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1.  A general binomial regression model to estimate standardized risk differences from binary response data 
Statistics in medicine  2012;32(5):808-821.
Estimates of absolute risks and risk differences are necessary for evaluating the clinical and population impact of biomedical research findings. We have developed a linear-expit regression model (LEXPIT) to incorporate linear and nonlinear risk effects to estimate absolute risk from studies of a binary outcome. The LEXPIT is a generalization of both the binomial linear and logistic regression models. The coefficients of the LEXPIT linear terms estimate adjusted risk differences, while the exponentiated nonlinear terms estimate residual odds ratios. The LEXPIT could be particularly useful for epidemiological studies of risk association, where adjustment for multiple confounding variables is common. We present a constrained maximum likelihood estimation algorithm that ensures the feasibility of risk estimates of the LEXPIT model and describe procedures for defining the feasible region of the parameter space, judging convergence, and evaluating boundary cases. Simulations demonstrate that the methodology is computationally robust and yields feasible, consistent estimators. We applied the LEXPIT model to estimate the absolute five-year risk of cervical precancer or cancer associated with different Pap and human papillomavirus test results in 167,171 women undergoing screening at Kaiser Permanente Northern California. The LEXPIT model found an increased risk due to abnormal Pap test in HPV-negative that was not detected with logistic regression. Our R package blm provides free and easy-to-use software for fitting the LEXPIT model.
doi:10.1002/sim.5553
PMCID: PMC3982929  PMID: 22865328
Absolute risk; Binomial regression; Constrained maximization; Logistic regression; Risk difference
2.  Frailty Status and Altered Glucose-Insulin Dynamics 
Background.
We examined women in their 80s and 90s and evaluated the hypothesis that abnormalities in the dynamic response of glucose and insulin to a glucose load are associated with frailty status.
Methods.
We performed a 75 g oral glucose tolerance test in 73 community-dwelling women aged 84–95 years without known diabetes enrolled in the Women’s Health and Aging Study II. We examined the association of frailty status (nonfrail, prefrail, or frail) with oral glucose tolerance test glucose and insulin levels at 0, 30, 60, 120, and 180 minutes using multiple linear regression models.
Results.
Using American Diabetes Association criteria, only 27% of older women had normal glucose status, 48% had prediabetes, and 25% had undiagnosed diabetes. Fasting glucose, fasting insulin, homeostasis model of assessment-insulin resistance, and Matsuda index were similar by frailty status, adjusting for age and body mass index. Conversely, mean oral glucose tolerance test glucose levels were higher at 60 minutes (44.6 ± 18.1 mg/dL higher) and 120 minutes (67.1 ± 23.5 mg/dL higher) and to a lesser extent at 180 minutes (44.3 ± 22.5 mg/dL higher) in frail versus nonfrail women as was integrated glucose area after adjustment. Mean 120-minute insulin level was also higher in frail versus nonfrail women (45.7 ± 22.4 μU/mL higher). Overall, glucose and insulin responses were more exaggerated and prolonged in frail versus nonfrail or prefrail women.
Conclusions.
Our data demonstrate dysregulation in response to glucose challenge as a component of physiologic vulnerability associated with frailty in old–old women. Future studies should examine the timing of abnormal glucose–insulin dynamics with respect to the pathogenesis of frailty.
doi:10.1093/gerona/glr141
PMCID: PMC3670159  PMID: 21873592
Glucose; Insulin; Dynamics; Elderly; Frailty
3.  A regression model for risk difference estimation in population-based case–control studies clarifies gender differences in lung cancer risk of smokers and never smokers 
Background
Additive risk models are necessary for understanding the joint effects of exposures on individual and population disease risk. Yet technical challenges have limited the consideration of additive risk models in case–control studies.
Methods
Using a flexible risk regression model that allows additive and multiplicative components to estimate absolute risks and risk differences, we report a new analysis of data from the population-based case–control Environment And Genetics in Lung cancer Etiology study, conducted in Northern Italy between 2002–2005. The analysis provides estimates of the gender-specific absolute risk (cumulative risk) for non-smoking- and smoking-associated lung cancer, adjusted for demographic, occupational, and smoking history variables.
Results
In the multiple-variable lexpit regression, the adjusted 3-year absolute risk of lung cancer in never smokers was 4.6 per 100,000 persons higher in women than men. However, the absolute increase in 3-year risk of lung cancer for every 10 additional pack-years smoked was less for women than men, 13.6 versus 52.9 per 100,000 persons.
Conclusions
In a Northern Italian population, the absolute risk of lung cancer among never smokers is higher in women than men but among smokers is lower in women than men. Lexpit regression is a novel approach to additive-multiplicative risk modeling that can contribute to clearer interpretation of population-based case–control studies.
doi:10.1186/1471-2288-13-143
PMCID: PMC3840559  PMID: 24252624
Additive risk; Absolute risk; Case–control study; EAGLE; Lung cancer; Risk assessment; Sex factors; Smoking
4.  Patterns of 12-Year Change in Physical Activity Levels in Community-Dwelling Older Women: Can Modest Levels of Physical Activity Help Older Women Live Longer? 
American Journal of Epidemiology  2012;176(6):534-543.
Few studies have addressed changes in physical activity participation over time among the elderly. The authors hypothesized that there were distinct trajectories of physical activity level over time and identifiable predictors of such trajectories, as well as that the maintenance of regular physical activity, even below recommended levels, was associated with lower mortality risk. Using longitudinal data (1994–2009) from 433 initially high-functioning older women aged 70–79 years at baseline, a joint latent class and survival mixture model identified 4 activity trajectory classes: always active (16.6%), fast declining (19.2%), stable moderate (32.3%), and always sedentary (31.9%). Obesity, coronary artery disease, chronic obstructive pulmonary disease, depressive symptoms, low self-efficacy, mobility disability, and low energy were associated with sedentary behavior and/or a fast decline in activity. Women in the fast declining and always sedentary classes had hazard ratios for death of 2.34 (95% confidence interval: 1.20, 4.59) and 3.34 (95% confidence interval: 1.72, 6.47), respectively, compared with the always active class; no mortality difference was found between the stable moderate and always active groups (hazard ratio = 1.24, 95% confidence interval: 0.63, 2.47). Our findings suggest that physical activity does not have to be vigorous to be beneficial and that the gain may be the greatest among women who reported the lowest levels of activity.
doi:10.1093/aje/kws125
PMCID: PMC3530350  PMID: 22935515
aging; exercise; healthy people programs; lifestyle; motor activity; risk factors; survival; walking
5.  Resting Metabolic Rate Among Old-Old Women With and Without Frailty: Variability and Estimation of Energy Requirements 
Objectives
Resting metabolic rate (RMR) is the largest component of total energy expenditure. It has not been studied in old-old adults living in the community, though abnormalities in RMR may play a critical role in the development of the clinical syndrome of frailty. The objective was to measure RMR and examine the association of measured RMR with frailty status and compare it to expected RMR generated by a predictive equation.
Design
Physiologic sub-study conducted as a home visit within an observational cohort study.
Setting
Baltimore City and County, Maryland.
Participants
77 women age 83–93 years enrolled in the Women’s Health and Aging Study II.
Measurements
RMR with indirect calorimetry; frailty status; fat-free mass; ambient and body temperature; expected RMR via the Mifflin-St. Jeor equation.
Results
Average RMR was 1119 kcal/d (s.d.± 205; range 595–1560). Agreement between observed and expected RMR was biased and very poor (between-subject coefficient of variation 38.0%, 95%CI: 35.1–40.8). Variability of RMR was increased in frail subjects (heteroscedasticity F test P value=0.02). Both low and high RMR were associated with being frail (Odds Ratio 5.4, P value=0.04) and slower self-selected walking speed (P value<0.001) after adjustment for covariates.
Conclusion
Equations to predict RMR that are not validated in old-old adults appear to correlate poorly with measured RMR. RMR values are highly variable among old-old women, with deviations from the mean predicting clinical frailty. These exploratory findings suggest a pathway to clinical frailty through either high or low RMR.
doi:10.1111/j.1532-5415.2012.04101.x
PMCID: PMC3458581  PMID: 22985142
resting metabolic rate; frailty; older adults
6.  Circulating selenium and carboxymethyl-lysine, an advanced glycation end product, are independent predictors of anemia in older community-dwelling adults 
Objective
To assess whether selenium and carboxymethyl-lysine (CML), two biomarkers of oxidative stress, are independent predictors of anemia in older, community-dwelling adults.
Methods
Plasma selenium, CML, folate, vitamin B12, testosterone, and markers of iron status and inflammation were measured at baseline in 1,036 adults, ≥65 years, in the InCHIANTI Study, a population-based cohort study of aging in Tuscany, Italy, and examined in relationship to prevalent anemia and incident anemia over 6 years of follow-up.
Results
At enrollment, 11.6% of participants were anemic. Of 472 participants who were non-anemic at enrollment 72 (15.3%) developed anemia within 6 years of follow-up. At enrollment, plasma CML in the highest quartile (>425 ng/mL) and plasma selenium in the lowest quartile (<66.6 μg/L) predicted incident anemia (Hazards Ratio [H.R.] 1.67, 95% Confidence Interval [C.I.] 1.07–2.59, P = 0.02; H.R. 1.55, 95% C.I.1.01–2.38, P = 0.05, respectively) in a multivariate Cox proportional hazards model that adjusted for age, education, body mass index, cognition, inflammation, red cell distribution width, ferritin, vitamin B12, testosterone, and chronic diseases.
Conclusion
Elevated plasma carboxymethyl-lysine and low plasma selenium are long-term independent predictors of anemia among older community-dwelling adults. These findings support the idea that oxidative stress contributes to the development of anemia.
doi:10.1016/j.nut.2011.11.005
PMCID: PMC3377823  PMID: 22325035
advanced glycation end products; aging; anemia; carboxymethyl-lysine; oxidative stress; selenium
7.  Support of personalized medicine through risk-stratified treatment recommendations - an environmental scan of clinical practice guidelines 
BMC Medicine  2013;11:7.
Background
Risk-stratified treatment recommendations facilitate treatment decision-making that balances patient-specific risks and preferences. It is unclear if and how such recommendations are developed in clinical practice guidelines (CPGs). Our aim was to assess if and how CPGs develop risk-stratified treatment recommendations for the prevention or treatment of common chronic diseases.
Methods
We searched the United States National Guideline Clearinghouse for US, Canadian and National Institute for Health and Clinical Excellence (United Kingdom) CPGs for heart disease, stroke, cancer, chronic obstructive pulmonary disease and diabetes that make risk-stratified treatment recommendations. We included only those CPGs that made risk-stratified treatment recommendations based on risk assessment tools. Two reviewers independently identified CPGs and extracted information on recommended risk assessment tools; type of evidence about treatment benefits and harms; methods for linking risk estimates to treatment evidence and for developing treatment thresholds; and consideration of patient preferences.
Results
We identified 20 CPGs that made risk-stratified treatment recommendations out of 133 CPGs that made any type of treatment recommendations for the chronic diseases considered in this study. Of the included 20 CPGs, 16 (80%) used evidence about treatment benefits from randomized controlled trials, meta-analyses or other guidelines, and the source of evidence was unclear in the remaining four (20%) CPGs. Nine CPGs (45%) used evidence on harms from randomized controlled trials or observational studies, while 11 CPGs (55%) did not clearly refer to harms. Nine CPGs (45%) explained how risk prediction and evidence about treatments effects were linked (for example, applying estimates of relative risk reductions to absolute risks), but only one CPG (5%) assessed benefit and harm quantitatively and three CPGs (15%) explicitly reported consideration of patient preferences.
Conclusions
Only a small proportion of CPGs for chronic diseases make risk-stratified treatment recommendations with a focus on heart disease and stroke prevention, diabetes and breast cancer. For most CPGs it is unclear how risk-stratified treatment recommendations were developed. As a consequence, it is uncertain if CPGs support patients and physicians in finding an acceptable benefit- harm balance that reflects both profile-specific outcome risks and preferences.
doi:10.1186/1741-7015-11-7
PMCID: PMC3565912  PMID: 23302096
Cancer; cardiovascular disease; chronic disease; COPD; diabetes; guidelines; randomized trials; risk assessment; stroke; treatment
8.  A framework for organizing and selecting quantitative approaches for benefit-harm assessment 
Background
Several quantitative approaches for benefit-harm assessment of health care interventions exist but it is unclear how the approaches differ. Our aim was to review existing quantitative approaches for benefit-harm assessment and to develop an organizing framework that clarifies differences and aids selection of quantitative approaches for a particular benefit-harm assessment.
Methods
We performed a review of the literature to identify quantitative approaches for benefit-harm assessment. Our team, consisting of clinicians, epidemiologists, and statisticians, discussed the approaches and identified their key characteristics. We developed a framework that helps investigators select quantitative approaches for benefit-harm assessment that are appropriate for a particular decisionmaking context.
Results
Our framework for selecting quantitative approaches requires a concise definition of the treatment comparison and population of interest, identification of key benefit and harm outcomes, and determination of the need for a measure that puts all outcomes on a single scale (which we call a benefit and harm comparison metric). We identified 16 quantitative approaches for benefit-harm assessment. These approaches can be categorized into those that consider single or multiple key benefit and harm outcomes, and those that use a benefit-harm comparison metric or not. Most approaches use aggregate data and can be used in the context of single studies or systematic reviews. Although the majority of approaches provides a benefit and harm comparison metric, only four approaches provide measures of uncertainty around the benefit and harm comparison metric (such as a 95 percent confidence interval). None of the approaches considers the actual joint distribution of benefit and harm outcomes, but one approach considers competing risks when calculating profile-specific event rates. Nine approaches explicitly allow incorporating patient preferences.
Conclusion
The choice of quantitative approaches depends on the specific question and goal of the benefit-harm assessment as well as on the nature and availability of data. In some situations, investigators may identify only one appropriate approach. In situations where the question and available data justify more than one approach, investigators may want to use multiple approaches and compare the consistency of results. When more evidence on relative advantages of approaches accumulates from such comparisons, it will be possible to make more specific recommendations on the choice of approaches.
doi:10.1186/1471-2288-12-173
PMCID: PMC3572426  PMID: 23163976
9.  Elevated Serum Carboxymethyl-Lysine, an Advanced Glycation End Product, Predicts Severe Walking Disability in Older Women: The Women's Health and Aging Study I 
Journal of Aging Research  2012;2012:586385.
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of sarcopenia. Our aim was to characterize the relationship between serum carboxymethyl-lysine (CML), a major circulating AGE, and incident severe walking disability (inability to walk or walking speed <0.4 m/sec) over 30 months of followup in 394 moderately to severely disabled women, ≥65 years, living in the community in Baltimore, Maryland (the Women's Health and Aging Study I). During followup, 154 (26.4%) women developed severe walking disability, and 23 women died. Women in the highest quartile of serum CML had increased risk of developing of severe walking disability in a multivariate Cox proportional hazards model, adjusting for age and other potential confounders. Women with elevated serum CML are at an increased risk of developing severe walking disability. AGEs are a potentially modifiable risk factor. Further work is needed to establish a causal relationship between AGEs and walking disability.
doi:10.1155/2012/586385
PMCID: PMC3437635  PMID: 22973514
10.  Endogenous Secretory Receptor for Advanced Glycation End Products and Chronic Kidney Disease in the Elderly Population 
American Journal of Nephrology  2011;33(4):313-318.
Background/Aims
The relationship of circulating endogenous secretory receptor for advanced glycation end products (esRAGE) and chronic kidney disease (CKD) has not been well characterized. The aim of the study was to determine whether plasma esRAGE is associated with CKD and is predictive of developing CKD in older adults.
Methods
The relationship between plasma esRAGE and CKD (more than stage 3 of the National Kidney Foundation classification; estimated glomerular filtration rate <60 ml/min/1.73 m2) and CKD over 6 years of follow-up was examined in a cross-sectional and prospective study design in 1,016 men and women, ≥65 years, in the InCHIANTI study, a population-based cohort study of aging in Tuscany, Italy.
Results
At enrollment, 158 (15.5%) had CKD. Mean (SD) plasma esRAGE was 0.45 (0.24) ng/ml. Plasma esRAGE (ng/ml) was associated with CKD (odds ratio per 1 SD = 1.30; 95% CI 1.1–1.6; p < 0.005) in a multivariable logistic regression model, adjusting for potential confounders. Plasma esRAGE was an independent predictor of incident CKD over 6 years of follow-up (hazard ratio per 1 SD = 1.37; 95% CI 1.1–1.7; p < 0.008) in a multivariable Cox proportional hazards model, adjusting for potential confounders.
Conclusions
Elevated plasma esRAGE is independently associated with CKD and is an independent predictor of incident CKD in older community-dwelling adults.
doi:10.1159/000324846
PMCID: PMC3064940  PMID: 21389696
Advanced glycation end products; Aging; Chronic kidney disease; Endogenous secretory receptor for advanced glycation end products
11.  Relationships of Cardiac, Pulmonary, and Muscle Reserves and Frailty to Exercise Capacity in Older Women 
Background
A decline in exercise capacity (EC) is a characteristic of frailty. We hypothesized that decline is the effect of decrements in several physiological systems. We assessed whether the relationship of three main physiological systems—cardiac, pulmonary, and musculoskeletal—to EC is independent or interactive and whether their effect on EC varies with respect to frailty status.
Methods
Observational study of 547 disabled women aged 65 years and older (Women’s Health and Aging Study I) including 131 frail who participated in a test of EC. EC (seated step test), cardiac function (chronotropic index), pulmonary function (forced vital capacity, FVC), musculoskeletal function (quadriceps strength, QS), and frailty status were measured and interactive effects were modeled using linear regression and differentiation.
Results
Each physiological system had a direct relationship with EC, which was lower in frail compared with nonfrail. The relationship between FVC and EC was positive and increased with increasing QS in nonfrail subjects. The effect of QS on EC was positive and increased with increasing FVC regardless of frailty. In subjects with low QS, frailty status was associated with lower EC and this effect became stronger with increasing FVC.
Discussion
Findings suggest but do not show that frailty status modifies the effects of physiological function in several systems on EC. Approaches to understanding emergent properties such as vulnerability to illness and death and clinical efforts to prevent and treat frailty should evaluate and possibly intervene on several physiological systems to be maximally effective.
doi:10.1093/gerona/glp147
PMCID: PMC2822279  PMID: 19822621
Frailty; Exercise capacity
12.  Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment 
Background
Frailty in older adults, defined as a constellation of signs and symptoms, is associated with abnormal levels in individual physiological systems. We tested the hypothesis that it is the critical mass of physiological systems abnormal that is associated with frailty, over and above the status of each individual system, and that the relationship is nonlinear.
Methods
Using data on women aged 70–79 years from the Women’s Health and Aging Studies I and II, multiple analytic approaches assessed the cross-sectional association of frailty with eight physiological measures.
Results
Abnormality in each system (anemia, inflammation, insulin-like growth factor-1, dehydroepiandrosterone-sulfate, hemoglobin A1c, micronutrients, adiposity, and fine motor speed) was significantly associated with frailty status. However, adjusting for the level of each system measure, the mean number of systems impaired significantly and nonlinearly predicted frailty. Those with three or more systems impaired were most likely to be frail, with odds of frailty increasing with number of systems at abnormal level, from odds ratios (ORs) of 4.8 to 11 to 26 for those with one to two, three to four, and five or more systems abnormal (p < .05 for all). Finally, two subgroups were identified, one with isolated or no systems abnormal and a second (in 30%) with multiple systems abnormal. The latter group was independently associated with being frail (OR = 2.6, p < .05), adjusting for confounders and chronic diseases and then controlling for individual systems.
Conclusions
Overall, these findings indicate that the likelihood of frailty increases nonlinearly in relationship to the number of physiological systems abnormal, and the number of abnormal systems is more predictive than the individual abnormal system. These findings support theories that aggregate loss of complexity, with aging, in physiological systems is an important cause of frailty. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes. It further suggests that replacement of any one deficient system may not be sufficient to prevent or ameliorate frailty.
doi:10.1093/gerona/glp076
PMCID: PMC2737590  PMID: 19567825
Frailty etiology; Aging
13.  Frailty and Impaired Cardiac Autonomic Control: New Insights From Principal Components Aggregation of Traditional Heart Rate Variability Indices 
Background
Age-related deterioration in homeostatic regulatory mechanisms leads to decreased complexity in their output. For example, the degradation of cardiac autonomic control results in loss of complexity in the heart rate signal. Frailty is a state of critically impaired homeostasis that results in heightened vulnerability to stressors. We propose a new measure of heart rate variability (HRV) to capture the impairment in cardiac autonomic control associated with frailty.
Methods
Traditional time and frequency domain indices of HRV were obtained from 2-hour ambulatory electrocardiograms (ECGs) of 276 women (65–101 years old) in the Women's Health and Aging Study-I. Principal components analysis was conducted on the correlation matrix of HRV indices. Frailty was defined using a validated instrument. Regression models were used to evaluate associations of HRV measures with age, frailty, and 5-year mortality.
Results
The first two principal components (PCs), PC1 and PC2, explained 90% of the variance in HRV indices. PC1 is the mean of log-transformed HRV indices. PC2 is a linear combination of log-transformed indices, with positive weights for very low frequency (VLF), low frequency (LF), and standard deviation of N-N intervals (SDNN), and negative weights for high frequency (HF), root-mean-squared differences of successive N-N intervals (RMSSD), and proportion of all N-N intervals that are larger than 50 ms (pNN50). Decreases in SDNN, VLF, LF, and LF/HF were associated with an increased risk of frailty. PC2 was more strongly associated with age (β = −.23, p < .001) and frailty (β = −.73, p < 10−5) than were the individual HRV indices and LF/HF. PC2 was also the best predictor of 5-year mortality (β = −.60, p < 10−6).
Conclusions
Cardiac autonomic control, as reflected by HRV, is impaired in frailty. A new measure derived from PC aggregation of traditional HRV indices provides a compact summary of this impairment.
doi:10.1093/gerona/glp013
PMCID: PMC2679422  PMID: 19223607
Frailty; Mortality; Homeostatic impairment; Frequency domain indices; Time-domain indices; Principal components analysis
14.  Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women 
Objective
To characterize the relationship between advanced glycation end products (AGEs) and circulating receptors for AGEs (RAGE) with cardiovascular disease mortality.
Methods
The relationships between serum AGEs, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, ≥65 years, in Baltimore, Maryland.
Results
During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGEs was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [H.R.] for highest versus lower three quartiles 1.94, 95% Confidence Interval [C.I.] 1.08-3.48, P = 0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (H.R. per 1 Standard Deviation [S.D.] 1.27, 95% C.I. 0.98-1.65, P = 0.07; H.R. 1.28, 95% C.I. 1.02-1.63, P = 0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (H.R. for highest versus lower three quartiles, 2.29, 95% C.I. 1.21-4.34, P = 0.01; H.R. per 1 S.D., 1.24, 95% C.I. 0.92-1.65, P = 0.16; H.R. per 1 S.D. 1.45, 95% C.I. 1.08-1.93, P = 0.01), after adjusting for the same covariates.
Conclusions
High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
PMCID: PMC2684987  PMID: 19448391
advanced glycation end products; aging; atherosclerosis; cardiovascular disease; mortality
15.  Physiological Complexity Underlying Heart Rate Dynamics and Frailty Status in Community-Dwelling Older Women 
OBJECTIVES
To assess whether less physiological complexity underlying regulation of heart rate dynamics, as indicated by lower approximate entropy for heart rate (ApEnHR), is associated with frailty. For supporting validity, relationships between frailty and traditional linear indices of heart rate variability (HRV) were also assessed.
DESIGN
Cross-sectional.
SETTING
Women’s Health and Aging Study I, a community-based observational study, 1992 to 1995.
PARTICIPANTS
Subset of 389 community-dwelling women aged years and older with moderate to severe disability with ApEnHR data (convenience sampling).
MEASUREMENTS
Electrocardiographic Holter recordings obtained over 2- to 3-hour periods were processed for ApEnHR and HRV measures. ApEnHR is a nonlinear statistic that quantifies the regularity of heart rate fluctuations over time. Lower ApEnHR is characteristic of heart rate time series containing a high proportion of repetitive patterns. Frailty was defined according to validated phenotype criteria.
RESULTS
Median ApEnHR was lower in frail than in nonfrail subjects (P = .02). Lower ApEnHR (top quartile) was associated with lower likelihood of frailty than higher ApEnHR (bottom three quartiles) (odds ratio = 0.47, 95% confidence interval = 0.26–0.86), even after adjustment for major confounders. Frailty was consistently associated with lower HRV as assessed using time- and frequency-domain indices.
CONCLUSION
This study supports the notion that less physiological complexity marks frailty and provides an empirical basis to the concept of frailty as a syndrome of homeostatic impairment. Future research will determine whether noninvasive measures of physiological complexity underlying heart rate dynamics might be useful for screening and monitoring of clinical vulnerability in older adults.
doi:10.1111/j.1532-5415.2008.01858.x
PMCID: PMC2848445  PMID: 19166446
frailty; approximate entropy; heart rate variability; elderly; physiological complexity
16.  Circulating Oxidized Low-Density Lipoproteins are Associated with Overweight, Obesity, and Low Serum Carotenoids in Older Community-Dwelling Women 
Objective
The objective of this study was to determine whether total serum carotenoids, alpha-tocopherol, selenium, and obesity were independently associated with oxidized low-density lipoproteins (ox-LDL) in moderately to severe disabled older women living in the community.
Methods
Serum ox-LDL, carotenoids, alpha-tocopherol, and selenium were measured in a population-based sample of 543 moderately to severely disabled women, aged 65 and older, in the Women’s Health and Aging Study I in Baltimore, Maryland.
Results
Total serum carotenoids, smoking, overweight (BMI 25-29.9 kg/m2), and obesity (BMI≥30 mg/kg2) were significantly associated with ox-LDL/LDL-cholesterol ratio after adjusting for age, C-reactive protein, and chronic diseases. Alpha-tocopherol and selenium were not significantly associated with ox-LDL/LDL-cholesterol ratio.
Conclusions
Older women who are overweight or obese or who have low total serum carotenoids are more likely to have higher lipoprotein oxidation. Weight reduction in overweight/obese women and increased intake of carotenoid-rich foods may potentially reduce lipoprotein oxidation.
doi:10.1016/j.nut.2008.04.006
PMCID: PMC2656364  PMID: 18585897
body mass index; carotenoids; low-density lipoproteins; obesity; oxidative stress
17.  Oxidative protein damage is associated with poor grip strength among older women living in the community 
Grip strength, an indicator of muscle strength, has been shown to be a predictor of poor outcomes among older adults. Protein carbonylation, an indicator of oxidative damage to proteins, leads to cellular dysfunction and a decline in tissue function. Oxidative stress has been implicated in the pathogenesis of sarcopenia. The objective was to determine whether serum protein carbonyl concentrations are associated with grip strength in older women living in the community. A cross-sectional study was conducted in 672 women, aged 65 and older, from the Women's Health and Aging Study (WHAS) I, the one-third most disabled women residing in the community in Baltimore, MD. Protein carbonyl and grip strength were measured in each patient. In a multivariate analysis adjusting for age, race, body mass index, and Mini-Mental Status Examination score, protein carbonyls (nmol/mg) were associated with grip strength (β = −6.77, P < 0.01). The statistical association was unchanged after the analysis adjusted for hypertension, congestive heart failure, and depression. Ordered logistic regression models adjusted for the above factors showed that protein carbonyls are associated with increased odds of being in the lower quartiles of grip strength (odds ratio 8.74, 95% confidence interval 1.06–71.89, P = 0.043). These results suggest oxidative protein damage is independently associated with low grip strength among older women living in the community. Increased oxidative stress may be contributing to loss of muscle strength in older adults.
doi:10.1152/japplphysiol.00133.2007
PMCID: PMC2646087  PMID: 17379753
aging; sarcopenia; interleukin-6; oxidative stress; protein carbonyls
18.  Low serum carotenoids and development of severe walking disability among older women living in the community: the Women’s Health and Aging Study I 
Age and ageing  2006;36(1):62-67.
Objective
to determine whether low serum carotenoid levels, an indicator of low intake of fruits and vegetables, are associated with the progression of disability in older women.
Design
longitudinal analysis in a population-based cohort.
Setting
moderately–severely disabled women, ≥65 years, living in the community in Baltimore, Maryland (the Women’s Health and Aging Study I).
Participants
554 women without severe walking disability (inability to walk or walking speed <0.4 m/s) at baseline.
Main outcome measure
incidence of severe walking disability assessed every 6 months over 3 years.
Results
155 women (27.9%) developed severe walking disability during follow-up. Rates of development of severe walking disability per 100 person-years among women in the lowest and in the three upper quartiles of total carotenoids were, respectively, 13.8 versus 10.9 (P = 0.0017). Adjusting for confounders, women in the lowest quartile of total carotenoids were more likely to develop severe walking disability (hazards ratio 1.57, 95% confidence interval 1.24–2.00, P = 0.0002) compared with women in the three upper quartiles.
Conclusion
low serum carotenoid levels, an indicator of low intake of fruits and vegetables, are independent predictors of the progression towards severe walking disability among older women living in the community.
doi:10.1093/ageing/afl122
PMCID: PMC2645669  PMID: 17114201
ageing; carotenoids; disability; risk factors; women; elderly
19.  Oxidative Stress Is Associated with Greater Mortality in Older Women Living in the Community 
Objectives
To determine whether oxidative stress, as implied by oxidative damage to proteins, is associated with greater mortality in older women living in the community.
Design
Longitudinal.
Setting
Women's Health and Aging Study I, Baltimore, Maryland.
Participants
Seven hundred forty-six moderately to severely disabled women, aged 65 and older, with baseline measures of serum protein carbonyls.
Measurements
Serum protein carbonyls, which consist of chemically stable aldehyde and ketone groups produced on protein side chains when they are oxidized, were measured using enzyme-linked immunosorbent assay. Multivariate logistic regression was used to adjust for potential confounders.
Results
During 5 years of follow-up, 202 (27.1%) participants died. Geometric mean serum protein carbonyls were 0.091 nmol/mg in women who died and 0.083 nmol/mg in those who survived (P = .02). Loge protein carbonyls (nmol/mg) were associated with greater risk of mortality (hazards ratio = 1.34, 95% confidence interval = 1.01–1.79, P = .04) in a multivariate Cox proportional hazards model adjusting for age, current smoking, and body mass index.
Conclusion
Greater oxidative stress, as indicated by elevated serum protein carbonyl concentrations, was associated with greater risk of death in older women living in the community who were moderately to severely disabled. Prevention of oxidative stress may reduce the risk of mortality.
doi:10.1111/j.1532-5415.2007.01308.x
PMCID: PMC2645668  PMID: 17767685
aging; mortality; oxidative stress; protein carbonyls; women
20.  Oxidative Protein Damage Is Associated With Elevated Serum Interleukin-6 Levels Among Older Moderately to Severely Disabled Women Living in the Community 
Background
Elevated interleukin (IL)-6 is associated with adverse outcomes. Our objective was to determine whether serum protein carbonyls, an indicator of oxidative protein damage and oxidative stress, were associated with IL-6.
Methods
Serum protein carbonyls and IL-6 were measured in 739 women, age ≥65 years, in the Women’s Health and Aging Study I.
Results
Geometric mean of protein carbonyls was 0.082 nmol/mg. After adjusting for age and smoking status, loge serum protein carbonyls were associated with loge IL-6 (β =0.143, standard error [SE] =0.048, p =.003) in linear regression analyses and with elevated IL-6 (≥2.5 pg/mL) (odds ratio =1.38, 95% confidence interval, 1.02–1.86, p =.037) in logistic regression analyses.
Conclusion
Oxidative damage to proteins is independently associated with serum IL-6 among older women living in the community. Increased oxidative stress may be a factor involved in the pathogenesis of the proinflammatory state that occurs in older adults.
PMCID: PMC2645655  PMID: 18314454
Inflammation; Interleukin-6; Oxidative stress; Protein carbonyls
21.  Low Micronutrient Levels as a Predictor of Incident Disability in Older Women 
Archives of internal medicine  2006;166(21):2335-2340.
Background
The role of nutritional status in the disablement process is still unclear. The objective of this study was to assess whether low concentrations of nutrients predict the development and course of disability.
Methods
Longitudinal study including community-dwelling women 65 years or older enrolled in the Women’s Health and Aging Study I. In total, 643 women were assessed prospectively at 6-month intervals from 1992 to 1995.
Results
Incidence rates of disability in activities of daily living (ADLs) during 3 years of follow-up. Incidence rates in the lowest quartile of each selected nutrient were compared with those in the upper quartiles. The hazard ratios were estimated from Cox models adjusted for potential confounders. Women in the lowest quartile of serum concentrations of vitamin B6 (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.03–1.67), vitamin B12 (HR, 1.40; 95% CI, 1.12–1.74), and selenium (HR, 1.38; 95% CI, 1.12–1.71) had significantly higher risk of disability in ADLs during 3 years of follow-up compared with women in the upper 3 quartiles.
Conclusions
Low serum concentrations of vitamins B6 and B12 and selenium predict subsequent disability in ADLs in older women living in the community. Nutritional status is one of the key factors to be considered in the development of strategies aimed at preventing or delaying the disablement process.
doi:10.1001/archinte.166.21.2335
PMCID: PMC2645646  PMID: 17130386
22.  Low serum selenium concentrations are associated with poor grip strength among older women living in the community 
BioFactors (Oxford, England)  2007;29(1):37-44.
Aging is associated with a loss of muscle strength, and, in turn, loss of muscle strength has been associated with increased risk of frailty, disability and mortality. The factors that contribute to loss of muscle strength with aging have not been well characterized. Selenium is important in normal muscle function because of its role in selenoenzymes that protect muscle against oxidative damage. We hypothesized that low serum selenium concentrations were associated with poor grip strength. We examined the association between serum selenium and hand grip strength among 676 moderately to severely disabled community-dwelling women in the Women’s Health and Aging Study I in Baltimore, Maryland. After adjusting for age, race, body mass index, Mini-Mental Status Examination score, current smoking, hypertension, congestive heart failure and depression, serum selenium was associated with grip strength (P = 0.04). This study supports the idea that selenium is important to muscle strength in older women.
PMCID: PMC2645637  PMID: 17611292
Aging; muscle; sarcopenia; selenium; strength; women
23.  Oxidative stress and severe walking disability among older women 
The American journal of medicine  2007;120(12):1084-1089.
Background
Oxidative stress has been implicated in sarcopenia and the loss of muscle strength with aging, but the relationship between oxidative stress and decline in muscle strength and physical performance has not been well characterized. Serum protein carbonyls are markers of oxidative damage to proteins and are caused by oxidative stress.
Methods
Serum protein carbonyls were measured at baseline and compared with a decline in walking speed and development of severe walking disability (inability to walk or walking speed <0.4 m/sec) over 36 months of follow-up in 545 moderately-severely disabled women, ≥65 years, living in the community in Baltimore, Maryland (the Women’s Health and Aging Study I).
Results
After adjusting for age, body mass index, smoking, and chronic diseases, loge protein carbonyls (nmol/mg) were associated with a decline in walking speed over 36 months (P = 0.002). During follow-up, 154 women (28.2%) developed severe walking disability. After adjusting for the same potential confounders, loge protein carbonyls were associated with incident severe walking disability (Hazards Ratio 1.42, 95% C.I. 1.02 – 1.98, P = 0.037).
Conclusion
High oxidative stress, as indicated by oxidative damage to proteins, is an independent predictor of decline in walking speed and progression to severe walking disability among older women living in the community.
doi:10.1016/j.amjmed.2007.07.028
PMCID: PMC2423489  PMID: 18060930
aging; disability; oxidative stress; protein carbonyls; walking
24.  Association Between Reduced Heart Rate Variability and Cognitive Impairment in Older Disabled Women in the Community: Women’s Health and Aging Study I 
OBJECTIVES
To examine the independent association between heart rate variability (HRV), a marker of cardiac autonomic function, and cognitive impairment.
DESIGN
Cross-sectional analysis of baseline data from Women’s Health and Aging Study I.
SETTING
Urban community in Baltimore, Maryland.
PARTICIPANTS
A subset of 311 physically disabled, community-dwelling women aged 65 and older whose HRV data were obtained.
MEASUREMENTS
Reduced HRV was defined as the lowest quartile of each of several HRV measures exploring time and frequency domains and compared with the remaining three quartiles. Cognitive impairment was defined as a Mini-Mental State Examination score less than 24. Multiple logistic regression was used to model the independent relationship between reduced HRV and prevalent cognitive impairment.
RESULTS
The age-, education-, and race-adjusted prevalence of cognitive impairment was higher in those with reduced HRV than in those with nonreduced HRV. After adjusting for relevant demographic and clinical characteristics, participants with reduced HRV were significantly more likely than those with nonreduced HRV to have cognitive impairment; these findings were consistent across different HRV indices. In particular, reduced high-frequency power, indicative of decreased parasympathetic activity, was associated with 6.7 times greater odds of cognitive impairment (95% confidence interval = 2.27–20.0).
CONCLUSION
Cardiac autonomic dysfunction, particularly decreased parasympathetic activity, was independently associated with cognitive impairment in older disabled women in the community. This finding may improve understanding of the pathophysiological basis of cognitive impairment. The potential role of HRV as a cause or consequence of cognitive impairment needs to be elucidated in future studies.
doi:10.1111/j.1532-5415.2006.00940.x
PMCID: PMC2276586  PMID: 17087704
heart rate variability; cognition; autonomic nervous system

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