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PubMed2004

Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care.

Three terms are commonly used interchangeably to identify vulnerable older adults: comorbidity, or multiple chronic conditions, frailty, and disability. However, in geriatric medicine, there is a growing consensus that these are distinct clinical entities that are causally related. Each, individually, occurs frequently and has high import clinically. This article provides a narrative review of current understanding of the definitions and distinguishing characteristics of each of these conditions, including their clinical relevance and distinct prevention and therapeutic issues, and how they are related. Review of the current state of published knowledge is supplemented by targeted analyses in selected areas where no current published data exists. Overall, the goal of this article is to provide a basis for distinguishing between these three important clinical conditions in older adults and showing how use of separate, distinct definitions of each can improve our understanding of the problems affecting older patients and lead to development of improved strategies for diagnosis, care, research, and medical education in this area.

Aged↗

PubMed1993

Cardiovascular, neuromuscular, and metabolic alterations with age leading to frailty.

As members of our society live longer, a greater percentage of the population will be older. These demographic changes will stress our social and medical delivery system, unless interventions can alter the course leading to frailty. Maximal aerobic power decreases with age, due to a decrease in cardiac output, and is exacerbated by cardiovascular disease. Asymptomatic aging does not reduce cardiovascular function to an extent that would lead to loss of function. Metabolism, endurance, and contraction velocity and muscle strength remain relatively high until 40, 50, and 60 years of age, respectively. After age 60, there are dramatic decreases (approximately 10% per year) which lead to loss of function and independence. The loss of muscle function leads to an increase in the likelihood of falls (approximately 4-fold). Exercise programs utilizing "aerobic" exercise activities do not lead to an increase in muscle function, whereas programs designed specifically for muscle can increase function and, presumably, reduce the risk of falls and injuries.

Adult↗

PubMed1990

How aging related frailty will influence the quality of care. Results from a 15-year follow-up of 70-year-old people in Gothenburg, Sweden.

This report exemplifies how aging in itself, frailty, and morbidity influence need of quality of care in the age interval 70-85 according to results obtained at the study of representative samples of elderly in Gothenburg, Sweden. A significant proportion of the elderly in the age interval 70-79 were lacking symptoms due to definable disease, which made possible studies of "normal aging" and a differentiation of manifestations of aging from symptoms of disease in the elderly. Usage of such knowledge is essential for the improvement of quality of care. The trainability of older people was generally good. Much more can be done to reactivate the older patient after episodes of acute disease. "Long-term care" should be considered as programs differentiated according to the need; shorter more active or longer forms of "long-term care." Many frail elderly need longer periods of reactivation than available in hospitals. Certain risk factors precipitate into functional decline only when we are old. Preventive/postponing measures are relevant also for the elderly.

Aged↗

PubMed1996

Estimability and interpretation of vaccine efficacy using frailty mixing models.

The authors consider estimability and interpretation of vaccine efficacy based on time to event data, allowing that some of the population might have a very low probability of acquiring disease, and the rest have partial, possibly continuously distributed, susceptibility. The efficacy parameters of interest in the frailty mixing model include the fraction highly unlikely to acquire the infection or disease due to the vaccine, the degree of partial protection in those still susceptible, and the average protection or summary measure of efficacy under heterogeneity. The efficacy estimates can still be usefully interpreted when the heterogeneity results from heterogeneity in contact patterns, contact rates, or infectiousness of the contacts, as long as these are equal in the vaccinated and unvaccinated groups. A likelihood-based method allows estimation of the efficacy parameters of interest from grouped time to event data. Simulated vaccine studies assuming different levels and distributions of efficacy demonstrate that ignoring heterogeneity in susceptibility or exposure to infection generally results in underestimation of vaccine efficacy as well as incorrect interpretation of the estimates. The approach is also applicable to other covariates affecting susceptibility or exposure to infection in infectious diseases. Exploitation of the dependent happening structure of infectious diseases to obtain a shape for the baseline hazard may help identifiability. The authors recommend fitting several models to time to event data in vaccine studies.

Effect Modifier, Epidemiologic↗

PubMedDate not supplied

Measuring frailty in the hospitalized elderly: concept of functional homeostasis.

Functional homeostasis is the ability of an individual to withstand illness without loss of function. We investigate whether the level of functional homeostasis predicts adverse outcomes in the 6 months posthospital discharge in older men and women. A prospective cohort study was conducted in an acute care geriatric inpatient unit of a university hospital. Subjects included a consecutive series of patients admitted to the unit. The Functional Independence Measure (FIM) instrument was used to assess patients at four time points: preillness, hospital admission, hospital discharge, and 6 months postdischarge. Of the 122 subjects available for analysis, 64 (52%) experienced a decline in functional level from preillness to hospital discharge and were defined as having poor functional homeostasis, whereas 58 (48%) experienced no change or an increase in functional status and were defined as having good functional homeostasis. Those with poor functional homeostasis had a higher 6-month readmission rate to the hospital (59.4 v 39.7%; P=0.03) and a higher rate of any adverse outcome (78.1 v 50%; P=0.001) than those with good functional homeostasis. In logistic regressive analyses, functional homeostasis remained a significant and powerful predictor of adverse outcomes independent of actual level of function at discharge, age, gender, living status, and other factors that might influence outcomes. Change in functional status associated with an acute illness is an independent predictor of adverse outcomes and, in this study, a better predictor than actual level of function at discharge. Functional homeostasis is one approach to the quantification of the important but elusive concept of frailty in the elderly.

Activities of Daily Living↗

PubMed1999

Multivariate survival analysis with positive stable frailties.

In this paper, we describe Bayesian modeling of dependent multivariate survival data using positive stable frailty distributions. A flexible baseline hazard formulation using a piecewise exponential model with a correlated prior process is used. The estimation of the stable law parameter together with the parameters of the (conditional) proportional hazards model is facilitated by a modified Gibbs sampling procedure. The methodology is illustrated on kidney infection data (McGilchrist and Aisbett, 1991).

Algorithms↗

PubMed2002

Frailty models with missing covariates.

We present a method for estimating the parameters in random effects models for survival data when covariates are subject to missingness. Our method is more general than the usual frailty model as it accommodates a wide range of distributions for the random effects, which are included as an offset in the linear predictor in a manner analogous to that used in generalized linear mixed models. We propose using a Monte Carlo EM algorithm along with the Gibbs sampler to obtain parameter estimates. This method is useful in reducing the bias that may be incurred using complete-case methods in this setting. The methodology is applied to data from Eastern Cooperative Oncology Group melanoma clinical trials in which observations were believed to be clustered and several tumor characteristics were not always observed.

Clinical Trials, Phase III as Topic↗

PubMed2004

Multivariate survival trees: a maximum likelihood approach based on frailty models.

A method of constructing trees for correlated failure times is put forward. It adopts the backfitting idea of classification and regression trees (CART) (Breiman et al., 1984, in Classification and Regression Trees). The tree method is developed based on the maximized likelihoods associated with the gamma frailty model and standard likelihood-related techniques are incorporated. The proposed method is assessed through simulations conducted under a variety of model configurations and illustrated using the chronic granulomatous disease (CGD) study data.

Biometry↗

PubMed2004

Penalized partial likelihood for frailties and smoothing splines in time to first insemination models for dairy cows.

In many epidemiological studies time to event data are clustered and the physiological relationship between (time-dependent) covariates and the log hazard is often not linear as assumed in the Cox model. Introducing frailties in the Cox model can account for the clustering of the data and smoothing splines can be used to describe nonlinear relations. These two extensions of the Cox model are introduced jointly and it is shown how penalized partial likelihood techniques can be used to fit the extended model. We demonstrate the need for such a model to study the relation between the physiological covariates milk ureum and protein concentration and the log hazard of first insemination in dairy cows, with the farms as clusters.

Animals↗

PubMed1993

The Atlanta FICSIT study: two exercise interventions to reduce frailty in elders.

This study examines the effect of two different exercise approaches on balance and frailty measures among more than 200 community-dwelling individuals greater than 70 years of age. Exercises are provided for 15 weekly sessions on an individual basis for participants randomly assigned to a Balance Training group. Training consists of center-of-mass feedback displayed on a motor under static conditions, or, in later sessions, as the floor surface is moved, with eyes open or closed. This high technology interface provides instantaneous information about displacement of body weight in space so that balance can be enhanced. An alternative procedure is comparatively simple and requires little expense or space. Tai Chi Quan was originally developed as a martial arts form but has been used for centuries in China as an exercise among elderly citizens. Participants randomly assigned to this intervention meet twice weekly for 15 weeks to learn a condensation of 108 Tai Chi forms into 10 that emphasize movement components often restricted or absent with aging. A third group serves as a control for exercise interventions by meeting weekly for 15 sessions to discuss topics of interest such as memory loss, drug management, and nutrition. All subjects are screened prior to assignment, and a host of physical, behavioral, and functional measures are assessed before and after the intervention as well as 4 months later. Measurements unique to the Atlanta site include: balance with eyes closed, programmed force-distribution changes when stance is perturbed, cardiovascular assessments, WAIS, Affects Balance Scale, and a survey of home environment.

Aged↗

PubMed1996

The relationship between physical performance measures and independence in instrumental activities of daily living. The FICSIT Group. Frailty and Injury: Cooperative Studies of Intervention Trials.

OBJECTIVES: Understanding the relationship between physical capacity and functional status is required to design exercise interventions to maintain independent living. This study assessed the importance of physical performance in maintaining independence in Instrumental Activities of Daily Living (IADL). DESIGN: A pre-planned meta-analysis of cross-sectional data from six sites of the Frailty and Injury: Cooperative Studies of Intervention Trials (FICSIT). Linear regression was used to estimate the relationship between physical performance and IADL. PARTICIPANTS: 2190 community-dwelling older subjects. MEASUREMENTS: IADL was the dependent variable; gait velocity, balance function, grip strength and chair rise time were the predictor variables. Age, gender, education, falls self-efficacy, and cognitive status were covariates. RESULTS: Gait velocity, balance function, and grip strength were independently related to IADL deficits, after correcting for covariates. The linear slopes were relatively steep. For gait, a decrease of 0.1 m s-1 was associated with 0.10 (95% Cl: 0.17, 0.04) increase in IADL deficits, which is equivalent to 1 ADL deficit in 10 subjects. The linear slopes for hand grip and balance were similar or steeper. In the sites where chair stand time was measured, an increase of 1 second in the time to rise was associated with a 0.14 (0.04, 0.24) increase in IADL deficits. The relationships found in the meta-analytic analysis were consistent across sites which enrolled subjects with widely varying levels of physical performance. CONCLUSION: Simple measures of physical performance were strongly associated with IADL independence after correcting for many previously identified predictors of functional status. The data from this meta-analysis support testing interventions designed to improve physical performance to determine whether improved performance can maintain or improve independence in IADLs.

Activities of Daily Living↗

PubMed2006

Regression analysis of doubly censored failure time data with frailty.

In doubly censored failure time data, the survival time of interest is defined as the elapsed time between an initial event and a subsequent event, and the occurrences of both events cannot be observed exactly. Instead, only right- or interval-censored observations on the occurrence times are available. For the analysis of such data, a number of methods have been proposed under the assumption that the survival time of interest is independent of the occurrence time of the initial event. This article investigates a different situation where the independence may not be true with the focus on regression analysis of doubly censored data. Cox frailty models are applied to describe the effects of covariates and an EM algorithm is developed for estimation. Simulation studies are performed to investigate finite sample properties of the proposed method and an illustrative example from an acquired immune deficiency syndrome (AIDS) cohort study is provided.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Physiological complexity, aging, and the path to frailty.

Healthy physiological processes require the complex interaction of multiple control systems operating over multiple time scales. The output of these processes (for example, heart rate, blood pressure, hormonal rhythms, or postural sway) demonstrates complex variability that can be quantified using the concept of fractals, derived from the field of nonlinear dynamics. Complex physiological dynamics enable an organism to rapidly respond to the internal and external perturbations of everyday life. Aging and disease are associated with a loss of complexity in the dynamics of many physiological systems. This loss of complexity may reduce the ability to adapt to stress and lead to the syndrome of frailty.

Aged↗

PubMed2004

Frailty--the search for underlying causes.

Research into the biological basis of frailty has been difficult to accomplish because of a lack of standardized definitions, disease and disability confounders, and complex multifactorial etiology. Multiple physiological systems are likely to be involved, including the skeletal muscle, endocrine, and immune/inflammation systems. Physiological characterization of frail older adults might provide etiologic clues. Translational research programs that connect mechanisms related to aging, such as oxidative damage and telomere shortening, to clinical aging-related syndromes will be necessary to further this critical area of geriatric research.

Aged↗

PubMed2000

Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty.

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

Age Factors↗

PubMed2006

Predicting clustered dental implant survival using frailty methods.

The purpose of this study was to predict future implant survival using information on risk factors and on the survival status of an individual's existing implant(s). We considered a retrospective cohort study with 677 individuals having 2349 implants placed. We proposed to predict the survival probabilities using the Cox proportional hazards frailty model, with three important risk factors: smoking status, timing of placement, and implant staging. For a non-smoking individual with 2 implants placed, an immediate implant and in one stage, the marginal probability that 1 implant would survive 12 months was 85.8% (95%CI: 77%, 91.7%), and the predicted joint probability of surviving for 12 months was 75.1% (95%CI: 62.1%, 84.7%). If 1 implant was placed earlier and had survived for 12 months, then the second implant had an 87.5% (95%CI: 80.3%, 92.4%) chance of surviving 12 months. Such conditional and joint predictions can assist in clinical decision-making for individuals.

Cluster Analysis↗

PubMed2005

A Bayesian analysis of amalgam restorations in the Royal Air Force using the counting process approach with nested frailty effects.

Survival analysis methods are increasingly used in dental research to measure risk of tooth eruption and caries as well as life spans of amalgam restorations. Analyses have been extended to account for lack of independence in the data, which arises from the clustering of observations within units such as tooth-surfaces, teeth and subjects. There are various analytical strategies and modelling approaches now available to us in dealing with clustered dental data. In this article, the modelling strategy of Cox's proportional hazards regression is formulated using the counting process approach, which can easily be extended to include time-variant covariates as well as nested random frailty effects. A semi-parametric Bayesian method is presented for the analysis of the proposed model. The methodology is applied to an analysis of nested clustered data on life-span of amalgam restorations in the UK Royal Air Force. These data have previously been analysed using a non-Bayesian approach. The Gibbs sampler, a Markov chain Monte Carlo method, is used to generate samples from the marginal posterior distribution of the parameters of this Bayesian model.

Bayes Theorem↗

PubMed2002

An additive genetic gamma frailty model for two-locus linkage analysis using sibship age of onset data.

Complex human diseases are often due to multiple disease genes with variable age of onset, as well as both genetic and environmental risk factors. In order to simultaneously consider two possible disease loci and to incorporate age of onset and covariate information into genetic linkage analysis, we introduce a two-locus genetic gamma frailty model for age of onset data within a family. We show that this model can be used for genetic linkage analysis of diseases due to two possible disease loci. This model simultaneously considers allele-sharing at two different loci, and can easily incorporate age of onset or age at censoring data, environmental covariates data, and population disease rate data in genetic linkage analysis. It also provides a flexible framework for mapping loci affecting the risk of developing diseases with complex etiology. This approach allows multipoint allele-sharing analysis to take evidence of the existence of a disease locus in one region into account in mapping other disease loci. Simulation studies indicate that the proposed tests have expected type 1 error rates and when the model assumptions are met, increased power over one-locus model for linkage analysis. A prostate cancer data set is used for illustrating the methods.

Journal Article↗