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PubMed2002

Frailty, fitness and late-life mortality in relation to chronological and biological age.

BACKGROUND: People age at remarkably different rates, but how to estimate trajectories of senescence is controversial. METHODS: In a secondary analysis of a representative cohort of Canadians aged 65 and over (n = 2914) we estimated a frailty index based on the proportion of 20 deficits observed in a structured clinical examination. The construct validity of the index was examined through its relationship to chronological age (CA). The criterion validity was examined in its ability to predict mortality, and in relation to other predictions about aging. From the frailty index, relative (to CA) fitness and frailty were estimated, as was an individual's biological age. RESULTS: The average value of the frailty index increased with age in a log-linear relationship (r = 0.91; p < 0.001). In a Cox regression analysis, biological age was significantly more highly associated with death than chronological age. The average increase in the frailty index (i.e. the average accumulation of deficits) amongst those with no cognitive impairment was 3 per cent per year. CONCLUSIONS: The frailty index is a sensitive predictor of survival. As the index includes items not traditionally related to adverse health outcomes, the finding is compatible with a view of frailty as the failure to integrate the complex responses required to maintain function.

Journal Article↗

PubMed1994

Multivariate survival analysis using piecewise gamma frailty.

In this note we propose a frailty model called piecewise gamma frailty for correlated survival data with random effects having a nested structure. In frailty models, a dependence function defined as a hazard ratio of one member given the failure time of another member in a unit is determined by the distributional assumptions on frailty. In the piecewise gamma frailty model, the nested structure of random effects or frailty allows the dependence function to vary over the time periods. This model includes existing models such as the piecewise exponential model (Breslow, 1974, Biometrics 30, 89-100) and the gamma frailty model (Clayton, 1978, Biometrika 65, 141-151; Oakes, 1982, Journal of the Royal Statistical Society, Series B 44, 414-428) as special cases. A study of familial aggregation of epilepsy is used to illustrate the proposed method.

Adult↗

PubMed1997

A dynamic frailty model for multivariate survival data.

We consider the statistical modeling of data consisting of many study subjects with serially correlated multivariate survival responses. The (ordinary) frailty model handles the serial correlation in such data by introducing an unobserved multiplicative random effect term, called the frailty, in the hazard function. The frailties are often assumed to be identical for the survival times from the same unit. We have generalized the frailty model by allowing the frailties to vary stochastically with the indices. We have proposed a simple scheme to update the dynamic frailties. This approach assumes that the random effects are gamma distributed. At each occurrence, the two gamma parameters are updated according to the past information. In terms of their marginal distributions, the dynamic frailties form a multiplicative random walk. This approach results in a tractable likelihood. The small sample behavior of the MLE is studied via a simulation experiment. The model is then illustrated with a data set from an animal carcinogenesis experiment.

Biometry↗

PubMed2025

Causal relationship between frailty and diabetes subtypes: A bidirectional Mendelian randomization study.

Frailty and diabetes mellitus (DM) are closely linked, but their causal relationship remains unclear. This study aims to determine the bidirectional causal relationship between frailty and different DM subtypes using Mendelian randomization (MR). We performed a 2-sample MR analysis using summary statistics from large-scale genome-wide association studies. The inverse-variance weighting method was the primary analytical approach, with MR-Egger regression and weighted median methods for sensitivity analysis. Horizontal pleiotropy and heterogeneity were assessed using MR-PRESSO and Cochran Q test. Genetically predicted frailty was significantly associated with an increased risk of type 2 diabetes (T2DM) and gestational diabetes (GDM) (odds ratio [OR] = 2.142, 95% confidence interval [CI]: 1.751-2.621, P < .001; OR = 2.280, 95% CI: 1.368-3.800, P = .002), but no causal relationship was observed for type 1 diabetes or glycemic traits (P > .05). Conversely, genetically predicted type 1 diabetes, T2DM, GDM, and postprandial glucose levels (2-hour post-load glucose) increased the risk of frailty (OR = 1.026, 95% CI: 1.014-1.038, P < .001; OR = 1.046, 95% CI: 1.033-1.058, P < .001; OR = 1.068, 95% CI: 1.040-1.096, P < .001; OR = 1.095, 95% CI: 1.049-1.144, P < .001). Sensitivity analyses confirmed the robustness of these findings. This study provides genetic evidence supporting a bidirectional causal relationship between frailty and diabetes, particularly T2DM and GDM. These findings highlight the need for early frailty screening in diabetic patients and better metabolic management in frail populations.

Humans↗

PubMed2026

Beyond multidimensionality: a systematic review of recurrent frailty archetypes in community-dwelling older adults.

BACKGROUND: Frailty is a clinically heterogeneous geriatric syndrome commonly summarised using physical or multidomain severity scores. Whether person-centred analyses identify recurring within-frailty configurations has not been systematically examined in community-dwelling older adults. METHODS: We searched PubMed, Embase, MEDLINE, and CINAHL (January 2000-November 2025) for cross-sectional studies using latent class, latent profile, or analogous clustering methods to derive frailty subgroups. Quality was assessed using the AHRQ checklist and a purpose-built appraisal of person-centred model reporting. Study-derived classes were mapped in duplicate to a structured archetype framework developed through comparison of class-defining features across studies. RESULTS: Fourteen reports representing 12 independent datasets from eight countries were included. Six configurations were identified: minimally impaired reference, mobility-physical, nutritional-metabolic, cognitive-predominant, combined cognitive-physical, and psychosocial/mood-predominant. Convergence was measurement-dependent. The reference and mobility-physical configurations recurred across physical-only and multidomain indicator sets, while the combined cognitive-physical configuration appeared across several multidomain frameworks but required cognition to be measured. The remaining configurations emerged only when their defining domains were included. Evidence of prognostic value beyond aggregate frailty severity came from one deficit-index study. Collapsing shared-provenance reports and excluding the boundary-eligible study did not alter recurrence; excluding the Croatian dataset left five configurations recurrent, with the cognitive-predominant configuration supported by one independent dataset. CONCLUSIONS: Person-centred analyses identify recurring within-frailty configurations, but their apparent stability is partly measurement-dependent. A five-configuration core persisted after exclusion of the Croatian dataset, whereas the cognitive-predominant configuration remained weakly replicated. Harmonised indicators and rigorous external validation are needed before clinical application.

Humans↗

PubMed2000

Cancer incidence for Swedish twins studied by means of bivariate frailty models.

Cancer incidence rates for Swedish twins born between 1928 and 1965 and who both were alive at age 30 are studied by means of bivariate frailty models. Altogether, 7,280 fraternal (DZ) and 4,699 identical (MZ) twin pairs were followed up through December 31, 1995, for cancer status. The association between cancer incidence rates was statistically greater among the MZ than among the DZ pairs and stronger between women than between men; however, the magnitude of this association is relatively small and decreases over time. The relative decrease in dependency (association) is most easily detected using shared frailty models but may also be demonstrated, at least for women, using correlated frailty models. We also demonstrate that estimates of the correlation coefficient are similar when using any correlated frailty models derived from the power variance family but that these estimates disagree regarding the age at which the dependence is most important. The relative importance of dependence across age may sometimes be more interesting than the correlation coefficient itself. The latter may usually be estimated using alternative methods. Furthermore, when estimating correlation coefficients close to the boundary of the parameter space, simulation studies indicate that the correlated inverse Gaussian frailty model is more robust than the gamma frailty model.

Adult↗

PubMed2004

Analysis of testicular cancer data using a frailty model with familial dependence.

Previously published papers have indicated a fairly strong familial dependence intesticular cancer patients. This is particularly evident in brothers. We have applied a frailty model with familial dependence to family data on brothers of testicular cancer patients from the Norwegian Radium Hospital. The model is a two-level frailty, with variation in susceptibility at both the family and the individual level. Specifically, the frailty variable is assumed to be compound Poisson distributed to allow individuals to be non-susceptible. The underlying Poisson parameter is gamma distributed to model how testicular cancer is distributed among families. This is an extension of a previous compound Poisson frailty model developed for individual testicular cancer data, and an alternative to traditional modelling of survival time family data. The likelihood construction and ascertainment problems are looked at in detail. To avoid ascertainment bias, the likelihood is based on the probability of observing the disease status for each brother in a family, given that at least one brother is ascertained. The estimated relative risk for brothers is 7.4. This paper expands on a previous analysis of the data by using a frailty model, which makes it possible to examine how the cancer is distributed among families. The estimated gamma-shaped parameter is 0.151 (95 per cent confidence interval 0.078-0.294), and this indicates that in order to obtain the high relative risks observed for brothers of testicular cancer patients, the distribution of susceptibility has to be strongly skewed among the families. The vast majority of families have a very low risk and a small proportion have a high risk. In addition, a quantity similar to the relative risk is derived to show that the susceptibility is skewly distributed also if the Poisson parameter is Bernoulli or stable distributed. This indicates that the results are valid also if other distributions are used to model familial dependence in the compound Poisson frailty model.

Genetic Predisposition to Disease↗

PubMed2006

Correcting for selection using frailty models.

Chronic diseases are roughly speaking lifelong transitions between the states: relapse and recovery. The long-term pattern of recurrent times-to-relapse can be investigated with routine register data on hospital admissions. The relapses become readmissions to hospital, and the time spent in hospital are gaps between subsequent times-at-risk. However, problems of selection and dependent censoring arise because the calendar period of observation is limited and the study population likely to be heterogeneous. We will theoretically verify that an assumption of conditional independence of all times-at-risk and gaps, given the latent individual frailty level, allows for consistent inference in the shared frailty model. Using simulation studies, we also investigate cases where gaps (and/or staggered entry) are informative for the individual frailty. We found that the use of the shared frailty model can be extended to situations, where gaps are dependent on the frailty, but short compared to the distribution of the times-to-relapse. Our motivating example deals with the course of schizophrenia. We analysed routine register data on readmissions in almost 9000 persons with the disorder. Marginal survival curves of time-to-first-readmission, time-to-second-readmission, etc. were estimated in the shared frailty model. Based on the schizophrenia literature, the conclusion of our analysis was rather surprising: one of a stable course of disorder.

Chronic Disease↗

PubMed2005

Small sample bias in the gamma frailty model for univariate survival.

The gamma frailty model is a natural extension of the Cox proportional hazards model in survival analysis. Because the frailties are unobserved, an E-M approach is often used for estimation. Such an approach is shown to lead to finite sample underestimation of the frailty variance, with the corresponding regression parameters also being underestimated as a result. For the univariate case, we investigate the source of the bias with simulation studies and a complete enumeration. The rank-based E-M approach, we note, only identifies frailty through the order in which failures occur; additional frailty which is evident in the survival times is ignored, and as a result the frailty variance is underestimated. An adaption of the standard E-M approach is suggested, whereby the non-parametric Breslow estimate is replaced by a local likelihood formulation for the baseline hazard which allows the survival times themselves to enter the model. Simulations demonstrate that this approach substantially reduces the bias, even at small sample sizes. The method developed is applied to survival data from the North West Regional Leukaemia Register.

Acute Disease↗

PubMed2005

Frailty, hospitalization, and progression of disability in a cohort of disabled older women.

PURPOSE: To determine the association between a previously validated frailty phenotype and the development of new-onset dependence in activities of daily living, independent of hospitalizations and other established predictors of disability. SUBJECTS: Seven hundred and forty-nine women enrolled in the Women's Health and Aging Study-I who were independent in all activities in daily living when enrolled in the cohort. METHODS: Assessments and interviews were conducted through home visits at 6-month intervals for 3 years. Frailty was classified using a validated phenotype (> or =3 of the following: weight loss, exhaustion, slow walking, sedentariness, and weak grip), and hospitalizations were identified by self-report. Grouped-time proportional hazard models assessed associations among frailty, hospitalization, and the development of dependence in activities in daily living, adjusting for other factors. RESULTS: Twenty-five percent of the cohort (186/749) were frail at baseline; 56% (104/186) of frail versus 20% (23/117) of nonfrail women developed dependence in activities in daily living (P <.001). In multivariate analysis, frailty was independently associated with the development of dependence in activities in daily living (hazard ratio [HR] = 2.2; 95% confidence interval [CI]: 1.4 to 3.6), adjusting for hospitalization status, age, race, education, baseline functional status, cognition, depressive symptoms, number of chronic diseases, and self-reported health status. Additionally, a dose-response relationship existed between the number of frailty criteria that a woman had and the hazard of subsequent dependence in activities in daily living. CONCLUSION: Frailty, conceptualized as an underlying vulnerability, and hospitalization, which marks an acute deterioration in health, were strongly and independently associated with new-onset dependence in activities in daily living. Additional research is needed to determine if dependence can be minimized by targeting resources and programs to frail older persons.

Activities of Daily Living↗

PubMed2006

The association of race with frailty: the cardiovascular health study.

PURPOSE: Frailty, which has been conceptualized as a state of decreased physiologic reserve contributing to functional decline, has a prevalence among older African Americans that is twice that in older whites. This study assesses the independent contribution of race to frailty. METHODS: We evaluated 786 African-American and 4491 white participants of the Cardiovascular Health Study (CHS). Frailty is defined as meeting three or more of five criteria derived from CHS measures: lowest quintile for grip strength, self-reported exhaustion, unintentional weight loss of 10 lbs or greater in 1 year, slowest quintile for gait speed, and lowest quintile for physical activity. Controlling for age, sex, comorbidity, socioeconomic factors, and race, multinomial logistic regression estimated the odds ratio (OR) of prefrail (one or two criteria) to not frail and frail to not frail. RESULTS: Among African Americans, 8.7% of men and 15.0% of women were frail compared with 4.6% and 6.8% of white men and women, respectively. In adjusted models, nonobese African Americans had a fourfold greater odds of frailty compared with whites. The increased OR of frailty associated with African-American race was less pronounced among those who were obese or disabled. CONCLUSION: African-American race is associated independently with frailty.

Black or African American↗

PubMed2005

Static and dynamic measures of frailty predicted decline in performance-based and self-reported physical functioning.

OBJECTIVE: To determine the effect of frailty on decline in physical functioning and to examine if chronic diseases modify this effect. METHODS: The study sample was derived from the Longitudinal Aging Study Amsterdam and included respondents with initial ages 65 and over at T(2) (1995/1996), who participated at T(1) (1992/1993) and T(2) and performed physical performance tests (n = 1,152) or reported functional limitations (n = 1,321) at T(2) and T(3) (1998/1999). Nine frailty markers were determined in two ways: low functioning at T(2) (static definition); and decline in functioning between T(1) and T(2) (dynamic definition). Using logistic regression analyses, the effect of frailty was examined on change in physical functioning between T(2) and T(3), adjusting for sex, age, education, and additionally chronic diseases. RESULTS: Static frailty was associated with performance decline only in the middle-old group (OR 2.43; 95%CI 1.23-4.80) and associated with decline in self-reported functioning (OR 2.44; 95%CI 1.77-3.36). Dynamic frailty was associated with decline in performance only in women (OR 1.72; 95%CI 1.11-2.67) and with self-reported functional decline (OR 1.77; 95%CI 1.29-2.43). These associations were independent of chronic diseases. CONCLUSION: Frailty is more strongly associated with self-reported functional decline in older persons than with performance decline.

Activities of Daily Living↗

PubMed1999

Frailty and the older man.

Frailty is a wasting syndrome of advanced age that leaves a person vulnerable to falls, functional decline, morbidity, and mortality. The cause of this syndrome is complex but likely has a biologic basis. Studies by the authors' research group have validated a phenotype of frailty [table: see text] and have established a gender difference in prevalence with women twice as likely to develop the syndrome as men. Using a biologic model that includes sarcopenia, neuroendocrine decline, and immune dysfunction as potential causes, several physiologic gender differences may explain these differing levels of frailty. First, higher baseline levels of muscle mass may protect men from reaching a threshold of weakness and muscle mass loss that may put them into a category of frailty. Specific neuroendocrine and hormonal factors that may make men less likely to develop frailty than women include testosterone and GH, which may provide advantages in muscle mass maintenance, and cortisol, which is likely less dysregulated in older men as compared to older women. There is also evidence of immune system dimorphism that is, in part, responsive to sex steroids, perhaps making men more vulnerable to sepsis and infection and women more vulnerable to chronic inflammatory conditions and muscle mass loss. The net effect of the hormonal dysregulation and immune system dysfunction is an accelerated loss of muscle mass. There is also evidence that lower levels of activity and lower caloric intake in women as compared to men may also influence the phenotype of frailty and make women more vulnerable then men to the syndrome.

Black or African American↗

PubMed2001

Diagnostic plots for assessing the frailty distribution in multivariate survival data.

In biomedical studies, frailty models are commonly used in analyzing multivariate survival data, where the objective of the study is to estimate both the covariate effect and the dependence between the multivariate survival times. However, inference based on these models are dependent on the distributional assumption of frailty. We propose a diagnostic plot for assessing the frailty assumption. The proposed method is based on the cross-ratio function and the diagnostic plot suggested by Oakes (1989). We use kernel regression smoothing with bandwidth choice by cross-validation, to obtain the proposed plot. The resulting plot is capable of differentiating between the gamma and positive stable frailty models when strong association is present. We illustrate the feasibility of our method using simulation studies under known frailty distributions. The approach is applied to data on blindness for each eye of diabetic patients with adult onset diabetes and a reasonable fit to the gamma frailty model is found.

Blindness↗

PubMed2026

Validation and refinement of a biomarker panel for frailty assessment and prediction of muscle weakness in older adults.

Frailty is a complex geriatric syndrome characterized by age-related declines in physiological function and cognitive reserve. To promote early prevention and intervention, minimally invasive and objective biomarkers that can detect frailty progression are required. We aimed to identify biomarkers associated with frailty progression and to elucidate their relevance to the Japanese version of the Cardiovascular Health Study (J-CHS) criteria, consist of five components (unintentional weight loss, self-reported exhaustion, muscle weakness, slow walking speed, and low physical activity). A total of 168 individuals (61 robust, 25 pre-frail, and 82 frail) enrolled in the NCGG (National Center for Geriatrics and Gerontology) Biobank were analyzed. Clinical information, blood-test data, aging-related factors, and gene-expression data were integrated for the analysis. First, linear regression identified one clinical factor, five aging-related factors, and 251 gene-expression factors associated with frailty. Subsequent logistic regression analyses examining each J-CHS components highlighted six candidate biomarkers. Cross-validation further suggested that three of these biomarkers-SMI, apelin, and GDF15-may represent potential biomarkers. Finally, retrospective and prospective analyses further demonstrated that those biomarkers were predictive of future muscle weakness, yielding a concordance index of 0.70. In conclusion, we validated and refined a biomarker panel consisting of SMI, apelin, and GDF15 that is associated with frailty, particularly muscle weakness (a major J-CHS component). These biomarkers may be useful for frailty assessment. Longitudinal analyses further suggested that they may be associated with the future development of muscle weakness in initially robust older adults, although validation in larger prospective cohorts is warranted.

Journal Article↗

PubMed2000

Low-intensity exercise as a modifier of physical frailty in older adults.

OBJECTIVE: To examine the effects of a 3-month low-intensity exercise program on physical frailty. DESIGN: Randomized clinical trial. SETTING: Regional tertiary-care hospital and academic medical center with an outpatient rehabilitation fitness center. PARTICIPANTS: Eighty-four physically frail older adults (mean age, 83 +/- 4 yrs). INTERVENTION: Three-month low-intensity supervised exercise (n = 48) versus unsupervised home-based flexibility activities (n = 36). MAIN OUTCOME MEASURES: Physical performance test, measures of balance, strength, flexibility, coordination, speed of reaction, peripheral sensation. RESULTS: Significant improvement was made by the exercise group on our primary indicator of frailty, a physical performance test (PPT) (29 +/- 4 vs 31 +/- 4 out of a possible 36 points), as well as many of the risk factors previously identified as contributors to frailty; eg, reductions in flexibility, strength, gait speed, and poor balance. Although the home exercise control group showed increases in range of motion, the improvements in flexibility did not translate into improvements in physical performance capacity as assessed by the PPT. CONCLUSIONS: Our results suggest that physical frailty is modifiable with a program of modest activities that can be performed by virtually all older adults. They also indicate that exercise programs consisting primarily of flexibility activities are not likely to reverse or attenuate physical frailty. Although results suggest that frailty is modifiable, it is not likely to be eliminated with exercise, and efforts should be directed toward preventing the condition.

Aged↗

PubMed2005

What would make a definition of frailty successful?

At present, frailty is defined variably. Some consensus on a definition is likely to emerge, but the basis for a successful definition needs to be explored. Here, a classic approach to validation is proposed: a successful definition of frailty should be multifactorial but must also manage the many factors in a way that takes their interactions into account. It is likely to be correlated with disability, co-morbidity and self-rated health, and should identify a group that is vulnerable to adverse outcomes. Ideally, it should also be susceptible to animal modelling. In that frailty and age are so bound together, it is also likely that there will be some age at which virtually all people will be frail, by any definition. Apart from being valid, the success of any definition of frailty will depend on it being useful to researchers and clinicians. The need for progress on our understanding of frailty is evident, but for now, there is insufficient evidence to accept a single definition of frailty.

Aged↗

PubMed2004

Nutritional frailty, sarcopenia and falls in the elderly.

PURPOSE OF REVIEW: There is currently intense interest in understanding why certain elderly individuals become frail and disabled with age whereas others do not. Is frailty the result of an acceleration of normal aging processes or is it the result of chronic medical conditions that are superimposed on the conventional mechanisms of aging? The clinical problem of falls has long been recognized as a threat to some elderly individuals, but too often is not considered worthy of objective study. The factors underlying falls are now being investigated as part of the increasing attention being paid to the evolution of frailty in the elderly. RECENT FINDINGS: Frailty in the elderly has been given many names, but increasing efforts are now being made to define frailty in a standardized way that would allow more objective study. The frail elderly patient usually shows loss of both neurological and muscle function. Falls in the elderly are an example in which deterioration may be present in both functions. Methods are being developed to separate the loss of muscle capacity from the associated loss of central and peripheral neurological function involved in gait and balance. SUMMARY: The definition of frailty has been centered around the onset of accelerated weight loss with an associated decrease of mass and strength of skeletal muscle. New studies are discussed that extend this definition. Methods for a more detailed analysis of the physiological and metabolic deficits leading to falls in the elderly may provide a better understanding of frailty in general.

Accidental Falls↗