Association of Education With Dementia Incidence Stratified by Ethnicity and Nativity in a Cohort of Older Asian American Individuals.

Importance: High education protects against dementia, but returns on educational attainment may be different across sociodemographic groups owing to various social factors. Asian American individuals are a growing and diverse group, but little research has assessed dementia determinants in this population. Objective: To examine the association of education with dementia in a large cohort of Asian American individuals, stratifying by ethnicity and nativity. Design, Setting, and Participants: This cohort study used electronic health record (EHR) and survey data from the Research Program on Genes, Environment, and Health and the California Men's Health Study surveys (2002-2020). Data are from Kaiser Permanente Northern California, an integrated health care delivery system. This study used a volunteer sample who completed the surveys. Participants included Chinese, Filipino, and Japanese individuals who were aged 60 to less than 90 years without a dementia diagnosis in the EHR at the time of the survey (baseline) and who had 2 years of health plan coverage before baseline. Data analysis was performed from December 2021 to December 2022. Exposures: The main exposure was educational attainment (college degree or higher vs less than a college degree), and the main stratification variables were Asian ethnicity and nativity (born in the US or born outside the US). Main Outcomes and Measures: The primary outcome was incident dementia diagnosis in the EHR. Dementia incidence rates were estimated by ethnicity and nativity, and Cox proportional hazards and Aalen additive hazards models were fitted for the association of college degree or higher vs less than a college degree with time to dementia, adjusting for age (timescale), sex, nativity, and an interaction between nativity and college degree. Results: Among 14 749 individuals, the mean (SD) age at baseline was 70.6 (7.3) years, 8174 (55.4%) were female, and 6931 (47.0%) had attained a college degree. Overall, among individuals born in the US, those with a college degree had 12% lower dementia incidence (HR, 0.88; 95% CI, 0.75-1.03) compared with those without at least a college degree, although the confidence interval included the null. The HR for individuals born outside the US was 0.82 (95% CI, 0.72-0.92; P = .46 for the college degree by nativity interaction). The findings were similar across ethnicity and nativity groups except for Japanese individuals born outside the US. Conclusions and Relevance: These findings suggest that college degree attainment was associated with lower dementia incidence, with similar associations across nativity. More work is needed to understand determinants of dementia in Asian American individuals and to elucidate mechanisms linking educational attainment and dementia.

Neighborhood disadvantage and dementia incidence in a cohort of Asian American and non-Latino White older adults in Northern California.

INTRODUCTION: Some evidence suggests that neighborhood socioeconomic disadvantage is associated with dementia-related outcomes. However, prior research is predominantly among non-Latino Whites. METHODS: We evaluated the association between neighborhood disadvantage (Area Deprivation Index [ADI]) and dementia incidence in Asian American (n = 18,103) and non-Latino White (n = 149,385) members of a Northern California integrated health care delivery system aged 60 to 89 at baseline. Race/ethnicity-specific Cox proportional hazards models adjusted for individual-level age, sex, socioeconomic measures, and block group population density estimated hazard ratios (HRs) for dementia. RESULTS: Among non-Latino Whites, ADI was associated with dementia incidence (most vs. least disadvantaged ADI quintile HR = 1.09, 95% confidence interval [CI] = 1.02-1.15). Among Asian Americans, associations were close to null (e.g., most vs. least disadvantaged ADI quintile HR = 1.01, 95% CI = 0.85-1.21). DISCUSSION: ADI was associated with dementia incidence among non-Latino Whites but not Asian Americans. Understanding the potentially different mechanisms driving dementia incidence in these groups could inform dementia prevention efforts.

Evaluation of multi-assay algorithms for cross-sectional HIV incidence estimation in settings with universal antiretroviral treatment.

BACKGROUND: Multi-assay algorithms (MAAs) are used to estimate population-level HIV incidence and identify individuals with recent infection. Many MAAs use low viral load (VL) as a biomarker for long-term infection. This could impact incidence estimates in settings with high rates of early HIV treatment initiation. We evaluated the performance of two MAAs that do not include VL. METHODS: Samples were collected from 219 seroconverters (infected < 1 year) and 4376 non-seroconverters (infected > 1 year) in the HPTN 071 (PopART) trial; 28.8% of seroconverter samples and 73.2% of non-seroconverter samples had VLs ≤ 400 copies/mL. Samples were tested with the Limiting Antigen Avidity assay (LAg) and JHU BioRad-Avidity assays. Antibody reactivity to two HIV peptides was measured using the MSD U-PLEX assay. Two MAAs were evaluated that do not include VL: a MAA that includes the LAg-Avidity assay and BioRad-Avidity assay (LAg + BR) and a MAA that includes the LAg-Avidity assay and two peptide biomarkers (LAg + PepPair). Performance of these MAAs was compared to a widely used MAA that includes LAg and VL (LAg + VL). RESULTS: The incidence estimate for LAg + VL (1.29%, 95% CI: 0.97-1.62) was close to the observed longitudinal incidence (1.34% 95% CI: 1.17-1.53). The incidence estimates for the other two MAAs were higher (LAg + BR: 2.56%, 95% CI 2.01-3.11; LAg + PepPair: 2.84%, 95% CI: 1.36-4.32). LAg + BR and LAg + PepPair also misclassified more individuals infected > 2 years as recently infected than LAg + VL (1.2% [42/3483 and 1.5% [51/3483], respectively, vs. 0.2% [6/3483]). LAg + BR classified more seroconverters as recently infected than LAg + VL or LAg + PepPair (80 vs. 58 and 50, respectively) and identified ~ 25% of virally suppressed seroconverters as recently infected. CONCLUSIONS: The LAg + VL MAA produced a cross-sectional incidence estimate that was closer to the longitudinal estimate than two MAAs that did not include VL. The LAg + BR MAA classified the greatest number of individual seroconverters as recently infected but had a higher false recent rate.

Estimating Vaccine Effectiveness by Linking Population-Based Health Registries: Some Sources of Bias.

The coronavirus disease 2019 (COVID-19) pandemic has underscored the importance of observational studies of real-world vaccine effectiveness (VE) to help answer urgent public health questions. One approach to rapidly answering questions about real-world VE relies on linking data from a population-based registry of vaccinations with a population-based registry of health outcomes. Here we consider some potential sources of bias in linked registry studies, including incomplete reporting to the registries, errors in linking individuals between registries, and errors in the assumed population size of the catchment area of the registries. We show that the direction of the bias resulting from one source of error by itself is predictable. However, if multiple sources of error are present, the direction of the bias can be either upward or downward. The biases can be so strong as to make harmful vaccines appear effective. We provide explicit formulas with which to quantify and adjust for multiple biases in estimates of VE which could be used in sensitivity analyses. While this work was motivated by COVID-19 vaccine questions, the results are generally applicable to studies that link population-based exposure registries with population-based case registries to estimate relative risks of exposures.

Differences in prevalence and risk factors of non-communicable diseases between young people living with HIV (YLWH) and young general population in Cambodia.

Understanding non-communicable diseases (NCDs) among young people living with HIV (YLWH) is critical given the potential for aging-associated comorbidities resulting from HIV, especially in Cambodia where such data are limited. Therefore, we examined the prevalence and correlates of NCDs in YLWH and compared it to a nationally representative sample of young people not otherwise infected. We collected data from a sample of 370 YLWH aged 18-29 years attending three HIV clinics in Cambodia between 2019 and 2020. Our comparison group were 486 young people who participated in the Ministry of Health/WHO 2016 Noncommunicable Disease Risk Factor Surveillance (STEP survey). Both surveys used a standardized questionnaire to collect information on lifestyle factors and World Health Organization protocols for physical and biochemical measurements. We compared the prevalence of diabetes, hypertension, and high cholesterolemia between the two groups and examined the relationship between these conditions and HIV. We found 16 (4%), 22 (6%), and 72 (20%) had diabetes, hypertension, and high cholesterolemia, respectively, among YLWH, compared to 4 (1%), 22 (4%), and 49 (11%) among the general population. In logistic regression, YLWH were at higher odds of diabetes/prediabetes and high cholesterolemia compared with the young general population, aOR = 6.64 (95% CI 3.62-12.19) and aOR = 7.95 (95% CI 3.98-15.87), respectively. Our findings demonstrate that YLWH in Cambodia face multiple metabolic disorders and NCDs despite their young age and that accessible screening measures and treatment for these conditions are needed in order to combat NCDs in the future.

The role of nativity in heterogeneous dementia incidence in a large cohort of three Asian American groups and white older adults in California.

INTRODUCTION: Literature shows lower dementia incidence in Asian American groups versus whites, varying by Asian ethnicity. One hypothesized driver is nativity differences (eg, healthy immigrant effect). METHODS: We followed a cohort of 6243 Chinese, 4879 Filipino, 3256 Japanese, and 141,158 white Kaiser Permanente Northern California members for incident dementia (2002 to 2020), estimating age-adjusted dementia incidence rates by ethnicity and nativity, and hazard ratios (HR) for nativity on dementia incidence using ethnicity-stratified age- and sex-adjusted Cox proportional hazards models. RESULTS: Dementia incidence appeared higher in foreign- versus US-born Filipinos (HR, 95% confidence interval: 1.39, 1.02 to 1.89); differences were small in Japanese (1.07, 0.88 to 1.30) and Chinese (1.07, 0.92 to 1.24). No nativity differences were observed among whites (1.00, 0.95 to 1.04). DISCUSSION: Nativity does not explain lower dementia incidence in Asian Americans versus whites, but may contribute to heterogeneity across Asian ethnicities. Future research should explore differential impacts of social and cardiometabolic factors.

Regression with interval-censored covariates: Application to cross-sectional incidence estimation.

A method for generalized linear regression with interval-censored covariates is described, extending previous approaches. A scenario is considered in which an interval-censored covariate of interest is defined as a function of other variables. Instead of directly modeling the distribution of the interval-censored covariate of interest, the distributions of the variables which determine that covariate are modeled, and the distribution of the covariate of interest is inferred indirectly. This approach leads to an estimation procedure using the Expectation-Maximization (EM) algorithm. The performance of this approach is compared to two alternative approaches, one in which the censoring interval midpoints are used as estimates of the censored covariate values, and another in which the censored values are multiply imputed using uniform distributions over the censoring intervals. A simulation framework is constructed to assess these methods' accuracies across a range of scenarios. The proposed approach is found to have less bias than midpoint analysis and uniform imputation, at the cost of small increases in standard error.

Fusion designs and estimators for treatment effects.

While randomized trials remain the best evidence for treatment effectiveness, lack of generalizability often remains an important concern. Additionally, when new treatments are compared against existing standards of care, the potentially small benefit of the new treatment may be difficult to detect in a trial without extremely large sample sizes and long follow-up times. Recent advances in "data fusion" provide a framework to combine results across studies that are applicable to a given population of interest and allow treatment comparisons that may not be feasible with traditional study designs. We propose a data fusion-based estimator that can be used to combine information from two studies: (1) a study comparing a new treatment to the standard of care in the local population of interest, and (2) a study comparing the standard of care to placebo in a separate, distal population. We provide conditions under which the parameter of interest can be identified from the two studies described and explore properties of the estimator through simulation. Finally, we apply the estimator to estimate the effect of triple- vs monotherapy for the treatment of HIV using data from two randomized trials. The proposed estimator can account for underlying population structures that induce differences in case mix, adherence, and outcome prevalence between the local and distal populations, and the estimator can also account for potentially informative loss to follow-up. Approaches like those detailed here are increasingly important to speed the approval and adoption of effective new therapies by leveraging multiple sources of information.

Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model.

Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence. Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence. Design, Setting, and Participants: This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival. Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.

Comparative impact of methamphetamine and other drug use on viral suppression among sexual minority men on antiretroviral therapy.

BACKGROUND: Substance use decreases the likelihood of achieving undetectable HIV viremia; however, the comparative effects by drug have not been fully described. In this study, we compare the effects of methamphetamine use versus other drugs on viremia in sexual minority men on antiretroviral therapy (ART). METHODS: HIV-positive participants currently on ART (N = 230) were selected from an ongoing cohort of diverse young sexual minority men (mSTUDY) enrolled from August 2014 to May 2018. Substance use and sociodemographic factors associated with viremia outcomes were assessed using ordinal regression analysis with generalized estimating equations. Viremia outcomes were grouped as undetectable (<20 copies/mL), low level suppressed (21-200 copies/mL), or not suppressed (>200 copies/mL). RESULTS: The prevalence of drug use across 825 study visits was 73 %, with methamphetamine use most prevalent (50 %). After adjusting for unstable housing and ART adherence, methamphetamine use, either alone (adjusted OR = 1.87; 95 % CI 1.03-3.40) or with other drugs (adjusted OR = 1.82; 95 % CI 1.12-2.95), was associated with higher odds of increasing viremia compared to no drug use. Other drug use excluding methamphetamine did not show a similar association (adjusted OR = 1.29; 95 % CI 0.80-2.09). Among our study population, nearly half the instances of viremia could be reduced if methamphetamine was discontinued (attributable fraction = 46 %; 95 % CI 3-71 %). CONCLUSIONS: Methamphetamine use, either alone or in combination with other drugs, is associated with failure of viral suppression among sexual minority men on ART independent of adherence and sociodemographic factors. This accounts for nearly half of the observed instances of unsuppressed viremia in this study.

Associations of social capital resources and experiences of homophobia with HIV transmission risk behavior and HIV care continuum among men who have sex with men in Los Angeles.

For men who have sex with men (MSM) in the US, the positive and negative aspects of social capital - access to resources within their social networks and experiences of homophobia - may explain their disproportionate burden of HIV infection. We analyzed data from 379 HIV seronegative and seropositive MSM in Los Angeles, collected between May 2017 and February 2018. Dependent variables were HIV transmission risk behaviors and care continuum outcomes. We used multivariable logistic regression to estimate the association between social capital resources and experiences of homophobia with dependent variables, adjusting for sociodemographics and drug use. Most participants were under age 40 and 41% identified as Black/African American and 36% as Hispanic/Latino. Social capital resources associated with likelihood of new sexually transmitted infections (-5.5% per standard deviation (SD), 95%CI -10.3, 0.7%) and HIV testing (5% per SD, 95%CI 0.8, 9.2%). Experiences of homophobia associated with likelihood of methamphetamine use during sex (10% per SD, 95%CI 7, 14%), receiving (4.3% per SD, 95%CI 1.9, 6.7%) and giving (7.2% per SD, 95%CI 4.5, 9.9%) exchange sex, and missing appointments (7.2% per SD, 95%CI 0.8, 13.6%). Findings that social capital associated with HIV transmission risk behaviors and HIV testing suggest interventions to increase social capital resources would impact the HIV-prevention continuum.

Excess Patient Visits for Cough and Pulmonary Disease at a Large US Health System in the Months Prior to the COVID-19 Pandemic: Time-Series Analysis.

BACKGROUND: Accurately assessing the regional activity of diseases such as COVID-19 is important in guiding public health interventions. Leveraging electronic health records (EHRs) to monitor outpatient clinical encounters may lead to the identification of emerging outbreaks. OBJECTIVE: The aim of this study is to investigate whether excess visits where the word "cough" was present in the EHR reason for visit, and hospitalizations with acute respiratory failure were more frequent from December 2019 to February 2020 compared with the preceding 5 years. METHODS: A retrospective observational cohort was identified from a large US health system with 3 hospitals, over 180 clinics, and 2.5 million patient encounters annually. Data from patient encounters from July 1, 2014, to February 29, 2020, were included. Seasonal autoregressive integrated moving average (SARIMA) time-series models were used to evaluate if the observed winter 2019/2020 rates were higher than the forecast 95% prediction intervals. The estimated excess number of visits and hospitalizations in winter 2019/2020 were calculated compared to previous seasons. RESULTS: The percentage of patients presenting with an EHR reason for visit containing the word "cough" to clinics exceeded the 95% prediction interval the week of December 22, 2019, and was consistently above the 95% prediction interval all 10 weeks through the end of February 2020. Similar trends were noted for emergency department visits and hospitalizations starting December 22, 2019, where observed data exceeded the 95% prediction interval in 6 and 7 of the 10 weeks, respectively. The estimated excess over the 3-month 2019/2020 winter season, obtained by either subtracting the maximum or subtracting the average of the five previous seasons from the current season, was 1.6 or 2.0 excess visits for cough per 1000 outpatient visits, 11.0 or 19.2 excess visits for cough per 1000 emergency department visits, and 21.4 or 39.1 excess visits per 1000 hospitalizations with acute respiratory failure, respectively. The total numbers of excess cases above the 95% predicted forecast interval were 168 cases in the outpatient clinics, 56 cases for the emergency department, and 18 hospitalized with acute respiratory failure. CONCLUSIONS: A significantly higher number of patients with respiratory complaints and diseases starting in late December 2019 and continuing through February 2020 suggests community spread of SARS-CoV-2 prior to established clinical awareness and testing capabilities. This provides a case example of how health system analytics combined with EHR data can provide powerful and agile tools for identifying when future trends in patient populations are outside of the expected ranges.

A METHOD FOR ESTIMATING THE PROPORTION OF HIV INFECTED PERSONS THAT HAVE BEEN DIAGNOSED AND APPLICATION TO CHINA.

Estimation of the proportion of living HIV infected persons that have been diagnosed is critical for tracking progress toward meeting the UNAIDS goal that all persons who need HIV treatment receive it. The objective of this article is to develop a method for estimating that proportion. The methodological problem is that persons with undiagnosed HIV infection are not directly observable and are a "hidden" population. Here we propose a methodology for estimating the proportion diagnosed that is relatively simple to implement. The key idea is that in many settings certain health conditions such as pregnancy or an upcoming surgery lead to mandatory HIV tests. The size of the undiagnosed infected population can be estimated from the numbers of infected persons diagnosed by mandatory tests and an estimate of the rate that persons in the undiagnosed infected population receive mandatory tests. We discuss approaches for estimating the rate of mandatory testing in the undiagnosed population, such as surgical or pregnancy rates. We develop estimators of the proportion diagnosed and confidence interval procedures. Sample size considerations and sensitivity analyses to underlying assumptions are considered. The proposed methods can be performed at a local level and within demographic strata. Implementation of the method is simple and requires neither historical HIV/AIDS surveillance data nor biomarkers such as CD4 cell counts. The methods are applied to data from Dehong Prefecture in Yunnan Province, China.

Depressive symptoms and substance use: Changes overtime among a cohort of HIV-positive and HIV-negative MSM.

BACKGROUND: The objective of this study was to examine depressive symptoms overtime and quantify the variance in symptoms attributable to substance use among a cohort of HIV-positive and HIV-negative men. METHODS: Participants were enrolled in an NIH/NIDA funded cohort, with 534 men resulting in 1,888 visits between August 2014 and June 2018. Participants were between 18 and 45 years, and half were HIV-positive. At baseline and semi-annual visits, information was collected on depressive symptoms, sexual behaviors, and substance use. Changes overtime in symptom scores were evaluated using individual growth curve modeling. RESULTS: The average CES-D20 score was 19.5 (SD = 12.7). Depressive symptoms were highest among daily/weekly methamphetamine users (56% vs. 39% occasional users and 27% non-users; p value<.01). Factors independently associated with depressive symptoms included methamphetamine use (adjusted OR = 1.5; 95% CI 1.1-2.3) and transactional sex (adjusted OR = 1.8; 95% CI 1.4-2.5). Based on growth curve modeling, methamphetamine was the most influential predictor of depressive symptoms, accounting for 10% of individual variance (p value<.01). Declines in depressive symptoms were noted for heavy users of a number of drugs, except for methamphetamine. For instance, those reporting daily/weekly heroin had a 3.38 point decline in CESD20 scores overtime (p value = 0.01). However, heavy methamphetamine users had much higher CESD20 scores and their scores remained high overtime (p value for change = 0.91). CONCLUSIONS: The prevalence of depressive symptoms among this cohort of HIV-negative and HIV-positive MSM was high, especially among frequent methamphetamine users. These findings suggest that reducing methamphetamine use may have the potential to reduce depressive symptoms.

Alterations to the Gastrointestinal Microbiome Associated with Methamphetamine Use among Young Men who have Sex with Men.

Methamphetamine (MA) use is a major public health problem in the United States, especially among people living with HIV (PLWH). Many MA-induced neurotoxic effects are mediated by inflammation and gut microbiota may play a role in this process, yet the effects of MA on the microbiome have not been adequately explored. Therefore, we performed 16S rRNA gene sequencing on rectal swab samples from 381 men who have sex with men, 48% of whom were PLWH and 41% of whom used MA. We compared microbiome composition between MA users and non-users while testing for potential interactions with HIV and controlling for numerous confounders using inverse probability of treatment weighting. We found that MA use explained significant variation in overall composition (R2 = 0.005, p = 0.008) and was associated with elevated Finegoldia, Parvimonas, Peptoniphilus, and Porphyromonas and reduced Butyricicoccus and Faecalibacterium, among others. Genera including Actinomyces and Streptobacillus interacted with HIV status, such that they were increased in HIV+ MA users. Finegoldia and Peptoniphilus increased with increasing frequency of MA use, among others. In summary, MA use was associated with a microbial imbalance favoring pro-inflammatory bacteria, including some with neuroactive potential and others that have previously been associated with poor HIV outcomes.

Improving the Youth HIV Prevention and Care Cascades: Innovative Designs in the Adolescent Trials Network for HIV/AIDS Interventions.

Dramatic decreases in HIV transmission are achievable with currently available biomedical and behavioral interventions, including antiretroviral therapy and pre-exposure prophylaxis. However, such decreases have not yet been realized among adolescents and young adults. The Adolescent Medicine Trials Network (ATN) for HIV/AIDS interventions is dedicated to research addressing the needs of youth at high risk for HIV acquisition as well as youth living with HIV. This article provides an overview of an array of efficient and effective designs across the translational spectrum that are utilized within the ATN. These designs maximize methodological rigor and real-world applicability of findings while minimizing resource use. Implementation science and cost-effectiveness methods are included. Utilizing protocol examples, we demonstrate the feasibility of such designs to balance rigor and relevance to shorten the science-to-practice gap and improve the youth HIV prevention and care continua.