Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Daytime Sleepiness Is Associated with Lower Cognitive Scores: The Look AHEAD Study.

Background: Daytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may be associated with cognition in older adults. Objectives: We investigated the association between self-reported daytime sleepiness and cognitive function in the Look AHEAD clinical trial. Design: Observational follow-up of a randomized clinical trial of an intensive lifestyle intervention. Setting: Clinic. Participants: Participants (n=1,778) aged 45-76 years at baseline with type 2 diabetes and overweight or obesity. Interventions: Participants were randomized to an intensive lifestyle intervention for weight loss or a control condition of diabetes support and education. Measurements: Participants provided self-reported levels of daytime sleepiness at baseline and years 12-13. Cognitive function was assessed with a neurocognitive battery at years 12-13 and 18-20. Results: Participants who reported having frequent daytime sleepiness (often or always) performed significantly worse than others on the cognitive composite (-0.35; p-value=0.014) after controlling for covariates. When stratified by intervention arm, participants assigned to the intensive lifestyle intervention who reported often/always having daytime sleepiness performed worse on Digit Symbol Coding (-0.63; p-value=0.05) and Trail Making Part-B (-0.56; p-value=0.02) after controlling for covariates. Statistical interactions revealed associations between daytime sleepiness and the following covariates: race and ethnicity, APOE ε4 carrier status, baseline history of cardiovascular disease, and depression. Conclusions: Daytime sleepiness over ~13 years predicted poorer cognitive performance in older individuals who, by virtue of having diabetes and overweight/obesity, are at high risk for sleep disorders and cognitive impairment.

Interactions between estradiol, diabetes, and brain aging and the risk for cognitive impairment.

The Women's Health Initiative Memory Study reported that older women using conjugated equine estrogens hormone therapy (HT) with or without medroxyprogesterone acetate were at increased risk for probable dementia and smaller brain volumes. These adverse effects were greatest among women who had type 2 diabetes mellitus (T2DM) at baseline or who developed the disease during follow-up. This review summarizes existing literature from randomized trials, observational studies, and preclinical studies to provide a fundamental understanding of the effects of the interaction between T2DM and HT on cognitive and metabolic health changes in brain aging.

Sustaining eHealth engagement in a multi-year weight gain prevention intervention.

INTRODUCTION: Digital tools are widely used and effective in weight management interventions; however, usage declines over time. Strategies to promote continued engagement should be explored. We examined the effects of offering additional modes of weight reporting as well as periodic online campaigns to promote engagement, assessed by frequency of weight reporting, in a weight gain prevention study for young adults. METHODS: Using an observational design, self-reported weights obtained through digital tools were pooled across participants assigned to two interventions (n = 312). Analysis examined the effects before during and after introduction of an additional reporting modality (email) and for three time-limited refresher campaigns over 2 years. RESULTS: Adding a new modality to the three existing modes (SMS, web, and mobile web) increased weight reporting as well as the number of modalities participants used to report weights. The use of several modes of reporting was associated with more weights submitted (p < 0.01). Refresher campaigns did not increase the proportion of participants reporting; however, the number of weights submitted during the 4-week campaigns increased compared with the 4 weeks before the campaign (p's ≥ 0.45, <0.001, respectively). CONCLUSION: Using multiple digital modalities and periodic campaigns shows promise for sustaining engagement with weight reporting in a young adult population, and incorporating such strategies may mitigate typical declines in eHealth and mHealth interventions.

Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis.

Growing evidence suggests chronic low-grade inflammation (LGI) as a possible mechanism underlying the aging process. Some biological and pharmaceutical compounds may reduce systemic inflammation and potentially avert functional decline occurring with aging. The aim of the present meta-analysis was to examine the association of pre-selected interventions on two established biomarkers of inflammation, interleukin-6 (IL-6), and C-reactive protein (CRP) in middle-age and older adults with chronic LGI. We reviewed the literature on potential anti-inflammatory compounds, selecting them based on safety, tolerability, acceptability, innovation, affordability, and evidence from randomized controlled trials. Six compounds met all five inclusion criteria for our systematic review and meta-analysis: angiotensin II receptor blockers (ARBs), metformin, omega-3, probiotics, resveratrol and vitamin D. We searched in MEDLINE, PubMed and EMBASE database until January 2017. A total of 49 articles fulfilled the selection criteria. Effect size of each study and pooled effect size for each compound were measured by the standardized mean difference. I2 was computed to measure heterogeneity of effects across studies. The following compounds showed a significant small to large effect in reducing IL-6 levels: probiotics (-0.68 pg/ml), ARBs (-0.37 pg/ml) and omega-3 (-0.19 pg/ml). For CRP, a significant small to medium effect was observed with probiotics (-0.43 mg/L), ARBs (-0.2 mg/L), omega-3 (-0.17 mg/L) and metformin (-0.16 mg/L). Resveratrol and vitamin D were not associated with any significant reductions in either biomarker. These results suggest that nutritional and pharmaceutical compounds can significantly reduce established biomarkers of systemic inflammation in middle-age and older adults. The findings should be interpreted with caution, however, due to the evidence of heterogeneity across the studies.

Weight gain prevention buffers the impact of CETP rs3764261 on high density lipoprotein cholesterol in young adulthood: The Study of Novel Approaches to Weight Gain Prevention (SNAP).

BACKGROUND AND AIMS: Two weight gain prevention strategies, one targeting small changes to diet and physical activity and a second targeting large changes, significantly reduced weight gain in young adulthood. We examined whether weight gain prevention blunts genetic risk for body weight increase and/or high density lipoprotein cholesterol (HDL-C) lowering over two years. METHODS AND RESULTS: Participants were 524 male and female young adults (mean age = 28.2, SD = 4.3; mean BMI = 25.5, SD = 2.6). Obesity-related SNPs accounting for ≥ 0.04% of the variance were genotyped and combined into a genetic risk score. For HDL-C, SNPs within CETP, LIPC and FADS2 were genotyped. The obesity-related genetic risk score did not predict change in BMI independently or in interaction with treatment arm. However, consistent with the prior literature, each copy of the HDL-C risk, C, allele at CETP rs3764261 was associated with lower HDL-C at baseline. Moreover, significant interaction between SNP and treatment arm for change in HDL-C was observed (p = 0.02). In the control group, HDL-C change was dependent upon rs3764261 (p = 0.004) with C allele carriers showing a continued reduction in HDL-C. In contrast, within the two intervention groups, HDL-C increased on average with no differential effect of rs3764261 (p > 0.24). Notably, even among carriers of the CC genotype, small and large change arms were associated with increased HDL-C and the control arm a reduction (p = 0.013). CONCLUSIONS: The C allele at CETP rs3764261 is a strong risk factor for low HDL-C in young adulthood but weight gain prevention may mitigate this risk. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: clinicaltrials.gov Identifier: NCT01183689, https://clinicaltrials.gov/.

Cost of intervention delivery in a lifestyle weight loss trial in type 2 diabetes: results from the Look AHEAD clinical trial.

OBJECTIVE: The Action for Health in Diabetes (Look AHEAD) trial was a randomized controlled clinical trial to compare the effects of 10 years of intensive lifestyle intervention (ILI) with a control condition of diabetes support and education (DSE) on health outcomes in over 5,000 participants with type 2 diabetes. The ILI had significantly greater weight losses than DSE throughout the trial. The goal of this analysis is to describe the cost of delivering the intervention. METHODS: The ILI was designed to promote weight loss and increase physical activity. It involved a combination of group plus individual intervention sessions, with decreasing frequency of contact over the 10 years. The intervention incorporated a variety of strategies, including meal replacement products, to improve weight loss outcomes. The costs of intervention delivery were derived from staff surveys of effort and from records of intervention materials from the 16 US academic clinical trial sites. Costs were calculated from the payer perspective and presented in 2012 dollars. RESULTS: During the first year, when intervention delivery was most intensive, the annual cost of intervention delivery, averaged (standard deviation) across clinical sites, was $2,864.6 ($513.3) per ILI participant compared with $202.4 ($76.6) per DSE participant. As intervention intensity declined, costs decreased, such that from years 5 to 9 of the trial, the annual cost of intervention was $1,119.8 ($227.7) per ILI participant and $102.9 ($33.0) per DSE participant. Staffing accounted for the majority of costs throughout the trial, with meal replacements and materials to promote adherence accounting for smaller shares. CONCLUSIONS: The sustained weight losses produced by the Look AHEAD intervention were supported by intervention costs that were within the range of other weight loss programmes. Future work will include an evaluation of the cost-effectiveness of the ILI and will contain additional follow-up data.

Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.

Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/-/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral ß-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aß deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aß oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aß production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

Particulate Air Pollutants, Brain Structure, and Neurocognitive Disorders in Older Women.

Introduction: An increasing number of studies have suggested that exposure to particulate matter (PM) may represent a novel - and potentially amendable - environmental determinant of brain aging. The current longitudinal environmental epidemiological study addressed some important knowledge gaps in this emerging field, which combines the study of air pollution and neuroepidemiology. The investigators hypothesized that long-term PM exposure adversely influences global brain volume and brain regions (e.g., frontal lobe or hippocampus) that are critical to memory and complex cognitive processing or that are affected by neuropathological changes in dementia. It was also hypothesized that long-term PM exposure results in neurovascular damage and may increase the risk of mild cognitive impairment (MCI) and -dementia. Methods: The investigators selected a well-characterized and geographically diverse population of older women (N = 7,479; average age = 71.0 ± 3.8 years at baseline) in the Women's Health Initiative (WHI) Memory Study (WHIMS) cohort (1996-2007), which included a subcohort (n = 1,403) enrolled in the WHIMS-Magnetic Resonance Imaging (WHIMS-MRI) study (2005-2006). Residence-specific yearly exposures to PM ≤ 2.5 µm in aerodynamic diameter (PM2.5) were estimated using a Bayesian maximum entropy spatiotemporal model of annual monitoring data (1999-2007) recorded in the U.S. Environmental Protection Agency (U.S. EPA) Air Quality System (AQS). Annual exposures (1996-2005) to diesel PM (DPM) were assigned to each residential census tract in a nationwide spatiotemporal mapping, based on a generalized additive model (GAM), to conduct census tract-specific temporal interpolation of DPM on-road estimates given by the U.S. EPA National-Scale Air Toxics Assessment Program. Multiple linear regression and multicovariate-adjusted Cox models were used to examine the associations, with statistical adjustment for multiple potential confounders. Results: The investigators found that participants had smaller brain volumes, especially in the normal-appearing white matter (WM), if they lived in locations with higher levels of cumulative exposure (1999-2006) to PM 2.5 before the brain MRI scans were performed. The associations were not explained by sociodemographic factors, socioeconomic status, lifestyle factors, or other clinical characteristics. Analyses showed that the adverse effect on brain structure in the participants was driven primarily by the smaller WM volumes associated with cumulative PM2.5 exposures, which were present in the WM divisions of the association brain area (frontal, parietal, and temporal lobes) and corpus callosum. Increased DPM exposures were associated with larger ventricular volume, suggesting an overall atrophic effect on the aging brains. The participants tended to have smaller gray matter (GM) volumes if they lived in areas with the highest (i.e., fourth quartile) estimated cumulative DPM exposure in the 10 years before the brain MRI scans, compared with women in the first to third quartiles. This observed association was present in the total brain GM and in the association brain cortices. The associations with normal-appearing WM varied by DPM exposure range. For women with estimated cumulative exposure below that of the fourth quartile, increased DPM estimates were associated with smaller WM volumes. However, for women with increased cumulative DPM exposures estimates in the fourth quartile, WM volumes were larger. This pattern of association was found consistently in the association brain area; no measurable difference was found in the volume of the corpus callosum. These observed adverse effects of cumulative exposure to PM2.5 (linking exposure with smaller WM volumes) and to DPM (linking exposure in the highest quartile with smaller GM volumes) were not significantly modified by existing cardiovascular diseases, diabetes mellitus, obesity, or measured white blood cell (WBC) count. MRI measurements of the structural brain showed no differences in small-vessel ischemic diseases (SVID) in participants with varying levels of cumulative exposure to PM2.5 (1999-2006) or DPM (1996-2005), and no associations between PM exposures and SVID volumes were noted for total brain, association brain area, GM, or WM. For neurocognitive outcomes followed until 2007, the investigators found no evidence for increased risk of MCI/dementia associated with long-term PM exposures. Although exploratory secondary analyses showed different patterns of associations linking PM exposures separately with MCI and dementia, none of the -results was statistically significant. A similar lack of associations between PM exposures and MCI/dementia was found across the subgroups, with no strong indications for effect modification by cardiovascular diseases, diabetes mellitus, obesity, or WBC count. Conclusions: The investigators concluded that their study findings support the hypothesized brain-structure neurotoxicity associated with PM exposures, a result that is in line with emerging neurotoxicological data. However, the investigators found no evidence of increased risk of MCI/dementia associated with long-term PM exposures.To better test the neurovascular effect hypothesis in PM-associated neurotoxic effects on the aging brain, the investigators recommend that future studies pay greater attention to selecting optimal populations with repeated measurements of cerebrovascular damage and address the possibility of selection biases accordingly. To further investigate the long-term consequence of brain-structure neurotoxicity on pathological brain aging, future researchers should take the pathobiologically heterogeneous neurocognitive outcomes into account and design adequately powered prospective cohort studies with improved exposure estimation and valid outcome ascertainment to assess whether PM-associated neurotoxicity increases the risks of pathological brain aging, including MCI and dementia.

Cognitive function and retinal and ischemic brain changes: the Women's Health Initiative.

OBJECTIVE: To examine the association between retinopathy and cognitive decline or brain lesions and volumes in older women. METHODS: This study included 511 women aged 65 and older who were simultaneously enrolled in the Women's Health Initiative Memory Study and the Sight Examination Study. In this analysis, we examined the link between retinopathy, assessed using fundus photography (2000-2002), cognitive performance over time assessed by the modified Mini-Mental State Examination (3MSE) (1996-2007), and white matter hyperintensities and lacunar infarcts in the basal ganglia. RESULTS: Presence of retinopathy was associated with poorer 3MSE scores (mean difference = 1.01, SE: 0.43) (p = 0.019) over a 10-year follow-up period and greater ischemic volumes in the total brain (47% larger, p = 0.04) and the parietal lobe (68% larger, p = 0.01) but not with measures of regional brain atrophy. CONCLUSIONS: The correspondence we found between retinopathy and cognitive impairment, along with larger ischemic lesion volumes, strengthens existing evidence that retinopathy as a marker of small vessel disease is a risk factor for cerebrovascular disease that may influence cognitive performance and related brain changes. Retinopathy may be useful as a clinical tool if it can be shown to be an early marker related to neurologic outcomes.

Combining graph and machine learning methods to analyze differences in functional connectivity across sex.

In this work we combine machine learning methods and graph theoretical analysis to investigate gender associated differences in resting state brain network connectivity. The set of all correlations computed from the fMRI resting state data is used as input features for classification. Two ensemble learning methods are used to perform the detection of the set of discriminative edges between groups (males vs. females) of brain networks: 1) Random Forest and 2) an ensemble method based on least angle shrinkage and selection operator (lasso) regressors. Permutation testing is used not only to assess significance of classification accuracy but also to evaluate significance of feature selection. Finally, these methods are applied to data downloaded from the Connectome Project website. Our results suggest that gender differences in brain function may be related to sexually dimorphic regional connectivity between specific critical nodes via gender-discriminative edges.

The diversity and radiation of the largest monophyletic animal group on New Caledonia (Trichoptera: Ecnomidae: Agmina).

In area, New Caledonia is the smallest of the world's 25 official biodiversity hotspots, but in many taxonomic groups, the island has the highest concentration of species on earth, particularly so in the freshwater insect order Trichoptera. This study aims at applying molecular data and morphology for estimating the real species diversity of the genus Agmina on New Caledonia and investigating potential effects of ultramafic rock substrate on diversification. A dated molecular phylogeny was applied to study diversity and diversification related to geological substrate using the dispersal-extinction-cladogenesis model, diva and Bayesian ancestral character reconstruction. More than 47 species (>63%) were unknown to science. Initial radiation occurred on ultramafic substrate followed by several independent dispersal events to nonultramafic substrate. The rate of shift from ultramafic to nonultramafic substrate was significantly higher than the rate of shift in the opposite direction, indicating a possible cost associated with living on ultramafic substrate.

Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study.

OBJECTIVES: To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions. METHODS: Brain MRI scans were obtained in a subset of 1,403 women aged 71-89 years who participated in the Women's Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women's Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables. RESULTS: Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm(3) lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm(3)) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90). CONCLUSIONS: Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy.

Consent for genetics studies among clinical trial participants: findings from Action for Health in Diabetes (Look AHEAD).

BACKGROUND: Increasingly, genetic specimens are collected to expand the value of clinical trials through study of genetic effects on disease incidence, progression or response to interventions. PURPOSE: and methods We describe the experience obtaining IRB-approved DNA consent forms across the 19 institutions in the Action for Health in Diabetes (Look AHEAD), a clinical trial examining the effect of a lifestyle intervention for weight loss on the risk of serious cardiovascular events among individuals with type 2 diabetes. We document the rates participants provided consent for DNA research, identify participant characteristics associated with consent, and discuss implications for genetics research. RESULTS: IRB approval to participate was obtained from 17 of 19 institutions. The overall rate of consent was 89.6% among the 15 institutions that had completed consenting at the time of our analysis, which was higher than reported for other types of cohort studies. Consent rates were associated with factors expected to be associated with weight loss and cardiovascular disease and to affect the distribution of candidate genes. Non-consent occurred more frequently among participants grouped as African-American, Hispanic, female, more highly educated or not dyslipidemic. LIMITATIONS: The generalizabilty of results is limited by the inclusion/exclusion criteria of the trial. CONCLUSIONS: Barriers to obtaining consent to participate in genetic studies may differ from other recruitment settings. Because of the potentially complex associations between personal characteristics related to adherence, outcomes and gene distributions, differential rates of consent may introduce biases in estimates of genetic relationships.

Baseline experience with Modified Mini Mental State Exam: The Women's Health Initiative Memory Study (WHIMS).

The Modified Mini Mental State Exam (3MS) is widely used for screening global cognitive functioning, however little is known about its performance in clinical trials. We report the distribution of 3MS scores among women enrolled in the Women's Health Initiative Memory Study (WHIMS) and describe differences in these scores associated with age, education, and ethnicity. The 3MS exams were administered to 7,480 women aged 65-80 who had volunteered for and were eligible for a clinical trial on postmenopausal hormone therapy. General linear models were used to describe demographic differences among scores. Factor analysis was used to characterize the correlational structure of exam subscales.The distribution of 3MS scores at baseline was compressed in WHIMS compared to population-based data. Mean 3MS scores (overall 95.1) tended to decrease with age and increase with education, however these associations varied among ethnic groups (p< 0.0001) even after adjustment for health, physical disability and occupation attainment. Four factors accounted for 37% of the total variance. Each varied with education and ethnicity; the two most prominent factors also varied with age. Despite relatively narrow distributions in WHIMS, baseline 3MS scores retained associations with age and education. These associations varied among ethnic groups, so that care must be taken in comparing data across populations.

Estrogen replacement and brachial artery flow-mediated vasodilation in older women.

It remains unclear whether estrogen therapy (with or without progestin) improves endothelial function in older postmenopausal women with or at risk for coronary heart disease. To address this issue, we analyzed brachial artery flow-mediated vasodilation in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in subjects over 65 years of age. At the tenth annual Cardiovascular Health Study examination, 1662 women returned for follow-up. Eighteen percent (n=291) were current users of estrogen replacement, most of whom (75.9%, n=221) took unopposed estrogen. Brachial artery ultrasound examinations measuring vasodilation in response to a flow stimulus (hyperemia) were performed on 1636 women. There were no statistical differences in brachial flow-mediated vasodilator responses between users and nonusers, even after adjustment for potential confounders. Absence of an effect was most notable in women over 80 years old and in those with established cardiovascular disease. However, among women without clinical or subclinical cardiovascular disease or its risk factors, there was a significant association between hormone replacement therapy use and flow-mediated vasodilator responses (P=0.01). Among older postmenopausal women, favorable vascular effects of estrogen may be limited to those who have not yet developed atherosclerotic vascular disease. These data emphasize the importance of ongoing efforts to determine the role of hormone replacement therapy for primary prevention of cardiovascular disease.

Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter.

BACKGROUND: Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform. METHODS: We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4,040 ultrasound examinations from subjects aged 14 to 98 years. RESULTS: Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 +/- 0.10% (mean +/- standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 +/- 0.87 mm and 0.15 +/- 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P< 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2,315) had significantly larger per cent change in diameter than men (n=1,725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001). CONCLUSIONS: Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.

Group comparisons involving missing data in clinical trials: a comparison of estimates and power (size) for some simple approaches.

When using 'intent-to-treat' approaches to compare outcomes between groups in clinical trials, analysts face a decision regarding how to account for missing observations. Most model-based approaches can be summarized as a process whereby the analyst makes assumptions about the distribution of the missing data in an attempt to obtain unbiased estimates that are based on functions of the observed data. Although pointed out by Rubin as often leading to biased estimates of variances, an alternative approach that continues to appear in the applied literature is to use fixed-value imputation of means for missing observations. The purpose of this paper is to provide illustrations of how several fixed-value mean imputation schemes can be formulated in terms of general linear models that characterize the means of distributions of missing observations in terms of the means of the distributions of observed data. We show that several fixed-value imputation strategies will result in estimated intervention effects that correspond to maximum likelihood estimates obtained under analogous assumptions. If the missing data process has been correctly characterized, hypothesis tests based on variances estimated using maximum likelihood techniques asymptotically have the correct size. In contrast, hypothesis tests performed using the uncorrected variance, obtained by applying standard complete data formula to singly imputed data, can provide either conservative or anticonservative results. Surprisingly, under several non-ignorable non-response scenarios, maximum likelihood based analyses can yield equivalent hypothesis tests to those obtained when analysing only the observed data.