Multi-Ethnic Study Research Articles

Abstract B125: Reproductive factors and thyroid cancer risk: The multiethnic cohort study

Abstract Background : Thyroid cancer is the most common endocrine cancer worldwide, with the incidence in women being three times that of men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and hormone replacement therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods : A prospective cohort study of women of diverse racial and ethnic groups in the Multiethnic Cohort Study (n=118,344) was used. Included were 373 papillary thyroid cancer cases, linked to SEER cancer incidence and statewide death certificate files in Hawaii and California. Exposures investigated include age at menarche, parity, menopausal status and type, birth control use, and outcomes of first pregnancy. Cox proportional hazards models of papillary thyroid cancer were used to obtain relative risk (RR) and 95% confidence intervals (CI) to examine the associations with reproductive/hormonal factors. Results : We observed a statistically significant increased risk of papillary thyroid cancer for hysterectomy, oophorectomy, surgical menopause, and not having a child by age 20. The adjusted estimates for oophorectomy RR 1.66 (95% CI: 1.31, 2.11) and hysterectomy RR 1.82 (95% CI: 1.42, 2.34). Menopause due to surgery was associated with a 55% increase in risk (RR 1.55, 95% CI: 1.22, 1.97) and nulliparity vs ≤ 20 years of age at first livebirth was related to a 51% increased risk (adjusted RR 1.51, 95% CI: 1.07, 2.15). Adjustment factors included age and race/ethnicity and menopausal status, menopausal type, and oral contraception where appropriate. Former use of estrogen menopausal hormone therapy was associated with a 35% increased risk (adjusted RR: 1.35, 95% CI: 1.02, 1.79). No significant heterogeneity was seen in these associations by race/ethnicity (p het >0.48). Conclusion : The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in our multiethnic population. Our analysis finds having a hysterectomy or oophorectomy and the use of MHT are associated with an increased risk of papillary thyroid cancer, and having a child at a younger age is associated with a reduction in thyroid cancer risk. Citation Format: Janine V. Abe, Song-Yi Park, Christopher A. Haiman, Loïc Le Marchand, Brenda Y. Hernandez, Lynne R. Wilkens. Reproductive factors and thyroid cancer risk: The multiethnic cohort study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B125.

Abstract A103: Joint associations of education and neighborhood socioeconomic status on smoking prevalence: The Multiethnic Cohort Study

Abstract Background: Smoking is the leading cause of cancer and cancer death. Individual- and neighborhood-level measures of socioeconomic status (SES) have been separately associated with racial and ethnic differences in smoking rates. However, the joint associations of individual- and neighborhood-level SES on smoking have not been studied. Thus, we examined the joint association of education and neighborhood SES (nSES) on smoking status in the Multiethnic Cohort (MEC) study. Methods: We conducted a cross-sectional study of the joint association of nSES and education with smoking for 166,475 MEC participants (26,350 African American, 50,207 Japanese American, 34,490 Latino, 12,326 Native Hawaiian, and 43,102 White participants) recruited from predominately Los Angeles County and Hawaii. Smoking status, education, and other demographics and health behaviors were reported at baseline (1993-1996). Neighborhood SES (nSES) was derived using 1990 US Census data on education, occupation, unemployment, household income, poverty, rent, and house values and assigned to geocoded baseline addresses; and categorized into quintiles using LA County and Hawaii nSES distributions. The joint nSES and education measure was categorized into 4 levels using high nSES (quintiles 4-5), low nSES (quintiles 1-3), high education (≥ high school), and low education (< high school). The study outcome was current smoking vs. non-smoking (never or former smoking). Poisson regression was used to estimate prevalence ratios (PR) and 95% CIs for the joint association of nSES and education with current smoking, adjusting for sex, race/ethnicity, marital status, physical activity, occupation, alcohol, obesity, 2015 healthy eating index, and clustering by census block group. Subgroup analyses were conducted by state (CA and HI), sex, and race/ethnicity. Results: For CA MEC participants, smoking prevalence was highest with low nSES and low education, followed by low nSES and high education, and high nSES and low education (PR=1.50, 1.33, and 1.29, respectively). This pattern was found in females but not males and in African American and Japanese American participants but not Latino or White participants. For HI MEC participants, smoking prevalence was highest with low nSES and low education, followed by high nSES and low education, and low nSES and high education (PR=1.41, 1.36, and 1.20, respectively). This pattern was found in males and females in HI and across all racial and ethnic groups. Interestingly, in Native Hawaiian participants, the smoking prevalence with low nSES and low education was similar to those with high nSES and low education (PR=1.54 and 1.52, respectively). Conclusion: In the MEC, smoking prevalence was highest in CA for females, African American, and Japanese American participants in joint SES categories with low nSES, while in HI, low education appeared more influential, especially among Native Hawaiian participants. These findings demonstrate the importance of considering both individual and neighborhood-level SES measures on smoking prevalence. Citation Format: Catherine P. Walsh, Younghan Lee, Salma Shariff-Marco, Lynne Wilkens, Loic Le Marchand, Christopher A. Haiman, Iona Cheng, S. Lani Park. Joint associations of education and neighborhood socioeconomic status on smoking prevalence: The Multiethnic Cohort Study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A103.

Abstract B113: A multi-ethnic population-based study of multiple myeloma disparities: Results from a recruitment pilot

Abstract To understand multiple myeloma (MM) incidence and survivorship disparities, we established the Precision MEDicine, EqUity and Disparities Research in MultipLe MyeLomA (MEDULLA) study. Our study contacted 400 MM patients reported to the Cancer Registry of Greater California (CRGC) between 2013-2018. We contacted 100 adult individuals from four racial/ethnic groups: Blacks, Whites, Latinos, and Asians with MM diagnosis. Data collection included variables reported to the CRGC, a self-administered survey, and biospecimen saliva collection. The survey focused on demographics, risk factors, cancer treatment, family history, quality of life, and social determinants of health. We also used census tract level features obtained by the American Community Survey 2007-2011. A total of 95 patients participated in the survey (overall response rate = 24%). We performed chi-square test, fisher’s exact test, or Wilcoxon test to obtain two-sided p-values for univariate testing for associations with responding to the survey. We further perform multivariable logistic regression using a stepwise approach under the Akaike information criterion with age and sex kept as covariates. These methods were stratified by Whites and Non-Whites separately which we were able to find important trends. The highest response received was from Whites at 44.2%, with significantly lower rates in all minority groups (<20% for all groups). Response rates were higher for patients living in areas with higher median annual incomes and education. For every 1% increase in poverty rates, Whites living in such neighborhoods were 3% less likely to respond to the survey (p=0.04). For every 10% increase in the proportion of individuals having a college degree, responding to the survey increased by 1.17 units for minorities in that neighborhood (p=0.07). Minorities living in neighborhoods with high proportions of adults without a high school diploma and high unemployment rates are less likely to respond (p=0.02 and p=0.047, respectively). In conclusion, we found significantly lower participation rates among minority groups, with socio-economic factors affecting response rates. We suggest that future studies develop community-focused and culturally tailored strategies to understand MM etiology and survivorship in such populations. Citation Format: April P. Vang, Angelica Perez, Juanita Elizabeth Quino, Ana Estrada, Eric Stewart, Rosemary Cress, Luis Carvajal-Carmona. A multi-ethnic population-based study of multiple myeloma disparities: Results from a recruitment pilot [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B113.

Abstract B085: Associations of African genetic ancestry and neighborhood social environment with cancer-specific mortality in the Multiethnic Cohort

Abstract Importance: Evaluating contributions of both genetic and social environmental factors to cancer mortality in Black populations is necessary for prioritizing interventions to reduce racial disparities and inequities. We examined multilevel associations of African genetic ancestry (AGA) and the neighborhood social environment with cancer-specific mortality in Black participants in the Multiethnic Cohort Study. Methods: From 1993 through 1996, participants who self-identified as Black as their primary race, and were aged 45-75 years residing in Los Angeles County completed baseline demographic, clinical, and lifestyle questionnaires to enroll into the Multiethnic Cohort Study. Residential addresses were collected and geocoded to the nearest parcel, and deaths were ascertained over follow-up through December 31, 2019. For this prospective study, we analyzed data on participants with genetic ancestry data and geocoded addresses (n=10,722). Global African and European genetic ancestry was estimated using approximately 21,000 ancestry specific markers, from which AGA was estimated for each participant against the 1000 Genomes referent panel (K=2). A neighborhood socioeconomic status (nSES) index and the Index of Concentration at Extremes (ICE) capturing spatial social polarization based on income and racial composition were computed from the 1990 decennial Census and linked to residential census tracts at baseline. Cancer-specific mortality was assigned based on ICD-09 and ICD-10 codes. We estimated subdistribution hazard ratios (SHR) from Fine-Gray competing risks models adjusted for birth cohort, sex, smoking, marital status, education, body mass index (BMI), BMI at age 21, history of hypertension, physical activity, diet quality, and nSES or African ancestry. Results: There were 1,715 cancer deaths over 226,327 person-years of follow-up. Mean age was 61.1 (SD=8.9) years, mean AGA was 76% (SD=15%). Most participants identified as Black (94%) while others reported mixed (White, Hispanic, or Asian) heritage. Higher AGA was associated with lower individual education and nSES (Both P<0.001). AGA was not associated with cancer mortality (SHR for 10% increase: 1.02, 95% CI: 0.99-1.06). Comparing quintile 5 to 1, there were inverse but not statistically significant associations of nSES (SHR: 0.88, 95% CI: 0.71-1.09, P trend=0.34), ICE Income (SHR: 0.92, 95% CI: 0.73-1.16, P trend=0.36), and racialized income ICE (SHR: 0.81, 0.58-1.13, P trend=0.033) with cancer mortality. Associations of AGA and nSES with cancer mortality did not vary across strata of the other exposure. Conclusions and Relevance: In this large prospective study of Black participants, after accounting for sociodemographic, lifestyle, and comorbidity-related factors, there were few associations between either genetic factors or social environment with cancer mortality. Additional studies in cohorts of Black adults residing in other geographic contexts, with additional measures of social determinants of health such as health care access, are needed to further evaluate these findings. Citation Format: Hari S. Iyer, Scarlett L. Gomez, Chidinma Opara, Nur Zeinomar, Loic LeMarchand, Christopher Haiman, Lynne Wilkens, Salma Shariff-Marco, David V. Conti, Iona Cheng, Timothy R. Rebbeck. Associations of African genetic ancestry and neighborhood social environment with cancer-specific mortality in the Multiethnic Cohort [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B085.

Tau pathway‐based gene analysis in the Alzheimer’s disease continuum identifies CLU and FYN associated with tau deposition on PET in a Korean Cohort

AbstractBackgroundAbnormal tau protein aggregation and spreading in the brain is closely linked to cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). The role of genetic variation in brain tau aggregation has not been fully elucidated. Here, we performed pathway‐based candidate gene association analysis to identify novel genes associated with brain tau deposition on PET in a well‐characterized Korean AD continuum Cohort.MethodWe analyzed data for 145 older adults (69 cognitively normal (CN), 38 mild cognitive impairment (MCI), and 38 AD) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE). We selected 15 candidate genes related to both tau pathways and AD, curated from existing pathway databases, literature mining, and genome‐wide association study findings. We performed gene‐based association analysis of tau deposition measured by 18F‐AV‐1451 PET scans using PLINK. In addition, we performed whole brain voxel‐wise association analysis of identified single nucleotide polymorphisms (SNPs) to investigate their topographic distributions of differences in tau deposition across the whole brain using SPM12. We examined the interaction of the identified SNPs with APOE ε4 carrier status.ResultGene‐based analysis identified CLU and FYN as significantly associated with tau deposition after adjusting for multiple testing. The most significant signals originated from rs149413552 in CLU and rs57650567 in FYN. A voxel‐wise analysis for the two SNPs showed that individuals carrying at least one minor allele demonstrated greater tau throughout the temporal, parietal, and frontal lobes than individuals having no minor alleles (Fig. 1). The two SNPs were associated with greater cortical atrophy of AD‐signature regions and worse global cognition. rs149413552 in CLU was also associated with longitudinal decline in global cognition and immediate verbal memory over two years. APOE ε4 and the two SNPs appeared to exert additive effects on tau levels (Fig. 2). An interaction between rs57650567 in FYN and APOE ε4 carrier status was observed (Fig. 2)Conclusion CLU and FYN may play a specific role in tau pathophysiology. These risk genes may prove useful for biomarker and therapeutic development. Larger and multiethnic studies are needed to confirm these findings and to determine generalizability across populations.

Abstract B061: Nonalcoholic fatty liver disease (NAFLD) polygenic risk score and risk of hepatocellular carcinoma in a multiethnic population

Abstract Purpose: Hepatocellular carcinoma (HCC) is the third cause of cancer mortality globally, with 10%-12% of cases attributable to nonalcoholic fatty liver disease (NAFLD). Genetic variants included in NAFLD polygenic risk scores (PRS) have been associated with HCC risk. Since these associations have been studied primarily among European ancestry populations, in the current study we assessed the transportability of a NAFLD PRS associated with HCC risk in a racially/ethnically diverse population. Methods: We conducted a nested case-control study including 275 incident HCC cases and 73,045 controls from the Multiethnic Cohort Study, using a 21-variant PRS for NAFLD created based on prior GWAS and replication studies on MEC participants and other populations. Associations between PRS (per standard deviation) and HCC were estimated using logistic regression adjusting for age, sex, and global ancestry. A stratified analysis was conducted by body mass index (BMI) due to the direct relationship of obesity with NAFLD and HCC. Results: The PRS was associated with HCC risk in the combined sample (ORper SD= 1.84, 95% CI: 1.64-2.06). Signifcant associations were observed in Japanese Americans [ORper SD=2.26 (1.87-2.72)], Latinos [ORper SD=1.89 (1.52-2.35)], Native Hawaiians [ORper SD=1.84 (1.26-2.69)], and with the associations being weaker and non-significant in whites [ORper SD=1.33 (0.92-1.93)] and African Americans [ORper SD=1.25 (0.90-1.75)]. The PRS association was stronger among those with BMI >= 25 kg/m2 for the combined sample (ORper SD :2.46, 95% CI:1.92-3.14), (P heterogeneity <0.0001); and all racial/ethnic groups [Latino: 3.01(1.88-4.81), African American: 2.72 (95% CI: 1.18-6.27), Hawaiian: 2.25 (1.17-4.32), Japanese: 2.13 (1.36-3.36), and White:2.11(1.10-4.04)]. Conclusion: A NAFLD PRS is applicable for HCC risk prediction across racial/ethnic populations. BMI may modifiy this PRS-HCC risk association. Citation Format: Homa Sadeghi, David Bogumil, David V. Conti, Christopher Haiman, Loïc Le Marchand, Veronica Wendy Setiawan. Nonalcoholic fatty liver disease (NAFLD) polygenic risk score and risk of hepatocellular carcinoma in a multiethnic population [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B061.

Association of Lipoprotein(a) Levels With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis.

Lipoprotein(a) (Lp[a]) has been identified as an emerging risk factor for adverse cardiovascular (CV) outcomes, including heart failure. However, the connections among Lp(a), myocardial fibrosis (interstitial and replacement), and cardiac remodeling as pathways to CV diseases remains unclear. This study investigated the relationship between Lp(a) levels and myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement, as well as cardiac remodeling by cine CMR, in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. The study included 2,040 participants with baseline Lp(a) measurements and T1 mapping for interstitial myocardial fibrosis (IMF) evaluation in 2010. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50mg/dL. Multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of extracellular volume (ECV fraction [ECV%]), native T1 time, and myocardial scar, as well as parameters of cardiac remodeling, in 2,826 participants. Higher Lp(a) levels were associated with increased ECV% (per log-unit Lp[a]; β=0.2%; P=0.007) and native T1 time (per log-unit Lp[a]; β=4%; P< 0.001). Similar relationships were observed between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (OR: 1.20; 95%CI: 1.04-1.43) and native T1 (OR: 1.2; 95%CI: 1.1-1.4) equal to 30% and 955ms, respectively. Clinically used Lp(a) cutoffs (30 and 50mg/dL) were associated with greater prevalence of myocardial scar (OR: 1.85; 95%CI: 1.1-3.2 and OR: 1.9; 95%CI: 1.1-3.4, respectively). Finally, higher Lp(a) levels were associated with left atrial enlargement and dysfunction. Elevated Lp(a) levels are linked to greater subclinical IMF, increased myocardial scar prevalence, and left atrial remodeling.

Systematic review/meta-analysis and a cross-sectional study to assess effects of potassium supplementation on the renin-angiotensin-aldosterone system (RAAS) and blood pressure

Abstract Introduction Nutritional medicine plays a key role in disease prevention and treatment, and we pharmacists must consider our contribution beyond our role in dispensing. Apart from the Dietary Approaches to Stop Hypertension (DASH) diet1, there is a paucity of data on the benefits of nutritional interventions in hypertension with no clear recommendation on potassium in the NICE guidelines. Potassium has been an area of interest in clinical medicine over the decades because of its effect on cardiovascular disease. However, its mechanism of action is poorly understood, and it is unclear it differs between different ethnic groups. Dietary potassium decreases blood pressure (BP) but can also stimulate aldosterone production2. However, the magnitude of potassium-dependent regulation of aldosterone secretion in humans is not fully characterised and it is not clear whether this is mediated by activation of the renin-angiotensin-aldosterone system (RAAS) as a result of a reduction in BP or other mechanisms. Aim To perform a (1) systematic review and meta-analysis of clinical trials assessing effects of potassium on plasma aldosterone and renin in adult individuals alongside a (2) cross-sectional multi-ethnic study to explore the relationship between potassium intake and aldosterone in hypertension. Methods (1) This study was carried out in accordance with PRISMA guidelines3. The full protocol can be found on the PROSPERO database. (2) Self-defined black or white hypertensives were recruited from the hypertension outpatient clinic at St. Thomas’ Hospital and had aldosterone, renin and a 24-hour urinary potassium collected. The systematic review and meta-analysis on already approved clinical trials and did not require ethnical approval. The cross-sectional study was approved by the local Research Ethics Committee in the UK and written informed consent was obtained from all patients. Results 6395 articles were retrieved, and 124 full-text articles were assessed for eligibility. 36 met the prespecified inclusion/exclusion criteria. Potassium supplementation caused a significant decrease in systolic BP (- 3.69 mmHg [-4.91, -2.46], P&amp;lt;0.001) and increase in serum potassium (+0.37 [0.23, 0.52] mmol/L, P&amp;lt;0.001). There was an increase in plasma aldosterone (standardised difference 0.414 [0.291, 0.537], P&amp;lt;0.001) but no effect on plasma renin activity (+0.033 [-0.07, 0.14], P=0.538]. Meta-regression showed a significant positive correlation between change in plasma aldosterone and change in serum potassium (P&amp;lt;0.001). (2) In 469 subjects (72% black), there was a positive association between the measured 24-hour potassium excretion and aldosterone in black (β = 0.200, P = 0.014) but not in white individuals (P = 0.531). Discussion/Conclusion Potassium supplementation increases plasma aldosterone but not renin. The increase in aldosterone correlates with the raise in serum potassium. In subjects with hypertension, potassium intake is related with aldosterone concentration only in black subjects. Overall, the data supports a RAAS-independent potassium regulation of aldosterone which could be particularly relevant in African origin subjects. Limitations: 1. the systematic review results could not be stratified by ethnicity because most of the studies were performed in Caucasian subjects, 2. Use of background therapy in some studies, variable doses of potassium supplementation and duration of supplementation.

Racial and Ethnic Residential Segregation and Monocyte DNA Methylation Age Acceleration

Neighborhood segregation and poverty may be important drivers of health inequities. Epigenomic factors, including DNA methylation clocks that may mark underlying biological aging, have been implicated in the link between social factors and health. To examine the associations of neighborhood segregation and poverty with 4 DNA methylation clocks trained to capture either chronological age or physiological dysregulation. This cohort study uses data from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal study that started in 2000 to 2002, with follow-up in 2002 to 2004, 2004 to 2005, 2005 to 2007, and 2010 to 2012. In 2000 to 2002, adults who identified as White or Black race or Hispanic or Chinese ethnicity in 6 US sites (Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; Northern Manhattan, New York; and St. Paul, Minnesota) were sampled for recruitment. A random subsample of 4 sites (Maryland, North Carolina, New York, and Minnesota) were selected for inclusion in the MESA epigenomics ancillary study at examination 5 (2010-2012). Participants who identified as White or Black race or Hispanic ethnicity, were aged 45 to 84 years, and did not have clinical cardiovascular disease were included in this analysis. Data were analyzed from May 2021 to October 2023. Information on 2000 census tract poverty and Getis-Ord G statistic segregation of Hispanic residents, non-Hispanic Black residents, or non-Hispanic White residents were linked to participant addresses at examination 1 (2000-2002). At examination 5, DNA methylation was measured in purified monocytes. DNA methylation age acceleration was calculated using 4 clocks trained on either chronological age or physiological dysregulation. Linear regressions were used to test associations. A total of 1102 participants (mean [SD] age, 69.7 [9.4] years; 562 [51%] women) were included, with 348 Hispanic participants, 222 non-Hispanic Black participants, and 533 non-Hispanic White participants. For non-Hispanic Black participants, living in tracts with greater segregation of Black residents was associated with GrimAge DNA methylation age acceleration, a clock designed to capture physiological dysregulation. A 1-SD increase in segregation was associated with 0.42 (95% CI, 0.20-0.64) years age acceleration (P < .001); this association was not observed with other clocks. This association was particularly pronounced for participants living in high poverty tracts (interaction term, 0.24; 95% CI, 0.07-0.42; P = .006). In the overall sample, census tract poverty level was associated with GrimAge DNA methylation age acceleration (β = 0.45; 95% CI, 0.20-0.71; adjusted P = .005). These findings suggest that epigenomic mechanisms may play a role in the associations of segregated and poor neighborhoods with chronic conditions.

EBV Prevalence and Overall Survival in the Multi ethnic Study of Hodgkin Lymphoma (MESH)

Background: Classic Hodgkin Lymphoma (CHL) is a B-cell lymphoma characterized by rare Hodgkin Reed-Sternberg (HRS) cells surrounded by immune cell infiltrates that define histological subtypes. In 1987, Weiss discovered that a minority of CHL tumors harbored an Epstein-Barr virus (EBV) genome integrated into the genome of the HRS cell (EBV+ tumors) (Weiss, et al., Am J Pathol, 1987). A population-based study conducted in California reported 27% of CHL tumors were EBV+ with a higher prevalence in younger and older patients compared to adolescents and young adults (AYA), and in Hispanics compared to other racial/ethnic groups (Keegan, et al., JCO, 2005). We evaluated EBV tumor status and demographic characteristics and survival in a multiethnic set of CHL patients the Multi Ethnic Study of Hodgkin lymphoma (MESH). Methods: We collected 891 multiethnic cases of formalin-fixed paraffin-embedded tumor blocks of CHL diagnosed between 1978 and 2018. Patients were identified from cancer centers and hospitals in Atlanta, Los Angeles County, Mexico City, Philadelphia, Detroit, and the Residual Tissue Repositories from Hawai'i and Los Angeles County. CHL diagnosis and histological subtype were confirmed by hematopathologist review. Demographic and clinical information was collected from patient medical charts and state cancer registries. EBV tumor status was assigned based on EBER1 in situ hybridization performed using the Novocastra™ Epstein-Barr virus ISH Kit (Ready-to-use [RTU], Leica Microsystems, Inc. Buffalo Grove, IL) on 2mm cores arranged on tissue microarrays. EBV+ cases were defined by nuclear or cytoplasmic positivity in &amp;gt;5% of HRS cells, determined by a study hematopathologist (IS). We tested associations between EBV tumor status and age at diagnosis (pediatric [&amp;lt;15 years], adolescent/young adult [AYA, 15-39 years], older adults [40+ years]), sex, race/ethnicity (Hispanic, Black, Non-Hispanic White [NHW], Asian, and Hawaiian/Pacific Islander [HPI]), and histology (Nodular Sclerosis [NS]; Mixed Cellularity [MC]; Lymphocyte Rich [LR]; Lymphocyte Depleted [LD]) using χ-squared tests. We also assessed the association between EBV tumor status and overall survival (OS) right censored at 5 years using Kaplan-Meier and multivariable Cox regression analysis adjusted for age at diagnosis (continuous), sex, race/ethnicity, and histology (NS vs. other histologic subtypes). Results: To date, EBV results were available for 638 cases enrolled in the study. Frequency among those with EBV results was as follows: pediatric=45 (7%), AYA=373 (59%), older adults=217 (34%), male=347 (54%), Hispanic=246 (39%), Black=118 (19%), NHW=179 (28%), Asian=60 (9%), and HPI=20 (3%). Overall, 30% of the cases were EBV+. EBV positivity was higher in MC compared to NS cases across all age groups (p=&amp;lt;0.001). By histology and age, EBV positivity for both NS and MC was higher in pediatric (NS [45%]; MC [90%]) and older adult (NS [29%]; MC [64%]), compared to AYA cases (NS [16%]; MC [39%]). The AYA age group comprised the largest number of cases, the majority of which were EBV− (Figure 1). EBV+ cases were more common among males compared to females, with higher prevalence among males of pediatric (62%) and older ages (46%) compared to AYA males (24%), following the same pattern as histology. EBV positivity also differed by race/ethnicity (p=0.002), with the highest prevalence in Hispanics (38%) and lowest in HPI (10%). Survival analyses showed a statistically significantly different OS by EBV status (p&amp;lt;0.001), but after adjusting for age, sex, race/ethnicity, and histology, there was no statistically significant difference in OS between EBV+ and EBV− tumor patients (HR=1.08, p=0.744). Conclusion: Our results were largely consistent with the previous literature on EBV positivity prevalence in CHL by demographic characteristics. We report low EBV positivity in HPI for the first time, albeit with small numbers in that group. The difference in EBV tumor status by sex is noteworthy, with females having a higher EBV− AYA peak, and males having a higher EBV+ AYA peak. Unlike previous reports, we did not observe an association between EBV status and survival with adjustment for demographic and clinical variables. More studies with diverse populations and larger sample sizes are needed to better understand the complex interplay of EBV patterns in CHL tumors and their significance in different populations.

Associations between muscle quality and N-terminal pro-B-type natriuretic peptide (NT-proBNP): The multi-ethnic study of atherosclerosis

IntroductionN-terminal pro-B-type natriuretic peptide (NT-proBNP) is widely used in clinical settings to identify cardiac stress, diagnose, and manage heart failure (HF). We explored the associations between NT-proBNP and both muscle area and density. MethodsA cross-sectional analysis including 1,489 participants from the MESA. Plasma NT-proBNP concentrations and inflammatory biomarkers and health history questionnaires were analyzed. Computed tomography quantified abdominal body composition. Separate multivariable linear regression models were used to assess the associations between both muscle (MA) area and density (MD) and NT-proBNP. ResultsIn models adjusted for sociodemographic characteristics, risk factors for cardiovascular disease, anthropometric variables, and subcutaneous and visceral adiposity, NT-proBNP was inversely associated with total abdominal and psoas MAs. Adjustment for inflammatory markers and MD attenuated these associations to the null. Stabilization MA and NT-proBNP were not significantly associated. Analyses per quartiles of MA confirmed lack of a consistent association between stabilization and total abdominal MAs and NT-proBNP. While the third and fourth quartiles of psoas MA were inversely associated with NT-proBNP, adding inflammation biomarkers and MD to the model attenuated the association to the null. Conversely, after full adjustment, NT-proBNP was inversely and significantly associated with total abdominal, stabilization and psoas MDs. For psoas MD, but not the other muscle density variables, the addition of MA to the model attenuated the association to the null. The quartiles of MD were consistently inversely associated with NT-proBNP, where higher MDs showed larger estimates of the association compared to the lowest quartiles, for all muscle groups investigated. ConclusionMuscle density is inversely associated with NT-proBNP, while muscle area is not after adjustment for inflammation and muscle density.

Linking African ancestral substructure to prostate cancer health disparities

Prostate cancer (PCa) is a significant health burden in Sub-Saharan Africa, with mortality rates loosely linked to African ancestry. Yet studies aimed at identifying contributing risk factors are lacking within the continent and as such exclude for significant ancestral diversity. Here, we investigate a series of epidemiological demographic and lifestyle risk factors for 1387 men recruited as part of the multi-ethnic Southern African Prostate Cancer Study (SAPCS). We found poverty to be a decisive factor for disease grade and age at diagnosis, with other notably significant PCa associated risk factors including sexually transmitted diseases, erectile dysfunction, gynaecomastia, and vertex or complete pattern balding. Aligned with African American data, Black ethnicity showed significant risk for PCa diagnosis (OR = 1.44, 95% CI 1.05–2.00), and aggressive disease presentation (ISUP ≥ 4: OR = 2.25, 95% CI 1.49–3.40). New to this study, we demonstrate African ancestral population substructure associated PCa disparity, observing increased risk for advanced disease for the southern African Tsonga people (ISUP ≥ 4: OR = 3.43, 95% CI 1.62–7.27). Conversely, South African Coloured were less likely to be diagnosed with aggressive disease overall (ISUP ≥ 3: OR = 0.38, 95% 0.17–0.85). Understanding the basis for PCa health disparities calls for African inclusion, however, lack of available data has limited the power to begin discussions. Here, focusing on arguably the largest study of its kind for the African continent, we draw attention to the contribution of within African ancestral diversity as a contributing factor to PCa health disparities within the genetically diverse region of southern Africa.

Heart rate fragmentation and brain MRI markers of small vessel disease in MESA.

Heart rate (HR) fragmentation indices quantify breakdown of HR regulation and are associated with atrial fibrillation and cognitive impairment. Their association with brain magnetic resonance imaging (MRI) markers of small vessel disease is unexplored. In 606 stroke-free participants of the Multi-Ethnic Study of Atherosclerosis (mean age 67), HR fragmentation indices including percentage of inflection points (PIP) were derived from sleep study recordings. We examined PIP in relation to white matter hyperintensity (WMH) volume, total white matter fractional anisotropy (FA), and microbleeds from 3-Tesla brain MRI completed 7 years later. In adjusted analyses, higher PIP was associated with greater WMH volume (14% per standard deviation [SD], 95% confidence interval [CI]: 2, 27%, P=0.02) and lower WM FA (-0.09 SD per SD, 95% CI: -0.16, -0.01, P=0.03). HR fragmentation was associated with small vessel disease. HR fragmentation can be measured automatically from ambulatory electrocardiogram devices and may be useful as a biomarker of vascular brain injury.

Reproductive Factors Linked With Myocardial Fibrosis: MESA (Multi-Ethnic Study of Atherosclerosis)

BackgroundRecent evidence has shown that reproductive factors are associated with an increased risk of heart failure with preserved ejection fraction in women. However, the pathogenic pathways underlying this relationship are unclear. Subclinical myocardial fibrosis has been found to be a common pathway in a large proportion of patients with heart failure with preserved ejection fraction. ObjectivesThis study examined the relationship between vital reproductive factors (parity, pregnancy, age at menopause, and use of hormone replacement therapy [HRT]) with interstitial myocardial fibrosis (IMF) and myocardial scar measured by cardiac magnetic resonance imaging (CMR) T1 mapping and late gadolinium enhancement, respectively. MethodsThere were 596 female participants (mean age 67 ± 8 years) enrolled in MESA (Multi-Ethnic Study of Atherosclerosis) who had complete parity data and underwent CMR. Parity was categorized as 0 live births, 1 to 2, 3 to 4, and ≥5 live births. Multivariable regression models were constructed to assess the associations of parity status, history of null gravidity, age at menopause and HRT with CMR obtained measures of IMF (extracellular volume [ECV], native-T1 time) and myocardial scar. ResultsWomen with a history of nulliparity had greater ECV% (β = 0.95 ± 0.28, P = 0.001) and native-T1 ms (β = 10.6 ± 4.9, P = 0.03) than those who had 1 to 2 live births. These associations were independent of age, traditional cardiovascular risk factors, and interim cardiovascular events. Similar associations were found for women with a history of null gravidity compared to those with a history of pregnancy (ECV% [β = 0.7 ± 0.3, P = 0.02] and native-T1 ms [β = 10.6 ± 5.2, P = 0.04]). There was no association between age at menopause and HRT with markers of IMF. There were no associations between parity status, null gravidity, and age of menopause with the presence of myocardial scar; however, those who used HRT were independently associated with a lesser risk of myocardial scar (OR: 0.20; 95% CI: 0.05-0.82). ConclusionsIn a multiethnic cohort, women with a history of nulliparity or null gravidity had greater IMF defined by CMR, while those who used HRT were less likely to have myocardial scar.

Platform for the interdisciplinary study of cardiovascular, metabolic and neurovascular diseases (PICMAN) protocol

Through extensive multisystem phenotyping, the central aim of Project PICMAN is to correlate metabolic flexibility to measures of cardiometabolic health, including myocardial diastolic dysfunction, coronary and cerebral atherosclerosis, body fat distribution and severity of non-alcoholic fatty liver disease. This cohort will form the basis of larger interventional trials targeting metabolic inflexibility in the prevention of cardiovascular disease. Participants aged 21–72 years with no prior manifest atherosclerotic cardiovascular disease (ASCVD) are being recruited from a preventive cardiology clinic and an existing cohort of non-alcoholic fatty liver disease (NAFLD) in an academic medical centre. A total of 120 patients will be recruited in the pilot phase of this study and followed up for 5 years. Those with 10-year ASCVD risk ≥ 5% as per the QRISK3 calculator are eligible. Those with established diabetes mellitus are excluded. Participants recruited undergo a detailed assessment of health behaviours and physical measurements. Participants also undergo a series of multimodality clinical phenotyping comprising cardiac tests, vascular assessments, metabolic tests, liver and neurovascular testing. Blood samples are also being collected and banked for plasma biomarkers, ‘multi-omics analyses’ and for generation of induced pluripotent stem cells (iPSC). Extensive evidence points to metabolic dysregulation as an early precursor of cardiovascular disease, particularly in Asia. We hypothesise that quantifiable metabolic inflexibility may be representative of an individual in his/her silent, but high-risk progression towards insulin resistance, diabetes and cardiovascular disease. The platform for interdisciplinary cardiovascular-metabolic-neurovascular diseases (PICMAN) is a pilot, prospective, multi-ethnic cohort study.

Prevalence of Subclinical Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction

BackgroundAtrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with poorer clinical outcomes. The prevalence of subclinical AF in patients with HFpEF remains unknown. ObjectivesThe aim of this study was to determine whether subclinical AF was more prevalent in individuals with HFpEF than in individuals without histories of heart failure (HF). MethodsPatients with HFpEF with no prior diagnoses of AF were screened for subclinical AF, and the prevalence of subclinical AF was compared with that among control subjects without HF drawn from MESA (Multi-Ethnic Study of Atherosclerosis) who underwent the same electrocardiographic monitoring. Multivariable logistic regression was used to adjust for demographic and clinical comorbidities. ResultsNinety patients with HFpEF and 1,230 MESA participants were included. Patients with HFpEF were younger (median age 69 years [Q1-Q3: 63-76 years] vs 72 years [Q1-Q3: 66-80 years]; P = 0.02), more obese (median body mass index 36 kg/m2 [Q1-Q3: 30-45 kg/m2] vs 27 kg/m2 [Q1-Q3: 24-30 kg/m2]; P < 0.001), and more likely to have diabetes (34% vs 21%; P = 0.01). The prevalence of subclinical AF was 8.9% in patients with HFpEF and 4.1% in non-HF participants. After multivariable adjustment for age, sex, race, body mass index, diabetes, smoking, and total analyzable time on electrocardiographic monitor, there was a significantly higher odds of subclinical AF in patients with HFpEF compared with MESA (OR: 3.01; 95% CI: 1.13-7.99; P = 0.03). ConclusionsPatients with HFpEF had a higher prevalence of subclinical AF than participants without HF from a community-based study. Screening for atrial arrhythmias may be appropriate among patients with HFpEF for timely initiation of thromboembolic prophylaxis and may identify individuals at greater risk for clinical decompensation.

Increasing risk of hepatocellular carcinoma with successive generations in the United States among Mexican American adults: The Multiethnic Cohort.

US-born Latinos have a higher incidence of hepatocellular carcinoma (HCC) than foreign-born Latinos. Acculturation to unhealthy lifestyle behaviors and an immigrant self-selection effect may play a role. In this study, the authors examined the influence of generational status on HCC risk among Mexican American adults. The analytic cohort included 31,377 self-reported Mexican Americans from the Multiethnic Cohort Study (MEC). Generational status was categorized as: first-generation (Mexico-born; n=13,382), second-generation (US-born with one or two parents born in Mexico; n=13,081), or third-generation (US-born with both parents born in the United States; n=4914). Multivariable Cox proportional hazards regression was performed to examine the association between generational status and HCC incidence. In total, 213 incident HCC cases were identified during an average follow-up of 19.5years. After adjusting for lifestyle and neighborhood-level risk factors, second-generation and third-generation Mexican Americans had a 37% (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.98-1.92) and 66% (HR, 1.66; 95% CI, 1.11-2.49) increased risk of HCC, respectively, compared with first-generation Mexican Americans (p for trend=0.012). The increased risk associated with generational status was mainly observed in males (second-generation vs. first-generation: HR, 1.60 [95% CI, 1.05-2.44]; third-generation vs. first-generation: HR, 2.08 [95% CI, 1.29-3.37]). Increasing generational status of Mexican Americans is associated with a higher risk of HCC. Further studies are needed to identify factors that contribute to this increased risk.

Higher HDL cholesterol levels are associated with increased markers of interstitial myocardial fibrosis in the MultiEthnic Study of Atherosclerosis (MESA)

Emerging research indicates that high HDL-C levels might not be cardioprotective, potentially worsening cardiovascular disease (CVD) outcomes. Yet, there is no data on HDL-C's association with other CVD risk factors like myocardial fibrosis, a key aspect of cardiac remodeling predicting negative outcomes. We therefore aimed to study the association between HDL-C levels with interstitial myocardial fibrosis (IMF) and myocardial scar measured by CMR T1-mapping and late-gadolinium enhancement (LGE), respectively. There were 1863 participants (mean age of 69 years) who had both serum HDL-C measurements and underwent CMR. Analysis was done among those with available indices of interstitial fibrosis (extracellular volume fraction [ECV]; N = 1172 and native-T1; N = 1863) and replacement fibrosis by LGE (N = 1172). HDL-C was analyzed as both logarithmically-transformed and categorized into < 40 (low),40–59 (normal), and ≥ 60mg/dL (high). Multivariable linear and logistic regression models were constructed to assess the associations of HDL-C with CMR-obtained measures of IMF, ECV% and native-T1 time, and myocardial scar, respectively. In the fully adjusted model, each 1-SD increment of log HDL-C was associated with a 1% increment in ECV% (p = 0.01) and an 18-ms increment in native-T1 (p < 0.001). When stratified by HDL-C categories, those with high HDL-C (≥ 60mg/dL) had significantly higher ECV (β = 0.5%, p = 0.01) and native-T1 (β = 7 ms, p = 0.01) compared with those with normal HDL-C levels. Those with low HDL-C were not associated with IMF. Results remained unchanged after excluding individuals with a history of myocardial infarction. Neither increasing levels of HDL-C nor any HDL-C category was associated with the prevalence of myocardial scar. Increasing levels of HDL-C were associated with increased markers of IMF, with those with high levels of HDL-C being linked to subclinical fibrosis in a community-based setting.

The Importance of Pelvic Obliquity in Assessing Spinal Coronal Alignment: Normative Values, Demographic, and Radiographic Correlations.

Prospective, cross-sectional study. In a geographically diverse population of asymptomatic volunteers, we sought to report the incidence of pelvic obliquity (PO), establish normative values of PO across patient factors, and assess the correlation of PO with radiographic parameters. PO is defined as the misalignment of the pelvis and can be assessed through several anatomic landmarks. Significant PO, whether caused by leg-length discrepancy or not, can lead to coronal malalignment which causes severe pain and disability. Significant emphasis has been placed on achieving appropriate sagittal alignment in recent decades; however, a greater understanding of coronal alignment is needed, and PO is a crucial aspect of evaluating the coronal plane in adult spinal deformity patients. Asymptomatic adult volunteers, ages 18-80 years, enrolled patients from 5 countries (France, Japan, Singapore, Tunisia, and the United States) in the "multiethnic alignment normative study" cohort (IRB 201812144). The included volunteers had no known spinal disorder(s), no significant neck or back pain (Visual Analog Scale: ≤2; Oswestry Disability Index: ≤20), and no abnormal alignment (Cobb ≤20°). PO was measured in the frontal plane as the distance between the highest points of each acetabulum, calculated along the vertical axis in millimeters (mm). The incidence of PO was defined as PO ≥10mm. Kruskal-Wallis, Wilcoxon rank-sum, Pearson correlation, and linear regression were used. A total of 467 patients were included, and PO values by age, sex, body mass index, and country were provided. The overall incidence of PO ≥10mm was 4.3%, and a nonsignificant trend toward increased PO with age was seen ( P = 0.077). No significant differences were seen in PO between sex, ethnicity, or body mass index groups. No significant correlation existed between PO and other commonly used coronal radiographic measurements. PO ≥10mm occurred in 4.3% of asymptomatic volunteers. Despite the importance of recognizing PO in preventing coronal malalignment, PO did not seem to be associated with other radiographic and demographic information, which underscores the importance of intentionally assessing for any PO before surgery. These results in an asymptomatic population provide a foundation for studying PO in patients with spinal pathology.

Second Primary Lung Cancer Among Lung Cancer Survivors Who Never Smoked

Lung cancer among never-smokers accounts for 25% of all lung cancers in the US; recent therapeutic advances have improved survival among patients with initial primary lung cancer (IPLC), who are now at high risk of developing second primary lung cancer (SPLC). As smoking rates continue to decline in the US, it is critical to examine more closely the epidemiology of lung cancer among patients who never smoked, including their risk for SPLC. To estimate and compare the cumulative SPLC incidence among lung cancer survivors who have never smoked vs those who have ever smoked. This population-based prospective cohort study used data from the Multiethnic Cohort Study (MEC), which enrolled participants between April 18, 1993, and December 31, 1996, with follow-up through July 1, 2017. Eligible individuals for this study were aged 45 to 75 years and had complete smoking data at baseline. These participants were followed up for IPLC and further SPLC development through the Surveillance, Epidemiology, and End Results registry. The data were analyzed from July 1, 2022, to January 31, 2023. Never-smoking vs ever-smoking exposure at MEC enrollment. The study had 2 primary outcomes: (1) 10-year cumulative incidence of IPLC in the entire study cohort and 10-year cumulative incidence of SPLC among patients with IPLC and (2) standardized incidence ratio (SIR) (calculated as the SPLC incidence divided by the IPLC incidence) by smoking history. Among 211 414 MEC participants, 7161 (3.96%) developed IPLC over 4 038 007 person-years, and 163 (2.28%) developed SPLC over 16 470 person-years. Of the participants with IPLC, the mean (SD) age at cohort enrollment was 63.6 (7.7) years, 4031 (56.3%) were male, and 3131 (43.7%) were female. The 10-year cumulative IPLC incidence was 2.40% (95% CI, 2.31%-2.49%) among ever-smokers, which was 7 times higher than never-smokers (0.34%; 95% CI, 0.30%-0.37%). However, the 10-year cumulative SPLC incidence following IPLC was as high among never-smokers (2.84%; 95% CI, 1.50%-4.18%) as ever-smokers (2.72%; 95% CI, 2.24%-3.20%), which led to a substantially higher SIR for never-smokers (14.50; 95% CI, 8.73-22.65) vs ever-smokers (3.50; 95% CI, 2.95-4.12). The findings indicate that SPLC risk among lung cancer survivors who never smoked is as high as among those with IPLC who ever-smoked, highlighting the need to identify risk factors for SPLC among patients who never smoked and to develop a targeted surveillance strategy.