Outcome risk model development for heterogeneity of treatment effect analyses: a comparison of non-parametric machine learning methods and semi-parametric statistical methods.

BACKGROUND: In randomized clinical trials, treatment effects may vary, and this possibility is referred to as heterogeneity of treatment effect (HTE). One way to quantify HTE is to partition participants into subgroups based on individual's risk of experiencing an outcome, then measuring treatment effect by subgroup. Given the limited availability of externally validated outcome risk prediction models, internal models (created using the same dataset in which heterogeneity of treatment analyses also will be performed) are commonly developed for subgroup identification. We aim to compare different methods for generating internally developed outcome risk prediction models for subject partitioning in HTE analysis. METHODS: Three approaches were selected for generating subgroups for the 2,441 participants from the United States enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial. An extant proportional hazards-based outcomes predictive risk model developed on the overall ASPREE cohort of 19,114 participants was identified and was used to partition United States' participants by risk of experiencing a composite outcome of death, dementia, or persistent physical disability. Next, two supervised non-parametric machine learning outcome classifiers, decision trees and random forests, were used to develop multivariable risk prediction models and partition participants into subgroups with varied risks of experiencing the composite outcome. Then, we assessed how the partitioning from the proportional hazard model compared to those generated by the machine learning models in an HTE analysis of the 5-year absolute risk reduction (ARR) and hazard ratio for aspirin vs. placebo in each subgroup. Cochran's Q test was used to detect if ARR varied significantly by subgroup. RESULTS: The proportional hazard model was used to generate 5 subgroups using the quintiles of the estimated risk scores; the decision tree model was used to generate 6 subgroups (6 automatically determined tree leaves); and the random forest model was used to generate 5 subgroups using the quintiles of the prediction probability as risk scores. Using the semi-parametric proportional hazards model, the ARR at 5 years was 15.1% (95% CI 4.0-26.3%) for participants with the highest 20% of predicted risk. Using the random forest model, the ARR at 5 years was 13.7% (95% CI 3.1-24.4%) for participants with the highest 20% of predicted risk. The highest outcome risk group in the decision tree model also exhibited a risk reduction, but the confidence interval was wider (5-year ARR = 17.0%, 95% CI= -5.4-39.4%). Cochran's Q test indicated ARR varied significantly only by subgroups created using the proportional hazards model. The hazard ratio for aspirin vs. placebo therapy did not significantly vary by subgroup in any of the models. The highest risk groups for the proportional hazards model and random forest model contained 230 participants each, while the highest risk group in the decision tree model contained 41 participants. CONCLUSIONS: The choice of technique for internally developed models for outcome risk subgroups influences HTE analyses. The rationale for the use of a particular subgroup determination model in HTE analyses needs to be explicitly defined based on desired levels of explainability (with features importance), uncertainty of prediction, chances of overfitting, and assumptions regarding the underlying data structure. Replication of these analyses using data from other mid-size clinical trials may help to establish guidance for selecting an outcomes risk prediction modelling technique for HTE analyses.

Cardiovascular Disease Risk Scores and Incident Dementia and Cognitive Decline in Older Men and Women.

INTRODUCTION: Risk factors for cardiovascular disease (CVD) also increase the risk of dementia. However, whether commonly used CVD risk scores are associated with dementia risk in older adults who do not have a history of CVD, and potential gender differences in this association, remains unclear. The aim of this study was to determine whether CVD risk scores are prospectively associated with cognitive decline and dementia in initially healthy older men and women. METHODS: A total of19,114 participants from a prospective cohort of individuals aged 65+ years without known CVD or dementia were recruited. The atherosclerotic cardiovascular disease risk score (ASCVDRS), Systematic Coronary Risk Evaluation 2-Older Persons (SCORE2-OP), and the Framingham risk score (FRS) were calculated at baseline. Risk of dementia (according to DSM-IV criteria) and cognitive decline (defined as a >1.5 standard deviation decline in global cognition, episodic memory, psychomotor speed, or verbal fluency from the previous year) were assessed using hazard ratio. RESULTS: Over a median follow-up of 6.4 years, 850 individuals developed dementia and 4,352 cognitive decline. Men and women in the highest ASCVDRS tertile had a 41% (95% CI 1.08, 1.85) and 45% (1.11, 1.89) increased risk of dementia compared to the lowest tertile, respectively. Likewise, men and women in the highest SCORE2-OP tertile had a 64% (1.24, 2.16) and 60% (1.22, 2.11) increased risk of dementia compared to the lowest tertile, respectively. Findings were similar, but the risk was slightly lesser when examining risk of cognitive decline for both ASCVDRS and SCORE2-OP. However, FRS was only associated with the risk of cognitive decline among women (highest vs. lowest tertiles: 1.13 [1.01-1.26]). CONCLUSION: These findings suggest the utility of the ASCVDRS and SCORE2-OP in clinical practice, to not only assess future risk of CVD, but also as potential early indicators of cognitive impairment, even in relatively healthy older men and women.

Correlates of missed or late versus timely diagnosis of dementia in healthcare settings.

INTRODUCTION: There is limited evidence about factors related to the timeliness of dementia diagnosis in healthcare settings. METHODS: In five prospective cohorts at Rush Alzheimer's Disease Center, we identified participants with incident dementia based on annual assessments and examined the timing of healthcare diagnoses in Medicare claims. We assessed sociodemographic, health, and psychosocial correlates of timely diagnosis. RESULTS: Of 710 participants, 385 (or 54%) received a timely claims diagnosis within 3 years prior to or 1 year following dementia onset. In logistic regressions accounting for demographics, we found Black participants (odds ratio [OR] = 2.15, 95% confidence interval [CI]: 1.21 to 3.82) and those with better cognition at dementia onset (OR = 1.48, 95% CI: 1.10 to 1.98) were at higher odds of experiencing a diagnostic delay, whereas participants with higher income (OR = 0.89, 95% CI: 0.81 to 0.97) and more comorbidities (OR = 0.94, 95% CI: 0.89 to 0.98) had lower odds. DISCUSSION: We identified characteristics of individuals who may miss the optimal window for dementia treatment and support. HIGHLIGHTS: We compared the timing of healthcare diagnosis relative to the timing of incident dementia based on rigorous annual evaluation. Older Black adults with lower income, higher cognitive function, and fewer comorbidities were less likely to be diagnosed in a timely manner by the healthcare system.

Gender-specific analysis of social connection patterns and risk of dementia in community-dwelling older people.

INTRODUCTION: Poor social connection is considered a risk factor for dementia. Since socializing behaviors may cluster together or act compensatorily, we aimed to investigate social connection patterns and their association with dementia, for men and women separately. METHODS: A total of 12,896 community-dwelling older adults (mean ± SD age: 75.2 ± 4.3 years, 54% women) without major cognitive impairment were included. Latent class analysis was conducted using 24 baseline social connection indicators. Cox proportional hazards regression was used to estimate the association between latent classes and incident dementia over 12 (median: 8.4) years follow-up. RESULTS: Three distinct classes were identified in both genders: strong social connections with an intermediate friend-relative network (Class 1: men, 43.8%; women, 37.9%), weak social connections (Class 2: men, 29.6%; women, 27.4%), and strong social connections with a larger friend-relative network (Class 3: men, 26.6%; women, 34.7%). Compared to Class 1, men in Class 2 (HR: 1.38, 95% CI: 1.08-1.77) and women in Class 3 (HR: 1.27, 95% CI: 1.01-1.60) had an increased risk of dementia. DISCUSSION: Dementia risk varies with different social connection patterns among older men and women. HIGHLIGHTS: Three distinct social connection patterns were identified based on 24 indicators. These patterns were related to dementia risk differently in men and women. In men, a weak social connection pattern was associated with a higher dementia risk. In women, a strong social connection with a relatively larger friend-relative network was associated with a greater dementia risk.

The effect of depressive symptoms on disability-free survival in healthy older adults: A prospective cohort study.

BACKGROUND: Gerontology and ageing research are increasingly focussing on healthy life span (healthspan), the period of life lived free of serious disease and disability. Late-life depression (LLD) is believed to impact adversely on physical health. However, no studies have examined its effect on healthspan. This study investigated the effect of LLD and subthreshold depression on disability-free survival, a widely accepted measure of healthspan. METHODS: This prospective cohort study used data from the ASPirin in Reducing Events in the Elderly study. Participants were aged ≥70 years (or ≥65 years for African-American and Hispanic participants) and free of dementia, physical disability and cardiovascular disease. Depressive symptoms were measured using the 10-item Centre for Epidemiological Studies Depression Scale (CES-D-10). LLD and subthreshold depression were defined as CES-D-10 scores ≥8 and 3-7, respectively. Disability-free survival was defined as survival free of dementia and persistent physical disability. RESULTS: A total of 19,110 participants were followed up for a maximum of 7.3 years. In female participants, LLD was associated with lower disability-free survival adjusting for sociodemographic and lifestyle factors, medical comorbidities, polypharmacy, physical function and antidepressant use (HR, 1.50; 95% CI, 1.23-1.82). In male participants, LLD was associated with lower disability-free survival adjusting for sociodemographic and lifestyle factors (HR, 1.30; 95% CI, 1.03-1.64). Subthreshold depression was also associated with lower disability-free survival in both sexes. CONCLUSIONS: LLD may be a common and important risk factor for shortened healthspan.

Prediabetes, diabetes and loss of disability-free survival in a community-based older cohort: a post-hoc analysis of the ASPirin in Reducing Events in the Elderly trial.

BACKGROUND: Evidence for the prognostic implications of hyperglycaemia in older adults is inconsistent. OBJECTIVE: To evaluate disability-free survival (DFS) in older individuals by glycaemic status. METHODS: This analysis used data from a randomised trial recruiting 19,114 community-based participants aged ≥70 years, who had no prior cardiovascular events, dementia and physical disability. Participants with sufficient information to ascertain their baseline diabetes status were categorised as having normoglycaemia (fasting plasma glucose [FPG] < 5.6 mmol/l, 64%), prediabetes (FPG 5.6 to <7.0 mmol/l, 26%) and diabetes (self-report or FPG ≥ 7.0 mmol/l or use of glucose-lowering agents, 11%). The primary outcome was loss of disability-free survival (DFS), a composite of all-cause mortality, persistent physical disability or dementia. Other outcomes included the three individual components of the DFS loss, as well as cognitive impairment-no dementia (CIND), major adverse cardiovascular events (MACE) and any cardiovascular event. Cox models were used for outcome analyses, with covariate adjustment using inverse-probability weighting. RESULTS: We included 18,816 participants (median follow-up: 6.9 years). Compared to normoglycaemia, participants with diabetes had greater risks of DFS loss (weighted HR: 1.39, 95% CI 1.21-1.60), all-cause mortality (1.45, 1.23-1.72), persistent physical disability (1.73, 1.35-2.22), CIND (1.22, 1.08-1.38), MACE (1.30, 1.04-1.63) and cardiovascular events (1.25, 1.02-1.54) but not dementia (1.13, 0.87-1.47). The prediabetes group did not have an excess risk for DFS loss (1.02, 0.93-1.12) or other outcomes. CONCLUSIONS: Among older people, diabetes was associated with reduced DFS, and higher risk of CIND and cardiovascular outcomes, whereas prediabetes was not. The impact of preventing or treating diabetes in this age group deserves closer attention.

Cognitive trajectories and incident dementia after a cardiovascular event in older adults.

INTRODUCTION: Cardiovascular disease (CVD) is a recognized risk factor for dementia. Here we determined the extent to which an incident CVD event modifies the trajectory of cognitive function and risk of dementia. METHODS: 19,114 adults (65+) without CVD or dementia were followed prospectively over 9 years. Incident CVD (fatal coronary heart disease, nonfatal myocardial infarction [MI], stroke, hospitalization for heart failure) and dementia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were adjudicated by experts. RESULTS: Nine hundred twenty-two participants had incident CVD, and 44 developed dementia after CVD (4.9% vs. 4.4% for participants without CVD). Following a CVD event there was a short-term drop in processing speed (-1.97, 95% confidence interval [CI]: -2.57 to -1.41), but there was no significant association with longer-term processing speed. In contrast, faster declines in trajectories of global function (-0.56, 95% CI: -0.76 to -0.36), episodic memory (-0.10, 95% CI: -0.16 to -0.04), and verbal fluency (-0.19, 95% CI: -0.30 to -0.01) were observed. DISCUSSION: Findings highlight the importance of monitoring cognition after a CVD event.

Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals.

INTRODUCTION: Recent genome-wide association studies identified new dementia-associated variants. We assessed the performance of updated polygenic risk scores (PRSs) using these variants in an independent cohort. METHODS: We used Cox models and area under the curve (AUC) to validate new PRSs (PRS-83SNP, PRS-SBayesR, and PRS-CS) compared with an older PRS-23SNP in 12,031 initially-healthy participants ≥70 years of age. Dementia was rigorously adjudicated according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: PRS-83SNP, PRS-SBayesR, and PRS-CS were associated with incident dementia, with fully adjusted (including apolipoprotein E [APOE] ε4) hazard ratios per standard deviation (SD) of 1.35 (1.23-1.47), 1.37 (1.25-1.50), and 1.42 (1.30-1.56), respectively. The AUC of a model containing conventional/non-genetic factors and APOE was 74.7%. This was improved to 75.7% (p = 0.007), 76% (p = 0.004), and 76.1% (p = 0.003) with addition of PRS-83SNP, PRS-SBayesR, and PRS-CS, respectively. The PRS-23SNP did not improve AUC (74.7%, p = 0.95). CONCLUSION: New PRSs for dementia significantly improve risk-prediction performance, but still account for less risk than APOE genotype overall.

Daily Written Care Summaries for Families of Critically Ill Patients: A Randomized Controlled Trial.

OBJECTIVES: To determine the effect of daily written updates on the satisfaction and psychologic symptoms of families of ICU patients. DESIGN: Randomized controlled trial. SETTING: Single, urban academic medical center. SUBJECTS: Surrogates of nondecisional, critically ill adults with high risk of mortality ( n = 252) enrolled from June 2019 to January 2021. INTERVENTIONS: Usual communication with the medical team with or without written communication detailing the suspected cause and management approach of each ICU problem, updated each day. MEASUREMENTS AND MAIN RESULTS: Participants completed surveys at three time points during the ICU stay: enrollment ( n = 252), 1 week ( n = 229), and 2 weeks ( n = 109) after enrollment. Satisfaction with care was measured using the Critical Care Family Needs Inventory (CCFNI). The presence of anxiety, depression, and acute stress were assessed using the Hospital Anxiety and Depression Scale (HADS) and Impact of Events Scale Revised (IES-R). CCFNI, HADS, and IES-R scores were similar among participants assigned to the intervention group and control group upon enrollment and during the first week after enrollment ( p > 0.05). From enrollment to the second week after enrollment, there was an improvement in CCFNI and HADS scores among participants assigned to the intervention group versus the control group. At week 2, CCFNI scores were significantly lower among participants in the intervention group versus the control group, indicating greater satisfaction with care: 15.1 (95% CI, 14.2-16.0) versus 16.4, (95% CI, 15.5-17.3); p = 0.04. In addition, 2 weeks after enrollment, the odds of symptoms of anxiety, depression, and acute stress among participants assigned to the intervention versus control group were 0.16 (95% CI, 0.03-0.82; p = 0.03); 0.15 (95% CI, 0.01-1.87; p = 0.14); and 0.27 (95% CI, 0.06-1.27; p = 0.10), respectively. CONCLUSIONS: Written communication improved satisfaction and the emotional well-being of families of critically ill patients, supporting its use as a supplement to traditional communication approaches.

The Relationship of John Henryism With Cognitive Function and Decline in Older Black Adults.

OBJECTIVE: This study aimed to investigate the relationship between John Henryism, a psychological trait typified by high-effort active coping that has been associated with adverse health outcomes among Blacks, and cognitive decline. METHODS: In a cohort of community-dwelling older Black adults ( N = 611), we investigated the relationship between John Henryism and cognitive decline. John Henryism was measured using the John Henryism Active Coping Scale (JHACS), a nine-item validated measure of self-reported high-effort coping (mean [standard deviation] = 16.9 [4.8]; range, 4-27). We implemented a three-step modeling process using mixed-effects models to assess the relationship between the JHACS and global cognitive function as well as five cognitive domains. We adjusted for demographics and for factors known to be associated with cognitive function and decline including vascular risk factors, discrimination, and income. RESULTS: The trait of high-effort active coping was associated with lower-average cognitive function ( ß = -0.07, 95% confidence interval = -0.10 to -0.03), but not with decline. The results remained after further adjustment for experiences of discrimination, income, and vascular risk factors. In domain-specific analyses, we found that the JHACS was associated with baseline levels of working memory, semantic memory, and visuospatial ability, but not decline. CONCLUSIONS: These results highlight the importance of using culturally specific measures in considering the heterogeneity of cognitive health outcomes in minoritized populations. Understanding how stress responses relate to late-life cognition among older Black adults could help promote aspects of behavioral resilience along with healthful coping responses.

Effects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial.

Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ2 (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ2 (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.

Subgroup analysis of the ASPirin in Reducing Events in the Elderly randomized clinical trial suggests aspirin did not improve outcomes in older adults with chronic kidney disease.

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m2 or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death, major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD.

Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly.

BACKGROUND: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly.

BACKGROUND: In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. METHODS: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. RESULTS: Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). CONCLUSIONS: Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Effect of Aspirin on Disability-free Survival in the Healthy Elderly.

BACKGROUND: Information on the use of aspirin to increase healthy independent life span in older persons is limited. Whether 5 years of daily low-dose aspirin therapy would extend disability-free life in healthy seniors is unclear. METHODS: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or physical disability. Participants were randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally. The primary end point was a composite of death, dementia, or persistent physical disability. Secondary end points reported in this article included the individual components of the primary end point and major hemorrhage. RESULTS: A total of 19,114 persons with a median age of 74 years were enrolled, of whom 9525 were randomly assigned to receive aspirin and 9589 to receive placebo. A total of 56.4% of the participants were women, 8.7% were nonwhite, and 11.0% reported previous regular aspirin use. The trial was terminated at a median of 4.7 years of follow-up after a determination was made that there would be no benefit with continued aspirin use with regard to the primary end point. The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 per 1000 person-years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). The rate of adherence to the assigned intervention was 62.1% in the aspirin group and 64.1% in the placebo group in the final year of trial participation. Differences between the aspirin group and the placebo group were not substantial with regard to the secondary individual end points of death from any cause (12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group), dementia, or persistent physical disability. The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Variability in comorbidites and health services use across homeless typologies: multicenter data linkage between healthcare and homeless systems.

BACKGROUND: Homelessness is associated with substantial morbidity. Data linkages between homeless and health systems are important to understand unique needs across homeless populations, identify homeless individuals not registered in homeless databases, quantify the impact of housing services on health-system use, and motivate health systems and payers to contribute to housing solutions. METHODS: We performed a cross-sectional survey including six health systems and two Homeless Management Information Systems (HMIS) in Cook County, Illinois. We performed privacy-preserving record linkage to identify homelessness through HMIS or ICD-10 codes captured in electronic medical records. We measured the prevalence of health conditions and health-services use across the following typologies: housing-service utilizers stratified by service provided (stable, stable plus unstable, unstable) and non-utilizers (i.e., homelessness identified through diagnosis codes-without receipt of housing services). RESULTS: Among 11,447 homeless recipients of healthcare, nearly 1 in 5 were identified by ICD10 code alone without recorded homeless services (n = 2177; 19%). Almost half received homeless services that did not include stable housing (n = 5444; 48%), followed by stable housing (n = 3017; 26%), then receipt of both stable and unstable services (n = 809; 7%). Setting stable housing recipients as the referent group, we found a stepwise increase in behavioral-health conditions from stable housing to those known as homeless solely by health systems. Compared to those in stable housing, prevalence rate ratios (PRR) for those without homeless services were as follows: depression (PRR = 2.2; 95% CI 1.9 to 2.5), anxiety (PRR = 2.5; 95% CI 2.1 to 3.0), schizophrenia (PRR = 3.3; 95% CI 2.7 to 4.0), and alcohol-use disorder (PRR = 4.4; 95% CI 3.6 to 5.3). Homeless individuals who had not received housing services relied on emergency departments for healthcare-nearly 3 of 4 visited at least one and many (24%) visited multiple. CONCLUSIONS: Differences in behavioral-health conditions and health-system use across homeless typologies highlight the particularly high burden among homeless who are disconnected from homeless services. Fragmented and high use of emergency departments for care should motivate health systems and payers to promote housing solutions, especially those that incorporate substance use and mental health treatment.

Hospitalization, Alzheimer's Disease and Related Neuropathologies, and Cognitive Decline.

OBJECTIVE: To test the hypothesis that Alzheimer's disease and related neuropathologies contribute to the association between hospitalization and cognitive decline in old age. METHODS: As part of a longitudinal clinical-pathologic cohort study, 526 older persons (mean age at death = 90.9 years, 71% female) without dementia at baseline completed annual cognitive testing and were autopsied at death. Hospitalization information was obtained from linked Medicare claims records. Neuropathologic examination assessed ß-amyloid burden, tau tangle density, neocortical Lewy bodies, hippocampal sclerosis, chronic gross and microscopic cerebral infarcts, and transactive response DNA binding protein 43 kDa. RESULTS: Over a mean of 5.1 years, a total of 1,383 hospitalizations occurred, and the mean annual rate of hospitalization was 0.5 (standard deviation = 0.6, median = 0.4). Higher rate of hospitalization was not directly related to higher burden for any of the neuropathologic markers. Higher rate of hospitalization was associated with more rapid cognitive decline (estimate = -0.042, standard error [SE] = 0.012, p < 0.001), and after controlling for all 7 neuropathologic markers, the association was essentially the same (estimate = -0.040, SE = 0.013, p = 0.002). In a multivariable model with 3-way interactions of neuropathologic markers with hospitalization rate and time, the association between hospitalization rate and faster cognitive decline was greater in persons with more tangle pathology (estimate for interaction = -0.007, SE = 0.002, p = 0.002) and in persons with neocortical Lewy bodies (estimate for interaction = -0.117, SE = 0.042, p = 0.005). INTERPRETATION: Older persons with more hospitalizations experienced faster rates of cognitive decline, and this association was more pronounced in persons with more tau tangle density and with neocortical Lewy body pathologies. ANN NEUROL 2019;86:844-852.

Representation of Older Latinxs in Cohort Studies at the Rush Alzheimer's Disease Center.

The Rush Alzheimer's Disease Center (RADC) conducts 5 harmonized prospective clinical-pathologic cohort studies of aging - with 1 study, the Latino Core, focused exclusively on Latinxs, 2 studies consisting of mostly non-Latinx whites, and 2 studies of mostly non-Latinx blacks. This paper contextualizes the Latino Core within the other 4 harmonized RADC cohort studies. The overall aim of the paper is to provide information from the RADC, so that researchers can learn from our participants and procedures to better advance the science of Alzheimer's disease and related dementias in Latinxs. We describe an annual clinical evaluation that assesses risk factors for Alzheimer's dementia among older adults without known dementia at enrollment. As all RADC cohort studies offer brain donation as a part of research participation, we discuss our approach to brain donation and subsequent participant decision-making among older Latinxs. We also summarize baseline characteristics of older Latinxs across the 5 RADC cohort studies in relation to the baseline characteristics of non-Latinx blacks and non-Latinx whites. Finally, we outline challenges and considerations as well as potential next steps in cognitive aging research with older Latinxs.

Attitudes toward advance care planning among persons with dementia and their caregivers.

OBJECTIVES: To examine factors that influence decision-making, preferences, and plans related to advance care planning (ACP) and end-of-life care among persons with dementia and their caregivers, and examine how these may differ by race. DESIGN: Cross-sectional survey. SETTING: 13 geographically dispersed Alzheimer's Disease Centers across the United States. PARTICIPANTS: 431 racially diverse caregivers of persons with dementia. MEASUREMENTS: Survey on "Care Planning for Individuals with Dementia." RESULTS: The respondents were knowledgeable about dementia and hospice care, indicated the person with dementia would want comfort care at the end stage of illness, and reported high levels of both legal ACP (e.g., living will; 87%) and informal ACP discussions (79%) for the person with dementia. However, notable racial differences were present. Relative to white persons with dementia, African American persons with dementia were reported to have a lower preference for comfort care (81% vs. 58%) and lower rates of completion of legal ACP (89% vs. 73%). Racial differences in ACP and care preferences were also reflected in geographic differences. Additionally, African American study partners had a lower level of knowledge about dementia and reported a greater influence of religious/spiritual beliefs on the desired types of medical treatments. Notably, all respondents indicated that more information about the stages of dementia and end-of-life health care options would be helpful. CONCLUSIONS: Educational programs may be useful in reducing racial differences in attitudes towards ACP. These programs could focus on the clinical course of dementia and issues related to end-of-life care, including the importance of ACP.

Racial/ethnic minority segregation and low birth weight in five North American cities.

Comparisons of communities across cities are rare in social epidemiology. Our prior work exploring racial/ethnic segregation and the prevalence of low birth weight (LBW) in communities from two large urban cities showed a strong relationship in Chicago and a very weak relationship in Toronto. This study extends that work by examining the association between racial/ethnic minority segregation and LBW in total of 307 communities in five North American cities: Baltimore, Boston, Chicago, Philadelphia, and Toronto. We used Pearson correlation coefficients and OLS regression models to examine potential variability in the association between racial/ethnic minority segregation and LBW, controlling for community-level unemployment. In a combined model with community-level data from all cities, a 10% increase in minority composition is associated with a 0.7% increase in LBW. While racial/ethnic minority segregation and unemployment are not associated with LBW in Toronto, these social determinants have strong and significant associations with LBW across communities in the four US cities in the analysis. Subsequent models revealed opposite effects for percentage non-Hispanic Black and percentage Hispanic. Across communities in the US cities in this analysis, there is considerable similarity in the strength of the effect of racial/ethnic segregation on LBW. Future work should incorporate communities from additional cities, looking to identify community assets and public policies that allow some minority communities to thrive, while other minority communities suffer from a high prevalence of LBW. More work is also needed on the generalizability of these patterns to other health outcomes.