School of Public Health
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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
Note: Prior to July 1, 2007, the School of Public Health was named the College of Health & Human Performance.
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Item EXPLORING ENVIRONMENTAL INJUSTICE AND AIR POLLUTION-RELATED HEALTH EFFECTS IN PRINCE GEORGE'S COUNTY, MARYLAND(2024) Ravichandran, Vivek; Wilson, Sacoby M; Maryland Institute for Applied Environmental Health; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Polluting facilities have been historically sited in disadvantaged communities of color, known as environmental justice (EJ) communities, due to limited perceived community resistance and mobilization. There is a plethora of air quality disparity research but a gap persists in ascertaining the health inequities associated with community exposure to air pollutants, such as particulate matter (PM) and black carbon (BC), at the neighborhood resolution. To address this gap in EJ science, this dissertation has four specific aims: (1) Implement the community-based participatory research (CBPR) framework to expand and enhance the community-engaged infrastructure to ensure the success of Aims 2-4; (2) Identify spatiotemporal pollution patterns across the Route 50-Sheriff Road-Kenilworth Ave Quadrant; (3) Determine short-term health impacts associated with community exposure to PM and BC via a panel study involving pulse oximeters to correlate elevated PM and BC levels to blood oxygen saturation (SpO2 levels); and (4) Conduct semi-structured interviews and use NVivo to perform thematic analysis on barriers and motivating factors towards passing EJ legislation. My findings demonstrated that a more diverse and representative community advisory board (CAB) allowed us to successfully conduct research while maintaining trust within the community, and bringing in voices from various demographic groups, including different ethnicities, ages, income levels, and geographic locations. This led to a more comprehensive understanding of the community's concerns, priorities, and needs related to air quality. Additionally, my findings revealed that both PM and BC levels were elevated during morning rush periods. PM levels did not exceed the Environmental Protection Agency (EPA) annual standards, but did exceed the more protective World Health Organization (WHO) guidelines. Robert Gray Elementary School exhibited higher PM levels than the other Quadrant sites. Furthermore, BC levels at Fairmount Heights High School were above the threshold defined in the literature above which cognitive inhibition and poor respiratory outcomes have been observed, highlighting the effect of air pollution exposure on vulnerable life stages in the Quadrant. BC peaks were also observed 10-15x these unofficial health-based thresholds. Using a pulse oximetry panel study, we found previous and concurrent day lagged fine particulate matter (PM2.5) was weakly associated with reductions in SpO2. Using NVivo, we identified 18 parent codes and 27 subcategories from our semi-structured interviews with Maryland policymakers/agency staff. Key barriers were: (1) the lack of strategic EJ plans; (2) limited community engagement particularly from those living in communities impacted by environmental injustice; and (3) interagency and policymaker collaboration exacerbated by a clear partisan divide. These findings provide evidence of previous misclassified exposure assessments from sparse existing regulatory monitors, present strategies for overcoming EJ barriers in the state, and underscore the importance of collaboration, community engagement, and policy reform to address environmental disparities and promote environmental justice.Item CLIMATE CHANGE RELATED EXTREME EVENTS AND ADVERSE HEALTH OUTCOMES AMONG HEMODIALYSIS PATIENTS(2024) Song, Hyeonjin; Sapkota, Amir AS; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The increased frequency and intensity of extreme heat events (EHEs) and wildfires due to climate change are posing significant threats to vulnerable communicates including end-stage kidney disease (ESKD) patients. The specific aims of this dissertation are to Aim 1) Examine the association between EHEs exposure and serum concentrations of sodium and potassium among hemodialysis patients in the Western U.S. (2008-2018), Aim 2) Quantify the mortality and hospitalization risk associated with exposure to 2023 Canadian wildfire-related air pollution in the Eastern U.S., and Aim 3) Investigate how EHEs modify the association between wildfire-related air pollution exposure and the risk of mortality and hospitalization among hemodialysis patients in the Western U.S. (2010-2018). We analyzed health records of patients who receiving hemodialysis treatment at Fresenius Kidney Care clinics. We used the 10°C increase in daily average temperature and daily extreme heat events (EHEs) of each county as the primary exposures. The presence of wildfire smoke plume and wildfire fine particulate matter (PM2.5) concentrations for each clinic were measured using satellite-derived smoke polygons (Hazard Mapping System) and ground-based PM2.5 monitors (Air Quality System). We estimated mean serum sodium and potassium change per 10 °C increase in daily average ambient temperature using random intercepts linear mixed-effects models. We employed a time-stratified case-crossover analysis with conditional quasi-Poisson model to investigate the risks of mortality and hospitalization associated with exposure to wildfire-related air pollution and EHEs. In the first study, a 10°C increase in daily average temperature was associated with 0.43 mEq/L (95% Confidence Interval [CI]: 0.47, 0.59) increase in serum sodium during July-August. The serum sodium was 0.15 mEq/L (95% CI: 0.10, 0.20) higher during EHE days compared to non-EHE days. The serum potassium level did not show a significant change. In the second study, during June-July 2023, the presence of wildfire smoke plume was associated with an 18% increase in all-cause mortality risk (Rate Ratio [RR]:1.18; 95% CI: 1.13, 1.24) and a 3% increase in all-cause hospitalization risk (RR:1.03; 95% CI: 1.00, 1.07). A 10-μg/m3 increase in wildfire-related PM2.5 was associated with a 139% increase in all-cause mortality (RR: 2.39; 95% CI: 1.79, 3.18) and a 33% increase in all-cause hospitalization (RR:1.33; 95% CI: 1.10, 1.62). In the third study, we observed significant interactions between EHEs and wildfire smoke plume for mortality RRs among the hemodialysis patients in the Western U.S. Mortality risk was considerably higher when hemodialysis patients were simultaneously exposed to wildfire smoke plume and EHE compared to wildfire smoke plume alone (RR: 1.52; 95% CI: 1.25, 1.86 vs. RR: 1.15; 95% CI: 1.08, 1.23). We did not observe a significant interaction for all-cause hospitalization. Our findings underscore the need to revise operational and care protocols to prepare for such potential join exposures to extreme events that are exacerbated by ongoing climate change. Future work should focus on developing early warning systems to enhance resilience against such threats.Item COVID-19 Vaccine Hesitancy and Uptake in the United States Considered Through the Lens of Health Behavior Theory(2024) Kauffman, Lauren Emily; Nguyen, Quynh; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Given the low COVID-19 vaccine uptake rates in many areas of the United States despite their demonstrated safety and effectiveness, COVID-19 vaccine hesitancy and vaccination barriers continue to be critical areas of research in epidemiology and behavioral health science. This series of studies focuses on COVID-19 vaccine hesitancy and vaccination barriers, as they relate to vaccination intention and vaccine uptake, considered in the context of established health behavior theories. The first study is a systematic review of existing research on COVID-19 vaccine hesitancy using one or more health behavior theories as key components of the design or analysis. This study examined the types of theories that are most often used, how they are used, and where research gaps exist. The remaining two studies use data from the U.S. COVID-19 Trends and Impact Survey, a national cross-sectional survey. The second study investigates the association between recent feelings of anxiety or depression and vaccination intention, as well as between these feelings and identifying with specific vaccine hesitancy reasons. The third study examines vaccine hesitancy and barriers among those with chronic illness or disease, a particularly vulnerable population. Factor analysis was conducted using constructs from the Theory of Planned Behavior as a framework, and the results were used in a regression model to investigate the association between these underlying factors and vaccination intention. This research demonstrated the usefulness of the Theory of Planned Behavior, the Health Belief Model, and the 3 Cs Model in existing and future COVID-19 vaccine hesitancy research, as well as identified Protection Motivation Theory as a promising area for future research. Additionally, psychological states were demonstrated to be significantly associated with vaccine hesitancy, adjusting for demographic, socioeconomic, and time factors. Lastly, the Theory of Planned Behavior was found to be applicable to those unvaccinated and with chronic illness, as the construct factor scores developed were significantly associated with vaccine hesitancy (adjusting for the presence of specific chronic conditions and demographic, socioeconomic, and time factors). These associations were also consistently demonstrated in subgroup analyses of participants with specific chronic conditions.Item Social Determinants of Cardiovascular Disease Across the Life Course(2023) Ng, Amanda Erin; Dyer, Typhanye; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)According to data from the National Center for Health Statistics, cardiovascular disease is one of the leading causes of death in the United States, contributing to about 697,000 (or 1 in 5) deaths in 2020 alone. Given the public health burden of this disease, it is imperative that research identifies and continues to investigate population factors that may contribute to or alleviate this burden in the United States. The proposed study aimed to analyze such factors across the life course. Study 1 examined associations between an expanded set of Adverse Childhood Experiences (ACEs) and childhood obesity among 10-17 year olds using the National Survey of Children’s Health, as well as sex and age differences within these associations. Study 2 investigated high optimism as a modifier and mediator of the association between childhood socioeconomic disadvantage and CVD in midlife, using the Midlife in the United States Study, a U.S. prospective cohort. Study 3 examined temporal trends in the associations between adult socioeconomic status and CVD mortality using nationally-representative data from the 1997-2018 National Health Interview Survey.Item EXHALED BREATH AEROSOL TRANSMISSION OF ACUTE RESPIRATORY INFECTIONS(2023) Lai, Jianyu; Milton, Donald K; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Acute respiratory infections (ARIs), which usually appear in the form of common colds and influenza, as well as outbreak brought on by emerging viruses such as SARS-CoV-2, result in millions of deaths and hospitalizations each year. Aerosols being exhaled by infected population and inhaled by susceptible population has been identified as an important transmission route for ARIs; yet few studies have compared the viral load in exhaled breath aerosol (EBA) in naturally and experimentally infected cases, as well as among various infections. The specific aims of this dissertation were: 1) examine the comparability of EBA viral shedding between experimentally and a full range of natural ambulatory influenza cases; 2) compare seasonal coronavirus, influenza, SARS-CoV-2 Omicron, and other SARS-CoV-2 variants in terms of viral loads in exhaled breath aerosols; and 3) examine the relative efficacy of face masks, KN95, and N95 respirators as source control for SARS-CoV-2. We analyzed data from four studies that collected 30-minute fine (≤5 μm) and coarse (>5 μm) EBA samples using a Gesundheit-II sampler. Viral RNA load in EBA was quantified using real-time RT-PCR. Nasal inoculation of influenza virus A/Wisconsin/67/2005 showed lower EBA viral shedding compared to the natural influenza A H3 infections. Among the viruses studied, SARS-CoV-2 Omicron variants demonstrated the highest viral RNA loads in both EBA size fractions, emphasizing its superior spread capability via inhalation. Furthermore, while all masks and respirators showed significant reductions in viral RNA load in exhaled aerosols, the duckbill N95 respirators stood out, providing reductions of up to 99% and outperforming both surgical and cloth masks, and KN95 respirators. Given the evident transmission risk via inhalation for the studied viruses, measures such as masking and indoor air hygiene are crucial. The pronounced efficacy of N95 respirators highlights their importance in healthcare settings and places with vulnerable populations, especially during periods of heightened respiratory viral infections.Item EXAMINING THE IMPACT OF PRECONCEPTION AND EARLY PREGNANCY SERUM LEVELS OF MATERNAL VITAMIN D ON CLINICAL MARKERS OF IMPLANTATION AND PREECLAMPSIA(2023) Alkhalaf, Zeina; Thoma, Marie; Public and Community Health; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Vitamin D is a hormone rather than a vitamin, that is essential for overall health and wellbeing, including but not limited to the reproductive system. Although vitamin D is available through several sources, such as natural ultraviolet sunlight, food, and supplements, low circulating 25-hydroxyvitamin D (25(OH)D) levels of <30 ng/mL are common among pregnant women, with up to 69% of the US population suffering from the condition. Epidemiologic studies have suggested that low maternal serum 25(OH)D levels may be associated with adverse pregnancy outcomes, such as early pregnancy loss and preeclampsia, which may be initiated early in the pregnancy process during implantation and placentation. From a life course perspective, the periconception and early pregnancy period marks a critical time for establishing a healthy pregnancy. Implantation and placentation occur early in pregnancy and involve a complex process that relies on optimal endometrial receptivity and a host of hormonal and immunologic signaling events. Disruptions to this process may be indicated by early clinical markers of pregnancy complications (e.g., vaginal bleeding or subchorionic hemorrhage) and associated with later adverse outcomes (e.g., preeclampsia). In contrast, higher Human Chorionic Gonadotropin (hCG) levels, which have been linked to nausea and vomiting, may be markers of robust implantation and placentation. Therefore, I sought to investigate the preconception and early gestation maternal serum 25(OH)D levels on: (i) vaginal bleeding and subchorionic hemorrhage; (ii) nausea and vomiting; (iii) preeclampsia. In Aim 1, an analysis of medical record documentation of vaginal bleeding and subchorionic hemorrhage found that women who were persistently deficient/insufficient in maternal serum 25(OH)D at both preconception and 8-week gestation had 2.18 times higher (95% CI: 1.13, 4.20) odds of having subchorionic hemorrhage compared to women who remained sufficient across both time periods, even after adjustment for potential confounders. Additionally, an analysis of daily diaries showed women with deficient 25(OH)D levels had a higher odds (OR: 3.02, 95% CI: 1.13, 8.13) of moderate/heavy bleeding versus none compared to women with sufficient 25(OH)D levels based on self-reported daily diaries on vaginal bleeding at the start of pregnancy. In Aim 2, women with persistently deficient 25(OH)D levels at both preconception and early gestation had lower odds (OR: 0.34, 95% CI: 0.20, 0.60) of experiencing nausea and vomiting based on medical records. In comparison, women who increased their 25(OH)D levels early in pregnancy (i.e., were deficient/insufficient at preconception then became sufficient at 8-week gestation) had 1.71 (95% CI: 1.12, 2.61) times higher odds of nausea and vomiting compared to those who were persistently sufficient across both time periods. Based on self-reported nausea and vomiting symptoms from daily diaries, deficient 25(O)D was associated with lower odds (OR 0.65; 95% CI 0.40, 1.06) of both nausea and vomiting when comparing to sufficient 25(OH)D levels. In Aim 3, women who had deficient 25(OH)D at preconception had an increased risk (RR: 1.45, 95% CI: 0.64, 3.29) of preeclampsia (as identified from medical records), although results were insignificant. Linear spline models demonstrated that the risk of preeclampsia declined with each 1 ng/mL increase of 25(OH)D levels up to 40-45 ng/mL (RR: 0.97, 95% CI: (0.93, 1.00), but that levels beyond this threshold show an increase in the risk of preeclampsia for each 1 ng/mL increase in 25(OH)D (RR: 1.03; 95% CI: 1.00, 1.06). This research highlights the importance of exploring the maternal serum levels of 25(OH)D at both preconception and early gestation and how it may affect adverse pregnancy outcomes, such as vaginal bleeding, subchorionic hemorrhage, preeclampsia, and pregnancy outcomes that signify a robust implantation response, such as nausea and or vomiting. It further underscores the importance of assessing maternal serum 25(OH)D levels prior to critical time of implantation and placentation and potential biologic mechanisms that may lead to adverse pregnancy outcomes. Supporting healthy implantation and placentation is of utmost importance as this may guide the remainder of the health of the pregnancy, and any disruption to this process may increase the mother and infant’s risk of maternal morbidity and mortality (e.g., preeclampsia, vaginal bleeding, subchorionic hemorrhage). Future studies are needed with more diverse, larger sample sizes, and both paternal and maternal nutrition to further assess preconception nutritional risk factors on adverse and robust pregnancy outcomes. Accordingly, this research is vital as it may aid in identifying early factors that may reduce adverse maternal and infant health outcomes.Item RACIAL AND ETHNIC DISPARITIES OF BREAST CANCER RISK: THE ROLE OF INDIVIDUAL AND NEIGHBORHOOD-LEVEL CARDIOMETABOLIC FACTORS(2023) Ogbenna, Bethany Townsend; Dallal, Cher; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: Observed racial and ethnic disparities in breast cancer are complex, in part, due to biological and behavioral factors at the individual and neighborhood level. Cardiometabolic factors such as the use of cholesterol-lowering drugs and engaging in healthy lifestyle behaviors may reduce breast cancer risk, however, the current understanding of these factors among diverse racial and ethnic populations remains limited. Moreover, at the neighborhood-level, the extent to which neighborhood socioeconomic status (nSES) influences inflammatory profiles among racially and ethnically diverse populations remains unclear. Using data from the Multiethnic Cohort Study (MEC), this dissertation investigates cholesterol-lowering drug use (Aim I) and a Healthy Lifestyle Index (HLI) (Aim II) in relation to postmenopausal breast cancer risk by race and ethnicity; and, assesses associations between nSES and inflammatory biomarkers among adults (Aim III). Methods: Prospective cohort analyses were conducted among postmenopausal women who completed the third MEC follow-up questionnaire in 2003 (Aim 1, n=41,394) or the baseline questionnaire in 1993-1996 (Aim 2, n=65,561) and were followed until 2017 for invasive breast cancer diagnoses (n=1,681 and 4,555 cases, respectively). Multivariable adjusted hazard ratios [HR] and 95% confidence intervals [95% CI] were estimated using Cox proportional hazards regression. For Aim III, multivariable linear regression assessed cross-sectional associations between nSES and inflammatory serum biomarkers (adiponectin, leptin and C-reactive protein) among adults residing in California (n=6,919) and Hawaii (n=6,899) (2000-2017). Results: Cholesterol-lowering drug use (Aim 1) and duration was not associated with breast cancer risk among all women with no statistically significant heterogeneity in associations by race and ethnicity (p-interaction >0.05). In Aim 2 analyses, women with a higher HLI score (Tertile (T)) had a reduced risk of breast cancer (HRT3 vs T1: 0.76; 95% CI: 0.69, 0.84; HRT2 vs T1: 0.88; 95% CI: 0.79, 0.97) compared to women in the lowest HLI tertile with a significant dose-response observed (p-trend <0.01). Similar patterns were observed across all racial and ethnic groups of women. In California and Hawaii, individuals living in low nSES neighborhoods had higher serum levels of CRP (p-trend <0.001; p-trend = 0.02, respectively) and leptin (p-trend <0.001) while adiponectin levels were lower (p-trend <0.01; p-trend = 0.03, respectively) compared to individuals living in neighborhoods with high nSES. Additional adjustment for body mass index attenuated these associations (p-trend >0.05) (Aim III). Public Health Impact: Findings from this dissertation further support engaging in healthy lifestyle behaviors as a preventative strategy for breast cancer reduction among multiethnic populations of postmenopausal women whereas cholesterol-lowering drug use was not associated with reductions in risk. In addition, residing in low nSES neighborhoods was associated with less favorable inflammatory biomarkers levels.Item UNCOVERING THE HIDDEN POPULATION IN THE TRANSMISSION OF COVID-19: ASYMPTOMATIC CASES(2023) Yu, Weijun; Nguyen, Quynh C.; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation investigates the impact of international and local mobility of asymptomatic versus symptomatic COVID-19 cases on the pandemic in Hong Kong.The first manuscript analyzed empirical data from 11,775 confirmed COVID-19 cases in Hong Kong from January 2020 to April 2021, building a retrospective cohort. The results indicated that COVID-19 asymptomatic airport or flight crew were ten times more likely to have inbound air travel history than symptomatic airport or flight crew (adjusted RR=10.00, 95% CI: 4.00–25.00), and the median flight duration of asymptomatic cases was 4.6 person-hours shorter than that of symptomatic cases (p<0.01). The second manuscript presented a social network analysis study that build networks for the three peaks of COVID-19 diagnosis in Hong Kong. The results showed that asymptomatic cases were 1.33 times more likely to be presented in the inbound flight cabin or airport with other COVID-19 cases simultaneously than symptomatic cases (95%CI: 1.21-1.45) at the early stage of the pandemic. Additionally, the study found that network percolation simulation targeted attacks were more efficient than random failures in dismantling networks with a low level of connectedness. The third manuscript used geocoded COVID-19 cases’ travel records in Hong Kong to conduct a spatial analysis study. The findings indicated that asymptomatic cases visited locations mostly clustered in the southern part of Hong Kong, while symptomatic cases visited locations mostly clustered in the middle and southern parts of Hong Kong. This study also found that Geographically Weighted Regression models performed better among symptomatic cases than asymptomatic cases, and median local travel time was higher (p<0.01) among asymptomatic (68.09 person-minutes) than symptomatic cases (59.46 person-minutes) based on 19,568 Origin-Destination Cost Matrix least-cost paths. Overall, this dissertation highlights the importance of promoting public health prevention strategies to contain future infectious disease pandemics at the early stage, regardless of the presence of symptoms. Moreover, it suggests that travel restriction may not be effective in dismantling networks with a low-level of connectedness. Local health authorities and policymakers should tailor detection and containment strategies based on spatial variability in different areas.Item Understanding the Risk of Drug Overdose and Alcohol-Induced Deaths Among Adults with Different Types of Disabilities(2023) Aram, Jonathan; Dallal, Cher M; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: Disability is associated with drug and alcohol morbidity and mortality, which have reached high levels in recent years. Previous disability studies often combine all disabilities into a single category or focus on a single type of limitation. This dissertation characterizes different types of disabilities among U.S. adults and assesses associations with drug and alcohol morbidity and mortality. Methods: Using the 2018-2019 National Survey on Drug Use and Health (NSDUH, Aim 1), a nationally representative cross-sectional survey (n=83,485), different individual disabilities and co-occurring disabilities were identified. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between disability type and prevalence of drug and alcohol use disorders. Disabilities were also characterized within the Mortality Disparities in American Communities Study (Aims 2 and 3), a nationally-representative prospective cohort with baseline data collected in 2008 and mortality follow-up through 2019 (n=3,324,000). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHRs) and CIs for associations between disability type and drug overdose death (OD, Aim 2) and alcohol-induced death (AID, Aim 3). Results: Within the NSDUH analysis, adults with cognitive disability had increased odds of drug (aOR=3.3; 95% CI=2.9–3.8), and alcohol use disorder (aOR=2.3; 95% CI=2.0–2.6), compared to adults without disability. Positive associations of lesser magnitude were observed between hearing/seeing and ambulatory disabilities and drug use disorder. In MDAC analyses, OD risk was elevated among adults with cognitive (aHR=2.6; 95% CI=2.4–2.9), ambulatory (aHR=2.8; 95% CI=2.6–3.1), ambulatory and hearing/seeing (aHR=2.5; 95% CI=2.0–3.1), and hearing/seeing disability (aHR=1.6; 95% CI=1.4–1.9), compared to adults without disability. The risk of AID was elevated for adults with co-occurring ambulatory and hearing/seeing disability (aHR=1.8; 95% CI=1.5–2.2), ambulatory disability only (aHR=1.5; 95% CI=1.3–1.7), and hearing/seeing disability only (aHR=1.2; 95% CI=1.0–1.4). Conclusions: The examination of specific disability categories reveals unique associations that are not apparent when all disabilities are combined. These findings can be used to improve access to recovery support services. Expansion of educational and occupational opportunities for adults with disabilities should be considered as strategies to reduce drug and alcohol morbidity and mortality.Item Effects of Tamoxifen Therapy on Breast Carcinogenesis: Epidemiological Associations and Biomechanisms of Action(2022) Ghosh, Rajrupa; Dallal, Cher; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: Tamoxifen, a key chemopreventive and adjuvant endocrine therapy (ET) for breast cancer, is suggested to alter breast cancer risk factors including circulating hormones (estrogen and insulin-like growth factors (IGFs)) and breast density. However, the biological underpinnings of tamoxifen’s effect on these factors remain unclear. This dissertation evaluated effects of tamoxifen on estrogen metabolites (EMs), explored associations between circulating IGFs (IGF-I and IGFBP-3) and volume average sound speed measures (VASS) of breast density, and synthesized evidence from real-world studies to meta-analyze adjuvant ET in relation to contralateral breast cancer (CBC) risk. Methods: Within the Ultrasound Study of Tamoxifen, serial serum samples collected prior to and 12 months after tamoxifen treatment were used to assess longitudinal changes (paired t-tests) in 15 circulating EMs among postmenopausal women (n=23) (Aim 1), and changes in IGFs and VASS (n=53) (Aim 2). Multivariable linear regression examined associations between metabolites of tamoxifen and estrogen among pre- (n=33) and postmenopausal women (n=27) (Aim 1) and concomitant changes in IGFs and VASS (n=53) (Aim 2), 12 months after treatment initiation. In Aim 3, a random effects meta-analysis of observational studies (n=17, 287,576 participants) estimated relative risks (RR) and 95% confidence intervals (CI) for associations between ET and CBC risk among primary breast cancer patients overall, by menopausal status and CBC estrogen receptor (ER)-subtype. Results: Circulating 2-OH and 16-OH pathway EMs, IGF-I, and IGF-I:IGFBP-3 decreased 12 months after tamoxifen initiation (p <0.05; Aims 1 and 2). No associations were observed between concomitant changes in IGFs and VASS among tamoxifen-treated patients (Aim 2). In meta-analyses (Aim 3), endocrine therapy was associated with reduced CBC risk (RR: 0.62, 95% CI: 0.53, 0.73), with a greater reduction observed among premenopausal (RR: 0.58, 95% CI: 0.43, 0.78) versus postmenopausal women (RR: 0.72, 95% CI: 0.60, 0.87). Endocrine therapy reduced the risk of ER-positive (RR: 0.55, 95% CI: 0.43, 0.70) but not ER-negative CBC. Conclusion: The tamoxifen mediated decline of circulating 2-OH, 16-OH and IGF-I provides etiologic insight into the biomechanisms of tamoxifen on breast carcinogenesis. Meta-analyses of observational studies further support a chemopreventive role of endocrine therapy on CBC risk, particularly, ER-positive CBC.