Epidemiology & Biostatistics Theses and Dissertations

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    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.
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    Intersectional stigma, self-efficacy, depression, and resilience: a Rasch analysis
    (2022) Reuben, Jacqueline; Liu, Hongjie; Turpin, Rodman; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Background: Black men who have sex with men (BMSM) are disproportionally affected by negative health outcomes associated with stigma related to both their racial and sexual minority status. Foundational to understanding stigma is the ability to correctly measure this latent construct. The Rasch model is a probabilistic model for analyzing categorical data that was developed to improve the measurement of latent traits. This study, grounded in intersectional minority stress theory, reviewed the application of Rasch analysis in the HIV/AIDS literature (Aim 1) and used the Rasch model to calibrate person measures to assess the interrelationships among internalized stigma, resilience, self-efficacy, and psychologic well-being among BMSM (Aims 2 and 3). Methods: For Aim 1, we conducted a systematic review of the literature following PRISMA guidelines. Aims 2 and 3 used data from a cross-sectional online survey of 151 HIV-negative BMSM in 2020. For Aim 2, we conducted Rasch analysis to assess the psychometric properties of the internalized racism (IR), internalized homophobia (IH), self-efficacy, and resilience scales. For Aim 3, we used linear regression and path analysis of the Rasch-calibrated person measures to examine the mediating and modifying effects of self-efficacy and resilience on the relationship between intersectional stigma and depressive symptoms. Results: For Aim 1, after screening 183 articles, 45 articles were included in the analysis. Strengths and weaknesses of using the Rasch approach were summarized. For Aim 2, the final IR scale had a person reliability and separation of 0.91 and 3.13, respectively, and an item reliability and separation of 0.94 and 4.01, respectively. The final IH scale had a person reliability and separation of 0.88 and 2.72, respectively, and an item reliability and separation of 0.79 and 1.95, respectively. For Aim 3, IR (β=0.296, 95% CI [0.133, 0.458]) and IH (β=0.414, 95% CI [0.204,0.623]) were independently and positively associated with depression in multivariable models controlling for age, income, and relationship status. Resilience and self-efficacy modified the relationship between IH and depression (βIHxRES=-0.034, 95% CI [-0.060, -0.008] and βIHxSE=-.056, 95% CI [-0.113, 0.00], respectively), but there was no evidence of effect modification by resilience or self-efficacy on the association between IR and depression. Public health implications: Our findings suggest that interventions targeting multiply marginalized groups such as BMSM that address co-occurring forms of stigma and foster positive self-evaluation and coping skills may reduce the negative consequences of internalized stigma on mental health outcomes.
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    The effects of HIV criminalization laws (and their enforcement) on HIV risk among Black and Hispanic populations
    (2022) Keralis, Jessica Maciel; Nguyen, Quynh C; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Background: In the U.S., 25 states have laws that explicitly criminalize the transmission or exposure of HIV. This study, grounded in Nancy Krieger's ecosocial theory, estimated the association between HIV criminalization laws and state- (Aim 1) and county-level (Aim 2) HIV incidence rates, as well as individual HIV testing history (Aim 3), and assessed effect modification by overpolicing, using incarceration rates as a proxy. Methods: The study uses data from state- and county-level HIV incidence data from AIDSVu (2010-2019), incarceration data from the Vera Institute of Justice (2010-2018), and HIV testing data from BRFSS (2016-2019). For Aim 1, a longitudinal analysis was conducted using multivariate marginal Poisson GEE models to estimate rate ratios. For Aim 2, count-rate hierarchical (multilevel) models were fitted to estimate rate ratios. For Aim 3, logistic regression models were fitted to estimate odds ratios. Results: The presence of a state HIV testing law was associated with a higher state HIV incidence in the general and Hispanic populations (aRR=1.48 and 1.68, respectively), but higher incarceration at the state level did not significantly modify the relationship between the law and HIV incidence. At the county level, being in a state with an HIV-specific criminalization statute was associated with a higher county-wide HIV incidence rate for all three populations (aRR=1.14, 1.30, and 1.32 for the general, Black, and Hispanic populations, respectively). Unlike the state-level analysis, this association was attenuated by a higher jailed population rate for the general and Black populations. The effect modification was statistically significant for the general population (p=0.01) and marginally significant for the Black population (p=0.06). Finally, the presence of a state HIV testing law (aOR=1.06) was associated with a greater likelihood of HIV testing history in the general population. However, in HIV criminalization states, heavier policing negatively modified the effect of the law on the likelihood of having ever received an HIV test (p<0.01). Public health implications: This study contributes to a gap in the literature by using recent data to estimate the association of HIV criminalization laws and their enforcement with HIV incidence rates and HIV testing behavior.
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    Metformin and statins in relation to ovarian cancer: implications for risk and potential etiologic pathways
    (2022) Irvin, Sarah Renee; Dallal, Cher; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Background: Metabolic factors, including obesity, diabetes, and circulating lipids are associated with increased risk of ovarian cancer, the most fatal gynecologic malignancy. Drugs targeting these conditions have drawn interest as potential chemopreventive agents, but limited studies have examined relationships with ovarian cancer overall, by possible benefit groups or with regards to related etiologic pathways. This dissertation examined medications that target metabolic abnormalities with risk of ovarian cancer, and expression of a pro-tumorigenic lipid pathway in ovarian cancer tissue.Methods: Nested case-control studies of metformin (Aim 1) and statin (Aim 2) use in relation to ovarian cancer (cases n=9,207 and 10:1 frequency-matched controls n=92,070) were conducted in Clinical Practice Research Datalink (CPRD) (1987-2020), a primary care database in the United Kingdom. Aim 3 was a case-only analysis from The Polish Ovarian Cancer Study (POCS) (2001-2003, n=166) determining expression of sphingosine-1-phosphate receptors S1PR1 and S1PR3 in ovarian cancer tissue. Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for associations between medication use and ovarian cancer in CPRD (Aims 1 and 2), and cancer characteristics with marker expression in POCS (Aim 3). Results: Within the CPRD analyses, metabolic conditions such as obesity (OR 1.19, 95% CI 1.11-1.28) and polycystic ovarian syndrome (OR 1.66, 95% CI 1.17-2.35) were significantly associated with increased ovarian cancer risk. However, neither metformin (OR 1.01, 95% CI 0.91-1.13) nor statin use (OR 1.02, 95% CI 0.96-1.08) was associated with ovarian cancer risk. Associations did not differ by drug indications (pint >0.05), individual statin or class. In Aim 3, strong expression of lipid markers in ovarian cancer tissue significantly differed by histotype (p<0.01). Lower marker expression was observed in non-serous tumors compared to serous, but expression was not associated with cancer risk factors or survival. Conclusion: Findings from this dissertation do not support use of metformin or statins as chemopreventive agents. However, as most CPRD users had an indication, it remains unclear whether findings are generalizable to the at-risk population for ovarian cancer. Strong expression of lipid markers in ovarian cancer tissue suggests involvement in carcinogenesis; additional molecular studies are needed to elucidate their role.
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    Exploring Psychosocial and Structural Syndemic Effects as Predictors for HIV-Related Outcomes among Black Women
    (2022) Watson, Lakeshia; Dyer, Typhanye; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Black women continue to be disproportionately affected by HIV with marked disparities in HIV incidence, prevalence, and care outcomes. There is a critical need to explore the role of psychosocial and structural factors and the negative impact of these factors on HIV-related outcomes, including HIV risk behaviors, HIV medication adherence, and healthcare utilization. This research uses the syndemic theory to measure the effects of both psychosocial and structural syndemics on HIV-related outcomes among Black women. Syndemic theory is a theoretical framework, which posits there are multiple, overlapping factors that form a cumulative and synergistic effect on HIV disease burden. The substance abuse, violence and AIDS (SAVA) syndemic, clustering effects of substance use, intimate partner abuse, and HIV/AIDS, have been applied in studies exploring HIV outcomes among women; however, the SAVA syndemic framework does not include additional psychosocial and structural factors such as food insecurity, housing instability, incarceration, post -traumatic stress disorder, and depression to better understand the syndemic profiles of Black women. Using study data from the HIV Prevention Trials Network 061 Women’s Seroincidence study and the Women’s Interagency HIV Study, we tested whether a cumulative syndemic of psychosocial and structural factors contributed to sexual risk behaviors and HIV care outcomes. The studies will assess three parameterizations of syndemic factors: cumulative syndemic index, syndemic group indices reflecting the level of influence (psychosocial, participant-level, and neighborhood), and number of syndemic groups (0, 1, 2, or 3). We also tested whether HIV status modified the relationships between a cumulative syndemic of psychosocial and structural factors and sexual risk behaviors. In study 1, a higher syndemic score was significantly associated with increased prevalence of unknown HIV status of last male sex partner (aPR = 1.07, 95% CI: 1.04-1.10), engaging in exchange sex (aPR = 1.17, 95% CI: 1.14-1.20), and having multiple sex partners (aPR = 1.07, 95% CI: 1.06-1.09) among a sample of 1,347 Black women. In study 2, generalized linear mixed models found that being in two syndemic groups was associated with increased odds of reporting unknown HIV status of last male sex partners (aOR=3.04, 95% CI: 1.24-7.44) and having multiple sex partners (aOR=4.29, 95% CI: 1.81-10.18) among 1,364 Black women living with and without HIV across twelve follow-up visits. We also found that being in all three syndemic groups was associated with increased odds of reporting inconsistent condom use (aOR= 2.15, 95% CI: 1.28-3.61), unknown HIV status of last male sex partners (aOR=5.26, 95% CI: 1.94-14.25), and having multiple sex partners (aOR=7.47, 95% CI: 2.85-19.58). Among a total of 969 Black women living with HIV in study 3, a higher cumulative syndemic score and a higher neighborhood-level structural syndemic group score was associated with increased odds of reporting sub-optimal HIV medication adherence (aOR=1.04, 95% CI: 1.01-1.06 and 1.08, respectively). Black women in all three syndemic groups had increased odds of reporting sub-optimal HIV medication adherence (OR=2.88, 95% CI: 1.32-6.29) and missed HIV appointments (OR=3.39, 95% CI: 1.06-10.92). Results from these studies highlight the evidence of psychosocial and structural syndemic effects on multiple HIV risk and care outcomes among Black women.