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PubMed2006

Frailty of older age: the role of the endocrine--immune interaction.

The so-called demographic transition has changed the age structure of the population worldwide, with profound effects on societal organization. The growing number and percentage of old and very old people has compelled the scientific community to focus on age related diseases and peculiar consequences of aging itself such as disability and frailty. Understanding the pathophysiology of frailty, a syndrome characterized by a reduced functional reserve and impaired adaptive capacity that results from cumulative declines of multiple subsystems, and causes increased vulnerability to adverse outcomes, is a major topic in aging research. Aging processes induce multiple changes in the hormones network (menopause, andropause, somatopause and adrenopause), in the immune system, and can modulate their efficiency and effectiveness in determining a response to stressors. These triggering events can unmask frailty in older people. Starting from these assumptions, we analyzed the relationship of the endocrine and immune networks in aging and in the different domains that are characteristically associated with the frailty syndrome, such as disability and sarcopenia, as well as in diseases related to aging such as Alzheimer's dementia and Congestive Heart Failure.

Aged↗

PubMed2006

The effect of ignoring individual heterogeneity in Weibull log-normal sire frailty models.

The objective of this study was, by means of simulation, to quantify the effect of ignoring individual heterogeneity in Weibull sire frailty models on parameter estimates and to address the consequences for genetic inferences. Three simulation studies were evaluated, which included 3 levels of individual heterogeneity combined with 4 levels of censoring (0, 25, 50, or 75%). Data were simulated according to balanced half-sib designs using Weibull log-normal animal frailty models with a normally distributed residual effect on the log-frailty scale. The 12 data sets were analyzed with 2 models: the sire model, equivalent to the animal model used to generate the data (complete sire model), and a corresponding model in which individual heterogeneity in log-frailty was neglected (incomplete sire model). Parameter estimates were obtained from a Bayesian analysis using Gibbs sampling, and also from the software Survival Kit for the incomplete sire model. For the incomplete sire model, the Monte Carlo and Survival Kit parameter estimates were similar. This study established that when unobserved individual heterogeneity was ignored, the parameter estimates that included sire effects were biased toward zero by an amount that depended in magnitude on the level of censoring and the size of the ignored individual heterogeneity. Despite the biased parameter estimates, the ranking of sires, measured by the rank correlations between true and estimated sire effects, was unaffected. In comparison, parameter estimates obtained using complete sire models were consistent with the true values used to simulate the data. Thus, in this study, several issues of concern were demonstrated for the incomplete sire model.

Animals↗

PubMed2000

The use of frailty models in genetic studies: application to the relationship between end-stage renal failure and mutation type in Alport syndrome. European Community Alport Syndrome Concerted Action Group (ECASCA).

BACKGROUND: Alport syndrome (AS) is a severe hereditary disease usually transmitted as an X dominant trait and involving a mutation of the COL4A5 gene. It leads to end-stage renal failure (ESRF), but this progression is heterogeneous. Mutations of the COL4A5 gene have been characterised in numerous families using molecular biology. Our objective was to evaluate the interfamilial heterogeneity of the disease and to study relationships between mutation types and progression to ESRF in the European Community Alport Syndrome Concerted Action group (ECASCA) registry database. METHODS: We used the frailty model framework. Frailty models have been developed to analyse censored data with non-independent observations. Random effects are introduced in a Cox proportional regression model to take into account the intracluster correlations. In this study, ESRF is considered a censored event and the intrafamilial correlations are taken into account in the frailty models. RESULTS: These approaches allow us to demonstrate the existence of an interfamilial heterogeneity; the role of the mutation type explains the interfamilial variability. In particular, the results suggest that some mutation types are associated with a higher risk of ESRF for males. CONCLUSIONS: This study shows the importance of characterising the mutation at the molecular level in genetic studies, to understand the relationship between genotype and phenotype. The frailty models constitute an attractive approach in this context, when the phenotype is characterised by a censored end-point.

Alleles↗

PubMedDate not supplied

Denture use, malnutrition, frailty, and mortality among older women living in the community.

BACKGROUND: The relationships between denture use, malnutrition, frailty, and mortality in older women have not been well characterized. OBJECTIVE: To determine whether women who use dentures and have difficulty chewing or swallowing are at higher risk of malnutrition, frailty, and mortality. DESIGN: Cross-sectional and longitudinal study of 826 women, aged 70-79, from the Women's Health and Aging Studies, two population-based longitudinal studies of community-dwelling women in Baltimore, Maryland. At enrollment, data on frailty and self-reported denture use and difficulty chewing or swallowing that limited the ability to eat was collected, and plasma vitamins A, D, E, B6, and B12, carotenoids, folate, and albumin were measured. RESULTS: 63.5% of women reported using dentures, of whom 11.6% reported difficulty chewing or swallowing food. Denture users with and without difficulty chewing or swallowing and those not using dentures had, respectively, geometric mean (95% Confidence Interval [C.I.]) total plasma carotenoid concentrations of 1.481 (1.302, 1.684), 1.616 (1.535, 1.700), and 1.840 (1.728, 1.958) micromol/L, respectively (P < 0.0001), and 25- hydroxyvitamin D of 50.90 (44.25, 58.55), 47.46 (45.15, 50.40), and 54.0 (50.9, 56.8) nmol/L (P < 0.0001). The proportion using dentures among non-frail, pre-frail, and frail women was 58%, 66%, and 73%, respectively (P = 0.018). Women who used dentures and reported difficulty chewing or swallowing had lower five-year survival (H.R. 1.43, 95% C.I. 1.05-1.97), after adjusting for potential confounders. CONCLUSIONS: Older women living in the community who use dentures and have difficulty chewing or swallowing have a higher risk of malnutrition, frailty, and mortality.

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PubMed1990

The biodemography of variation in human frailty.

A population is composed of individuals who are heterogeneous in their susceptibility to death and disease. This heterogeneity is reflected in the age-specific incidence or mortality (hazard) function. This variation has typically been hidden--that is, not measured directly--and has generally been modeled in a purely empirical statistical way, because there is no theory in demography for the distribution of frailty. A substantial fraction of variation in frailty, however, has an underlying genetic basis, for which there is a formal theory. This theory, based on evolutionary biology and on the nature of mendelian transmission, provides prior constraints on the distribution of variation in the population as well as providing methods for identifying genes involved in many important diseases. The accumulating effects of environmental exposures with age are another major component of variation in frailty. In some important instances, this variation and its effect on the age-specific hazard function can also be understood in terms of cause-specific biological processes. These biological considerations may enable demographers to model frailty, and thus mortality, in a better way.

Disease Susceptibility↗

PubMed2006

Effect of weight loss and exercise on frailty in obese older adults.

BACKGROUND: Obesity exacerbates the age-related decline in physical function and causes frailty in older persons. However, appropriate treatment for obese older persons is unknown. We evaluated the effects of weight loss and exercise therapy on physical function and body composition in obese older persons. METHODS: We screened 40 obese older volunteers and eventually randomized 27 frail obese older volunteers to treatment or control groups. Treatment consisted of 6 months of weekly behavioral therapy for weight loss in conjunction with exercise training 3 times per week. Physical function was evaluated with measurements of frailty (Physical Performance Test, peak oxygen consumption, and Functional Status Questionnaire); strength, gait, and balance tests; body composition with dual-energy x-ray absorptiometry; and quality of life using the Medical Outcomes Survey 36-Item Short-Form Health Survey. Results are reported as mean +/- SD. RESULTS: Two subjects in the treatment group did not comply with the intervention, and 1 subject in the control group withdrew. Analyses included all 27 subjects originally randomized to the treatment and control groups. The treatment group lost 8.4% +/- 5.6% of body weight, whereas weight did not change in the control group (+0.5% +/- 2.8%; P<.001). Compared with the control group, fat mass decreased (-6.6 +/- 3.4 vs +1.7 +/- 4.1 kg; P<.001), without a change in fat-free mass (-1.2 +/- 2.1 vs -1.0 +/- 3.5 kg; P = .75) in the treatment group. The Physical Performance Test score (2.6 +/- 2.5 vs 0.1 +/- 1.0; P = .001), peak oxygen consumption (1.7 +/- 1.6 vs 0.3 +/- 1.1 mL/min per kilogram; P = .02), and Functional Status Questionnaire score (2.9 +/- 3.7 vs -0.2 +/- 3.9; P = .02) improved in treated subjects compared with control subjects. Treatment also improved strength, walking speed, obstacle course, 1-leg limb stance time, and health survey physical subscale scores (all P<.05). CONCLUSION: These findings suggest that weight loss and exercise can ameliorate frailty in obese older adults. Trial Registration clinicaltrials.gov Identifier: NCT00146133.

Activities of Daily Living↗

PubMed1999

Assessing heterogeneity and correlation of paired failure times with the bivariate frailty model.

We consider bivariate survival times for heterogeneous populations, where heterogeneity induces deviations in an individual's risk of an event as well as associations between survival times. The heterogeneity is characterized by a bivariate frailty model. We measure the heterogeneity effects through deviations associated with hazard functions and an association function defined through the conditional hazard functions: the cross-ratio function proposed by Oakes. We show how the deviation and association measures are determined by the frailty distribution. A Gibbs sampling method is developed for Bayesian inferences on regression coefficients, frailty parameters and the heterogeneity measures. The method is applied to a mental health care data set.

Algorithms↗

PubMed1995

Genetic analysis of durations: correlated frailty model applied to survival of Danish twins.

Population studies of changes in human morbidity and mortality require models which take into account the influence of genetic and environmental factors on life-related durations, such as age at onset of the disease or disability, age at death, etc. In this paper we show how a bivariate survival model based on the concept of correlated individual frailty can be used for the genetic analysis of durations. Six genetic models of frailty are considered and applied to Danish twin survival data. The results of statistical analysis allow us to conclude that at least 50% of variability in individual frailty is determined by environmental factors. The approach suggests a method of estimation of the lower bound for the biological limit of human longevity. Directions for further research are discussed.

Adult↗

PubMed2007

A correlated frailty model with long-term survivors for estimating the heritability of breast cancer.

The aim of this study is to investigate the role of genetics and environment in susceptibility to breast cancer (frailty). An interdisciplinary approach was adopted, combining a correlated frailty-mixture model with genetic equations, allowing for decomposition of the frailty variance into genetic and environmental components. In addition, the possibility that a fraction of the population under study is 'immune' to the disease is evaluated, and changes in heritability estimates introducing a fraction of non-susceptible individuals are determined. The methodology is applied to breast cancer data from the Swedish Twin Registry, including information about all female monozygotic and dizygotic twin pairs born in Sweden between 1886 and 1967. The inferential problem is solved in a Bayesian framework and the numerical work is carried out using Markov chain Monte Carlo (MCMC) methods.

Breast Neoplasms↗

PubMed1993

A bivariate survival model with modified gamma frailty for assessing the impact of interventions.

Bivariate survival analysis models that incorporate random effects or 'frailty' provide a useful framework for determining the effectiveness of interventions. These models are based on the notion that two paired survival times are correlated because they share a common unobserved value of a random variate from a frailty distribution. In some applications, however, investigators may have some information that characterizes pairs and thus provides information about their frailty. Alternatively, there may be an interest in assessing whether the correlation within certain types of pairs is different from the correlation within other types of pairs. In this paper, we present a method to incorporate 'pair-wise' covariate information into the dependence parameter of the bivariate survival function. We provide an example using data from the Framingham Heart Study to investigate the times until the occurrence of two events within an individual: the first detection of hypertension and the first cardiovascular disease event. We model the dependence between these two events as a function of the age of the individual at the time of enrollment into the Framingham Study.

Adult↗

PubMed1995

A comparison of frailty models for multivariate survival data.

This paper reviews some of the main approaches to the analysis of multivariate censored survival data. Such data typically have correlated failure times. The correlation can be a consequence of the observational design, for example with clustered sampling and matching, or it can be a focus of interest as in genetic studies, longitudinal studies of recurrent events and other studies involving multiple measurements. We assume that the correlation between the failure or survival times can be accounted for by fixed or random frailty effects. We then compare the performance of conditional and mixture likelihood approaches to estimating models with these frailty effects in censored bivariate survival data. We find that the mixture methods are surprisingly robust to misspecification of the frailty distribution. The paper also contains an illustrative example on the times to onset of chest pain brought on by three endurance exercise tests during a drug treatment trial of heart patients.

Angina Pectoris↗

PubMed2004

Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty.

BACKGROUND AND AIMS: The geriatric syndrome of frailty has been conceptualized as a loss of physiologic reserve associated with endocrine dysregulation and immune dysfunction. Our prior studies suggest that the frailty syndrome is associated with elevated serum IL-6 levels. In the present study, our aim is to evaluate the possible role of endocrine dysregulation and its relationship with serum IL-6 in the pathogenesis of this syndrome. METHODS: Using a recently validated screening algorithm for frailty, we identified 18 frail and 33 non-frail community-dwelling older adults for inclusion in this study. Serum levels of insulin-like growth factor-I (IGF-I), DHEA-S, and IL-6 were measured by immunoassays. The inter-relationships among serum levels of IL-6, DHEA-S, and IGF-I were determined by linear regression analysis. RESULTS: Age-adjusted serum levels of IGF-I (88+/-49 vs 122+/-47 [ng/mL], p<0.023) and DHEA-S (0.30+/-0.21 vs 0.53+/-0.25 [microg/mL], p=0.016) were significantly lower in frail vs non-frail individuals, respectively. There was a trend for IL-6 to be inversely correlated with IGF-I in the frail (r=-0.42; p=0.082) but not the non-frail group (r=0.12, p=0.521). CONCLUSIONS: Frail subjects have lower levels of serum IGF-I and DHEA-S and higher levels of IL-6 than do non-frail, age-matched individuals. The trend toward an inverse correlation between IGF-I and IL-6 in the frail, but not the non-frail group, suggests potential interaction between endocrine and immune/cytokine dysregulation that requires further study in larger cohorts.

Aged↗

PubMed2004

Genetic influences on CHD-death and the impact of known risk factors: comparison of two frailty models.

The importance of some recognized risk factors on genetic influences for coronary heart disease (CHD) needs further clarification. The aim of the present study was therefore to study the impact of known risk factors on genetic influences for CHD-death. Both twin (correlated gamma-frailty) and non-twin models (univariate gamma-frailty) were utilized and compared regarding their suitability for genetic analyses. The study population consisted of twins born in Sweden between 1886 and 1925. As expected, our findings indicate that genetic influences are important for CHD-death. Inclusion of risk factors in the twin-model increased heritability estimates, primarily due to a substantial reduction in non-shared environmental variances. The genetic influences for CHD-death are only marginally mediated through the risk factors among males, but more so among females. Although the outcome phenotype used in the present study is not behavioral, the analyses demonstrate the potential of frailty models for quantitative genetic analyses of categorical phenotypes.

Body Mass Index↗

PubMed2005

Graphical tests for the assumption of gamma and inverse Gaussian frailty distributions.

The common choices of frailty distribution in lifetime data models include the Gamma and Inverse Gaussian distributions. We present diagnostic plots for these distributions when frailty operates in a proportional hazards framework. Firstly, we present plots based on the form of the unconditional survival function when the baseline hazard is assumed to be Weibull. Secondly, we base a plot on a closure property that applies for any baseline hazard, namely, that the frailty distribution among survivors at time t has the same form as the original distribution, with the same shape parameter but different scale parameter. We estimate the shape parameter at different values of t and examine whether it is constant, that is, whether plotted values form a straight line parallel to the time axis. We provide simulation results assuming Weibull baseline hazard and an example to illustrate the methods.

Greece↗

PubMed1995

How long can humans live? Lower bound for biological limit of human longevity calculated from Danish twin data using correlated frailty model.

How long can people live? Opinions of the researchers diverge and debates continue. Is there any systematic way to address this question? In this paper, we suggest an approach to the estimation of the biological limit of human longevity using survival data for twins from different zygocity groups. The approach is based on the genetic model of individual frailty. It combines ideas used in demography and survival analysis with methods of quantitative genetics and genetic epidemiology. The association between the life-spans of related individuals is described by the correlated frailty model of bivariate survival. A version of this model is used in order to estimate heritability of the individual frailty and to calculate the lower bound of human longevity. The limitations of this approach and directions of further research are discussed.

Aged↗

PubMed1994

The oldest old; autonomy in the face of frailty.

Autonomy, a core American value, is routinely invoked as a goal in gerontological discussions of the aging process, yet frailty, another commonly used term in gerontology, suggests that functional losses may interfere with individuals' ability to maintain autonomy in everyday life. Older persons who are impaired are seldom asked how they view themselves with respect to autonomy and frailty, or what autonomy means. The meanings older persons attach to autonomy and decreases in physical abilities are explored through in-depth interviews with 28 persons age 80 or older. While autonomy encompassed a wide range of self-descriptions, respondents never used the word, frail, to describe themselves. I explore the potential of the construct of the lived body for a holistic approach to aging that values embodied knowledge and experiences of those who are old. I conclude that gerontological views of autonomy promote a cultural ideal that does not reflect elders' perspectives, and that the notion of frailty has the potential to stereotype elders, with negative effects on well being.

Aged↗

PubMed2005

Frailty and age-related macular degeneration: the Beaver Dam Eye Study.

PURPOSE: To investigate the associations of measures of frailty to prevalent age-related maculopathy (ARM). DESIGN: Cross-sectional population-based study. METHODS: Time to walk a measured course (gait-time), handgrip strength, peak expiratory flow rate, ability to stand from a sitting position without using arms, self-reported co-morbidities, and ARM were assessed at the third examination of the Beaver Dam Eye Study (n = 2,962). ARM was determined by grading stereoscopic color fundus photographs. RESULTS: While controlling for age, smoking, and the number of co-morbid conditions, weaker handgrip strength was associated with early ARM (odds ratio [OR]/10 kg decrease 1.28, confidence interval [CI] 1.08, 1.52, P = .004) and late ARM (OR 1.55, 95% CI 1.02, 2.36) in men but not women. Other measures of frailty were not related to ARM. CONCLUSIONS: A weak cross-sectional association of handgrip strength with ARM (in men) was found after controlling for co-morbid conditions. These data suggest that ARM is due to a specific disease process, albeit age-related, rather than to biologic aging, as reflected by measures of frailty.

Adult↗

PubMed2005

Frailty, heart disease, and stroke: the Compression of Morbidity paradigm.

Frailty, the loss of physiologic organ reserve with age, and chronic illness, such as heart disease and stroke, which may accelerate the development of frailty, become the dominant determinants of ill-health in those who escape the hazards of early and mid-life. The Compression of Morbidity paradigm holds that if the average age at first chronic infirmity is postponed, and if this postponement is greater than increases in life expectancy, then average cumulative lifetime morbidity will decrease, squeezed between a later onset and the time of death. The National Long-Term Care Survey, National Health Interview Survey, and other data document declining U.S. disability trends since 1982; accelerating recently, at about 2% per year. The decline in mortality is only 1% a year, documenting Compression of Morbidity in the U.S. population. Frailty, increasing exponentially because of linear declines in multiple organ systems, mandates converging morbidity and mortality rates as longevity increases. Longitudinal studies now link good health risk status with reduced lifetime disability; those with few health risks have only one-fourth the disability of those who have more risks, and the onset of disability is postponed from 7 to 12 years. Randomized controlled trials of senior health enhancement programs have shown reduction in health risks, improved health status, and decreased medical costs. Current health enhancement opportunities can increase health gains for seniors under the umbrella paradigm of the Compression of Morbidity. Effective interventions to prevent or postpone heart disease and stroke will decrease lifetime morbidity.

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