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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. [ABSTRACT FROM AUTHOR]

Background: This study examined the associations of body mass index (BMI) and waist circumference (WC), as well as their short‐ and long‐term changes over time, with incident dementia in older individuals. Methods: Data came from 18,837 community‐dwelling individuals aged 65+ years from Australia and the United States, who were relatively healthy without major cognitive impairment at enrolment. Anthropometric measures were prospectively assessed at baseline, as well as change and variability from baseline to year two (three time‐points). In a subgroup (n = 11,176), self‐reported weight at age 18 and 70+ years was investigated. Dementia cases satisfied DSM‐IV criteria. Cox regression was used to examine the associations between anthropometric measures and incident risk of dementia. Results: Compared to normal weight, an overweight (HR: 0.67, 95%CI: 0.57–0.79, p < 0.001) or obese BMI (HR: 0.73, 95%CI: 0.60–0.89, p = 0.002), or a larger WC (elevated, HR: 0.71, 95%CI: 0.58–0.86, p < 0.001; highly elevated, HR: 0.65, 95%CI: 0.55–0.78, p < 0.001; relative to low) at baseline was associated with lower dementia risk. In contrast, substantial increases in BMI (>5%) over 2 years after baseline were associated with higher dementia risk (HR: 1.49, 95% CI: 1.17–1.91, p = 0.001). Increased dementia risk was also seen with an underweight BMI at baseline and a 2‐year BMI decrease (>5%), but these associations appeared only in the first 4 years of follow‐up. Compared to normal weight at both age 18 and 70+ years, being obese at both times was associated with increased dementia risk (HR: 2.27, 95%CI: 1.22–4.24, p = 0.01), while obesity only at age 70+ years was associated with decreased risk (HR: 0.70, 95%CI: 0.51–0.95, p = 0.02). Conclusions: Our findings suggest that long‐term obesity and weight gain in later life may be risk factors for dementia. Being underweight or having substantial weight loss in old age may be early markers of pre‐clinical dementia. [ABSTRACT FROM AUTHOR]

Background: Surrogates and physicians may differ in their priorities and perspectives when making decisions for incapacitated, critically ill patients. Objectives: To determine the extent to which surrogate and physician decisions to sustain life support are associated with their expectations for patient outcomes. Setting/Subjects: Surrogates and physicians of 100 mechanically ventilated patients at an academic, tertiary care medical center in the United States were surveyed. Measurements: Linear regression was used to determine if participant expectations for patient survival, good quality of life, and confidence in these expectations were associated with their agreement that mechanical ventilation should be continued if required for patient survival. Results: Surrogates were more likely than physicians to expect that patients would be alive in three months (91% interquartile range [IQR 70–95%] vs. 65% [IQR 43–77%], p < 0.001) and have good quality of life in three months (71% [IQR 50–90%] vs. 40% [IQR 19–50%], p < 0.001). Surrogates who were most confident in their prognostic abilities were also the most optimistic for good patient outcomes. As such, expectations for patient survival and good quality of life were not associated with level agreement that mechanical ventilation should be continued among confident surrogates, (R2 = 0.03, p = 0.13) and (R2 = 0.01, p = 0.53), respectively. In contrast, among physicians, confidence was not synonymous with optimism. Instead, the significant associations between expectations for patient survival and good quality of life with the agreement that mechanical ventilation should be continued were strengthened when physicians were confident, (R2 = 0.34, p < 0.01) and (R2 = 0.47, p < 0.001), respectively. Conclusion: Surrogates and physicians have different approaches to incorporating their expectations for patient prognosis and their confidence in these expectations when they are making decisions for incapacitated critically ill patients. [ABSTRACT FROM AUTHOR]

Frailty is a state of heightened vulnerability and susceptibility to physiologic stressors that increases with age. It has shown increasing utility in predicting a range of adverse health outcomes. Here, we characterize a 67-item deficit-accumulation frailty index (FI) in 19 110 community-dwelling individuals in the ASPirin in Reducing Events in the Elderly clinical trial. Participants aged 65-98 years were recruited from the United States and Australia and were without diagnosed dementia and cardiovascular disease, and major physical disability. The median FI score was .10 (interquartile range: .07-.14) at baseline, and the prevalence of frailty (FI > .21) increased from 8.1% to 17.4% after 6 years. FI was positively associated with age, and women had significantly higher scores than men at all ages. The FI was negatively correlated with gait speed (r = -.31) and grip strength (r = -.46), and strongly associated with a modified Fried's frailty phenotype (p < .0001, for all comparisons). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (hazard ratio: 21.3, 95% confidence interval: 15.6-28.9). It added significantly to the predictive capacity of these outcomes above age, sex, and ethnicity alone. The FI is thus a useful biomarker of aging even among relatively healthy older individuals and provides important information about an individual's vulnerability to and risk of disease. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular events, dementia, and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults.Methods: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100 mg aspirin versus placebo recruited 19 114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the United States. Six basic ADLs were assessed every 6 months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after 6 months. Proportional hazards modeling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk.Results: Over a median of 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing, and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 vs 5.3 events/1000 py; hazard ratio [HR] = 0.81, 95% confidence interval [CI]: 0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability, there were more deaths in the aspirin group (24 vs 12).Discussion: Low-dose aspirin in initially healthy older people did not reduce the risk of incident ADL disability, although there was evidence of reduced persistent ADL disability. [ABSTRACT FROM AUTHOR]

Background: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.Methods: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.Results: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).Conclusions: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group. [ABSTRACT FROM AUTHOR]

Importance: Depression is associated with increased inflammation, which may precede its onset, especially in older people. Some preclinical data suggest potential antidepressant effects of aspirin, supported by limited observational data suggesting lower rates of depression in individuals treated with aspirin. There currently appears to be no evidence-based pharmacotherapies for the primary prevention of depression.Objective: To determine whether low-dose aspirin (100 mg) reduces the risk of depression in healthy older adults.Design, Setting, and Participants: This double-blinded, placebo-controlled randomized clinical trial was a substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which examined if aspirin increased healthy life span, defined as survival free of dementia and disability. The prespecified secondary outcome was depression. Individuals of all races/ethnicities older than 70 years in Australia, as well as white individuals older than 70 years and black and Hispanic individuals older than 65 years in the United States, were included.Interventions: Participants were randomized to aspirin (100 mg daily) or placebo, with a median (interquartile range) follow-up of 4.7 (3.5-5.6) years.Main Outcomes and Measures: The primary outcome was a proxy measure of major depressive disorder defined as a score of 8 or more on the Center for Epidemiologic Studies Depression 10-item (CES-D-10) scale.Results: Of the 19 114 participants enrolled in the trial, 9525 received aspirin and 9589 received a placebo. The mean (SD) age was 75.2 (4.0) years in the aspirin group and 75.1 (4.5) years in the placebo group; 9531 (56.4%) were women. Participants' demographics and clinical characteristics at baseline were similar between groups. A total of 79 886 annual CES-D-10 measurements were taken, with a mean of 4.2 measurements per participant. There were no significant differences at annual visits in the proportions of CES-D-10 scores of 8 or more between the aspirin and placebo groups. The incidence rate of new CES-D-10 scores of 8 or more was 70.4 events per 1000 person-years in the aspirin group and 69.1 in the placebo group (hazard ratio, 1.02 [95% CI, 0.96-1.08]; P = .54).Conclusions and Relevance: Low-dose aspirin did not prevent depression in this large-scale study of otherwise healthy older adults.Trial Registration: ClinicalTrials.gov Identifier: NCT01038583. [ABSTRACT FROM AUTHOR]

Background: A small number of older adults in the United States who agree to brain donation for clinical research belong to diverse racial, ethnic, and economic groups. Those who agree, however, are less likely to have completed brain autopsies compared with older non-Latino Whites of higher socioeconomic status. As such, our understanding of Alzheimer's disease and related dementias remains limited in these underrepresented and understudied populations. Here, we examine perceived impediments to completed brain autopsies among diverse older adults who have agreed to brain donation for clinical research.Methods: Participants (N=22) were older adults (mean age=77 years) who self-identified as African American (n=8), Latino (n=6), or White of lower income (n=8). All participants had previously agreed to brain donation via the Uniform Anatomical Gift Act. Each participant took part in a one-time, semi-structured focus group. Data were analyzed using a Grounded Theory Approach with both Open Coding and Constant Comparative Coding.Results: Perceived impediments to completed brain autopsies varied by group. Older African Americans and older Latinos expressed concern about a lack of follow-through by family members regarding their brain donation wishes. Older Whites of lower income indicated that their own uncertainty surrounding the processes of brain donation and brain autopsy might serve as an impediment.Discussion: Diverse older adults expressed different perceived impediments to having brain autopsies completed upon their death. Continuous education for diverse older adults and their family members regarding brain donation for clinical research, including clear guidelines and processes, may facilitate completed brain autopsies among diverse older adults. [ABSTRACT FROM AUTHOR]

BACKGROUND Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP. METHODS We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control. RESULTS Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US). CONCLUSIONS High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population. CLINICAL TRIALS REGISTRATION NCT01038583. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to estimate prevalence rates and factors associated with depressive symptoms indexed by the Centre for Epidemiological Studies-Depression (CES-D-10) score in a large sample of community-dwelling healthy older adults from Australia and the United States. Convergent and divergent validity of the CES-D-10 were also examined.Methods: A total of 19 114 individuals aged greater than or equal to 65 years old were enrolled from a primary prevention clinical trial. Depressive symptoms were classified using the CES-D-10 score greater than or equal to 8 and greater than or equal to 10. Gender-specific prevalence for subgroups according to sociodemographic characteristics were reported, and factors associated with depressive symptoms were estimated.Results: The overall prevalence rates of depressive symptoms were 9.8%, 95% CI, 8.5-11.2 and 5.0%, 95% CI, 4.0-6.0, according to the CES-D-10 score greater than or equal to 8 and greater than or equal to 10, respectively. Depressive symptoms were more common in women, individuals with less than 12 years of education, those living alone or in a residential care, ethnic minorities, current smokers, and former alcohol users. Convergent and divergent validities of the CES-D-10 were confirmed by observing strong negative association with the SF-12 mental health component and a modest negative association with SF-12 physical component, respectively.Conclusions: This study reports the prevalence of depressive symptoms in Australian and US community-dwelling healthy older populations. These findings emphasize the high burden of the condition and factors associated with depressive symptoms, to better inform clinicians and help with early detection and treatment of depression in this age group. [ABSTRACT FROM AUTHOR]

Objective: To present normative performance data on the Modified Mini-Mental State (3MS) examination for healthy community-dwelling older individuals according to gender, age, education level, and ethno-racial group. Method: More than 19,000 generally healthy older men and women without a diagnosis of dementia were recruited from the general population in Australia and the U.S. for the ASPirin in Reducing Events in the Elderly (ASPREE) study. The 3MS exam was administered as part of the baseline screening and individuals scoring above 77 were eligible to participate. Results: The sample comprised 16,360 Australian whites, 1080 U.S. whites, 895 African-Americans and 316 Hispanic/Latinos. The median age of participants was 74 years (range 65–98), with an average of 12 years of education and 56% were female. Increasing age and fewer years of completed education were associated with lower scores on the 3MS. Women scored higher than men in most age and education categories. Differences across ethno-racial groups were found. With factor analysis, four factors were identified which accounted for 35% of the between-person variance in 3MS scores for white Australians. Conclusions: This large cohort of older individuals provides some of the most comprehensive 3MS normative data to be generated for whites (Australian and U.S.), Hispanic/Latinos and African-Americans, by age, gender, and educational attainment. These findings will serve as important reference standards for monitoring cognitive function in generally healthy older individuals, becoming increasingly important as this fraction of the population increases. [ABSTRACT FROM AUTHOR]

Purpose: To explore the relationship between sociodemographic and lifestyle variables with health-related quality of life (HRQoL) of a large cohort of 'healthy' older individuals.Methods: The sample included individuals aged 65+ years from Australia (N = 16,703) and the USA (N = 2411) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) multicentre placebo-controlled trial study and free of cardiovascular disease, dementia, serious physical disabilities or 'fatal' illnesses. The associations with the physical (PCS) and mental component scores (MCS) of HRQoL (SF-12 questionnaire) were explored using multiple linear regression models from data collected at baseline (2010-2014).Results: The adjusted PCS mean was slightly higher in the USA (49.5 ± 9.1) than Australia (48.2 ± 11.6; p < 0.001), but MCS was similar in both samples (55.7 ± 7.5 and 55.7 ± 9.6, respectively; p = 0.603). Males, younger participants, better educated, more active individuals, or those currently drinking 1-2 alcoholic drinks/day showed a better HRQoL (results more evident for PCS than MCS), while current heavy smokers had the lowest physical HRQoL in both countries. Neither age, walking time, nor alcohol intake was associated with MCS in either cohort.Conclusions: Baseline HRQoL of ASPREE participants was higher than that reported in population-based studies of older individuals, but the associations between sociodemographic and lifestyle variables were consistent with the published literature. As the cohort ages and develops chronic diseases, ASPREE will be able to document HRQoL changes. [ABSTRACT FROM AUTHOR]

Background: There are no primary prevention trials of aspirin with relevant geriatric outcomes in elderly people. ASPirin in Reducing Events in the Elderly (ASPREE) is a placebo-controlled trial of low-dose aspirin that will determine whether 5 years of daily 100-mg enteric-coated aspirin extends disability-free and dementia-free life in a healthy elderly population and whether these benefits outweigh the risks.Methods: Set in primary care, this randomized double-blind placebo-controlled trial has a composite primary endpoint of death, incident dementia or persistent physical disability. Participants aged 70+ years (non-minorities) or 65+ years (U.S. minorities) were free of cardiovascular disease, dementia, or physical disability and without a contraindication to, or indication for, aspirin. Baseline data include physical and lifestyle, personal and family medical history, hemoglobin, fasting glucose, creatinine, lipid panel, urinary albumin:creatinine ratio, cognition (3MS, HVLT-R, COWAT, SDMT), mood (CES-D-10), physical function (gait speed, grip strength), Katz activities of daily living and quality of life (SF-12).Results: Recruitment ended in December 2014 with 16,703 Australian and 2,411 U.S. participants, a median age of 74 (range 65-98) years and 56% women. Approximately 55% of the U.S. cohort were from minority groups; 9% of the total cohort. Proportions with hypertension, overweight, and chronic kidney disease were similar to age-matched populations from both countries although lower percentages had diabetes, dyslipidemia, and osteoarthritis.Discussion: Findings from ASPREE will be generalizable to a healthier older population in both countries and will assess whether the broad benefits of daily low-dose aspirin in prolonging independent life outweigh the risks. [ABSTRACT FROM AUTHOR]

The article highlights the challenges between technologies advancing large scale health data sharing and health data privacy and security in the U.S. Topics discussed include precision medicine and population health research in health care industry; laws defined by the U.S. Food and Drug Administration; provisions of the Health Insurance Portability and Accountability Act; and advances in addition to mobile technologies and patient partnerships.

The author reflects on the various innovations and invention related with improvement of health system in the U.S. with reference to David E Barmes Global Health Lecture given by the author at the National Institutes of Health in Bethesda on February 15, 2011. He discusses the benefits of the U.S. President, Barack Obama's Global Health Initiative (GHI) program which aims at providing higher vaccine availability at low price, life-saving care for infants and HIV infection prevention.

Background: The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers.Methods: We analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically).Results: From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33-1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57-0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15-0.97; combined HR = 0.29; 95% CI = 0.23-0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age.Conclusion: Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk. [ABSTRACT FROM AUTHOR]