Multiethnic Cohort Research Articles

A very-low-calorie diet (VLCD) intervention for the management of prediabetes and early Type 2 diabetes mellitus in a multi-ethnic cohort in Aotearoa New Zealand: The PROGRESS NZ feasibility study.

Very-low calorie diets (VLCD) achieve weight loss and remission of Type 2 diabetes (T2DM), but efficacy and acceptability in non-European populations is less clear. This feasibility study examines the impact of 10% weight loss through VLCD on metabolic and body composition outcomes in a multi-ethnic cohort of Aotearoa New Zealand (AoNZ) men with prediabetes/early T2DM, and VLCD tolerability/cultural acceptability. Participants followed a VLCD intervention (mean energy 3033kJ/day) until achievement of 10% weight loss. An oral glucose tolerance test (OGTT), hyperinsulinaemic isoglycaemic clamp with stable isotopes, hood calorimetry and dual-energy Xray absorptiometry (DXA) were undertaken before and after intervention. Qualitative data on VLCD tolerability/cultural acceptability were collected. Fifteen participants were enrolled; nine achieved 10% weight loss. In this group, mean HbA1c reduced by 4.8mmol/mol (2.4-7.1) and reverted to normoglycaemia in n=5/9; mean body weight reduced by 12.0 kg (11.0-13.1) and whole-body glucose disposal improved by 1.5 mg kgFFM-1 min-1 (0.7-2.2). Blood pressure and fasting triglycerides improved significantly. No changes in hepatic glu-cose metabolism were found. In all participants who attended completion testing, HbA1c reduced by 3.4mmol/mol (SD 3.5) and total weight by 9.0kg (SD 5.7). The intervention was highly tolerable/culturally acceptable however challenges with fulfilment of cultural obligations were described. Results support VLCD use in AoNZ however further work to investigate ethnic differences in physiological response to VLCDs and to optimise protocols for multi-ethnic populations are required.

Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.

Genetics of Neonatal Lupus Erythematosus Risk and Specific Manifestations.

Neonatal lupus erythematosus (NLE) is a passively acquired autoimmune disease in infants born to anti-Ro and/or anti-La autoantibody-positive mothers. Genetics may affect NLE risk. We analyzed the genetics of infants and anti-Ro antibody-positive mothers, with NLE and NLE-specific manifestations. Infants and mothers from a tertiary care clinic underwent genotyping on the Global Screening Array. We created additive non-HLA and HLA polygenic risk scores (PRS) for systemic lupus erythematosus (SLE), from one of the largest genome-wide association studies. Outcomes were any NLE manifestations, cardiac NLE, and cutaneous NLE. We tested the association between SLE-PRS in the infant, mother, and the PRS difference between the mother and infant with NLE outcomes, in logistic regression and generalized linear mixed models (Bonferroni P < 0.02). We also performed HLA-wide analyses for the outcomes (P < 5.00 × 10-8). The study included 332 infants, 270 anti-Ro antibody-positive mothers, and 253 mother-infant pairs. A large proportion of mothers (40.4%) and infants (41.3%) were European, and 50% of infants were female. More than half of the infants had NLE (53%), including 7.2% with cardiac NLE and 11.7% with cutaneous NLE. We did not identify significant associations between infant PRS, maternal PRS, or maternal-infant PRS difference and any NLE outcomes. HLA-wide analyses did not identify NLE risk alleles. In a multiethnic cohort of infants and anti-Ro antibody-positive mothers, we did not identify a significant association between SLE genetics and risk of NLE outcomes.

Joint consideration of LDL-C and polygenic risk for incident coronary heart disease in a multi-ethnic cohort of 48,881 individuals

Joint consideration of LDL-C and polygenic risk for incident coronary heart disease in a multi-ethnic cohort of 48,881 individuals

Proteomic profiling of bronchoalveolar lavage fluid uncovers protein clusters linked to survival in idiopathic forms of interstitial lung disease.

Idiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways. Proteomic profiling successfully differentiated IIP from controls. k-means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity. The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

Dietary Patterns and New-Onset Diabetes Mellitus in Southwest China: A Prospective Cohort Study in the China Multi-Ethnic Cohort (CMEC).

(1) Background: There is little known about the relationship between Dietary Approaches to Stop Hypertension (DASH) pattern and diabetes in cohort studies, and the dietary patterns in the Chongqing natural population are unknown. (2) Methods: 14,176 Chinese adults, aged 30-79 years old, participated in this prospective study, from September 2018 to October 2023. A dietary assessment was conducted using a food frequency questionnaire, and three main dietary patterns were extracted from the principal component analysis. DASH patterns were calculated by standards. (3) Results: During the 4.64 y follow-up, 875 developed diabetes (11.3/1000 person-years). Each posteriori diet pattern is named after its main dietary characteristics (meat pattern, dairy products-eggs pattern, and alcohol-wheat products pattern). The high consumption of DASH pattern diet reduced the risk of diabetes (Q5 vs. Q1 HR: 0.71; 95% CI: 0.40-0.56) while high consumption of alcohol-wheat product pattern diet was associated with a high risk of diabetes (Q5 vs. Q1 HR: 1.32; 95% CI: 1.04, 1.66). The other two dietary patterns were not associated with diabetes. In subgroup analysis, there was an interaction between DASH pattern and sex (P for interaction < 0.006), with a strong association in females. (4) Conclusions: DASH pattern may be associated with a reduced new-onset diabetes risk and Alcohol-wheat products pattern may be positively associated with new-onset diabetes. These findings may provide evidence for making dietary guidelines in southwest China to prevent diabetes.

A digital twin model incorporating generalized metabolic fluxes to identify and predict chronic kidney disease in type 2 diabetes mellitus

We have developed a digital twin-based CKD identification and prediction model that leverages generalized metabolic fluxes (GMF) for patients with Type 2 Diabetes Mellitus (T2DM). GMF digital twins utilized basic clinical and physiological biomarkers as inputs for identification and prediction of CKD. We employed four diverse multi-ethnic cohorts (n = 7072): a Singaporean cohort (EVAS, n = 289) and a North American cohort (NHANES, n = 1044) for baseline CKD identification, and two multi-center Singaporean cohorts (CDMD, n = 2119 and SDR, n = 3627) for 3-year CKD prediction and risk stratification. We subsequently conducted a comprehensive study utilizing a single dataset to evaluate the clinical utility of GMF for CKD prediction. The GMF-based identification model performed strongly, achieving an AUC between 0.80 and 0.82. In prediction, the GMF generated with complete parameters attained high performance with an AUC of 0.86, while with incomplete parameters, it achieved an AUC of 0.75. The GMF-based prediction model utilizing complete inputs is the standard implementation of our algorithm: HealthVector Diabetes®. We have established the GMF digital twin-based model as a robust clinical tool capable of predicting and stratifying the risk of future CKD within a 3-year time horizon. We report the correlation of GMF with basic input parameters, their ability to differentiate between future health states and medication status at baseline, and their capability to quantify CKD progression rates. This holistic methodology provides insights into patients’ health states and CKD progression rates based on GMF metabolic profile differences, enabling personalized care plans.

#2213 APOL1 high-risk genotype in in a Dutch multi-ethnic population

Abstract Background and Aims The presence of 2 APOL1 high-risk alleles (high-risk APOL1 genotype) is associated with an increased risk of ESKD. In the USA, the prevalence of these high-risk alleles is high in people of West African descent and almost absent in patients from European descent. In Amsterdam, there is a significant number of people from Surinam, and (West-) Africa. A big group of Surinamese individuals have a West African heritage. The prevalence, however, of high-risk APOL1 genotype in the Netherlands and thereby the significance is unknown. The aim of this research was to investigate the prevalence of the APOL1 risk alleles in a multi-ethnic cohort of the Amsterdam general population consisting of individuals of African Surinamese, Ghanaian, Moroccan and Dutch origin. Second we correlate the presence of these risk alleles to blood pressure, kidney function and proteinuria. Method HELIUS is a multi-ethnic prospective cohort study including people aged 18-70 who were randomly selected, stratified by ethnic origin, from the Amsterdam general population. Baseline examination took place tween 2011 and 2015. We analysed a population of 5971 individuals with available genotype data, of whom 1287 were of Dutch, 3048 of Moroccan, 1156 of African Suriname and 480 of Ghanaian descent. APOL1 risk was determined by genotyping two APOL1 missense variants, rs73885319A&amp;gt;G, S342G; rs60910145T&amp;gt;G, I384M, together constitute the G1 high-risk allele and the 6-base pair deletion allele, rs71785313 RRRATAA/−, N388Y399/−−, is the G2 high risk allele. Logistic regression analyses were performed to determine correlation between creatinine, eGFR, and systolic blood pressure and apol1 high risk genotype, with additional adjustments for age, sex, and BMI. Results The prevalence of high-risk APOL1 genotype was 4.17% in the total sample, in African Surinamese 9.5%, and in the Ghanaian 29.0%. There were no individuals with high risk genotype in the Moroccan or Dutch descent population. The presence of high risk APOL1 genotype was associated with an elevated creatinine level of 10.68 µmol/L (SD 0.91) in the whole cohort. Also, in the Surinamese and Ghanaian populations population the presence of the high-risk APOL1 genotype was associated with an increased creatinine of 2.6 µmol/L (SD 1.00) as compared to the black population with low-risk APOL1 genotype. People with high-risk APOL1 genotype had significantly higher systolic blood pressure 10.69 mmHg (SD 0.091) than those without. Nevertheless, there was no significant difference in systolic blood pressure in the black population with high-risk APOL1 genotype in comparison with the black population with low-risk APOL1 genotype 1.38 mmHg (SD 1.17). Also, there was no significant difference in eGFR (CKD CKD-EPI 2009) in any analysis and no differences in proteinuria was seen, between those with and without the high-risk APOL1 genotype. Conclusion In this population, the overall prevalence of the APOL1 risk alleles seems to conform to the African American population in the USA. There is however a much higher prevalence of high-risk APOL1 genotype in the Ghanaian in comparison to the African Surinamese. The group with high-risk APOL1 genotype had significantly higher creatinine levels and higher systolic blood pressure. However there was no significant difference in blood pressure within the black population between APOL1 high-risk genotype and low-risk genotype. There was no significant difference in eGFR, possibly because the CKD-EPI 2009 formula was used which overestimates the eGFR in the black population. Better calculation with cysteine C possibly gives different outcomes. In conclusion, this is the first study in Europe investigating the prevalence of APOL1 high-risk genotype in a large population-based cohort. APOL1 risk alleles, and high-risk genotype, are prevalent in our population of African descent. More analysis in this cohort are pending and also longitudinal data will follow.

#2489 The prevalence of chronic kidney disease in different altitude areas: results from the China multi-ethnic cohort study

Abstract Background and Aims Chronic Kidney Disease (CKD) poses a significant public health challenge with substantial implications for human well-being. In China, there are significant geographical differences in the prevalence of CKD, with the highest prevalence in the southwest region, which may be related to differences in geographical environment and lifestyle. This study aimed to investigate variances in the prevalence of CKD across different altitude areas in southwest China. Method In this cross-sectional study, we used data from the China Multi-Ethnic Cohort (CMEC). CMEC was established in five provinces of Southwest China and recruited a total of 99,556 participants between 2018 and 2019. Altitude information for each participant was extracted from the Shuttle Radar Topography Mission (SRTM) (version 4) data based on their residential address. To facilitate analysis, we categorized them into groups of low altitude (0-1499 m) and high altitude (≥1500 m). CKD was defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2, using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Crude and age-standardized prevalence of CKD was calculated by using R. Results A total of 92,163 participants were included in the study, and 39.7% were men. Among the current cohort, 30,904 were high-altitude residents, and 61,259 were from low altitude. Among the participants, 1636 cases of CKD were identified, corresponding to a prevalence of 1.78%. We found, the prevalence of CKD in high altitude group was higher than that in low altitude group, and the former is 2.53%, the latter is 1.40%. The age-standardized prevalence were 1.35% and 2.73% for the low and high altitude groups, respectively, and 1.38% and 2.57% for the sex-standardized groups. Conclusion In southwestern China, the prevalence of CKD was higher in the high altitude group than the low altitude group. And after adjusting for age and gender, the prevalence of CKD remained lower in the low-altitude group, and the gap slightly increased.

Door to needle time trends after transition to tenecteplase: A Multicenter Texas stroke registry

BackgroundTenecteplase (TNK) is considered a promising option for the treatment of acute ischemic stroke (AIS) with the potential to decrease door-to-needle times (DTN). This study investigates DTN metrics and trends after transition to tenecteplase. MethodsThe Lone Star Stroke (LSS) Research Consortium TNK registry incorporated data from three Texas hospitals that transitioned to TNK. Subject data mapped to Get-With-the-Guidelines stroke variables from October 1, 2019 to March 31, 2023 were limited to patients who received either alteplase (ALT) or TNK within the 90 min DTN times. The dataset was stratified into ALT and TNK cohorts with univariate tables for each measured variable and further analyzed using descriptive statistics. Logistic regression models were constructed for both ALT and TNK to investigate trends in DTN times. ResultsIn the overall cohort, the TNK cohort (n = 151) and ALT cohort (n = 161) exhibited comparable population demographics, differing only in a higher prevalence of White individuals in the TNK cohort. Both cohorts demonstrated similar clinical parameters, including mean NIHSS, blood glucose levels, and systolic blood pressure at admission. In the univariate analysis, no difference was observed in median DTN time within the 90 min time window compared to the ALT cohort [40 min (30–53) vs 45 min (35-55); P = .057]. In multivariable models, DTN times by thrombolytic did not significantly differ when adjusting for NIHSS, age (P = .133), or race and ethnicity (P = .092). Regression models for the overall cohort indicate no significant DTN temporal trends for TNK (P = .84) after transition; nonetheless, when stratified by hospital, a single subgroup demonstrated a significant DTN upward trend (P = 0.002). ConclusionIn the overall cohort, TNK and ALT exhibited comparable temporal trends and at least stable DTN times. This indicates that the shift to TNK did not have an adverse impact on the DTN stroke metrics. This seamless transition is likely attributed to the similarity of inclusion and exclusion criteria, as well as the administration processes for both medications. When stratified by hospital, the three subgroups demonstrated variable DTN time trends which highlight the potential for either fatigue or unpreparedness when switching to TNK. Because our study included a multi-ethnic cohort from multiple large Texas cities, the stable DTN times after transition to TNK is likely applicable to other healthcare systems.

Intake of Sugar and Food Sources of Sugar and Colorectal Cancer Risk in the Multiethnic Cohort Study

BackgroundThe influence of sugar intake on the risk of colorectal cancer (CRC) remains controversial, and there is a need to investigate the heterogeneity of effects among racial and ethnic groups. ObjectivesTo examine the association of intake of simple sugars and their food sources with CRC risk according to race/ethnicity in a multiethnic cohort study. MethodsWe analyzed data from 192,651 participants who participated in the Multiethnic Cohort Study comprising African American, Japanese American, Latino, Native Hawaiian, and White older adults living in Hawaii and California with an average follow-up of 19 y. Intakes of total and specific types of sugars and sugary foods were estimated from a quantitative food frequency questionnaire completed by the participants in 1993–1996. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC risk according to quintiles (Q) of sugar and food intakes using Cox models adjusted for potential confounders. ResultsAs of December 2017, 4403 incident CRC cases were identified. Among all participants, multivariable-adjusted CRC HRs for Q2, Q3, Q4, and Q5 compared with Q1 for total sugars were 1.03 (95% CI: 0.94, 1.13), 1.05 (95% CI: 0.96, 1.16), 1.12 (95% CI: 1.01, 1.24), and 1.13 (95% CI: 1.01, 1.27), respectively. A similar positive association was observed for total fructose, glucose, fructose, and maltose but not for added sugars and sugary foods. The increased risk appeared to be limited to colon cancer and to be strongest among younger participants (i.e., 45–54 y at baseline); an association with CRC was observed for sugar-sweetened beverages in the latter group. Among racial and ethnic groups, increased risk of CRC was most apparent in Latinos. ConclusionsIn this diverse cohort, intakes of total sugar, total fructose, glucose, fructose, and maltose were associated with an increased risk of CRC, and the association was strongest for colon cancer, younger participants, and Latinos.

Temporal relationship between hepatic steatosis and blood pressure elevation and the mediation effect in the development of cardiovascular disease.

The temporal relationship between non-alcoholic fatty liver disease (NAFLD) and hypertension remains highly controversial, with ongoing debates on whether NAFLD induces hypertension or vice versa. We employed cross-lagged panel models to investigate the temporal relationship between hepatic steatosis (assessed by Fatty Liver Index [FLI] in the main analysis, and by Proton Density Fat Fraction [PDFF] in the validation study) and blood pressure (systolic and diastolic blood pressure [SBP/ DBP]). Subsequently, we employed causal mediation models to explore the mediation effect in CVD development, including ischemic heart disease and stroke. The main analysis incorporated repeated measurement data of 5,047 participants from the China Multi-Ethnic Cohort (CMEC) and 5,685 participants from the UK Biobank (UKB). In both cohorts, the path coefficients from FLI to blood pressure were significant and greater than the path from blood pressure to FLI, with βFLI→SBP = 0.081, P < 0.001 versus βSBP→FLI = 0.020, P = 0.031; βFLI→DBP = 0.082, P < 0.001 versus βDBP→FLI = -0.006, P = 0.480 for CEMC, and βFLI→SBP = 0.057, P < 0.001 versus βSBP→FLI = -0.001, P = 0.727; βFLI→DBP = 0.061, P < 0.001, versus βDBP→FLI = -0.006, P = 0.263 for UKB. The validation study with 962 UKB participants using PDFF consistently supported these findings. In the mediation analyses encompassing 11,108 UKB participants, SBP and DBP mediated 12.2% and 5.2% of the hepatic steatosis-CVD association, respectively. The proportions were lower for ischemic heart disease (SBP: 6.1%, DBP: non-statistically significant -6.8%), and relatively stronger for stroke (SBP: 19.4%, DBP: 26.1%). In conclusion, hepatic steatosis more strongly contributes to elevated blood pressure than vice versa. Blood pressure elevation positively mediates the hepatic steatosis-CVD association, particularly in stroke compared to ischemic heart disease.

Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).

Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN. Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.

Determinants of urinary dialkyl phosphate metabolites in midlife women: the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS).

Biomonitoring data and determinants of urinary dialkylphosphate (DAP) metabolites, markers of organophosphate pesticides, in racially diverse, non-occupationally exposed populations are scarce. This study evaluated urinary concentrations and potential determinants of DAP metabolites of organophosphate pesticides in a multi-site, multi-racial/ethnic cohort of women aged 45-56 years, the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). We analyzed 963 urine samples collected in 1999-2000, the baseline of SWAN-MPS for longitudinal studies, and quantified DAP metabolites, including dimethyl alkylphosphates (DMAPs): dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP); and diethyl alkylphosphates (DEAPs): diethylphosphate (DEP), diethylthiophosphate (DETP), diethyldithiophosphate (DEDTP), using gas chromatography and triple quadrupole mass spectroscopy. Adjusted least squared geometric means (LSGMs) and 95% confidence intervals (CIs) were computed to compare DAP concentrations by socio-demographic, behavioral and dietary factors. The geometric means (geometric standard deviations) of total DAPs, DMAPs, and DEAPs were 141 (2.63) nmol/L, 102 (2.99) nmol/L, and 26.8 (2.46) nmol/L, respectively. Body mass index (BMI) was inversely associated with DMAPs and DEAPs: LSGM (95% CI) = 68.8 (55.7-84.9) and 21.0 (17.7-25.0) nmol/L for women with obesity vs. 102 (84.7-123) and 30.1 (25.7-35.1) nmol/L for women with normal/underweight, respectively. Fruit consumption was positively (74.9 (62.1-90.2) for less than 5-6 servings/week vs. 105 (84.8-130) nmol/L for 1 serving/day and more) whereas meat consumption was inversely associated with DMAPs (110 (95.0-128) for seldom vs. 82.3 (59.5-114) nmol/L for often consumption). Fresh apple consumption appears to be attributed to the DMAP differences. Alcohol consumption was positively associated with DEAPs (27.5 (23.1-32.7) for 2 drinks/week and more vs. 23.0 (20.0-26.6) nmol/L for less than 1 drink/month). Black women had higher concentrations of DEAPs compared with White women (27.3 (21.2-35.2) vs. 23.2 (20.2-26.7) nmol/L). Organophosphate pesticides (OPs) are synthetic chemicals and currently the most widely used type of insecticides. We examined multi-site, multi-ethnic cohort of midlife women in the U.S. that offers a unique opportunity to evaluate major determinants of OP exposure. We improved OP metabolite detection rates and obtained accurate concentrations using an improved analytical technique. Our findings suggest that consumptions of fruit, meat and alcohol are important determinants of OP exposure for midlife women. Higher concentrations of diethyl OP metabolites in Black women compared to White women, even after accounting for dietary intake, suggests additional, but unknown racial-ethnic differences that affect exposure.

Prevalence and Associated Factors of Cataract, Cataract Surgery and Postoperative Outcome in an Old Population in Russia: The Ural Very Old Study

PurposeTo assess prevalence of cataract and cataract surgery in a very old population in Russia. DesignPopulation-based study. ParticipantsThe Ural Very Old Study included 1526 (81.1%) participants out of 1882 eligible individuals aged 85+ years. MethodsBased on anterior and posterior segment imaging, we assessed the prevalence of cataract, cataract surgery and other ocular disorders affecting best corrected visual acuity (BCVA). Main outcome measuresPrevalence of cataract and cataract surgery. ResultsThe study included 1163 (76.3%) individuals with lens information. Cataract surgery had been performed in 469 right eyes (41.0%;95%CI:38.1,43.9) (92.1% with posterior chamber IOL; 4.7% with multifocal IOL) and 479 left eyes (41.6%;95%CI:38.7,44.4) (92.7% with posterior chamber IOL; 4.2% with multifocal IOL). Among the 1163 study participants, 610 (52.5%) individuals had undergone cataract surgery in at least one eye. Higher prevalence of previous cataract surgery correlated (multivariable analysis) with lower IOP (OR:0.92;95%CI:0.88,0.95;P<0.001), glaucomatous optic nerve damage stage (OR:1.20;95%CI:1.05,1.36;P=0.006), and better visual acuity (OR:0.67;95%CI:0.51,0.89;P=0.005). Postoperative BCVA (mean:0.83±1.43logMAR) was reduced to moderate-to-severe vision impairment (MSVI) in 202 eyes (44.6%;95%CI:40.0,49.2) and to blindness in 53 eyes (11.7%;95%CI:8.7,14.7). Causes of postoperative MSVI were age-related macular degeneration (AMD) (34.2%), glaucoma (13.9%), and secondary cataract (5.4%). Causes for blindness were AMD (24.5%), glaucoma (18.9%), corneal opacifications (15.8%) and myopic macular degeneration (11.3%). YAG-laser capsulotomy had been performed in 6 (1.3%) out 469 right eyes after cataract surgery and in 12 (2.5%) out of 479 left eyes after cataract surgery. Prevalence of nuclear cataract and cortical cataract was 604/671 (90.0% in phakic eyes 51.9% in the whole study population) and 97.9% eyes (48.4% in total study population). Cataract caused bilateral MSVI and blindness in 28.2% (95%CI:25.6,30) and 2.9% (95%CI:1.9,3.9), respectively, of all study participants. ConclusionsDespite a relatively high prevalence of cataract surgery, this multiethnic cohort aged 85+ years from Russia showed a high prevalence of cataract-related MSVI and blindness, due to the old age of the participants. After cataract surgery, main causes for MSVI (prevalence:44.6%) and blindness (prevalence:11.7%) were AMD, glaucoma, corneal opacifications, and myopic macular degeneration. Almost all individuals aged 85+ years need cataract surgery, despite limited chance of postoperative good vision.

Associations between hysterectomy and metabolic syndrome: the Multi-Ethnic Study of Atherosclerosis

Metabolic syndrome is linked to an increased risk of incident cardiovascular disease and all-cause mortality. Notable associations exist between hysterectomy with bilateral salpingo-oophorectomy and metabolic syndrome. However, there is emerging evidence that even with ovarian conservation, hysterectomy may be independently associated with long-term cardiovascular disease risk. To examine the associations between hysterectomy with ovarian preservation and metabolic syndrome risk in a multiethnic cohort. We studied 3367 female participants in the Multi-Ethnic Study of Atherosclerosis who had data on self-reported history of hysterectomy, oophorectomy, hystero-oophorectomy, and metabolic syndrome at baseline (2000-2002). We used adjusted logistic regression to assess the cross-sectional associations between hysterectomy and or oophorectomy subgroups and prevalent metabolic syndrome at baseline. Furthermore, we investigated 1355 participants free of baseline metabolic syndrome and used adjusted Cox regression models to evaluate incident metabolic syndrome from examinations 2 (2002-2004) to 6 (2016-2018). The mean age was 59.0±9.5 years, with 42% White, 27% Black, 19% Hispanic, and 13% Chinese American participants. 29% and 22% had a history of hysterectomy and oophorectomy, respectively. Over a median follow-up of 10.5 (3.01-17.62) years, there were 750 metabolic syndrome events. Hysterectomy (hazard ratio, 1.32 [95% confidence interval, 1.01-1.73]) and hystero-oophorectomy (hazard ratio, 1.40 [95% confidence interval, 1.13-1.74]) were both associated with incident metabolic syndrome compared with having neither hysterectomy nor oophorectomy. Hysterectomy, even with ovarian preservation, may be independently associated with a higher risk of metabolic syndrome. If other studies confirm these findings, screening and preventive strategies focused on females with ovary-sparing hysterectomies and the mechanisms underpinning these associations may be explored.

Abstract PO5-08-12: Ethnic Admixture Affects Breast Cancer Incidence in Native Hawaiians: The Multiethnic Cohort

Abstract Background Native Hawaiians (NH) have the highest breast cancer incidence and the poorest survival of any ethnic group in Hawaii [1]. Since it has been shown that different ethnic groups have disparate risk of breast cancer in Hawaii and NHs are commonly of mixed ancestry, it is possible that the specific ethnic admixture may present an altered risk profile. For example, NH with Asian admixture was associated with higher risk for type 2 diabetes independent of known risk factors [2] compared to those without. The objective of this study was to calculate crude and age-adjusted breast cancer incidences by ethnic admixture group among participants of the Multiethnic Cohort (MEC). Methods: Based on self-reports, 106,525 eligible women were categorized by broad ethnic categories: Native Hawaiian, White, Black, Latino, and Japanese. In total there were 9257 breast cancer cases in the MEC cohort (1996-2019) at time of analysis. The Native Hawaiian population was further categorized into the following subgroups: Native Hawaiian only, Native Hawaiian &amp; White, Native Hawaiian &amp; Chinese, Native Hawaiian &amp; White &amp; Chinese. Crude and age-adjusted incidence rates (per 1000 person-years) were calculated for the various groups. The direct method of age adjustment using the US 2000 Standard population was used. Results: The ethnicity with the highest crude incidence were White=88.46, followed by Black=85.20, Latino=84.27, Japanese=84.90, and Native Hawaiian=81.28. However, after age-adjustment the highest were Japanese=159.1, White=153.8, Latino=148.3, Black=147.4, and Native Hawaiian=139.1. Crude incidence rates for Native Hawaiian ethnic admixture was found to be highest for Native Hawaiian &amp; White=83.5, Native Hawaiian only=82.5, Native Hawaiian &amp; Chinese=80.8, and Native Hawaiian &amp; White &amp; Chinese=80.4. After age adjustment, the highest was Native Hawaiian &amp; Chinese=173.9, followed by Native Hawaiian &amp; White=154.3, Native Hawaiian only=148.7, and finally Native Hawaiian &amp; White &amp; Chinese=120.8. Conclusion: These findings indicate that ethnic admixture in Native Hawaiians may be at elevated age-adjusted breast cancer incidence when compared to Native Hawaiian alone. When a woman was Native Hawaiian and Chinese the incidence was notably higher than any other group at 173.9 when compared to all Native Hawaiian=139.1. Furthermore, the group that had the lowest age-adjusted incidence was the mixed group of Native Hawaiian &amp; White &amp; Chinese=120.8 which seems to account for why the overall Native Hawaiian group=139.1 had one of the lowest incidence rates of the 5 major ethnic groups. 1. Loo, L.W., M. Williams, and B.Y. Hernandez, The high and heterogeneous burden of breast cancer in Hawaii: A unique multiethnic US Population. Cancer epidemiology, 2019. 58: p. 71-76. 2. Maskarinec, G., et al., Ethnic admixture affects diabetes risk in native Hawaiians: the Multiethnic Cohort. Eur J Clin Nutr, 2016. 70(9): p. 1022-7. Citation Format: Dustin Valdez, Arianna Bunnell, David Bogumil, Gertraud Maskarinec, John Shepherd. Ethnic Admixture Affects Breast Cancer Incidence in Native Hawaiians: The Multiethnic Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-12.

Abstract PO5-25-10: Clinical and Epidemiologic Significance of HER2-Low Expression in Breast Cancer in the Pathways Study

Abstract Background: A subset of breast cancers (BC) typically classified as HER2-negative do express low levels of the protein and can be responsive to targeted therapy trastuzumab-deruxtecan. It is unclear if HER2-low tumors have a biology distinct from that in HER2 negative BC. The goal of this study was to evaluate the clinical and epidemiologic features of tumors with HER2-low expression compared with those classified as HER2-negative in a large population study. Material and methods: The Pathways Study is a prospective multi-ethnic cohort study of women with BC enrolled between 2006-2013 within Kaiser Permanente Northern California (KPNC). Breast biomarker results were extracted from pathology reports and underwent centralized pathology review. HER2-low was defined as 1+ or 2+ (negative by in situ hybridization); HER2-negative was defined as 0+. Other data were collected by self-report or extraction from electronic health records at the KPNC cancer registry, including BC risk factors, tumor characteristics [AJCC stage, ER/PR positive or negative status], treatment modality (chemotherapy, radiation therapy, hormonal therapy, and type of surgery), and survival outcomes [recurrence free survival (RFS), breast cancer specific mortality (BCSM), and overall survival (OS)]. The clinical and epidemiologic variables were tested in association with HER2 status (low/negative) by t-tests. Associations of HER2-low with survival outcomes were calculated by proportional hazards regression. Women were included in this analysis if they had a documented HER2 value that was not classified as HER2-positive. Results: Of the 2,200 eligible cases, 1,295 (57.2%) had tumors that were HER2-low. Hormone receptors (HR) were positive in 1,956 (88.9%) cases. HER2-low expression was observed more often in HR-positive cases than in HR-negative, 1,144 (58.4%) vs. 115 (47.1%), respectively (p=.0005). Patients with HER2-low tumors were less likely than those with HER2-negative BC to have family history: 232 of 1259 (18.6%) vs. 214 of 941 (22.8%), respectively (p=.015). This difference was true for patients with HR-positive tumors but not for HR-negative. HER2-low expression appeared to be more common in Asian patients in the HR-negative group than in patients from any other race or ethnicity group. In the HR-negative group, patients with HER2-low had better OS, BCSM, and RFS (p=.019, .014, and .034, respectively) than those with HER2-negative disease. Multivariable analyses were performed for the HR-negative group and adjusted for age at diagnosis, tumor AJCC stage, and type of treatment. Compared with patients with HER2-negative status, patients with HER2-low tumors had lower risk for OS (hazard ratio=0.48, 95% confidence interval: 0.28 to 0.81, p= .006); for RFS (hazard ratio=0.49, 95% confidence interval: 0.27 to 0.90, p= .021); and for BCSM (hazard ratio=0.36, 95% confidence interval: 0.17 to 0.76, p= .007). In analyses stratified by race and ethnicity and controlled for age at diagnosis, AJCC stage and treatment type, Black patients with HER2-low tumors had lower risk for RFS (hazard ratio=0.44, 95% confidence interval: 0.21 to 0.94, p= .035) compared with patients with HER2-negative tumors. Conclusions: In this large prospective study with well annotated epidemiologic, clinical, and outcome data, we observed some clinical and epidemiologic differences between HER2-low and HER2-negative patients, raising the possibility that HER2-low might be a unique biologic entity. Citation Format: Thaer Khoury, Rochelle Payne Ondracek, Song Yao, Lucas Mendocino, Warren Davis, Angela Omilian, Marilyn Kwan, Janise Roh, Lia D'Addario, Emily Valice, Daniel Fernandez, Isaac Ergas, Christine Ambrosone, Lawrence Kushi. Clinical and Epidemiologic Significance of HER2-Low Expression in Breast Cancer in the Pathways Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-10.

Phenotypic characterization of Multiple System Atrophy in a multi-ethnic Asian cohort

Phenotypic characterization of Multiple System Atrophy in a multi-ethnic Asian cohort

Plant-based dietary patterns and mortality from all causes, cardiovascular disease, and cancer: The Multiethnic Cohort Study

Background and aimsPlant-based dietary patterns have been associated with lower risk of cardiovascular disease (CVD), some cancers, and related mortality in U.S. populations. However, the quality of plant foods has rarely been considered in the association between plant-based diets and mortality, especially in a population with various racial and ethnic backgrounds. We investigated whether the adherence to plant-based dietary patterns and the healthiness of plant foods are associated with mortality from all causes, CVD, and cancer and evaluated how the association varies by race and ethnicity MethodsA total of 144,729 African American, Japanese American, Latino, Native Hawaiian, and White men and women who participated in the Multiethnic Cohort Study (1993-2019) were included. Cox models were used to estimate HR and 95% CI of mortality from all causes, CVD, and cancer across quintiles of three plant-based diet scores: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). ResultsOver an average 21 years of follow-up, we identified 65,087 deaths, including 18,663 from CVD and 16,171 from cancer. Comparing the highest versus lowest quintiles, greater scores of PDI and hPDI were associated with a lower risk of all-cause mortality in both men (HR=0.85, 95% CI: 0.82-0.89 for PDI; HR=0.88, 95% CI: 0.85-0.91 for hPDI; both P for trend <0.0001) and women (HR=0.89, 95% CI: 0.86-0.93 for PDI; HR=0.86, 95% CI: 0.83-0.89 for hPDI; both P for trend <0.0001). An increased risk of all-cause mortality with uPDI was observed only in women (HR=1.11, 95% CI: 1.07-1.15, P for trend <0.0001; P for heterogeneity by sex =0.019). A similar trend was shown for CVD mortality with a significant increase in risk with uPDI for both men and women. PDI was associated with a lower risk of cancer mortality in men (HR=0.86, 95% CI: 0.80-0.92, P for trend <0.0001), while neither hPDI nor uPDI was associated in either sex. Compared with the other racial and ethnic groups within each sex, the association of uPDI with all-cause mortality was stronger in White men (P for heterogeneity by race and ethnicity = 0.009) and weaker in Latino women (P for heterogeneity = 0.002). ConclusionA healthy plant-based dietary pattern emphasizing the quality of plant foods was associated with a lower risk of all-cause and CVD mortality in both men and women, although the magnitude of the associations varied across racial and ethnic groups.