Systemic lupus erythematosus (SLE) is a major public health problem in the U.S. Cardiovascular disease (CVD) risk increases significantly in SLE patients, resulting in serious morbidity and mortality. Accelerated atherosclerosis and markedly higher prevalence of CVD risk factors (intermediate phenotypes) are thought to directly contribute to these consequences. Given the significant mortality and morbidity associated with SLE and high prevalence of CVD in SLE, identifying genetic variation associated with both SLE risk and intermediate phenotypes of CVD is of significant importance. C-reactive protein (CRP) is a sensitive marker of inflammation. Increased CRP levels have been found to be associated with cardiovascular events in a large number of healthy populations and may contribute to atherosclerosis. The gene coding for CRP is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Moreover, two single nucleotide polymorphisms (SNPs) in the CRP gene have recently been shown to be associated with CRP levels and/or SLE risk in a British family-based cohort. This study was aimed to assess the genetic association between five CRP tagSNPs with SLE risk and intermediate phenotypes of CVD. The association between CRP and SLE risk, assessed in two independently-ascertained SLE cohorts, was tested in a case-control Caucasian sample of 337 SLE and 448 healthy controls from Pittsburgh and a family-based sample of 203 Caucasian SLE trios from Los Angeles. While none of the SNPs were found to be associated with SLE risk individually, global haplotype statistics revealed significant association (p < 0.000001) in the Pittsburgh cohort whereas all those haplotypes containing two potentially functional SNPs (-390 and +90) showed association with SLE risk in the Los. Angeles cohort (p = 0.01 0.06). The association study between CRP and intermediate phenotypes of CVD and stroke risk was tested in 237 of the SLE women from the Pittsburgh cohort. Four of the five tagSNPs (-861, -390, +90, and +838) examined revealed significant association with risk of intermediate phenotypes of CVD (p < 0.001 to 0.04). In summary, our data did not confirm previously observed individual SNP association with SLE, but suggested that unique haplotype combinations in the CRP gene may modify the risk of developing SLE, and that variation in CRP may contribute to the accelerated atherosclerosis in SLE.

Physical inactivity is a major risk factor for complex metabolic diseases such as obesity, diabetes, and hypertension. Traditionally, these diseases and conditions have been the specific burden of adulthood, but they are now being diagnosed more frequently in younger populations. There has been some suggestion that, as is true in adults, children are becoming less physically active and that this decline in physical activity may help to explain the sudden increase in the incidence of metabolic diseases among children. Understanding the factors that are impacting on decreased physical activity levels in children will provide clues on how to approach this problem. Similar to findings in obesity, where obese parents tend to have overweight and obese children, physical activity appears to be related between parent and offspring. Although the literature regarding familial aggregation of physical activity levels is limited, it does allude to an association of physical activity levels among parents and children to varying degrees. Using several different approaches, we examined the familial resemblance of physical activity levels, determined by pedometry, in 96 extended Native American families from three geographic locations (Arizona, North/South Dakota, Oklahoma) in the Strong Heart Family Study. Based upon correlational analyses, physical activity levels were significantly and positively related among parent-offspring pairs. More specifically, correlations between father-daughter pairs (&lt,18 years of age) and father-son pairs (&gt,18-30 years of age) were rho = 0.30 and 0.26, respectively (p = 0.01). No significant associations were noted between physical activity levels of mother-offspring pairs. For our main investigation, we examined the familial effects, of physical activity using variance components analyses. Despite the fact that this study was conducted in three separate geographic locations, had limited household data, was not designed specifically to examine aggregation of physical activity levels, and was not limited to 2-parent families, when modeled as a heritable effect, physical activity achieved statistical significance (p = 0.007) explaining approximately 9% of the trait variance. Since physical activity can provide health benefits in youth, and since many young people are not meeting established guidelines, improving physical activity levels of youth is a key public health challenge. However, in order to develop effective physical activity interventions for youth, factors that impact on a childs physical activity levels need to be better understood. The findings of the current study indicate a significant, albeit weak, degree of aggregation of physical activity levels among parent-offspring pairs and among families. This supports the need to establish family based lifestyle interventions studies where both parent and child may benefit.

There has been renewed interest in recent years in the short- and long-term effects of prenatal maternal anxiety (PMA) on offspring. Although relations between PMA and adverse birth outcomes have been established previously, the nature of these relations is not well-characterized. Furthermore, it is unknown whether the effects of PMA last into late childhood and adolescence to increase the offspring&rsquo;s risk of depression. The goals of this dissertation were: 1) Characterize the relations between PMA and birth outcomes; 2) Determine the correlates of Major Depressive Disorder (MDD) among offspring; 3) Determine whether PMA predicts depressive symptoms in offspring at 10 to 16 years. Women (n=829) of low socioeconomic status, recruited from a prenatal clinic, were assessed for trait anxiety (PMA) during their fourth and seventh gestational months, and at delivery, in a study of prenatal substance use. There were 763 live singleton births. At 10, 14, and 16 years post-partum, trait anxiety and depressive symptoms were measured in women and their offspring. Offspring were assessed at 16 years for MDD. Demographic, social, substance use, medical, psychological, and psychiatric status were controlled. It was demonstrated in the first paper that PMA predicted lower birth weight, shorter birth length, and shorter gestational length, controlling for confounders. Women who reported chronic, severe trait anxiety were at the highest risk of having shorter gestations and delivering smaller babies. The second paper established that female gender, a history of childhood maltreatment, and a maternal history of MDD independently increased the odds of MDD in the 16-year-olds. Daughters of women with a history of MDD were particularly vulnerable. The third paper found that PMA was related to level of depressive symptoms in late childhood and adolescence. These effects were significant, controlling for current maternal depression. Female gender and lower maternal education also predicted depressive symptoms in children ages 10-16 years. There was a significant interaction between gender and follow-up assessment. These findings have public health implications: maternal psychological health during pregnancy and throughout the child&rsquo;s development should be monitored in order to improve birth outcomes and psychological health of children and adolescents.

Although environmental and occupational lead exposure has decreased over the recent decades, the health outcomes associated with past lead exposure continue to be a significant clinical and public health issue. Lead is a multitargeted toxicant, that effect skeletal, cardiovascular and nervous system. Mounting evidence supports a link between lead at levels previously considered safe, to morbidity and mortality. The objective of this dissertation was to examine association of lead biomarkers with changes in bone mineral density (BMD), incident fractures and falls, cognition and mortality. We utilized data from two epidemiological studies: a) The Study of Osteoporotic Fractures (SOF) that enrolled a population of elderly women (age 65-87), and b)The Lead Occupational study that followed a cohort of male lead exposed and control workers through middle age (40-76 years,63% exposed, 37% controls). In the longitudinal SOF analysis, baseline total hip BMD was lower in women with high blood lead levels. The annualized rate of decline in hip BMD was greater among women with the high blood lead level, who also experienced a two-fold increased risk of fracture and falls. In the longitudinal SOF mortality analysis, women with higher blood lead levels at baseline had increased risk of all cause, and cardiovascular mortality compared to women with lower blood lead levels. No association with cancer mortality was found. These relationships were independent of age and shared risk factors between blood lead levels and BMD, fractures, falls and mortality. In the Lead Occupational study, compared to controls, lead exposed workers had lower total cognitive scores cross sectionally. In longitudinal analysis, cognitive scores of lead exposed workers declined more in compared to controls. Age and important risk factors of lead exposure and cognitive change did not explain this association. Overall, our findings provide epidemiological evidence of an association between lead exposure, morbidity, and mortality in community residing elderly women as well as a male occupational cohort. A more stringent control of lead exposure and better understanding of the mechanism of its effects may help reduce the public health burden of disease.

The environment plays an important role in the health of communities. However, few health systems exist at the state and/or local levels to efficiently track the potential health effects associated with environmental exposure. The objectives of this dissertation are 1) to use secondary data for assessing the possible associations between health outcomes and environmental exposure and/or hazard; 2) to explore possible methods of data linkage and analyses which can be used by state and local environmental health tracking agencies and 3) to bring positive contributions to the development of national Environmental Public Health Tracking Network (EPHT). In this project, the Three Mile Island (TMI) cohort data (1979-1995) and Pennsylvania (PA) Cancer registry data were used to evaluate the associations between cigarette smoking and adult leukemia. A case-crossover analysis was performed with PA cardiopulmonary hospital admission data and local air pollution data to assess the health effects of air pollutants on cardiopulmonary disease before and after the elimination of a major point source of air pollution. A case-control study was also conducted to examine the associations between term low birth weight and particulate air pollution. The results showed that cigarette smoking could increase the risk of acute myeloid leukemia (AML). In addition, particulate air pollution is significantly associated with cardiovascular hospitalization and low birth weight in term infant. In conclusion, the findings suggest that environmental hazards have adverse health effects on a number of health endpoints. Secondary data can be a great resource for environmental public health tracking, which is of public health relevance. The use of existing data is an effective way to assess the potential health effects associated with environmental exposures after an appropriate study design with a feasible data linkage and correct methods of data analyses was developed.

Cardiovascular disease remains the leading cause of mortality and morbidity in the 21st century accounting for about one-fifth of deaths overall each year in the United States. Percutaneous coronary intervention (PCI), used initially in the 1970s, is now the most commonly performed non-surgical procedure for atherosclerotic coronary disease. PCI, in the last three decades, witnessed rapid advancements, both technologically (from balloons to stents and atherectomy devices) as well as in adjunct therapy (antithrombotics, fibrinolytics and antiplatelet agents). The purpose of this dissertation, designed as three research papers, was to capture this evolution and the associated impact on clinical and patient-reported outcomes, in the prospective, multicenter NHLBI-sponsored 1985-86 PTCA (era of balloon angioplasty) and 1997-2004 Dynamic (era of stents, brachytherapy and drug-eluting stents) registries. Temporal trends in clinical practice revealed the heterogeneity in patients (and lesions) undergoing PCI and yet, consistent dramatic improvements were seen in procedural success with reduced need for repeat procedures; little impact was observed in one-year mortality rates. In the Dynamic Registry, significant reductions in one year prevalence and risk of patient-reported angina were observed concurrent to use of new evidence-based secondary pharmacological therapy. In contemporary practice, women and patients with prior/repeat PCI continued to be at high-risk for post-procedural symptoms. Supplemental therapy, following initial PCI, was more often pharmacological with concomitant reduction in bypass surgery and repeat PCI. On average, patient-reported quality of life improved over time and was influenced by both symptom status and the need and type of supplemental therapy. Indeed, these findings reflect the dynamic nature of PCI with an increasingly heterogeneous treatment population and yet favorable procedural outcomes (procedural success, reduced repeat procedures, greater relief of symptoms). More importantly, they highlight the continued lack of impact on mortality and identify symptom-prone subsets in contemporary practice. This time-sensitive documentation is especially fitting given the 300% increase in the number of PCIs since its initial use. From a public health point of view, any treatment modality applied in this magnitude warrants constant surveillance, more so with the emerging safety concerns, and this underscores the importance of well-designed registries.

Background: Growth hormone (GH) SNPs are associated with breast cancer and colon cancer. The author investigated the association of prostate cancer with genetic polymorphisms in GH SNPs in the Ancillary MrOS study. Methods: Included in the current investigation were 128 men with prostate cancer and 743 healthy men, 65 years of age or older. SNPs were tested in Growth Hormone 1 (GH1, n=4), Growth Hormone Receptors (GHR, n=15), Growth Hormone-Releasing Hormone (GHRH, n=4), Growth Hormone-Releasing Hormone Receptors (GHRHR, n=10), Ghrelin (GHRL, n=8), and Growth Hormone Secretagogue Receptor (GHSR, n=9) genes for an association with prostate cancer risk. SNPs were selected based on HapMap Phase 1 and based on functional variation. The SNPs were genotyped using Illumina Assay and were included if the minor allele frequency was 1% or greater. Logistic regression analysis was used to examine associations, adjusted for age, weight, BMI, truncal % fat, total % fat, and diabetes. Similarly, tests of trends and tests of dominant/recessive effect were performed. Results: After adjusting for potential confounding factors, two GH1 SNPs, one GHR SNP, one GHRH SNP, two GHRHR SNPs, one GHRL SNP, and one GHSR SNP showed significant associations with prostate cancer risk. Public Health Significance: If the relationships observed in this study are confirmed, it would justify the investigation of approaches that would reduce the activity of GH in those at high risk for prostate cancer. Conclusions: The results of the current study suggest that GH SNPs are associated with prostate cancer risk. This provides support for replication of these findings in other studies.

Public Health Significance: The objective of this study is to establish a clinical decision-making rule for mild head injury in young children, an extremely common type of injury seen in emergency departments. These children appear to respond differently to mild head injuries and face different developmental issues than do older children and management guidelines remain unclear. Methods: Subjects were 97 children less than three years old with mild head injury (ICD9 codes 800-804 and 850-854) and an initial Glasgow Coma Scale score of 14 or 15, consecutively evaluated at a Level 1 Pediatric Emergency Department. Demographic, injury, symptom and treatment characteristics were abstracted from the medical records. A classification and regression tree (CART) program was used to identify characteristics that were correlated with intracranial injury (ICI) among children in the study. The information garnered from the tree was used to construct a clinical decision-making rule for the evaluation of very young children with mild head injuries. A cost analysis was done to determine potential cost savings from the new decision-making rule. Results: Forty-six percent of the children were less than 12 months, 24% were 12-23 months and 30% were 24-35 months old at the time of injury. Three-quarters of all injuries occurred from falls. Almost 25% of the children had evidence of an ICI on the CT scan; more than two-thirds of the ICIs occurred in children less than 12 months old (p=0.03). We examined multiple CART models to assess the impact of different misclassification penalties and missing data. The main parent node on the final CART model was the presence of vision changes; splits also occurred with the presence of scalp lacerations, vomiting, the child being inconsolable, sex and area of residence. Minor changes in the way children without ICIs are treated could result in cost savings as much as $90,000 per year. Conclusion: While similarity exists between decision-making rules for older children and that found for this cohort, very young children have unique characteristics that merit further study and may require a separate decision-making process.

Introduction: Spatial, temporal and racial patterns of cancer remain largely unexplained in the United States. Time trends of cancer incidence and mortality can be used to estimate the current cancer burden, anticipate clinical care needs, and suggest hypotheses regarding possible etiologic explanations for underlying trends. Methods: Using U.S. 1979-2003 cancer incidence and 1969-2003 cancer mortality data, age-period-cohort and Joinpoint regression models were fit to summarize gender- and race-specific temporal trends for three broad cancer categories that include tobacco-related cancer, screen-detectable cancer, and cancer unrelated to tobacco and screening. Demographic patterns and time trends of non-Hodgkins lymphoma (NHL) incidence between Pennsylvania and the U.S. from 1985 to 2004 were compared. Using Idaho cancer incidence, 1990-2005, and arsenic levels in ground water, 1990-2005, spatial analysis was conducted to identify geographic patterns of cancer incidence and to evaluate the relationship between arsenic exposure in ground water and cancer incidence in Idaho. Results: Over the last three decades, tobacco-related cancer incidence declined among men and increased among women. Screen-detectable cancer incidence increased, more rapidly among men than women. For cancer unrelated to tobacco and screening, incidence increased in every gender-and-race group. Though not identical, NHL incidence patterns, with substantial increases, were similar in the U.S. and Pennsylvania. NHL incidence was higher in Pennsylvania counties with a greater percentage of urban residents. Although spatial clustering was demonstrated in Idaho cancer incidence, no relationship was found between arsenic exposure in ground water and Idaho cancer incidence. Conclusion: NHL and other cancers unrelated to smoking or screening have increased in the U.S. in the past two decades in white and black men and women. Etiologic research should attempt to identify modifiable risk factors, including environmental exposures, responsible for the increasing incidence of NHL and cancer unrelated to tobacco and screening. The ecologic association observed in Pennsylvania between NHL incidence and urban residence may be relevant to NHL risk in the entire United States. Additional environmental and demographic information should be evaluated in order to clarify the arsenic-related cancer risk in Idaho counties where ground water has been found to contain higher levels of arsenic. Public Health Significance: Age, period and cohort modeling of cancer incidence and mortality provides important indications of current and future health care needs and also suggests hypotheses for future research. The results of this analysis provide health professionals, researchers, and policy-makers with detailed information and an understandable overview of cancer patterns in the United States. Hypotheses should be generated about these unexplained patterns of cancer so that avoidable cancer risks can be identified that will decrease the cancer burden and associated requirements for health care.

In contemporary clinical practice, percutaneous coronary intervention (PCI) is one of the most common methods to treat ischemic heart disease. It has proven to be very effective in appropriately selected patients. However, clinical discretion among interventional clinicians in the absence of definitive evidence-based guidelines results in significant variation in clinical practice of PCI. The objective of this dissertation research is to study the effect of such variation in three aspects on patient outcomes following PCI: (i) post-discharge statin prescription versus no prescription in the setting of otherwise aggressive medical therapy; (ii) use of multiple stents versus a single stent when either approach is clinically feasible; (iii) use versus no use of stent postdilation. Patients were evaluated from multiple data sources. The first source included the multi-center National Heart, Lung, and Blood Institute (NHLBI) Dynamic registry recruitment Wave 4 (2004) and Wave 5 (2006). For Aim 1 (post-discharge statin vs. no post-discharge statin), patient eligibility criteria included receipt of aspirin, thienopyridines and at least one type of cardiovascular protective medication (angiotensin-converting enzyme inhibitors, Beta blockers, or Calcium channel blockers) after the PCI procedure, and no in-hospital death. Risk of adverse events was compared between post-discharge statin recipients and non-recipients at one-year follow up. Results showed that post-discharge statin use was associated with a reduced risk of mortality and the composite endpoint of death/MI, death/MI/CABG. These data support the routine use of post-PCI statin therapy in the presence of otherwise aggressive medical therapy. For Aim 2 (multiple versus single stents), the DEScover Registry, a prospective, multicenter, observational study among 140 clinical centers in the United States, was used. The eligibility criteria for this analysis included: receipt of at least one stent for a lesion treated with PCI and the following characteristics: lesion not previously treated; lesion length of 10 to 32mm (i.e. able to be treated with either a single or multiple stents); and an angiographically successful procedure. Survival analysis over 1-year post-PCI showed that patients who received multiple stents had a similar risk of adverse events compared to patients who received a single long stent for each lesion treated. Thus, this analysis was unable to provide definitive evidence for a preference of single versus multiple stents for lesions in the range of 10 to 32 mm. For Aim 3 (postdilation versus no postdilation), the Dynamic registry recruitment Wave 4 (2004) and Wave 5 (2006) were used. Patient eligibility criteria for this analysis included receipt of greater than or equal to 1 stent and an angiographically successful PCI procedure. Survival analysis over 1-year post-PCI showed that among PCI patients who presented with acute MI, postdilation appears to significantly increase the risk of death by as much as 3-fold. However, because this finding was observed only among patents with one lesion treated but not among patients with multiple lesions treated, the possibility of a chance finding exists. Moreover, among PCI patients who had no acute MI, lesion postdilation did not appear to be associated with either a benefit or increased risk of adverse cardiac events. Thus, this analysis indicated no obvious clinical benefit associated with postdilation in the setting of PCI patients who had no acute MI, and a potential hazardous effect in the setting of acute MI. Our study has significant public health importance. Heart disease is the leading cause of mortality in nearly every region of the world, accounting for an estimated 30% of all deaths. Coronary heart disease (CHD) is the principal type of heart disease. The public health significance of our study is that investigating the effect of variation in clinical PCI practice can be a benefit to numerous CHD patients all over the world.