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A relaxation of the gamma frailty (Burr) model.

Frailty models are used in univariate data to account for individual heterogeneity. In the popular gamma frailty model the marginal hazard has the form of a Burr model. Although the Burr model is very useful and can offer insight on the data, it is far from perfect. The estimation of the covariate effects is linked to the baseline hazard and this makes the model coefficients hard to interpret. At the same time, the frailties are assumed constant over time, while biological reasoning in some cases may indicate that frailties may be time dependent. In this paper we present a relaxation of the Burr model which is based on loosening the link between the estimation of the covariate effects and the baseline hazard. This can be achieved by replacing the cumulative baseline hazard in the Burr model by a set of time functions, and the frailty variance by a vector of coefficients directly estimated from the data using a partial likelihood. We illustrate the similarities of the model with the Burr model and a further extension of the latter, a model with an autoregressive stochastic process for the frailty. We compare the models on simulated data sets with constant and time-dependent frailties and show how the relaxed Burr models performs on two different real data sets. We show that the relaxed Burr model serves as a good approximation to the Burr model when the frailty is constant, and furthermore it gives better results when the frailty is time dependent.

Adolescent↗

Frailty syndrome and skeletal muscle: results from the Invecchiare in Chianti study.

BACKGROUND: Frailty is a common condition in elders and identifies a state of vulnerability for adverse health outcomes. OBJECTIVE: Our objective was to provide a biological face validity to the well-established definition of frailty proposed by Fried et al. DESIGN: Data are from the baseline evaluation of 923 participants aged > or =65 y enrolled in the Invecchiare in Chianti study. Frailty was defined by the presence of > or =3 of the following criteria: weight loss, exhaustion, low walking speed, low hand grip strength, and physical inactivity. Muscle density and the ratios of muscle area and fat area to total calf area were measured by using a peripheral quantitative computerized tomography (pQCT) scan. Analyses of covariance and logistic regressions were performed to evaluate the relations between frailty and pQCT measures. RESULTS: The mean age (+/-SD) of the study sample was 74.8 +/- 6.8 y, and 81 participants (8.8%) had > or =3 frailty criteria. Participants with no frailty criteria had significantly higher muscle density (71.1 mg/cm(3), SE = 0.2) and muscle area (71.2%, SE = 0.4) than did frail participants (69.8 mg/cm(3), SE = 0.4; and 68.7%, SE = 1.1, respectively). Fat area was significantly higher in frail participants (22.0%, SE = 0.9) than in participants with no frailty criteria (20.3%, SE = 0.4). Physical inactivity and low walking speed were the frailty criteria that showed the strongest associations with pQCT measures. CONCLUSION: Frail subjects, identified by an easy and inexpensive frailty score, have lower muscle density and muscle mass and higher fat mass than do nonfrail persons.

Aged↗

Phenotype of frailty: characterization in the women's health and aging studies.

BACKGROUND: "Frailty" is an adverse, primarily gerontologic, health condition regarded as frequent with aging and having severe consequences. Although clinicians claim that the extremes of frailty can be easily recognized, a standardized definition of frailty has proved elusive until recently. This article evaluates the cross-validity, criterion validity, and internal validity in the Women's Health and Aging Studies (WHAS) of a discrete measure of frailty recently validated in the Cardiovascular Health Study (CHS). METHODS: The frailty measure developed in CHS was delineated in the WHAS data sets. Using latent class analysis, we evaluated whether criteria composing the measure aggregate into a syndrome. We verified the criterion validity of the measure by testing whether participants defined as frail were more likely than others to develop adverse geriatric outcomes or to die. RESULTS: The distributions of frailty in the WHAS and CHS were comparable. In latent class analyses, the measures demonstrated strong internal validity vis à vis stated theory characterizing frailty as a medical syndrome. In proportional hazards models, frail women had a higher risk of developing activities of daily living (ADL) and/or instrumental ADL disability, institutionalization, and death, independently of multiple potentially confounding factors. CONCLUSIONS: The findings of this study are consistent with the widely held theory that conceptualizes frailty as a syndrome. The frailty definition developed in the CHS is applicable across diverse population samples and identifies a profile of high risk of multiple adverse outcomes.

Aged↗

Endocrine and inflammatory markers as predictors of frailty.

OBJECTIVE: To examine the association of serum concentrations of 25-hydroxyvitamin D [25(OH)D], interleukin-6 (IL-6), C-reactive protein (CRP) and IGF-1 with prevalent and incident frailty. DESIGN: The Longitudinal Aging Study Amsterdam (LASA), a prospective cohort study with 3-yearly measurement cycles. Setting General population-based sample. PARTICIPANTS: The respondents were men and women aged 65 and over, who participated at T1 (1995/1996, N = 1720) and T2 (1998/1999, N = 1509). Blood samples were obtained at T1 (N = 1271). Measurements The presence of frailty at T1 and 3-year incidence of frailty. Frailty is defined as the presence of three out of nine frailty indicators. RESULTS: At T1, 242 (19.0%) of all respondents were frail. Those who were frail at T1 had higher CRP and lower 25(OH)D levels. Serum 25(OH)D remained associated with frailty after adjustment for potential confounders with an odd ratios (OR) of 2.60 [95% confidence interval (95% CI) 1.60-4.21] for 25(OH)D < 25 nmol/l and 1.72 (95% CI 1.19-2.47) for 25(OH)D 25-50 nmol/l vs. high levels of 25(OH)D. Of the nonfrail at T1, 125 respondents (14.1%) became frail at T2. After adjustment, moderately elevated CRP levels (3-10 microg/ml) (OR 1.69, 95% CI 1.09-2.63) and low 25(OH)D (OR 2.04, 95% CI 1.01-4.13) were associated with incident frailty. No consistent associations were observed for IL-6 and IGF-1. CONCLUSION: Low 25(OH)D levels were strongly associated with prevalent and incident frailty; moderately elevated levels of CRP were associated with incident frailty.

Aged↗

Operationalizing a frailty index from a standardized comprehensive geriatric assessment.

OBJECTIVES: To construct and validate a frailty index (FI) that is clinically sensible and practical for geriatricians by basing it on a routinely used comprehensive geriatric assessment (CGA) instrument. DESIGN: Secondary analysis of a 3-month randomized, controlled trial of a specialized mobile geriatric assessment team. SETTING: Rural Nova Scotia. Participants were seen in their homes. PARTICIPANTS: Frail older adults, of whom 92 were in the intervention group and 77 in the control group. MEASUREMENTS: A standard CGA form that accounts for impairment, disability, and comorbidity burden was scored and summed as a frailty index (FI-CGA). The FI-GCA was stratified to describe three levels of frailty. Patients were followed for up to 12 months to determine how well the index predicted adverse outcomes (institutionalization or mortality, whichever came first). RESULTS: The three levels of frailty were mild (FI-CGA 0-7), moderate (FI-CGA 7-13), and severe (FI-CGA>13). Demographic and social traits were similar across groups, but greater frailty was associated with worse function (r=0.55) and mental status (r=0.33). Those with moderate and severe frailty had a greater risk of adverse outcomes than those with mild frailty (unadjusted hazard ratio=1.9 and 5.5, respectively). There was no difference between frailty groups in mean 3-month goal-attainment scaling scores. Intrarater reliability was 0.95. CONCLUSION: The FI-CGA is a valid, reliable, and sensible clinical measure of frailty that permits risk stratification of future adverse outcomes.

Aged↗

Sex differences in the risk of frailty for mortality independent of disability and chronic diseases.

OBJECTIVES: To determine the effect of static and dynamic frailty on mortality in older men and women. DESIGN: A prospective cohort study with three 3-year measurement cycles. SETTING: Population based. PARTICIPANTS: The sample was derived from the Longitudinal Aging Study Amsterdam and consisted of respondents who participated in two cycles (T1: 1992/1993 and T2: 1995/1996) and for whom there was complete data on disability and chronic diseases (N=2,257). MEASUREMENTS: Nine frailty markers were assessed at T1 and T2. The frailty markers were defined in two ways: low functioning at T2 (static frailty) and change in functioning between T1 and T2 (dynamic frailty). Survival time, calculated in days from T2 to January 1, 2000, was used as the outcome variable. Predictive ability was examined using Cox proportional hazards analyses separately for men and women. RESULTS: Women were frailer than men. Static frailty was significantly associated with mortality in men (relative risk (RR)=2.4) and in women (RR=2.6). Dynamic frailty was also associated with mortality in women (RR=2.6), but it was not significantly associated with mortality in men (RR=1.3). When disability and chronic diseases were included in the model as possible mediators, these RRs dropped to 1.6, 2.0, 2.1, and 1.2, respectively, of which the first three were still significant. CONCLUSION: Frailty was associated with mortality to a greater extent in women than in men, and this effect was independent of disability and chronic disease. In men, the static definition of frailty was more predictive of mortality than the dynamic definition.

Aged↗

The association between obesity and the frailty syndrome in older women: the Women's Health and Aging Studies.

OBJECTIVES: To determine whether obesity is associated with the frailty phenotype and, if so, whether comorbid conditions or inflammatory markers explain this association. DESIGN: Cross-sectional analysis of baseline data from the Women's Health and Aging Studies I (1992) and II (1994), complementary population-based studies. SETTING: Twelve contiguous ZIP code areas in Baltimore, Maryland. PARTICIPANTS: Five hundred ninety-nine community-dwelling women aged 70 to 79 with a body mass index (BMI) greater than 18.5 kg/m(2). MEASUREMENTS: The dependent variables were the frailty syndrome, including prefrailty, defined as presence of one or two of five frailty indicators (weakness, slowness, weight loss, low physical activity, exhaustion), and frailty, defined as three or more indicators. Independent variables included BMI, categorized using World Health Organization criteria as normal (18.5 to <25 kg/m(2)), overweight (25 to <30 kg/m(2)), and obese (>/=30 kg/m(2)); chronic diseases; C-reactive protein; and serum carotenoids. RESULTS: Being overweight was significantly associated with prefrailty, and obesity was associated with prefrailty and frailty. In all frail women, regardless of BMI group, a similar pattern of three defining frailty indicators was found: slowness, weakness, and low activity (with the addition of weight loss in the normal weight group.) In multinomial regression models, obesity was significantly associated with prefrailty (odds ratio (OR)=2.23, 95% confidence interval (CI)=1.29-3.84) and frailty (OR=3.52, 95% CI=1.34-9.13), even when controlling for covariates. CONCLUSION: Obesity is associated with the frailty syndrome in older women in cross-sectional data. This association remains significant even when multiple conditions associated with frailty are considered. Prospective studies are needed to confirm this finding.

Activities of Daily Living↗

Relationship of measures of frailty to visual function: the Beaver Dam Eye Study.

PURPOSE: To investigate the association of standard measures of frailty to visual acuity and contrast sensitivity. METHODS: Time to walk a measured course, handgrip strength, peak expiratory flow rate, ability to stand from a sitting position without using arms, best-corrected visual acuity, and contrast sensitivity were assessed at the third examination (1998-2000) of the Beaver Dam Eye Study. The study is population-based with the initial census in 1988-1990. RESULTS: All measures of frailty and vision were significantly associated with age (poorer function at older ages). In general, women had poorer function than men in each age category. An "index of frailty" consisting of highest quartile (slowest) gait time, lowest quartile of peak expiratory flow rate, lowest quartile of handgrip strength, and inability to stand from sitting in one try (for those not in a wheelchair) was constructed for women and men. A score of 0 was the minimum amount of frailty, while a score of 4 indicated the maximum amount. Controlling for age, those with no evidence of frailty (score = 0) were likely to have the best visual acuity and best contrast sensitivity, while those with maximum evidence of frailty (score = 4) were likely to have poorest visual acuity and contrast sensitivity. CONCLUSION: Greater frailty was associated with poorer visual functions. Including a measure of visual function when assessing frailty may improve upon the usefulness of an index of frailty in predicting incidence of chronic systemic diseases and survival.

Adult↗

Effectiveness of Multidomain Cardiac Rehabilitation After Myocardial Infarction by Patient Frailty: Prespecified Subgroup Analysis of the PIpELINe Trial.

BACKGROUND: Frailty is common among older patients surviving myocardial infarction, is associated with adverse outcomes, and is often perceived as a barrier to cardiac rehabilitation (CR). The aim of this study is to determine whether frailty influences prognosis after myocardial infarction, and whether frailty modifies the clinical benefit of multidomain CR. METHODS: We performed a prespecified subgroup analysis of the PIpELINe (Physical Activity Intervention in Elderly Patients With Myocardial Infarction) randomized clinical trial conducted in Italy, which enrolled 512 patients aged &#x2265;65 years recovering from myocardial infarction and randomized them in a 2:1 ratio to CR or usual care. Frailty was assessed using the Fried Frailty Phenotype, and patients were categorized as nonfrail (robust) or prefrail/frail. Time-to-event outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models, including treatment-by-frailty interaction terms to evaluate effect modification of the multidomain CR. The primary outcome was a composite of cardiovascular death or unplanned hospitalization for cardiovascular causes within 1 year after randomization. RESULTS: Overall, 350 patients (68.4%) were classified as prefrail/frail, of whom 232 were randomized to intervention arm (66%). Frail patients were older (median age, 80 [75-85] years) and more frequently female (41.7% versus 24.7%). Compared with robust patients, prefrail/frail patients had a higher risk of the primary outcome (16 [9.9%] versus 62 [17.7%]; hazard ratio, 1.59 [95% CI, 0.89-2.82]; adjusted P=0.117). Among prefrail/frail patients, assignment to multidomain CR was associated with a lower risk of the primary outcome compared with usual care (hazard ratio, 0.57 [95% CI, 0.34-0.94]; P=0.028), with no statistically significant interaction in the treatment effect on the primary end point (P=0.57). CONCLUSIONS: Among older patients recovering from myocardial infarction, frailty is associated with worse prognosis but does not diminish the benefit of multidomain CR. These findings support the use of frailty assessment to guide rather than limit access to CR. REGISTRATION: ClinicalTrials.gov; Unique identifier: NCT04183465.

Humans↗

Generalized gamma frailty model.

In this article, we present a frailty model using the generalized gamma distribution as the frailty distribution. It is a power generalization of the popular gamma frailty model. It also includes other frailty models such as the lognormal and Weibull frailty models as special cases. The flexibility of this frailty distribution makes it possible to detect a complex frailty distribution structure which may otherwise be missed. Due to the intractable integrals in the likelihood function and its derivatives, we propose to approximate the integrals either by Monte Carlo simulation or by a quadrature method and then determine the maximum likelihood estimates of the parameters in the model. We explore the properties of the proposed frailty model and the computation method through a simulation study. The study shows that the proposed model can potentially reduce errors in the estimation, and that it provides a viable alternative for correlated data. The merits of proposed model are demonstrated in analysing the effects of sublingual nitroglycerin and oral isosorbide dinitrate on angina pectoris of coronary heart disease patients based on the data set in Danahy et al. (sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977; 55:381-387).

Angina Pectoris↗

Nested frailty models using maximum penalized likelihood estimation.

The frailty model is a random effect survival model, which allows for unobserved heterogeneity or for statistical dependence between observed survival data. The nested frailty model accounts for the hierarchical clustering of the data by including two nested random effects. Nested frailty models are particularly appropriate when data are clustered at several hierarchical levels naturally or by design. In such cases it is important to estimate the parameters of interest as accurately as possible by taking into account the hierarchical structure of the data. We present a maximum penalized likelihood estimation (MPnLE) to estimate non-parametrically a continuous hazard function in a nested gamma-frailty model with right-censored and left-truncated data. The estimators for the regression coefficients and the variance components of the random effects are obtained simultaneously. The simulation study demonstrates that this semi-parametric approach yields satisfactory results in this complex setting. In order to illustrate the MPnLE method and the nested frailty model, we present two applications. One is for modelling the effect of particulate air pollution on mortality in different areas with two levels of geographical regrouping. The other application is based on recurrent infection times of patients from different hospitals. We illustrate that using a shared frailty model instead of a nested frailty model with two levels of regrouping leads to inaccurate estimates, with an overestimation of the variance of the random effects. We show that even when the frailty effects are fairly small in magnitude, they are important since they alter the results in a systematic pattern.

Adult↗

A simple frailty model for family studies with covariates.

A simple, easily analysed frailty model based on logistic regression and employing only binary frailties is developed and analysed. Methods for testing for frailty and estimates of frailty parameters and covariate effects are presented. The effects of ignoring or mis-specifying frailty are examined in detail and shown to downwardly bias the estimates of covariate effects in a variety of situations, even when frailty is over-estimated. When the true frailty is large it can be difficult to estimate accurately because of the flatness of the likelihood. However, it is shown that this does not have a large influence on the estimates of the effects of the observed covariates. Methods for dealing with multiple frailties, for example, sibships and spouse pairs, are also developed. The results are illustrated on a large data set examining the risk factors associated with palmar keratoses.

Epidemiologic Methods↗

Assessing gamma frailty models for clustered failure time data.

Proportional hazards frailty models use a random effect, so called frailty, to construct association for clustered failure time data. It is customary to assume that the random frailty follows a gamma distribution. In this paper, we propose a graphical method for assessing adequacy of the proportional hazards frailty models. In particular, we focus on the assessment of the gamma distribution assumption for the frailties. We calculate the average of the posterior expected frailties at several followup time points and compare it at these time points to 1, the known mean frailty. Large discrepancies indicate lack of fit. To aid in assessing the goodness of fit, we derive and estimate the standard error of the mean of the posterior expected frailties at each time point examined. We give an example to illustrate the proposed methodology and perform sensitivity analysis by simulations.

Adult↗

Evaluation of a frailty index based on a comprehensive geriatric assessment in a population based study of elderly Canadians.

BACKGROUND AND AIMS: Objectives were to develop a frailty index (FI) based on a standard comprehensive geriatric assessment (CGA) derived from a clinical examination; to assess the validity of the FI-CGA and to compare its precision with other frailty measures. METHODS DESIGN: Secondary analysis of a prospective cohort study, with five-year follow-up data. SETTING: Second phase of the Canadian Study of Health and Aging (CSHA-2); clinical examinations were performed in clinics, nursing homes, and patients' homes. PARTICIPANTS: People selected (as either cognitively impaired cases or unimpaired controls) to receive the CSHA-2 clinical examination (n = 2305; women = 1431). MEASUREMENTS: Clinical and performance-based measures and diagnostic data were extracted to correspond to the 10 impairment domains and the single comorbidity domain of a CGA. The proportion of deficits accumulated in each domain was calculated to yield the FI-CGA. The FI-CGA was validated and its predictive ability compared with other frailty measures. RESULTS: Within the seven grades of fitness/frailty identified, subjects with greater frailty were older, less educated, and more likely to be women. The FI-CGA correlated highly with a previously validated, empirically-derived frailty index (r = 0.76). Frailty was associated with higher risk of death (for each increment in frailty, the hazard ratio, adjusted for age, sex and education, was 1.23 (95% CI 1.18-1.29) and institutionalization (HR 1.20; 1.10-1.32). CONCLUSIONS: In a population survey, the FI-CGA is a valid means of quantifying frailty from routinely collected data.

Aged↗

Frailty and age-related cataract.

OBJECTIVE: To determine whether there is an association between age-related cataract and frailty that persists after controlling for visual acuity (VA) and comorbid conditions. DESIGN: Cross-sectional. PARTICIPANTS: Two thousand three hundred seventy Beaver Dam Eye Study cohort members at 10-year (third) examination with cataract information. Ninety-nine percent of the population was Caucasian. METHODS: Medical history, blood pressures, height, weight, measures of frailty, and lens photographs were obtained during the study evaluation. Lens photographs were graded according to standardized protocols. MAIN OUTCOME MEASURES: Four of frailty (gait time, peak expiratory flow rate, handgrip strength, chair stand) and an index combining all 4 measures. RESULTS: After controlling for age, age squared, comorbidity index, pack-years, sedentary lifestyle, education, and VA, nuclear cataract in women was not associated significantly with any frailty measures; in men, nuclear cataract was associated with slower gait time (P = 0.01) and a poorer frailty index score (P = 0.01) in multivariable analyses. Cortical cataract was associated in women with a lower peak expiratory flow rate (P<0.01) and in men with weaker handgrip strength (P = 0.02) and a poorer frailty index score (P</=0.01) in multivariable analyses. Posterior subcapsular cataract in women was associated significantly with a lower peak expiratory flow rate (P = 0.01). Nuclear and cortical cataract add significant information in explaining frailty index scores in men. CONCLUSIONS: Three common types of age-related cataract are associated with some measures of frailty independent of VA and systemic comorbidities. It is possible that age-related cataract may be an indicator of general functional decline in older adults.

Adult↗

Prevalence, attributes, and outcomes of fitness and frailty in community-dwelling older adults: report from the Canadian study of health and aging.

BACKGROUND: Frailty and fitness are important attributes of older persons, but population samples of their prevalence, attributes, and outcomes are limited. METHODS: The authors report data from the community-dwelling sample (n = 9008) of the Canadian Study of Health and Aging, a representative, 5-year prospective cohort study. Fitness and frailty were determined by self-reported exercise and function level and testing of cognition. RESULTS: Among the community-dwelling elderly population, 171 per 1000 were very fit and 12 per 1000 were very frail. Frailty increased with age, so that by age 85 years and older, 44 per 1000 were very frail. The risk for adverse health outcomes increased markedly with frailty: Compared with older adults who exercise, those who were moderately or severely frail had a relative risk for institutionalization of 8.6 (95% confidence interval, 4.9 to 15.2) and for death of 7.3 (95% confidence interval, 4.7 to 11.4). These risks persist after adjustments for age, sex, comorbid conditions, and poor self-rated health. At all ages, men reported higher levels of exercise and less frailty compared with women. Decreased fitness and increased frailty were also associated with poor self-ratings of health (42% in the most frail vs 7% in the most fit), more comorbid illnesses (6 vs 3), and more social isolation (34% vs 29%). CONCLUSIONS: Fitness and frailty form a continuum and predict survival. Exercise influences survival, even in old age. Relative fitness and frailty can be determined quickly in a clinical setting, are potentially useful markers of the risk for adverse health outcomes, and add value to traditional medical assessments that focus on diagnoses.

Aged↗

Low nutrient intake is an essential component of frailty in older persons.

BACKGROUND: Poor nutrient intake is conceptualized to be a component of frailty, but this hypothesis has been little investigated. We examined the association between low energy and nutrient intake and frailty. METHODS: We used data from 802 persons aged 65 years or older participating to the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study. Frailty was defined by having at least two of the following criteria: low muscle strength, feeling of exhaustion, low walking speed, and reduced physical activity. The European Prospective Investigation into Cancer and nutrition (EPIC) questionnaire was used to estimate the daily intake of energy and nutrients. Low intake was defined using the value corresponding to the lowest sex-specific intake quintile of energy and specific nutrients. Adjusted logistic regression analyses were used to study the association of frailty and frailty criteria with low intakes of energy and nutrients. RESULTS: Daily energy intake < or =21 kcal/kg was significantly associated with frailty (odds ratio [OR]: 1.24; 95% CI: 1.02-1.5). After adjusting for energy intake, a low intake of protein (OR: 1.98; 95% CI: 1.18-3.31); vitamins D (OR: 2.35; 95% CI: 1.48-3.73), E (OR: 2.06; 95% CI: 1.28-3.33), C (OR: 2.15; 95% CI: 1.34-3.45), and folate (OR: 1.84; 95% CI: 1.14-2.98); and having a low intake of more than three nutrients (OR: 2.12; 95% CI: 1.29-3.50) were significantly and independently related to frailty. CONCLUSIONS: This study provides evidence that low intakes of energy and selected nutrients are independently associated with frailty.

Aged↗

Estimation of multivariate frailty models using penalized partial likelihood.

There exists a growing literature on the estimation of gamma distributed multiplicative shared frailty models. There is, however, often a need to model more complicated frailty structures, but attempts to extend gamma frailties run into complications. Motivated by hip replacement data with a more complicated dependence structure, we propose a model based on multiplicative frailties with a multivariate log-normal joint distribution. We give a justification and an estimation procedure for this generally structured frailty model, which is a generalization of the one presented by McGilchrist (1993, Biometrics 49, 221-225). The estimation is based on Laplace approximation of the likelihood function. This leads to estimating equations based on a penalized fixed effects partial likelihood, where the marginal distribution of the frailty terms determines the penalty term. The tuning parameters of the penalty function, i.e., the frailty variances, are estimated by maximizing an approximate profile likelihood. The performance of the approximation is evaluated by simulation, and the frailty model is fitted to the hip replacement data.

Biometry↗