Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality.

Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using "second and third generation clocks," PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.

Dried blood spot based biomarkers in the Health and Retirement Study: 2006 to 2016.

INTRODUCTION: The Health and Retirement Study (HRS) has collected biomarker data over multiple waves. Such data can help improve our understanding of health changes in individuals and the causal pathways related to health. There are, however, technical challenges to using the HRS dried blood spots (DBS) biomarker data due to changes over time in assay protocols, platforms, and laboratories. We provide technical and summary information on biological indicators collected as part of the HRS from 2006 to 2016 that should be helpful to users of the data. METHODS: We describe the opportunities and challenges provided by the HRS DBS data as well as insights provided by the data. The HRS collected DBS from its nationally representative sample of respondents 51 years of age or older from 2006 to 2016. DBS-based biomarkers were collected from half the sample in 2006, 2010, and 2014, and from the other half of the sample in 2008, 2012, and 2016. These DBS specimens were used to assay total and HDL cholesterol, glycosylated hemoglobin, C-reactive protein, and cystatin C from 2006 to 2016, and Interleukin 6 was added in 2014/2016. Samples included approximately 6000 individuals at each wave, and completion rates ranged from 81% to 90%. HRS transformed DBS values into venous blood equivalents to make them more comparable to those of the whole blood-based assays collected in most other studies and to facilitate longitudinal analysis. RESULTS: Distribution of changes over time by age shows that total cholesterol levels decreased for each age, while HbA1c levels increased. Cystatin C shows a clear age gradient, but a number of other markers do not. Non-Hispanic Black persons and Hispanic respondents have a higher incidence of risk levels of each biomarker except for CRP among non-Hispanic Black older persons. CONCLUSION: These public-use DBS data provide analysis opportunities that can be used to improve our understanding of health change with age in both populations and among individuals.

The Health and Retirement Study Harmonized Cognitive Assessment Protocol Project: Study Design and Methods.

INTRODUCTION: The Harmonized Cognitive Assessment Protocol (HCAP) Project is a substudy within the Health and Retirement Study (HRS), an ongoing nationally representative panel study of about 20,000 adults aged 51 or older in the United States. The HCAP is part of an international research collaboration funded by the National Institute on Aging to better measure and identify cognitive impairment and dementia in representative population-based samples of older adults, in the context of ongoing longitudinal studies of aging in high-, middle-, and low-income countries around the world. METHODS: The HCAP cognitive test battery was designed to measure a range of key cognitive domains affected by cognitive aging (including attention, memory, executive function, language, and visuospatial function) and to allow harmonization and comparisons to other studies in the United States and around the world. The HCAP included a pair of in-person interviews, one with the target HRS respondent (a randomly selected HRS sample member, aged 65+) that lasted approximately 1 h and one with an informant nominated by the respondent that lasted approximately 20 min. The final HRS HCAP sample included 3,496 study subjects, representing a 79% response rate among those invited to participate. CONCLUSION: Linking detailed HCAP cognitive assessments to the wealth of available longitudinal HRS data on cognition, health, biomarkers, genetics, health care utilization, informal care, and economic resources and behavior will provide unique and expanded opportunities to study cognitive impairment and dementia in a nationally representative US population-based sample. The fielding of similar HCAP projects in multiple countries around the world will provide additional opportunities to study international differences in the prevalence, incidence, and outcomes of dementia globally with comparable data. Like all HRS data, HCAP data are publicly available at no cost to researchers.

Contemporaneous Social Environment and the Architecture of Late-Life Gene Expression Profiles.

Environmental or social challenges can stimulate a cascade of coordinated physiological changes in stress response systems. Unfortunately, chronic activation of these adaptations under conditions such as low socioeconomic status (SES) can have negative consequences for long-term health. While there is substantial evidence tying low SES to increased disease risk and reduced life expectancy, the underlying biology remains poorly understood. Using pilot data on 120 older adults from the Health and Retirement Study (United States, 2002-2010), we examined the associations between SES and gene expression levels in adulthood, with particular focus on a gene expression program known as the conserved transcriptional response to adversity. We also used a bioinformatics-based approach to assess the activity of specific gene regulation pathways involved in inflammation, antiviral responses, and stress-related neuroendocrine signaling. We found that low SES was related to increased expression of conserved transcriptional response to adversity genes and distinct patterns of proinflammatory, antiviral, and stress signaling (e.g., sympathetic nervous system and hypothalamic-pituitary-adrenal axis) transcription factor activation.

GENOME-WIDE ASSOCIATION STUDY (GWAS) AND GENOME-WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN.

BACKGROUND: Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. METHODS: Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. RESULTS: No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10(-8) ) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10(-7) ). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10(-7) ) and rs4542757 (intronic to DCC, P = 7.31 × 10(-7) ). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10(-10) ; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. CONCLUSIONS: Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

Genetic diversity is a predictor of mortality in humans.

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease. RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%. CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

Identifying diabetics in Medicare claims and survey data: implications for health services research.

BACKGROUND: Diabetes health services research often utilizes secondary data sources, including survey self-report and Medicare claims, to identify and study the diabetic population, but disagreement exists between these two data sources. We assessed agreement between the Chronic Condition Warehouse diabetes algorithm for Medicare claims and self-report measures of diabetes. Differences in healthcare utilization outcomes under each diabetes definition were also explored. METHODS: Claims data from the Medicare Beneficiary Annual Summary File were linked to survey and blood data collected from the 2006 Health and Retirement Study. A Hemoglobin A1c reading, collected on 2,028 respondents, was used to reconcile discrepancies between the self-report and Medicare claims measures of diabetes. T-tests were used to assess differences in healthcare utilization outcomes for each diabetes measure. RESULTS: The Chronic Condition Warehouse (CCW) algorithm yielded a higher rate of diabetes than respondent self-reports (27.3 vs. 21.2, p < 0.05). A1c levels of discordant claims-based diabetics suggest that these patients are not diabetic, however, they have high rates of healthcare spending and utilization similar to diabetics. CONCLUSIONS: Concordance between A1c and self-reports was higher than for A1c and the CCW algorithm. Accuracy of self-reports was superior to the CCW algorithm. False positives in the claims data have similar utilization profiles to diabetics, suggesting minimal bias in some types of claims-based analyses, though researchers should consider sensitivity analysis across definitions for health services research.

Development and validation of a brief dementia screening indicator for primary care.

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives. METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening. RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78). CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

Educational Attainment and Later-Life Cognitive Function in High- and Middle-Income Countries: Evidence From the Harmonized Cognitive Assessment Protocol.

OBJECTIVES: Identifying social policies that can promote cognitive health is crucial for reducing the global burden of dementia. We evaluated the importance of educational attainment for later-life cognitive function in various social and geographic settings. METHODS: Using harmonized data for individuals aged ≥65 years from the United States Health and Retirement Study (HRS) and its international partner studies in England, Mexico, China, and India, and each study's respective Harmonized Cognitive Assessment Protocol (HCAP), we conducted a cross-national comparative study to examine the role of educational attainment in later-life cognitive function across countries (n = 14,980, 2016-2019). We used multivariable-adjusted regression to estimate associations between educational attainment and harmonized global cognitive function scores. RESULTS: In Mexico, China, and India, the general cognitive function scores on average are approximately one standard deviation of the HRS-HCAP cognitive function score distribution lower compared to the United States and England, paralleling patterns of educational attainment across countries. In all countries, higher educational attainment was associated with progressively higher later-life cognitive function scores. Population-level differences in educational attainment explained about 50%-90% of the observed differences in cognitive function scores across countries. DISCUSSION: The relationship between education and later-life cognitive function across social and geographic contexts underscores the crucial role of education to promote cognitive health and reduce dementia risk. Continual improvement of educational attainment in low- and middle-income settings may yield a significant pay-off in later-life cognitive health.

Association analysis between an epigenetic alcohol risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Association analysis between an epigenetic risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

The Mode Effect of Web-Based Surveying on the 2018 U.S. Health and Retirement Study Measure of Cognitive Functioning.

OBJECTIVES: Measuring cognition in an aging populabtion is a public health priority. A move towards survey measurement via the web (as opposed to phone or in-person) is cost-effective but challenging as it may induce bias in cognitive measures. We examine this possibility using an experiment embedded in the 2018 wave of data collection for the U.S. Health and Retirement Study (HRS). METHODS: We utilize techniques from multiple group item response theory to assess the effect of survey mode on performance on the HRS cognitive measure. We also study the problem of attrition by attempting to predict dropout and via approaches meant to minimize bias in subsequent inferences due to attrition. RESULTS: We find evidence of an increase in scores for HRS respondents who are randomly assigned to the web-based mode of data collection in 2018. Web-based respondents score higher in 2018 than experimentally matched phone-based respondents, and they show much larger gains relative to 2016 performance and subsequently larger declines in 2020. The differential in favor of web-based responding is observed across all items, but is most pronounced for the Serial 7 task and numeracy items. Due to the relative ease of the web-based mode, we suggest a cutscore of 12 being used to indicate CIND (cognitively impaired but not demented) status when using the web-based version rather than 11. DISCUSSION: The difference in mode may be nonignorable for many uses of the HRS cognitive measure. In particular, it may require reconsideration of some cutscore-based approaches to identify impairment.

Decision Making for Patients With Severe Dementia Versus Normal Cognition Near the End of Life.

Background and Objectives: The clinical progression of severe dementia frequently leads to situations where surrogate decision makers must quickly make choices about potentially burdensome treatments that offer limited clinical benefit. We examined whether the number of decision makers and their access to advance directives were related to treatment choice for patients with severe dementia in comparison to those with normal cognition. Research Design and Methods: We retrospectively linked survey responses about end-of-life treatment decisions to Medicare claims for Health and Retirement Study respondents dying between 2002 and 2015 whose next-of-kin reported a need for surrogate decision making. We estimated multivariable logistic regression models to study measures of aggressive care in the last 6 months of life; in-hospital death, burdensome transfers, and burdensome treatments. Results: Compared to patients who were cognitively normal near the end of life (n = 1 198), patients with severe dementia (n = 722) were less likely to experience burdensome treatments (18% [95% confidence interval {CI} 14-21] vs 32% [95% CI 29-35]), burdensome transfers (20% [95% CI 17-24] vs 30% [95% CI 27-33]), and in-hospital death (24% [95% CI 20-28] vs 30% [95% CI 26-33]) when surrogates were involved. Rates of burdensome treatments, transfers, or in-hospital death for decedents with severe dementia did not vary with single versus multiple decision makers or when decision makers were informed by advance directives. However, among decedents with normal cognition, a single decision maker informed by an advance directive was associated with the lowest rates of burdensome treatments and in-hospital death. Discussion and Implications: Surrogate decision makers made similar choices around end-of-life care for patients with severe dementia regardless of the number of decision makers and availability of advance directives. However, both advance directives and single decision makers were associated with less aggressive care for cognitively normal decedents.

A cultural neuropsychological approach to harmonization of cognitive data across culturally and linguistically diverse older adult populations.

OBJECTIVE: To describe a cultural neuropsychological approach to prestatistical harmonization of cognitive data across the United States (U.S.) and Mexico with the Harmonized Cognitive Assessment Protocol (HCAP). METHOD: We performed a comprehensive review of the administration, scoring, and coding procedures for each cognitive test item administered across the English and Spanish versions of the HCAP in the Health and Retirement Study (HRS) in the U.S. and the Ancillary Study on Cognitive Aging in Mexico (Mex-Cog). For items that were potentially equivalent across studies, we compared each cognitive test item for linguistic and cultural equivalence and classified items as confident or tentative linking items, based on the degree of confidence in their comparability across cohorts and language groups. We evaluated these classifications using differential item functioning techniques. RESULTS: We evaluated 132 test items among 21 cognitive instruments in the HCAP across the HRS and Mex-Cog. We identified 72 confident linking items, 46 tentative linking items, and 14 items that were not comparable across cohorts. Measurement invariance analysis revealed that 64% of the confident linking items and 83% of the tentative linking items showed statistical evidence of measurement differences across cohorts. CONCLUSIONS: Prestatistical harmonization of cognitive data, performed by a multidisciplinary and multilingual team including cultural neuropsychologists, can identify differences in cognitive construct measurement across languages and cultures that may not be identified by statistical procedures alone. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Incidence of dementia and cognitive impairment, not dementia in the United States.

OBJECTIVE: Estimates of incident dementia, and cognitive impairment, not dementia (CIND) (or the related mild cognitive impairment) are important for public health and clinical care policy. In this paper, we report US national incidence rates for dementia and CIND. METHODS: Participants in the Aging, Demographic, and Memory Study (ADAMS) were evaluated for cognitive impairment using a comprehensive in-home assessment. A total of 456 individuals aged 72 years and older, who were not demented at baseline, were followed longitudinally from August 2001 to December 2009. An expert consensus panel assigned a diagnosis of normal cognition, CIND, or dementia and its subtypes. Using a population-weighted sample, we estimated the incidence of dementia, Alzheimer disease (AD), vascular dementia (VaD), and CIND by age. We also estimated the incidence of progression from CIND to dementia. RESULTS: The incidence of dementia was 33.3 (standard error [SE], 4.2) per 1,000 person-years and 22.9 (SE, 2.9) per 1,000 person-years for AD. The incidence of CIND was 60.4 (SE, 7.2) cases per 1,000 person-years. An estimated 120.3 (SE, 16.9) individuals per 1,000 person-years progressed from CIND to dementia. Over a 5.9-year period, about 3.4 million individuals aged 72 and older in the United States developed incident dementia, of whom approximately 2.3 million developed AD, and about 637,000 developed VaD. Over this same period, almost 4.8 million individuals developed incident CIND. INTERPRETATION: The incidence of CIND is greater than the incidence of dementia, and those with CIND are at high risk of progressing to dementia, making CIND a potentially valuable target for treatments aimed at slowing cognitive decline.

LINKING SURVEY AND ADMINISTRATIVE RECORDS: MECHANISMS OF CONSENT.

Survey records are increasingly being linked to administrative databases to enhance the survey data and increase research opportunities for data users. A necessary prerequisite to linking survey and administrative records is obtaining informed consent from respondents. Obtaining consent from all respondents is a difficult challenge and one that faces significant resistance. Consequently, data linkage consent rates vary widely from study-to-study. Several studies have found significant differences between consenters and non-consenters on socio-demographic variables, but no study has investigated the underlying mechanisms of consent from a theory-driven perspective. In this study, we describe and test several hypotheses related to respondents' willingness to consent to an earnings and benefit data linkage request based on mechanisms related to financial uncertainty, privacy concerns, resistance towards the survey interview, level of attentiveness during the interview, the respondents' preexisting relationship with the administrative data agency, and matching respondents and interviewers on observable characteristics. The results point to several implications for survey practice and suggestions for future research.

Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10-7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples (n = 5613 cases) or UK Biobank (n = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

Regional variation in the association between advance directives and end-of-life Medicare expenditures.

CONTEXT: It is unclear if advance directives (living wills) are associated with end-of-life expenditures and treatments. OBJECTIVE: To examine regional variation in the associations between treatment-limiting advance directive use, end-of-life Medicare expenditures, and use of palliative and intensive treatments. DESIGN, SETTING, AND PATIENTS: Prospectively collected survey data from the Health and Retirement Study for 3302 Medicare beneficiaries who died between 1998 and 2007 linked to Medicare claims and the National Death Index. Multivariable regression models examined associations between advance directives, end-of-life Medicare expenditures, and treatments by level of Medicare spending in the decedent's hospital referral region. MAIN OUTCOME MEASURES: Medicare expenditures, life-sustaining treatments, hospice care, and in-hospital death over the last 6 months of life. RESULTS: Advance directives specifying limits in care were associated with lower spending in hospital referral regions with high average levels of end-of-life expenditures (-$5585 per decedent; 95% CI, -$10,903 to -$267), but there was no difference in spending in hospital referral regions with low or medium levels of end-of-life expenditures. Directives were associated with lower adjusted probabilities of in-hospital death in high- and medium-spending regions (-9.8%; 95% CI, -16% to -3% in high-spending regions; -5.3%; 95% CI, -10% to -0.4% in medium-spending regions). Advance directives were associated with higher adjusted probabilities of hospice use in high- and medium-spending regions (17%; 95% CI, 11% to 23% in high-spending regions, 11%; 95% CI, 6% to 16% in medium-spending regions), but not in low-spending regions. CONCLUSION: Advance directives specifying limitations in end-of-life care were associated with significantly lower levels of Medicare spending, lower likelihood of in-hospital death, and higher use of hospice care in regions characterized by higher levels of end-of-life spending.

Sources of variability in estimates of the prevalence of Alzheimer's disease in the United States.

BACKGROUND: The prevalence of Alzheimer's disease (AD) in the United States was estimated at 2.3 million in 2002 by the Aging, Demographics, and Memory Study (ADAMS), which is almost 50% less than the estimate of 4.5 million in 2000 derived from the Chicago Health and Aging Project. METHODS: We considered how differences in diagnostic criteria may have contributed to these differences in AD prevalence. RESULTS: We identified several important differences in diagnostic criteria that may have contributed to the differing estimates of AD prevalence. Two factors were especially noteworthy. First, the Diagnostic and Statistical Manual of Mental Disorders III-R and IV criteria of functional limitation documented by an informant used in ADAMS effectively concentrated the diagnosis of dementia toward a relatively higher level of cognitive impairment. ADAMS separately identified a category of cognitive impairment not dementia and within that group there were a substantial number of cases with "prodromal" AD (a maximum of 1.95 million with upweighting). Second, a substantial proportion of dementia in ADAMS was attributed to either vascular disease (representing a maximum of 0.59 million with upweighting) or undetermined etiology (a maximum of 0.34 million), whereas most dementia, including mixed dementia, was attributed to AD in the Chicago Health and Aging Project. CONCLUSION: The diagnosis of AD in population studies is a complex process. When a diagnosis of AD excludes persons meeting criteria for vascular dementia, when not all persons with dementia are assigned an etiology, and when a diagnosis of dementia requires an informant report of functional limitations, the prevalence is substantially lower and the diagnosed cases most likely have a relatively higher level of impairment.

Reducing case ascertainment costs in U.S. population studies of Alzheimer's disease, dementia, and cognitive impairment-Part 1.

Establishing methods for ascertainment of dementia and cognitive impairment that are accurate and also cost-effective is a challenging enterprise. Large population-based studies often using administrative data sets offer relatively inexpensive and reliable estimates of severe conditions including moderate to advanced dementia that are useful for public health planning, but they can miss less severe cognitive impairment which may be the most effective point for intervention. Clinical and epidemiological cohorts, intensively assessed, provide more sensitive detection of less severe cognitive impairment but are often costly. In this article, several approaches to ascertainment are evaluated for validity, reliability, and cost. In particular, the methods of ascertainment from the Health and Retirement Study are described briefly, along with those of the Aging, Demographics, and Memory Study (ADAMS). ADAMS, a resource-intense sub-study of the Health and Retirement Study, was designed to provide diagnostic accuracy among persons with more advanced dementia. A proposal to streamline future ADAMS assessments is offered. Also considered are algorithmic and Web-based approaches to diagnosis that can reduce the expense of clinical expertise and, in some contexts, can reduce the extent of data collection. These approaches are intended for intensively assessed epidemiological cohorts where goal is valid and reliable case detection with efficient and cost-effective tools.