Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disorder among women in the United States. Women with PCOS experience acne, excessive hair, weight gain and irregular periods. Unfortunately, these women also have cardiovascular disease (CVD) risk factors including obesity, inflammation and type 2 diabetes. It is challenging to determine when and if atherosclerosis is accelerated in women with PCOS compared to controls as many studies investigate subclinical atherosclerosis in young women and are limited by small sample sizes. The purpose of this dissertation is to investigate markers for subclinical atherosclerosis in women with PCOS and non-PCOS controls. The meta-analysis on carotid intima-media thickness (CIMT) showed that women with PCOS have greater CIMT compared to controls. The summary estimates of the difference are comparable to a seven year progression in CIMT. This analysis also revealed CIMT estimates were more constant across studies with higher quality assessments of CIMT. The investigation of serum complement protein C3 (C3) suggested C3 may be an inflammatory risk marker for CVD in women with PCOS and controls. C3 was associated with traditional CVD risk factors in women with PCOS and controls, and was associated with coronary artery calcium (CAC) after adjusting for case control status, age, and either insulin or BMI. In the fully adjusted model with African American race, C3 was significantly associated with the presence of CAC. The trajectory analysis of flow-mediated dilation in women with PCOS and controls identified three patterns of change in lumen diameter that were labeled as non-dilators, dilators and enhanced dilators. Baseline lumen diameter, insulin and HDLc were associated with group membership, and an interactive effect between PCOS status and total cholesterol on group membership was detected. The findings from this dissertation clarify the mechanisms of subclinical atherosclerosis in women with PCOS and controls. This is of public health importance because many women with PCOS may not realize they are at risk for CVD. It is critical to evaluate factors that put these women at an increased risk of CVD so researchers can monitor risk factors and develop interventions to prevent atherosclerosis in this high risk population.

Despite the significant amount of research conducted on the epidemiology of seasonal influenza, the patterns in the annual oscillations of influenza epidemics have not been fully described or understood. Furthermore, the current understanding of the intrinsic properties of influenza epidemics is limited by the geographic scales used to evaluate the data. Analyses conducted at larger spatial scales may potentially conceal local trends in disease structure which may reveal the effect of population structure or environmental factors on disease spread. By using influenza incidence data from the Commonwealth of Pennsylvania and United States influenza mortality data, this dissertation characterizes seasonal influenza epidemics, evaluates factors that drive local influenza epidemics, and provides an initial assessment in how administrative borders influence surveillance for local and regional influenza epidemics. Evidence of spatial heterogeneity existed in the distribution of influenza epidemics for Pennsylvania counties resulting in a cluster of elevated incidence in the South Central region of the state that persisted during the entire study period (2003-2009). Lower monthly precipitation levels during the influenza season (OR = 0.52, p = 0.0319), fewer residents over age 64 (OR = 0.27, p = 0.01) and fewer residents with more than a high school education (OR = 0.76, p = 0.0148) were significantly associated with membership in this cluster. In addition, significant synchrony in the timing of epidemics existed across the entire state and decayed with distance (regional correlation r = 62%). Synchrony as a function of population size displayed evidence of hierarchical spread with more synchronized epidemics occurring among the most populated counties. A gravity model describing movement between two populations was the best predictor of influenza spread suggesting that non-routine and leisure travel drive local epidemics. Within the United States, clusters of epidemic synchronization existed, most notably in densely populated regions where connectivity is stronger. Observation of county and state epidemic clusters highlights the importance and necessity of correctly identifying the ontologic unit of epidemicity for influenza and other diseases. Recognition of the appropriate geographic unit to implement effective surveillance and prevention methods can strengthen the public health response and minimize inefficient mechanisms.

Chronic obstructive pulmonary disease (COPD) is the most frequent chronic disease in developed countries and is predicted to be the third cause of death in 2020. Lung cancer is the leading cause of cancer death both in men and women. A vast majority of patients diagnosed with lung cancer have COPD, a history of tobacco use, or both. Shared inflammatory pathways may govern the pathogenesis of COPD and lung cancer. Several studies imply a relationship between COPD and lung cancer, but there is very limited information in the literature about emphysema and lung cancer risk. The Carinal Registry is a prospectively collected case series of patients diagnosed with lung cancer at the University of Pittsburgh. Among other data, it contains information on COPD that was acquired from the medical record (yes/no entry). Our goal was to evaluate the data quality and decide if the COPD variable could be used to score for emphysema. For this purpose, we adapted a subjective, semi-quantitative, visual emphysema scoring method (VESM) to score emphysema severity on CT scans and compared this emphysema severity score with the presence or absence of emphysema as defined in the Carinal Registry. We defined the best CT to score emphysema to be obtained preferably within one year preoperatively, with lung edge-enhancing reconstruction algorithm. Training in VESM showed high reproducibility scores and high sensitivity of the trainee to detect emphysema when compared to the standard expert score. Our results showed that there was poor correlation between the COPD status as recorded from the COPD variable from medical records and the VESM. The VESM was a more accurate measure of COPD status among lung cancer patients enrolled in the Carinal Registry. Moreover, we compared the distribution of COPD among lung cancer patients and the community adapted from Wilson et al. manuscript who carried out a community based screening study for lung cancer among smokers. Our results showed that the distribution of COPD was similar among both populations, suggesting the possibility of an underlying common pathway of lung cancer and emphysema. Public Health Significance: The public health significance of this study is clearly explained by the high frequency of both emphysema and lung cancer and the dismal prognosis of lung cancer. We have studied a sample of a large case series of lung cancer patients and scored their emphysema severity with a semi-quantitative method based on CT scan reading. We have also compared this method with simply retrieving emphysema data from the medical record and assessed the validity of these methods. All the above mentioned are very important reasons that can affect the public health as well as research purposes.

The age structure of the U.S. population is expected to change with the segment of the population aged over 65 years experiencing the largest increase in size. Given the expected change in the U.S. population, efforts aimed at screening and diagnosis, in addition to the prevention and treatment of diseases with a significant burden in older adults should be at the forefront of public health efforts. Accordingly, in order to obtain an appreciation of the significance of cardiovascular diseases in older adults we initially performed a literature review of the burden and prevention of cardiovascular diseases, the leading cause of morbidity and mortality in older adults. Subsequently, we focused our research efforts on cardiorespiratory fitness in older adults. Cardiorespiratory fitness is a determinant of morbidity and mortality in middle-aged and older adults which can be measured objectively by either exercise testing or walk-based tests. Few studies of community-dwelling older adults have characterized the relationship between fitness as assessed by exercise testing versus walk-based testing, with subclinical cardiovascular, or the prognostic significance of walk-based test performance. We sought to characterize these relationships among community-dwelling adults participating in the Cardiovascular Health Study (CHS). In an analysis of the Arterial Calcification in the Elderly (ACE-CHS), 6 Minute Walk test (6 MWT) performance was a useful measure of treadmill test capability and performance. A second analysis of ACE-CHS failed to identify subclinical cardiovascular disease as quantified by the coronary artery calcification score as a significant determinant of exercise duration in exercise treadmill testing. However, the coronary artery calcification score was associated with ischemia as detected by electrocardiographic changes during exercise testing. Finally, in the full CHS cohort, the 6 MWT performance was independently associated with all-cause mortality, demonstrating a prognostic value for submaximal fitness assessment using the 6 MWT across a wide range of function present in community-dwelling older adults. The public health relevance of these finding is the potential clinical utility of the 6 MWT, a quick, safe and inexpensive alternative to exercise treadmill testing, in the assessment of cardiorespiratory fitness and the prediction of mortality in community-dwelling older adults.

Vitamin B12 deficiency affects 5-20% of older adults, with up to 40% with low B12 levels [<260pmol/L]. The risk of B12 deficiency increases with age. Vitamin B12 is essential for neurological function, and B12 deficiency is a known cause of clinical neuropathy and has been associated with cognitive impairment. However, little is known about the relationship between low B12 levels and peripheral nerve function and information processing speed, cross-sectionally or longitudinally, in older adults. The purpose of this dissertation is to examine whether low B12 levels or change in B12 levels were associated with peripheral nerve function or information processing speed. We examined whether low B12 or high homocysteine [&ge;13µmol/L] and 3-year change in B12 and homocysteine was associated with 6-year change in peripheral nerve function or neurological signs in older Italian adults from the InCHIANTI Study. We found high homocysteine was associated with lower nerve conduction amplitude and greater inability to detect 4g monofilament. In the Health ABC Study, we studied whether low [<260pmol/L] or deficient [<260pmol/L & methylmalonic acid [MMA] >271nmol/L & MMA>2-methylcitrate] B12 were associated with peripheral sensory and motor nerve function, and evaluated whether there was a threshold effect of serum B12 levels on peripheral nerve function in older black and white adults. We found poor B12 were associated with greater insensitivity to 1.4g monofilament and worse nerve conduction velocity [NCV] and there was a significant serum B12 threshold level of 390 pmol/L for NCV. To consider cognitive function, we examined whether low B12 or 7-year change in B12 were associated with decline in Digit Symbol Substitution Test [DSST] scores over 6-years. We found low B12 was associated with greater DSST decline and a serum B12 level of 410 pmol/L was associated with lower DSST decline. These results have important public health significance, because low B12 levels, above clinical deficiency [<148 pmol/L], were associated with worse peripheral nerve function and decline in information processing speed, which may lead to decreased cognitive and physical function, and disability in older adults. Vitamin B12 supplementation is widely available, adequately absorbed, well-tolerated, and potentially may prevent declines in neurological function.

Lung cancer and chronic obstructive pulmonary disease (COPD) are the leading causes of morbidity and mortality in the US. Despite the appreciation of the central role of smoking in the development of both diseases, only a relatively small number of smokers (15%-20%) develops lung cancer and/or COPD. This suggests that other factors including inherited genetic variation may play a role. Cigarette smoking induces inflammation; therefore, functionally relevant polymorphisms in inflammation-related genes may affect risk of smoking-associated lung cancer and/or COPD. The primary goals of this research were to evaluate eicosanoid pathway (IL1B, COX-2, PPARã) gene polymorphisms and cytokine (TGFB1, IL6, IL10) gene polymorphisms in relation to lung cancer risk (484 cases/866 controls); and cytokine (TGFB1, IL6, IL10) gene polymorphisms in relation to COPD (airflow obstruction and emphysema) risk (N=866). We utilized data and specimens from Project 4 of the University of Pittsburgh Cancer Institute Specialized Program of Research Excellence (SPORE) in Lung Cancer. In our study population, IL1B rs1143634 minor allele carriers had a decreased risk of lung cancer (OR=0.73, 95%CI=0.56-0.95) compared to major allele homozygote. There was a strong interaction between PPARã rs1801282 and sex (Pinteraction=0.003), female minor allele carriers were at a reduced risk of lung cancer (OR=0.58, 95%CI=0.37-0.91), while male minor allele carriers showed a non-significant increased risk (OR=1.45, 95%CI=0.96-2.19) compared to major allele homozygotes. In the analyses of COPD, TGFB1 rs2241712 was found associated with airflow obstruction severity as measured by Global Initiative for Obstructive Lung Disease (GOLD) (Cochran-Mantel-Haenszel 1degree freedom nonzero correlation P=0.02), minor allele carriers were at a decreased risk of developing the disease (any vs. no airflow obstruction, dominant model OR=0.73, 95%CI=0.55-0.98). Enhancing our knowledge of lung cancer and COPD genetics is a significant contribution to public health as it may result in the development of new prevention and treatment strategies.

Emphysema, a form of chronic obstructive pulmonary disease (COPD) is a disease of significant public health importance that remains a major cause of morbidity and mortality within the US population and elsewhere in the industrialized world. An emerging body of literature appears to suggest gender differences in susceptibility to emphysema, with women showing significantly less emphysematous changes on high resolution Computed Tomography radiography compared to men. A pertinent but yet to be addressed question in the literature however, is whether these apparent differences in emphysematous structural lung disease result from differential exposures and or lifestyle choices on the one hand, or if on the other hand, these gender differences in CT-emphysema are related to certain biological mechanisms such as female hormonal influences or genetic differences in toxin metabolism. The present study evaluated differences in CT-emphysema status among 1834 women with different hormone replacement therapy (HRT) exposure profiles. In an unadjusted generalized logistic regression model, current use of HRT was statistically significantly associated with a 38% reduction in the risk of moderate to severe CT-emphysema, OR 0.62 (95% CI=0.39-0.99). After adjusting for the effects of age and smoking dose intensity, current HRT-users had a 34% reduction in the risk of mild to moderate CT-emphysema compared to never-users. Although this effect is quite sizable, it was marginally statistically insignificant, OR=0.66 (95% CI=0.41-1.07). We conclude that current use of hormone replacement therapy may be associated with a lower risk of moderate to severe CT-emphysema.

Asthma is a complex respiratory disease that has been increasing in prevalence in the United States since 1980 despite advances in treatment. Approximately 32.6 million Americans have had asthma at one point in their lives; while 22.2 million Americans are currently diagnosed with asthma. Severe asthma occurs in approximately 10% of those asthmatics. A distinct racial disparity exists within the severe asthma population, with Blacks having a greater likelihood of having poorly controlled disease compared to their White counterparts. The factors that contribute to this disparity are not truly known; however, it has been suggested that genetics, the environment, and socioeconomics play a role in the disparity. This dissertation focused on the role that biologic, genetic, and socioeconomic factors play in the development of severe asthma using data from the Severe Asthma Research Program (SARP). The overall hypothesis was that Blacks are predisposed to an allergic, early onset asthma phenotype, which fundamentally differs from the asthma observed in Whites on the basis of biologic/genetic differences in disease process. The overall aim of this study is to assess the extent to which the racial disparity in asthma is attributable to the differences in the pathobiology of asthma. The first paper sought to assess the extent to which racial disparities between Black and White adult asthmatics with severe asthma are attributable to physiologic, immunoinflammatory, and sociodemographic variables. The second paper, utilizing the results from paper 1, examined the factors that drive the increased production of immunoglobulin E (IgE) in Blacks, as well as the primary factors that contribute to severe asthma in Blacks with high IgE. The third paper presents some of the policy issues that affect the racial disparity seen in severe asthma and five recommendations that will aid in the reduction of the widening gap between Black and White asthmatics. IgE, along with family history of asthma, were shown to be a strong predictors of severe asthma in Blacks, while comorbidities were predictors for Whites. The public health significance of this study is that different interventions can now be created to effectively treat asthma in Blacks versus Whites.

It is estimated that more than 1.7 million nosocomial infections and 98,000 deaths occur annually in the U.S. Nosocomial infections are associated with a longer length of stay (LOS), which is in-turn associated with higher costs and is a risk factor for additional infections. Infection prevention measures may allow a significant number of cases to be averted, although consensus has not been reached about the ultimate epidemiologic and economic value of prevention strategies. A multifaceted program of nosocomial infection prevention evaluating the surveillance test attributes, target population, and intervention implementation has potential to both improve patient outcomes and reduce healthcare costs. I developed models to evaluate and estimate the impact of these infection control interventions. First, testing adult hospital inpatients has the potential to prevent transmission of MRSA among patients. However, policy makers and hospital administrators must consider the diagnostic test used in a screening program. Increasing the number of anatomic sites tested with surveillance cultures does not appear to have as great an impact as decreasing turnaround time on the economic value of a MRSA testing strategy. Second, weekly surveillance of neonates in the neonatal intensive care unit (NICU) and isolation of those who test positive is a technique that hospitals could use to decrease the incidence on nosocomial infections, selecting neonates as a target population where MRSA infections have substantial morbidity. Hospitals with moderate to high adherence to isolation protocols have the potential to prevent adverse clinical outcomes and mortality among NICU populations. Third, routine dispensing of home-based preoperative chlorhexidine bathing kits has the potential to prevent post-operative surgical site infections (SSIs). Our model suggests that preoperative bathing would have substantial economic value throughout a wide range of intervention implementation scenarios: patient compliance levels, cloth efficacies, costs, and SSI-attributable LOS, supporting the distribution of chlorhexidine cloths preoperatively. The public health significance is that decision makers can use the models described here to benchmark the test characteristics, potential target populations, and intervention implementation strategies to utilize in local infection prevention programs. A comprehensive approach including the interventions modeled here may help move towards the elimination of healthcare acquired infections.

In response to in utero insults, male vs. female infants have greater disadvantages in pregnancy outcome. We asked if this differential impact of fetal sex might extend to fetal growth in utero during preeclampsia. We first investigated the influence of relevant variables in normotensive pregnancy. We evaluated whether the impact of maternal pre-pregnancy body mass index (BMI), smoking and socioeconomic status were modified by sex and/or race in singleton offspring of 8,801 primiparous normotensive women enrolled in the Collaborative Perinatal Project. The mean head-to-chest circumference (HCC) decreased more or each 1kg/m2 increase in pre-pregnancy BMI, while mean birthweight and ponderal index (PI) increased more for each 1kg/m2 increase in pre-pregnancy BMI among term females vs. males (p=0.07, p<0.01 and p=0.08, interaction respectively). We then investigated whether the relationship between preeclampsia and fetal growth was modified by sex in offspring of 516 preeclamptic and 8801 normotensive primiparous women. Male vs. female preterm offspring of preeclamptic mothers had greater reductions in mean birthweight, head and chest circumferences (p=0.05, p=0.02, p=0.01; interaction respectively). The influence of preeclampsia on growth of term offspring was more modest, and the influence of sex was opposite that in preterm infants. Next we investigated placentas from 735 preeclamptic and 21,185 normotensive primiparous and multiparous women, to determine which dimensions of placental growth are reduced in preeclamptic pregnancies. We then investigated if the relationship between these measures and birthweight was constant between offspring of normotensive and preeclamptic women, as well as across infant sex. We found that the smaller but not the larger placental diameter was an independent predictor of preeclampsia ((smaller diameter <15cm OR 1.27 95% CI 1.01, 1.59) and larger diameter <18 cm (OR 1.18 95% CI 0.90, 1.54)). We also found higher rates of increase in birth weight at lower placental weight and placental diameters in offspring of preeclamptic vs. normotensive women (all p<0.05, interaction). Additionally, we found that among the offspring of preeclamptic women, female offspring with smaller diameters above 20cm, had a reduction in birth weight while males did not (p=0.02, interaction). This work yields meaningful public health findings by providing evidence that influences upon fetal and placental growth are different by infant sex. Studies of mechanisms affecting fetal growth should investigate interactions with fetal sex. We hope studies of the involved biological pathways will direct future research to reduce rates of growth restriction and later life chronic diseases.