings, other genes should be evaluated to assess if an association exists with body composition and blood pressure in Tobago population. These studies are of public health relevance or importance because they contribute epidemiologic information to the body of scientific inforamtion available especially regarding Tobago men.

The dissertation uses health related quality of life (HRQoL) for evaluating treatment effectiveness. The research settings in the dissertation include observational cohort study and randomized clinical trial. The first research project examines the effect of Sahaja Yoga Meditation on quality of life. The study investigates whether the post intervention HRQoL, perceived anxiety assessment and hypertensive control is different in patients treated with meditation plus conventional therapy than patients treated with conventional therapy alone. The study shows that Sahaja Yoga Meditation treatment is associated with significant improvements in quality of life, anxiety reduction and blood pressure control. The second research project examines the association of age on clinical and quality of life outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D); specifically, among patients with both type 2 diabetes and coronary heart disease, whether a treatment strategy (prompt revascularization or medical therapy for heart disease and insulin sensitizing or insulin providing drugs for type 2 diabetes) is more preferable for older individuals in terms of clinical and HRQoL endpoints. The study shows that older patients are at greater risk for cardiovascular events but the effectiveness of cardiac treatment strategies and glycemic control strategies does not differ by age. Older patients experience an accelerated decline in health status than their younger peers. The third research project investigates the longitudinal relationship between body mass index (BMI) and heath status outcomes in BARI 2D. The study reports an inverse association between BMI and health status outcomes in patients with both stable ischemic heart disease and type 2 diabetes. Weight reduction is desirable for obese patients, but may not be necessary for overweight but non-obese patients to achieve improvements in functional capacity and perceived Energy outcomes. The public health significance of the dissertation lies in the research findings on treatments that result in better clinical or quality of life outcomes for patients with chronic diseases, but also contrasts the strength and weakness of HRQoL studies and demonstrates strategies to overcome the methodological challenges in conducting HRQoL research in clinical studies.

Individuals with type 1 diabetes (T1D) have significantly higher mortality rates than their peers in the general population. Major advances in the management of T1D occurred during the 1980s and 1990s, but recent data on their long-term effects on overall and cause-specific mortality are limited, especially in the United States. A phenomenon, known as dead-in-bed syndrome, is of particular concern as it occurs in young, healthy T1D individuals who are unexpectedly found dead in bed. Using follow-up data from a large population-based cohort, this dissertation provides contemporary mortality rates in persons with long-standing T1D. Cause-specific mortality is also explored, focusing on how mortality rates from major causes compare to the general population and on characterizing T1D deaths that meet the criteria for dead-in-bed syndrome. Overall, the mortality of individuals with T1D is seven times higher than seen in the general population. T1D individuals diagnosed more recently have significantly lower mortality rates than those diagnosed earlier, even after controlling for age. The greatest improvements in mortality have occurred in deaths from diabetes-related causes (diabetic coma, renal disease, cardiovascular disease, or infection), suggesting long-term benefits to improved T1D care. In a pattern quite contrary to what is seen in the general population, females with T1D have a higher mortality than males with T1D, especially from diabetes-related causes. While African-Americans with T1D have much higher mortality rates than T1D Caucasians in this cohort, this racial difference was similar to that seen in the general population. Finally, dead-in-bed syndrome in this population appears associated with male sex, low BMI, and disturbed metabolic control (high HbA1c, high daily insulin dose, and a history of severe hypoglycemia). The public health implications of this dissertation are considerable, as it provides insight into the causes of premature mortality in T1D, permitting the development of more effective and targeted preventative strategies. These findings also have the potential to change routine care practices to address disparities by race and sex in T1D mortality, and resolve disparities in health and life insurance provisions, since antiquated T1D mortality estimates are currently used, which do not account for recent advances in T1D treatments.

Lung cancer is the leading cause of cancer death in the United States. However, few new and effective treatments are available for lung cancer. A comprehensive understanding of the multiple signaling pathways that lead to tumor growth is a prerequisite for more effective and targeted cancer treatments. The purpose of this research was to investigate the relationship between proteins [hepatocypte growth factor (HGF), c-Met, and estrogen receptor-beta (ER-beta)] and gene expression of ER-beta (ESR2) and lung cancer survival along with identifying meaningful expression patterns of seven biomarkers [HGF, c-Met, ER-alpha, ER-beta, progesterone receptor (PR), aromatase, and epidermal growth factor receptor (EGFR)]. We used immunohistochemistry to quantify the expression of seven proteins in primary lung tumor tissues from the Lung Cancer Specialized Program of Research Excellence substudy (N=204). The generalized linear mixed model approach, which controlled for sample type (tissue microarray vs. whole-section), showed high HGF expression associated negatively with advanced cancer stage (Pglobal=0.05) and positively with smoking (Pglobal=0.14). After accounting for stage and other factors, neither HGF nor c-Met expression predicted survival. Using a cluster algorithm, two groups were identified: (Cluster 1: high expression of ER-alpha ER-beta, cytoplasmic PR, EGFR, and aromatase; Cluster 2: high expression of HGF, c-Met, and nuclear PR). Two lung cancer subgroups exhibiting dissimilar 7-protein IHC expression patterns were similar in terms of host and tumor characteristics and in terms of overall survival (log rank test: p=0.69). Among 22 htSNPs of ESR2 gene, we have identified that rare allele of rs1256061 is associated with the maximum ER-beta expression among patients with adenocarcinoma, but not with squamous cell carcinoma. The results of this research enhanced the knowledge of the role of HGF and c-Met on lung cancer survival and also suggested that the relationship between genetic variation of ESR2 gene and protein expression may differ by lung cancer histology. Understanding the roles, the expression patterns, and the genetic of steroid hormones, growth factors and their receptors in lung cancer is of great public health significance because it may enable biologically directed and individually tailored treatment and their possible use as biomarkers for early detection and prevention.

Cardiovascular disease (CVD) is a critical public health challenge, and the leading cause of death for both genders in the United States and worldwide. Much research has focused on addressing the health burden associated with CVD, and has identified a number of modifiable risk factors (i.e., lipid abnormalities, hypertension, obesity, the metabolic syndrome, diabetes, and physical inactivity). One issue affecting CVD risk factors may be the built environment, which includes all things that are developed and altered by man. The built environment may impact health, yet, the underlying mechanisms by which it influences health remains unknown. The purpose of this study was to examine the association between the built environment and CVD risk, the degree to which these associations are influenced by race, and the extent to which assessments of the environment differ by the method applied. Significant inverse relationships were found between the built environment and BMI, obesity, diabetes mellitus, hypertension, and physical inactivity. Physical activity was found to partially mediate the relationship between the built environment and BMI. In Whites, significant inverse relationships were found between the built environment and BMI, obesity, and physical inactivity. Again, physical activity was found to mediate the relationship between the built environment and BMI. No significant relationships were found between the built environment and measures of CVD risk in Blacks. Environmental assessments revealed fair agreement between ratings from participants and independent evaluators, although agreement was better for more objective items. Agreement was also higher for racially mixed neighborhoods. Measurement of objective attributes revealed a significant difference in the mean distance between neighborhood ratings for participants and independent evaluators for the presence of sidewalks; and among participants, there was a significant difference in the mean distance to trees. Information from this study is of considerable public health significance, as it emphasizes the need to consider race in future interventions and modifications to the built environment, and highlights some of the measurement issues surrounding the built environment. By investigating relationships between the built environment and other measures of CVD risk, additional insights on adequate and appropriate CVD interventions for all populations are gained.

Background: Major chronic diseases such as cardiovascular disease, renal dysfunction and metabolic syndrome are having excessive impact on African Americans with higher prevalence rates, mortality and morbidity. But, relatively very few studies have been conducted among populations of African ancestry to evaluate the disease burden and etiology. This proposed study was built upon seven large, multigenerational families of African descent, residing on the island of Tobago, to investigate the genetic impact on major chronic diseases, and to evaluate the association of novel biochemical markers with subclinical cardiovascular measurements. Methods: Lipid profiles, subclinical cardiovascular measurements and renal function biomarkers were measured in 402 Afro-Caribbean individuals, aged 18 to 103 years, from 7 large, multi-generation pedigrees (average family size: 50; range: 19 to 96; 3535 relative pairs). Estimated GFR was calculated using the Modification of Diet in Renal Disease Study (MDRD) formula for standardized serum creatinine. Heritability (h2) of cardio-metabolic renal traits was estimated employing maximum likelihood methods using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Multivariate regression analysis was performed to assess the association between renal function biomarkers and the subclinical cardiovascular measures, incorporating the effects of the relatedness of family members. Results: We determined that, among these Afro-Caribbeans of Tobago, renal function and metabolic syndrome related traits are all heritable phenotypes. The additive genetic effects accounted for 20-30% of the residual variation of several kidney function related traits. The heritability of each metabolic component ranged from 21% for large waist circumference to 46% for HDL-cholesterol (P<0.05). Using the National Cholesterol Education Program Expert Panel (NCEP) and Treatment of High Blood Cholesterol in Adults (Adult Treatment panel III) (ATP III) definition, 18.6% (23.3% women and 11.8% men) of the participants had metabolic syndrome. As a novel renal function biomarker, Cystatin C has heritability of 0.32 &#x00B1; 0.1 (P<0.0001), after adjusting for age, gender, hypertension, triglyceride and insulin level. Not only does cystatin C indicate renal function, but it was also significantly associated with ABI (P=0.02) and PWV (P=0.04) in this Afro-Caribbean population. Serum creatinine, microalbuminuria and eGFR were not found to be related to subclinical cardiovascular disease. Public Health Significance: This work was the first to estimate the heritability of renal function biomarkers and metabolic syndrome related traits among an African ancestry population living in the Caribbean. The significant finding of the association between serum Cystatin C level and subclinical cardiovascular disease suggest a promising biomarker for both renal function and cardiovascular disease. If this result is confirmed, Cystatin C could be a useful prognostic tool in this high risk population.

Patients with breast cancer metastases have very poor survival. Delays in the initiation of breast cancer treatment may adversely affect survival. Comorbid illness is more common in older women. Comorbid illness may explain effects of age on metastatic breast cancer survival outcomes. Comorbid illness may affect treatment delay. The purpose of the present study was to 1) identify factors related to survival following metastatic breast cancer diagnosis, 2) assess the impact of delay in treatment on survival while controlling for immortal time bias, and 3) evaluate the role of comorbidity as a mediator of survival disparity between younger (&le; 51 years) and older (> 51 years) patients. A total of 557 patients with the initial breast cancer metastasis diagnosis have been followed up between January 1, 1999 and June 30, 2008. Prognostic factors and outcomes of these patients were analyzed using log-rank test and Cox regression model, demonstrating that hypertension, ER/PR, HER2 status, number of metastatic sites, and BMI at metastatic breast cancer diagnosis were the most relevant prognostic factors for survival. Backward stepwise selection of covariates was conducted among 553 patients and showed that treatment delays of > 12 weeks had a marginal impact on poor survival (HR 1.76, 95% CI 0.99-3.13). Moreover, the interval of 12-24 weeks, compared to the interval of 4-12 week was a prognostic factor for survival from first treatment (HR 2.39, 95% CI 1.19-4.77). To assess comorbidity variable as a mediator of age-survival relationship among 553 patients, we applied two approaches: 1) Baron Kenny approach, and 2) alternative assessment to compute the percentage change in the HRs. Hypertension was related to survival (HR 1.45, 95% CI 1.12-1.89) and hypertension augmented Charlson comorbidity score (hCCS) explained survival disparity between young and old patients by 44% compared to 40 % of hypertension and 14% of the Charlson comorbidity score (CCS). Looking for opportunities to improve public health, the present study identifies modifiable factors associated with variable outcomes after diagnosis of metastatic breast cancer.