Influence of Stress, Gender, and Minority Status on Cardiovascular Disease Risk in the Hispanic/Latino Community: Protocol for a Longitudinal Observational Cohort Study

Background Hispanic/Latino sexual and gender minorities (SGM) are the fastest growing ethnic group of SGM in the United States. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among Hispanics/Latinos. SGM inequities in CVD risk have been identified as early as young adulthood, and minority stress has been identified as a potential mediator. Yet, the small number of ethnic or racial minority participants in SGM studies have precluded the examination of the intersections of sexual orientation, gender identity, and race and ethnicity. Objective Minority stress models conceptualize relationships between stressors in minority groups and health outcomes. In this study, we will (1) examine the influence of sexual orientation and gender identity on CVD risk among all Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants at visit 3 (2021-2024; N~9300); (2) model pathways from sexual orientation and gender identity to CVD risk through stigma, discrimination, and stress in a 1:2 matched subcohort of SGM and non-SGM participants at visit 3 (n~1680); and (3) examine the influence of resilience factors on sexual orientation or gender identity and CVD risk relationships among subcohort participants at visit 3 (n~1680). Methods This study will leverage existing data from the parent HCHS/SOL study (collected since 2008) while collecting new data on sexual orientation, gender identity, stigma, discrimination, stress, coping, social support, and CVD risk. Data analysis will follow the SGM minority stress model, which states that excess stigma against SGM populations leads to minority stress that increases CVD risk. In this model, coping and social support serve as resilience factors that can mitigate the impact of minority stress on CVD risk. Cross-sectional and longitudinal regression models as well as structural equation models will be used to test these relationships. Results This study was funded by the National Heart, Lung, and Blood Institute in March 2020. Recruitment is scheduled to begin in the first quarter of 2021 and continue through 2024. Conclusions Understanding the influence of stigma-induced stress on CVD risk among Hispanic/Latino SGM has significant implications for the development of culturally specific CVD risk reduction strategies. Study findings will be used to build on identified Hispanic/Latino cultural strengths to inform adaptation and testing of family and community acceptance interventions. International Registered Report Identifier (IRRID) PRR1-10.2196/28997

1 R01 HL149778-01 2 HDEP POTEAT, T 1R01HL149778-01 POTEAT, TONIA RESUME AND SUMMARY OF DISCUSSION: The application proposes to examine the influence of sexual and gender minority (SGM) status on cardiovascular disease (CVD) risk as an ancillary study to an existing cohort study of Hispanic adults. The timely and moderately innovative examination of pathways including stigma and stress on CVD outcomes may inform evidence-based community interventions to address disparities among at-risk adults. This is a highly significant area of inquiry with a rigorous examination of prior research regarding SGM disparities. The study builds on prior work by a strong and complementary team of investigators. The rigorous study design includes clearly described biomarkers and metabolic measures in an approach appropriately guided by a conceptual framework. Minor weaknesses include the lack of clarity regarding the conceptualization of SGM identity. Some reviewers questioned whether the category will potentially mask heterogeneity in identity and behavior. Others found the justification to examine any aspect of sexual attraction as appropriate. Alternative strategies for data collection are not addressed. Overall, the strengths outweigh minor weaknesses and reviewers were enthusiastic that the application has potential for high scientific impact on CVD disparities among sexual and gender minority adults.

DESCRIPTION (provided by applicant):
Hispanic/Latino sexual and gender minorities (SGM) are the fastest growing ethnic group of SGM in the U.S. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among Hispanic/Latinos. SGM inequities in cardiovascular disease (CVD) risk have been identified as early as young adulthood; and minority stress has been identified as a potential moderator. Yet, small numbers of ethnic minority participants in SGM studies have precluded examination of the intersections of sexual orientation, gender identity, and ethnicity. We propose a costeffective ancillary study that will leverage existing data from the parent Hispanic Community Health Study/Study of Latinos (HCHS/SOL) while collecting new data on sexual orientation, gender identity, stigma, discrimination, stress, coping, social support, and CVD risk. The proposed study is timely because HCHS/SOL participants will be scheduled for their third in-person visits (V3) starting in November 2019. In this study, we will (1) examine the influence of sexual orientation and gender identity on CVD risk among all HCHS/SOL participants at V3 (~9300); (2) model pathways from sexual orientation and gender identity to CVD risk through stigma, discrimination, and stress among a 1:2 matched sub-cohort of SGM and non-SGM participants at V3 (~1680); and (3) examine the influence of stigma/discrimination on sexual orientation and CVD risk relationships among sub-cohort participants at V3. Data analysis will follow a conceptual model derived from the LGBT Minority Stress Model in which excess stigma discrimination against SGM leads to minority stress that increases CVD risk. In this model, coping and social support serve as resilience factors that mitigate the impact of minority stress on CVD risk. Cross-sectional and longitudinal regression models as well as structural equation models will be used to test these relationships. Understanding the influence of stigma-induced stress on CVD risk among Hispanic/Latino SGM has significant implications for the development of culturally-specific CVD risk reduction strategies. Study findings will be used to build on identified Hispanic/Latino cultural strengths to inform adaptation and testing of family and community acceptance interventions. .

PUBLIC HEALTH RELEVANCE:
The cardiovascular health of Hispanic/Latino sexual and gender minorities has been understudied. The goal of this study is to examine relationships between sexual/gender minority stress, coping, social support, and heart disease -a leading cause of morbidity and mortality among Hispanic/Latinos in the U.S. Findings will inform development of culturallyappropriate interventions to address psychosocial factors that may contribute to cardiovascular health disparities by sexual orientation and gender identity.

CRITIQUE 1
Significance: 2 Investigator(s): 1 1 R01 HL149778-01 3 HDEP POTEAT, T Innovation: 3 Approach: 2 Environment: 1 Overall Impact: The proposed study is likely to have high impact on public health science. Scoredriving strengths include the strong conceptual foundation, rigor of scientific premise, excellent investigative team, and synergy with ongoing parent study, which makes the new knowledge this study would add relatively cost effective. Minor weaknesses include some ambiguity in the precise operationalization of SGM status in analytic models (as opposed to in screening questions) and the fact that the hypothesized associations are consistent with such a large body of literature on stigma, stress, and CVD. On balance, the addition of data on a cohort of people with multiple minority statuses outweighs this weakness on innovation and promises to add valuable new data on a neglected population.

Significance: Strengths
• Good foundation in Minority Stress Model, with complementary support from framework of intersectionality. • Strong scientific premise for likelihood of increased vulnerability to CVD among Latino sexual and gender minorities (SGM). • Elevated CVD among SGMs are a disparity in need of study and intervention.

Weaknesses
• Conceptualization of SGM is not particularly nuanced. The category of SGM masks substantial heterogeneity in sexual orientation, identity, and behavior, and one would expect hypothesized associations to vary along these lines.

Investigator(s): Strengths
• Multiple PIs complement one another well.
• Demonstrated record of collaboration and productivity among HCHS/SOL researchers.
• Strong coverage of multiple disciplines required for the study.
• Excellent record of accomplishment in scientific productivity across the team. Weaknesses • None noted.

Innovation: Strengths
• Study adds needed data on intersection of multiple minority identities, notably SGM among Latinos. • Longitudinal designs remain too uncommon among studies of minority stress and health.
• Measures of stigma as separate from stress add valuable new data.

Weaknesses
• As application argues convincingly, there are already strong reasons to expect that SGM is associated with elevated CVD risk among Latinos.

Approach: Strengths
• Ancillary study builds on successful HCHS/SOL, the largest longitudinal cohort study of US Hispanic/Latinos. • Large parent cohort study (N=9300 expected for V3) should yield adequate sample of Latinos identifying as SGM (~560). • Addition of CRP to other cardiometabolic risk markers is valuable.
• Strong link between conceptual model and validated measures for key constructs. • Good attention to power and sample size • Consideration of scientific rigor, quality control, and potential problems and alternatives.

Weaknesses
• Data cited concerning feasibility of collecting data on sexual and gender minority identity are not tailored to the cohort. A particular problem is that the evidence cited indicates that "most respondents" do not find such questions difficult or sensitive. But "most" is not the point: Do people who hold the minority status find it difficult or sensitive to report? Given the application's argument about stigma, there needs to be stronger evidence that stigma wouldn't prevent stigmatized people from disclosing their identities. • Argument for screening with a question on sexual attraction is sound, but it is unclear precisely how SGM versus non-SGM will be classified in analyses. Do the researchers expect a difference in effect of stigma or discrimination between people who report same-sex attraction versus those who report identity or behavior?

Environment: Strengths
• Strong intellectual environment with support for interdisciplinary exchange and collaboration.
• Ample research infrastructure, including libraries, computing, and collaboration centers.

Biohazards:
Acceptable • Specific biohazards are not addressed, but the team has experience collecting and protecting biomarker data.

Budget and Period of Support:
Recommend as Requested

CRITIQUE 2
Significance: 2 Investigator(s): Overall Impact: The proposed study intends to develop an ancillary project to the existing SOL study to examine relationships between CVD risk factor and sexual orientation, gender identify, stigma, discrimination, stress, coping and social support. Cross-sectional and longitudinal analyses will be used to tests the proposed relationships. Key strengths of the application include; strong scientific premise and clear public health significance to conduct this ancillary study. Excellent team of co-PIs and co-Is with the appropriate methodological and conceptual expertise to conduct the proposed study. Innovative population, strong theoretical model and a rigorous study design with validated measures and clear analytical plan for each of the study hypothesis. No major weaknesses were identified in this proposal. Overall, this is a significant, innovative and rigorous study that intends to address a critical gap in understanding the health of the SGM Latino population in the U.S. This study can make a significant contributions to the fields of SGM health disparities research and Latinx health research.

Significance: Strengths
• This study is significant since cardiovascular health of SGM Latinos has been understudied and this is the fastest growing ethnic group within the SGM population in the U.S. • A strong scientific premise and theoretical framework supports the proposed study.

Weaknesses
• None noted

Investigator(s): Strengths
• The study Co-PIs bring complementary expertise in SMG health disparities, Latino CVD health, survey methodologies and leading and designing rigorous epidemiological studies. They both have the necessary expertise and experiences to conduct the proposed study. • A strong team of co-investigators supports the proposed study. This team has a history of previous collaborations and are well connected with the SOL study. • This is the right team for this innovative study.

Weaknesses
• None noted

Innovation: Strengths
• The examination of the intersection of sexual orientation, gender identity, Latinx ethnicity on CVD risk in a state-of-the-art on-going cohort epidemiological study is novel. Results from this study can make substantial contributions to this important literature. • The focus on SGM Latinx population is novel given the scarcity of research in this growing and diverse population. • The proposed longitudinal analyses are also novel.

Approach: Strengths
• Clear study aims and hypotheses inform the proposed study.
• The proposed study leverages the infrastructure and rigorousness of the existing and ongoing SOL study. • Measuring stigma and discrimination with well validated measures separately is a key strength of the approach. • The study builds upon previous analyses using the SOL data to examine the relationships between many of the proposed concepts which inform the proposed analyses. • A strong theoretical framework supports the proposed analyses.
• Rigorous study procedures to recruit and collect data on the SGM subsample are being used.
• Rigorous and well-validated measures using objective indicators of CVD risk, MetS and CMR will be used in the proposed study. • Clear analytical plans are presented for each study hypotheses, including primary, secondary and exploratory analyses.

Weaknesses
• If sample size permits, exploratory analysis examining differences between Latinx subgroups (e.g., country of birth, etc) could be considered for each of the study aims.

Environment: Strengths
• Excellent institutional support and research infrastructure supports the proposed study. Weaknesses • None noted. Overall Impact: This ancillary study adds new dimensions to Latinx health and CVD studies by focusing on the SGM population. This application makes good use of existing data and adds to the existing literature. The analytic plans are strong, there is a strong team in place. While this is significant, there are weaknesses in the approach that are noted. Another concern is about the start time. If wave 3 starts in November, it is unclear if there will be enough time to prepare for recruiting participants. Overall, this remains a strong study. Consultants are required to absent themselves from the room during the review of any application if their presence would constitute or appear to constitute a conflict of interest.