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PubMed1991

Regression with frailty in survival analysis.

In studies of survival, the hazard function for each individual may depend on observed risk variables but usually not all such variables are known or measurable. This unknown factor of the hazard function is usually termed the individual heterogeneity or frailty. When survival is time to the occurrence of a particular type of event and more than one such time may be obtained for each individual, frailty is a common factor among such recurrence times. A model including frailty is fitted to such repeated measures of recurrence times.

Adolescent↗

PubMed1993

The physics of frailty.

The contribution of frailty to human morbidity and mortality is immense. Yet it lacks a conceptual framework. By borrowing from the hypotheses provided by the thermophysicists, frailty can be understood in a way that both interrelates the relationship between form and function and provides medical science with an operational insight that yields clinical benefit. Frailty results where the organism is uncoupled from its environment yielding a break in the forward feedback cycle of stimulus to reaction to growth to increased functional competence to improved response to stimulus. Recognition of the centrality of this interrelatedness to health becomes a key theme for illness prevention and therapy.

Adaptation, Physiological↗

PubMed1997

Estimation of variance in Cox's regression model with shared gamma frailties.

The Cox regression model with a shared frailty factor allows for unobserved heterogeneity or for statistical dependence between the observed survival times. Estimation in this model when the frailties are assumed to follow a gamma distribution is reviewed, and we address the problem of obtaining variance estimates for regression coefficients, frailty parameter, and cumulative baseline hazards using the observed nonparametric information matrix. A number of examples are given comparing this approach with fully parametric inference in models with piecewise constant baseline hazards.

Adult↗

PubMed1998

Are osteoporotic fractures due to osteoporosis? Impacts of a frailty pandemic in an aging world.

Osteoporosis is a major risk factor for fractures in the elderly. Osteoporotic (hip, forearm, and vertebral) fractures today strike hard on Western populations, with a lifetime risk in women similar to the risk for cardiovascular disease. The risk of dying from hip fracture equals breast cancer mortality. Osteoporotic fractures are associated with pain, crippling and social dependency; annual costs in the United States are between $7 to $20 billion, and the contribution from hip fractures is above 60%. Of all hospital beds in Europe, 1 to 1.5% are occupied by osteoporotic patients, a figure expected to more than double during the next fifty years. Whereas vertebral fractures mainly seem to be caused by osteoporosis alone, hip fractures are heavily affected by an age-dependent contributory risk factor, frailty. Frailty might act as an involutionary phenomenon or as comorbidity, particularly neurological; it affects fracture risk along several causal paths, but the increasing frequency and severity of falls are essential. Results of attempts to prevent falls are discouragingly poor. Nevertheless, identification of risk possessors, particularly demented elderly living in institutions, is substantial for directing preventive and treatment programs, mainly acting on general health and on osteoporosis. Frailty of populations increases with longevity. Consequently, projections of fracture occurrence are too conservative. The annual hip fracture incidence in Asia in 2050 might pass 10 million, rather than the hitherto forecasted 3.2 million, thus shifting tomorrow's burden of age-related fractures from the wealthier to the poorer countries. There is an immediate call for vigorous global actions to reallocate resources, to reorganize health care, and to institute high-risk prevention programs.

Aged↗

PubMedDate not supplied

The role of frailty models and accelerated failure time models in describing heterogeneity due to omitted covariates.

In survival analysis, deviations from proportional hazards may sometimes be explained by unaccounted random heterogeneity, or frailty. This paper recalls the literature on omitted covariates in survival analysis and shows in a case study how unstably frailty models might behave when asked to account for unobserved heterogeneity in standard survival analysis with no replications per heterogeneity unit. Accelerated failure time modelling seems to avoid these difficulties and also to yield easily interpretable results. We propose that it would be advantageous to upgrade the accelerated failure time approach alongside the hazard modelling approach to survival analysis.

Algorithms↗

PubMed2006

Repeated events survival models: the conditional frailty model.

Repeated events processes are ubiquitous across a great range of important health, medical, and public policy applications, but models for these processes have serious limitations. Alternative estimators often produce different inferences concerning treatment effects due to bias and inefficiency. We recommend a robust strategy for the estimation of effects in medical treatments, social conditions, individual behaviours, and public policy programs in repeated events survival models under three common conditions: heterogeneity across individuals, dependence across the number of events, and both heterogeneity and event dependence. We compare several models for analysing recurrent event data that exhibit both heterogeneity and event dependence. The conditional frailty model best accounts for the various conditions of heterogeneity and event dependence by using a frailty term, stratification, and gap time formulation of the risk set. We examine the performance of recurrent event models that are commonly used in applied work using Monte Carlo simulations, and apply the findings to data on chronic granulomatous disease and cystic fibrosis.

Algorithms↗

PubMedDate not supplied

Modelling survival data with a cured fraction using frailty models.

Cure models have historically been utilized to analyse time-to-event data with a cured fraction. We consider the use of frailty models as an alternative approach to modelling such data. An attractive feature of the models is the allowance for heterogeneity in risk among those individuals experiencing the event of interest in addition to the incorporation of a cured component. Utilizing maximum likelihood techniques, we fit models to data concerning the recurrence of leukaemia among patients receiving autologous transplantation treatment. The analysis suggests that the gamma frailty mixture model and the compound Poisson improve on the fit of the leukaemia data as compared to the standard cure model.

Humans↗

PubMed2004

Sarcopenia and frailty in geriatric patients: implications for training and prevention.

Sarcopenia, the loss of muscle mass and strength, is a constant phenomenon in aging. Physiologic age-dependent changes (drop in growth hormone (GH), IGF-1, menopause/andropause) explain the impaired protein synthesis, the decline of muscle mass, strength, and bone density. Harmful consequences of sarcopenia in old age are loss of muscle strength, inducing itself loss of mobility, neuromuscular impairment, and homeostatic balance failure syndrome with gait and balance disorders. All these sarcopenia-induced disabilities are important factors for an increased rate of falls and fractures in old age. Both falls and fractures cause hospitalisation and immobilisation which again induces sarcopenia. Once the physiological age-dependent decline of protein synthesis has started, some connected "vicious loops" occur in frail elderly patients, forming a typical pattern in geriatric medicine. There is a vicious loop between sarcopenia and immobilisation: sarcopenia --> neuromuscular impairment --> falls and fractures --> immobilisation --> sarcopenia. Another loop is the "nutritional" vicious loop between sarcopenia and malnutrition: sarcopenia --> immobilisation --> decline of nutrition skills ("empty refrigerator") --> malnutrition --> impaired protein synthesis --> sarcopenia. There is also a third "metabolic" vicious loop between sarcopenia and the decline of the protein reserve of the body: sarcopenia --> decline of the protein reserve of the body --> diminished capacity to meet the extra demand of protein synthesis associated with disease and injury --> sarcopenia. Frailty, a term not precisely defined, results from these different "vicious loops" including sarcopenia, neuromuscular impairment, falls and fractures, immobilisation, malnutrition, impaired protein synthesis, and decreased protein reserve of the body. Implications for training: main possibilities for training and prevention (of sarcopenia and frailty) are: a) continuous neuromuscular training (including training of balance) b) mobilisation c) prevention of falls d) training of nutrition skills and improvement of nutrition e) improvement of the impaired protein synthesis (with hormones etc.), and f) avoidance of dangerous drugs (drugs which cause neuromuscular impairment).

Accidental Falls↗

PubMed2005

[The concept of frailty--from phenomenology to therapeutic approaches].

Frailty--the weakness of many (oldest) old persons--induces a lot of human sorrow with functional disabilities as well as health-economic costs. Sarcopenia (loss of muscle mass) is also a form of frailty and a co-factor of two of the "geriatric Is"--immobility and instability. Pathophysiologically, both phenomena show signs of an inflammatory state. Physical activity and a healthy diet can partially reverse these health problems. Therefore, therapeutic strategies emerge to treat these frequent and clinically relevant phenomena.

Aged↗

PubMed2005

Estimation in the positive stable shared frailty Cox proportional hazards model.

Shared frailty models are of interest when one has clustered survival data and when focus is on comparing the lifetimes within clusters and further on estimating the correlation between lifetimes from the same cluster. It is well known that the positive stable model should be preferred to the gamma model in situations where the correlated survival data show a decreasing association with time. In this paper, we devise a likelihood based estimation procedure for the positive stable shared frailty Cox model, which is expected to obtain high efficiency. The proposed estimator is provided with large sample properties and also a consistent estimator of standard errors is given. Simulation studies show that the estimation procedure is appropriate for practical use, and that it is much more efficient than a recently suggested procedure. The suggested methodology is applied to a dataset concerning time to blindness for patients with diabetic retinopathy.

Denmark↗

PubMed2004

[Impact of frailty factors in elderly people older than 75 years with prosthesis of the hip].

OBJECTIVE: Hip pathology of hip requiring a surgical assumption of responsibility (coxarthrose invalidating, hip fracture) is increasing, and after the year 2025, the number of interventions will double. In parallel, the number of elderly people (older than 75 years) with malnutrition associated with cognitive impairment and reduced autonomy is on the increase. So the concept of frail elderly identified by specific criteria allows for better defining the health needs of heterogeneous elderly people. The objective of this study was to determine the influence of frailty factors on autonomy and clinical outcome after intervention for prosthesis of the hip. METHODOLOGY: This prospective work, completed over 8 months, included 55 patients with total or intermediate prostheses of hip, whatever the cause, recruited from rehabilitation wards. Results from a pre-established questionnaire defined the personal status and social framework of these patients. A medical examination evaluated cognitive function Mini Mental State (MMS), nutritional state (IMC) and the level of autonomy immediately after surgery (the first 2 weeks) by the measurement of functional independence (MIF). The second MIF was carried out by the same operator at the end of the assumption of responsibility by the institution. RESULTS: Three factors of frailty influenced progress at the time of reacquisition of autonomy: cognitive impairment (P < 0001; 1 patient out of 2 [50%] had an MMS score < 22); reduced nutrition? (P < 0.0026; [29% had a BMI score < 20 or a perimeter of the calf < 30 cm]; and accommodations before the intervention (P < 0.028; [15% lived in an institution]). CONCLUSION: Nutritional state, cognitive level and social activity must be evaluated regularly in elderly subjects with hip prosthesis to evaluate optimal load and adaptation.

Aged↗

PubMed2004

Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study.

Aging is associated with an impaired capacity of the immune system to respond properly to danger signals, such as infection and cancer. Here, we provide evidence that an impaired innate immune response, as measured by a low production capacity of pro- and anti-inflammatory cytokines upon ex vivo standardized danger signalling with bacterial LPS, is predictive for frailty in elderly people: participants who at age 85-year produced low levels of LPS-induced IL-1beta, IL-6, TNF-alpha and IL-1Ra and IL-10, were found to have a more than 2-fold elevated overall mortality risk, independent of chronic illnesses (relative risk is 2.21, 95% confidence interval 1.27-3.82, P = 0.005), compared to peers with a higher production of any of the pro- and/or anti-inflammatory cytokines. A significant genetic association with the IL-10 promoter gene was found, indicating that people who are genetically predisposed low cytokine producers are at a higher risk of losing the capacity to respond properly to danger signals with aging. We conclude that a malfunctioning innate immune response predicts frailty in old age and is under specific (immuno-) genetic control.

Aged↗

PubMed2005

Hierarchical components of physical frailty predicted incidence of dependency in a cohort of elderly women.

OBJECTIVE: To identify the most important predictors of early disability incidence and devise a simple score of physical frailty. METHODS: A cohort of 545 high-functioning women aged 75 years and older was followed for 7 years. Every year, the self-reported loss of at least one instrumental activity of daily living was chosen as definition of disability. An extension of the logistic regression for repeated responses, the random-effect model, was used to assess the effects of baseline predictors. The regression coefficients of the final multivariate model were scaled and rounded to create a practical score. RESULTS: The proportion of women reporting disability increased from 22.1% to 52.1% throughout the follow-up. In the multivariate model, increasing age, lower performances in mobility and balance tests, bad perceived health, lower muscle strength, higher body mass index, lower educational level, and lower reported physical activity were strong predictors of disability. Evaluating the predictive value of the simplified predictive score on an independent cohort gave a c-statistic equal to .71. CONCLUSION: The use of a powerful fitting method allows to establish a hierarchy between the components of physical frailty and to provide a predictive score with substantial practical value for clinicians and public health professionals.

Activities of Daily Living↗

PubMed2006

Vulnerability in the elderly: frailty.

In scenarios that predict the future of health service delivery in the Western world, the rapid increase in frail elderly patients is seen as one of the major challenges of health care in addition to the care of the chronic medically ill. In this article the relation between age, frailty, comorbidity, and disability is elaborated further, a method to detect frail patients quickly is introduced, and its relation to complexity is explored. An argument for patient-tailored integrated care in frail elderly patients is made. At the same time, the argument will be made that standard evidence-based care can be delivered for patients who have a negative screen on frailty.

Aged↗

PubMed2006

Frailty.

Frailty is a common condition in older people. It now can be objectively defined by the Fried criteria. When recognized, early intervention should begin with the institution of endurance, resistance, and balance exercises. In men with testosterone deficiency a trial of testosterone replacement should be considered. Vitamin D deficiency needs to be recognized and treated. Appropriate treatment of underlying diseases, such as anemia, diabetes mellitus, and congestive heart failure, are a key management principle. In people who have frailty aggressive health promotion and disease prevention techniques can lead to an inhibition of the downward spiral to disability.

Aged↗

PubMed1997

Gender, self-reported depressive symptoms, and sleep disturbance among older community-dwelling persons. FICSIT group. Frailty and Injuries: Cooperative Studies of Intervention Techniques.

The purposes of this report are: (1) to investigate the association between sleep disturbances and depressive symptomatology in older adults; (2) to evaluate the degree to which gender serves to mediate this relationship; and (3) to determine whether several predefined covariates help to explain the association between sleep disturbance and depressive symptoms. This is a retrospective and cross-sectional analysis of baseline data from 485 elderly adults enrolled in three of the eight clinical sites participating in the Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) trials. FICSIT was a linked series of randomized clinical trials which evaluated the impact of various exercise interventions on several measures of frailty in older adults. Women reported more depressive symptoms and more sleep disturbances than men. Sleep disturbances were independently associated with depressive symptoms, bodily pain, a history of falling, limited education, being married, and being female. Gender interactions suggest that, although women reported more depressive symptoms and more chronic health conditions than men, both may be more important predictors of sleep disturbance in men. By contrast, being married may be more predictive in women. Finally, the data suggest a stronger relationship between sleep disturbance and depressive symptoms in men than in women.

Activities of Daily Living↗

PubMed2001

Disability and frailty among elderly Canadians: a comparison of six surveys.

The first wave of the Canadian Study of Health and Aging (CSHA) constituted a large health survey of a representative sample of elderly Canadians. Other Canadian surveys from the same era provided equivalent figures, and the present report compares the results of 6 surveys on a variety of health indicators. Agreement was close on self-reported chronic health conditions, adequate for several indicators of functional limitation, but was lower for overall self-ratings of the impact of health problems on day-to-day life. Using the CSHA data to compare alternative operational definitions of frailty, a definition based on ADL limitations appeared to offer an underestimate; addition of IADL questions or cognitive limitations provided figures that appeared more plausible. Survey estimates of chronic health conditions appear consistent, as are estimates of certain ADL disabilities. Care must be taken with interpreting more subjective reports, while prevalence of frailty varies considerably according to the definition used.

Activities of Daily Living↗

PubMed2001

Using frailties in the accelerated failure time model.

The accelerated failure time (AFT) model is an important alternative to the Cox proportional hazards model (PHM) in survival analysis. For multivariate failure time data we propose to use frailties to explicitly account for possible correlations (and heterogeneity) among failure times. An EM-like algorithm analogous to that in the frailty model for the Cox model is adapted. Through simulation it is shown that its performance compares favorably with that of the marginal independence approach. For illustration we reanalyze a real data set.

Algorithms↗