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PubMed2004

Hospitalization, restricted activity, and the development of disability among older persons.

CONTEXT: Preventing the development of disability in activities of daily living is an important goal in older adults, yet relatively little is known about the disabling process. OBJECTIVES: To evaluate the relationship between 2 types of intervening events (hospitalization and restricted activity) and the development of disability and to determine whether this relationship is modified by the presence of physical frailty. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study, conducted in the general community in greater New Haven, Conn, from March 1998 to March 2003, of 754 persons aged 70 years or older, who were not disabled (ie, required no personal assistance) in 4 essential activities of daily living: bathing, dressing, walking inside the house, and transferring from a chair. Participants were categorized into 2 groups according to the presence of physical frailty (defined on the basis of slow gait speed) and were followed up with monthly telephone interviews for up to 5 years to ascertain exposure to intervening events and determine the occurrence of disability. MAIN OUTCOME MEASURE: Disability, defined as the need for personal assistance in bathing, dressing, walking inside the house, or transferring from a chair. RESULTS: During the 5-year follow-up period, disability developed among 417 (55.3%) participants, 372 (49.3%) were hospitalized and 600 (79.6%) had at least 1 episode of restricted activity. The multivariable hazard ratios for the development of disability were 61.8 (95% confidence interval [CI], 49.0-78.0) within a month of hospitalization and 5.54 (95% CI, 4.27-7.19) within a month of restricted activity. Strong associations were observed for participants who were physically frail and those who were not physically frail. Hospital admissions for falls were most likely to lead to disability. Intervening events occurring more than a month prior to disability onset were not associated with the development of disability. The population-attributable fractions associated with new exposure to hospitalization and restricted activity, respectively, were 0.48 and 0.19; 0.40 and 0.20, respectively, for frail participants and 0.61 and 0.16, respectively, for nonfrail participants. CONCLUSIONS: Illnesses and injuries leading to either hospitalization or restricted activity represent important sources of disability for older persons living in the community, regardless of the presence of physical frailty. These intervening events may be suitable targets for the prevention of disability.

Activities of Daily Living↗

PubMed2005

A class of goodness of fit tests for a copula based on bivariate right-censored data.

The copula of a bivariate distribution, constructed by making marginal transformations of each component, captures all the information in the bivariate distribution about the dependence between two variables. For frailty models for bivariate data the choice of a family of distributions for the random frailty corresponds to the choice of a parametric family for the copula. A class of tests of the hypothesis that the copula is in a given parametric family, with unspecified association parameter, based on bivariate right censored data is proposed. These tests are based on first making marginal Kaplan-Meier transformations of the data and then comparing a non-parametric estimate of the copula to an estimate based on the assumed family of models. A number of options are available for choosing the scale and the distance measure for this comparison. Significance levels of the test are found by a modified bootstrap procedure. The procedure is used to check the appropriateness of a gamma or a positive stable frailty model in a set of survival data on Danish twins.

Algorithms↗

PubMed2002

A multistate model for the genetic analysis of the ageing process.

In this paper a multivariate frailty model is suggested that can be used in the genetic analysis of the ageing process as a whole, simplified to consisting of the states 'healthy', 'disabled' and 'deceased'. The model allows us to evaluate simultaneously the relative magnitude of genetic and environmental influences on frailty variables corresponding to the period of good health and to the life span. The frailty variables can be interpreted as susceptibility to illness or death. The model can be applied to data on groups of related individuals (twins, siblings, a litter). One of the major advantages of this model is that it allows one to include groups of individuals where some or all members of the group are already deceased at the time of observation. The current health status of the living individuals and the exact life span of individuals who are already deceased is the only information necessary for the application of the model. Questions concerning the identifiability of the model based on current health status data and estimation strategies are discussed in the context of specifying the model for twins. Finally, the results of a sample analysis of twin data on prostate cancer are presented.

Aged↗

PubMed2004

Modelling clustered survival data from multicentre clinical trials.

In randomized clinical trials, subjects are recruited at multiple study centres. Factors that vary across centres may exert a powerful independent influence on study outcomes. A common problem is how to incorporate these centre effects into the analysis of censored time-to-event data. We survey various methods and find substantial advantages in the gamma frailty model. This approach compares favourably with competing methods and appears minimally affected by violation of the assumption of a gamma-distributed frailty. Recent computational advances make use of the gamma frailty model a practical and appealing tool for addressing centre effects in the analysis of multicentre trials.

Humans↗

PubMed2006

Reduced-rank hazard regression for modelling non-proportional hazards.

The Cox proportional hazards model is the most common method to analyse survival data. However, the proportional hazards assumption might not hold. The natural extension of the Cox model is to introduce time-varying effects of the covariates. For some covariates such as (surgical)treatment non-proportionality could be expected beforehand. For some other covariates the non-proportionality only becomes apparent if the follow-up is long enough. It is often observed that all covariates show similar decaying effects over time. Such behaviour could be explained by the popular (gamma-) frailty model. However, the (marginal) effects of covariates in frailty models are not easy to interpret. In this paper we propose the reduced-rank model for time-varying effects of covariates. Starting point is a Cox model with p covariates and time-varying effects modelled by q time functions (constant included), leading to a pxq structure matrix that contains the regression coefficients for all covariate by time function interactions. By reducing the rank of this structure matrix a whole range of models is introduced, from the very flexible full-rank model (identical to a Cox model with time-varying effects) to the very rigid rank one model that mimics the structure of a gamma-frailty model, but is easier to interpret. We illustrate these models with an application to ovarian cancer patients.

Biometry↗

PubMed2007

Analysis of interval-censored data from circular migrant and non-migrant sexual partnerships using the EM algorithm.

In epidemiological studies where subjects are seen periodically on follow-up visits, interval-censored data occur naturally. The exact time the change of state (such as HIV seroconversion) occurs is not known exactly, only that it occurred sometime within a specific time interval. Methods of estimation for interval-censored data are readily available when data are independent. However, methods for correlated interval-censored data are not well developed. This paper considers an approach for estimating the parameters when data are interval-censored and correlated within sexual partnerships. We consider the exact event times for interval-censored observations as unobserved data, only known to be between two time points. Dependency induced by sexual partnerships is modelled as frailties assuming a gamma distribution for frailties and an exponential distribution on the time to infection. This formulation facilitates application of the expectation-maximization (EM) algorithm. Maximization process maximizes the standard survival frailty model. Results show high degree of heterogeneity between sexual partnerships. Intervention strategies aimed at combating the spread of HIV and other sexually transmitted infections (STI)s should treat sexual partnerships as social units and fully incorporate the effects of migration in their strategies.

Adolescent↗

PubMed2002

One-leg standing balance and functional status in an elderly community-dwelling population in northeast Italy.

BACKGROUND AND AIMS: Development of simple and accurate indicators of frailty is an important research goal in aging societies. One-leg standing balance (OLSB) has been proposed as a component of a clinical index of frailty. METHODS: We analyzed relationships between results of OLSB testing and multiple health risk factors and impairment/disability indicators in a sample of elderly subjects (N=102) participating in the Anchyses Project. Subjects were aged >65, lived in a home for the aged in Rovigo, Italy, and had no ADL dependencies or recent acute illnesses. RESULTS: More than half (53%) failed the OLSB test while 36% were able to balance without difficulty. Significant differences were observed among OLSB performance groups in forced vital capacity (p=0.025), dynamometry (p=0.001), age, physical activity, and IADL dependency (all p<0.001). CONCLUSIONS: OLSB performance is a marker of frailty and thus a potentially useful predictor of functional decline.

Activities of Daily Living↗

PubMed2003

Cortisol, DHEAS and aging: resistance to cortisol suppression in frail institutionalized elderly.

Convincing evidences has linked the hypothalamus-pituitary-adrenal (HPA) axis to aging patterns. F excess is implicated in the development of frailty characteristics whereas DHEAS is positively correlated to successful aging. We compared serum F and DHEAS levels of independent community-living (successful group, 19 M and 28 F, 69 to 87 yr) with those of institutionalized elderly (frail group, 20 M and 30 F, 65 to 95 yr). Serum F was determined at 1) baseline (08:00 h, 16:00 h and 23:00 h), 2) after 2 overnight dexamethasone (DEX) suppression tests (DST, using 0.25 and 1.0 mg doses), and 3) 60 min after ACTH stimulation (250 microg i.v. bolus); serum DHEAS was determined at 08:00 h. Basal serum F at 08:00 h, 16:00 h and 23:00 h and serum DHEAS levels were similar in both groups; however F: DHEAS ratio at 08:00 h was higher in the frail, compared to the successful group (mean +/- SD: 0.55 +/- 0.53 and 0.35 +/- 0.41, respectively; p = 0.04). In response to DST, F suppression was less effective in frail elderly after either 0.25 or 1.0 mg doses (9.0 +/- 6.0 and 2.0 +/- 0.9 microg/dl), as compared to the successful group (5.8 +/- 4.4 and 1.5 +/- 0.5 microg/dl) (p = 0.01). In addition, a significant correlation was observed between post-DEX F levels (both doses) and parameters of cognitive and physical frailty. Normal and similar F levels were observed after ACTH stimulation in both groups. Our data suggest a deficient feedback regulation of the HPA axis in frail institutionalized elderly, as demonstrated by a higher set point for F suppression. This augmented HPA tonus enforces the hypothesis that even milder F excess may be related to characteristics of frailty in the elderly.

Activities of Daily Living↗

PubMed2004

Laxative treatment elevates plasma homocysteine: a study on a population-based Swedish sample of old people.

OBJECTIVES: Elevated plasma homocysteine might indicate an increased risk of cancer, and cardiovascular and neurological diseases. The homocysteine level depends on the supply of folate and cobalamine, and constipation and/or laxative treatment might compromise this supply. The present study examined the impact of constipation and laxative treatment on the blood levels of homocysteine, folate and cobalamine in a population-based sample of aged people, including consideration of frailty and impaired renal function, both of which may also influence the homocysteine level. METHODS: The study was based on biochemical tests in 341 females and 183 males aged 82 years or older. The concentrations of homocysteine (plasma), folate, cobalamine and urea (serum) were measured in subjects with and without ongoing treatment with laxative drugs. Values were adjusted for age, gender and frailty, as well as for clinical diagnoses and drug therapies known to affect homocysteine levels. RESULTS: Homocysteine levels were increased and those of folate reduced in aged subjects on laxatives. Homocysteine remained elevated after adjusting for frailty and various neurological disorders. There was no significant effect on homocysteine and folate in constipated subjects without laxatives.

Aged↗

PubMed2004

The development of insidious disability in activities of daily living among community-living older persons.

PURPOSE: To determine how often disability in essential activities of daily living develops insidiously, and to evaluate whether the likelihood of insidious disability differs on the basis of physical frailty. METHODS: We conducted a prospective study of 754 nondisabled, community-living persons aged 70 years or older. Participants were categorized according to the presence or absence of physical frailty, which was defined on the basis of gait speed. Participants were subsequently followed with monthly telephone interviews for 3 years to determine the occurrence of disability in bathing, dressing, walking, or transferring, and to ascertain exposure to precipitating events, which included acute hospital admissions and other illnesses, injuries, or problems leading to restricted activity. RESULTS: For first episodes of disability, 73 (36%) of 203 developed insidiously among the 322 participants who were physically frail and 26 (18%) of 141 developed insidiously among the 432 participants who were not physically frail (P <0.001). Physical frailty was the only factor that was associated significantly with the development of insidious disability, with an adjusted odds ratio of 2.4 (95% confidence interval: 1.4 to 4.1). The likelihood that an episode of disability was insidious increased progressively, from 29% of the 344 first episodes to 65% of the 155 fourth or higher episodes (P for trend <0.001). CONCLUSION: Disability in essential activities of daily living often occurs insidiously, particularly among older persons who are physically frail or who have had prior episodes of disability.

Activities of Daily Living↗

PubMed2005

Low BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study.

We have previously shown that center- and sex-specific fall rates explained one-third of between-center variation in upper limb fractures across Europe. In this current analysis, our aim was to determine how much of the between-center variation in fractures could be attributed to repeated falling, bone mineral density (BMD), and other risk factors in individuals, and to compare the relative contributions of center-specific BMD vs. center-specific fall rates. A clinical history of fracture was assessed prospectively in 2451 men and 2919 women aged 50-80 from 20 centers participating in the European Prospective Osteoporosis Study (EPOS) using standardized questionnaires (mean follow-up = 3 years). Bone mineral density (BMD, femoral neck, trochanter, and/or spine) was measured in 2103 men and 2565 women at these centers. Cox regression was used to model the risk of incident fracture as a function of the person-specific covariates: age, BMD, personal fracture history (PFH), family hip fracture history (FAMHIP), time spent walking/cycling, number of 'all falls' and falls not causing fracture ('fracture-free') during follow-up, alcohol consumption, and body mass index. Center effects were modeled by inclusion of multiplicative gamma-distributed random effects, termed center-shared frailty (CSF), with mean 1 and finite variance theta (theta) acting on the hazard rate. The relative contributions of center-specific fall risk and center-specific BMD on the incidence of limb fractures were evaluated as components of CSF. In women, the risk of any incident nonspine fracture (n = 190) increased with age, PFH, FAMHIP, > or =1 h/day walking/cycling, and number of 'all falls' during follow-up (all P < 0.074). 'Fracture-free' falls (P = 0.726) and femoral neck BMD did not have a significant effect at the individual level, but there was a significant center-shared frailty effect (theta = 0.271, P = 0.001) that was reduced by 4% after adjusting for mean center BMD and reduced by 19% when adjusted for mean center fall rate. Femoral trochanter BMD was a significant determinant of lower limb fractures (n = 53, P = 0.014) and the center-shared frailty effect was significant for upper limb fractures (theta = 0.271, P = 0.011). This upper limb fracture center effect was unchanged after adjusting for mean center BMD but was reduced by 36% after adjusting for center mean fall rates. In men, risk of any nonspine fracture (n = 75) increased with PFH, fall during follow-up (P < 0.026), and with a decrease in trochanteric BMD [RR 1.38 (1.08, 1.79) per 1 SD decrease]. There was no center effect evident (theta = 0.081, P = 0.096). We conclude that BMD alone cannot be validly used to discriminate between the risk of upper limb fractures across populations without taking account of population-specific variations in fall risk and other factors. These variations might reflect shared environmental or possibly genetic factors that contribute quite substantially to the risk of upper limb fractures in women.

Accidental Falls↗

PubMed2006

Selective prescribing led to overestimation of the benefits of lipid-lowering drugs.

OBJECTIVE: Observational studies have found beneficial effects of lipid-lowering drugs on diverse outcomes, including venous thromboembolism, hip fracture, dementia, and all-cause mortality. Selective use of these drugs in frail people may confound these relationships. STUDY DESIGN AND SETTING: We measured 1-year mortality in two cohorts of New Jersey residents, aged 65-99 years, enrolled in state-sponsored drug benefits programs: 112,463 persons hospitalized during the years 1991-1994 and 106,838 nonhospitalized enrollees. Use of lipid-lowering drugs and other medications, as well as diagnoses, were evaluated before follow-up. RESULTS: In age- and sex-adjusted analyses, users of lipid-lowering drugs had a 43% reduced death rate relative to nonusers among hospitalized enrollees and a 56% reduction in the nonhospitalized sample. Available markers of frailty and comorbidity predicted decreased use of these drugs. Control for the propensity to use lipid-lowering drugs attenuated but did not eliminate these effects. After such adjustment, users had a 30% reduction in death rate (95% confidence interval [CI]: 25%-35%) among hospitalized enrollees and a 41% reduction (95% CI: 35%-47%) in the nonhospitalized sample. Unmeasured frailty associated with a 26%-33% reduced odds of receiving lipid-lowering therapy could explain this effect. CONCLUSION: Frailty and comorbidity that influence use of preventive therapies can substantially confound apparent benefits of lipid-lowering drugs on outcomes.

Age Factors↗

PubMed2006

Limits to deficit accumulation in elderly people.

We evaluated limits to the accumulation of deficits (symptoms, diseases, disabilities) for 33,069 people aged 65+ years. We combined deficits in a frailty index (theoretical range 0-1) and found that the 99% limit varied little between samples, representing a frailty index value of about 0.65 +/- 0.05. This near-maximum shows no relationship with age. It is the same in community and institutional samples, even though the mean value is much higher in the latter. The data suggest a level of frailty beyond which, even in developed countries, further deficit accumulation is not sustainable.

Aged↗

PubMed1998

Serum fructosamine level and the risk of hip fracture in elderly women: a case-cohort study within the study of osteoporotic fractures.

PURPOSE: While a high serum fructosamine level may be an indicator of undiagnosed diabetes, a low level may be indicative of poor nutrition or frailty. As malnutrition is a risk factor for osteoporosis, low serum fructosamine levels may be associated with an increased risk of osteoporotic fracture. We examined the association between serum fructosamine levels and the risk of subsequent hip and vertebral fracture. SUBJECTS AND METHODS: We performed a case-cohort study within the Study of Osteoporotic Fractures. Subjects were elderly, ambulatory, community-dwelling, Caucasian, women. Fructosamine levels were measured in baseline serum. Incident vertebral fractures were identified by comparing baseline spinal radiographs to those obtained an average of 3.5 years later. Hip fractures were confirmed by radiograph. We randomly selected 101 women who suffered a hip fracture, 100 women who developed a vertebral fracture, and 276 controls. We compared fructosamine levels in women with subsequent osteoporotic fractures to controls. All analyses were adjusted for age, weight, and use of estrogens. RESULTS: Women with fructosamine levels in the lowest decile (< or = 223 micromol/L) had a three-fold increase in the risk of hip fracture (95% confidence interval 1.4-6.4), compared with all other women. Adjustment for markers of frailty, including smoking, functional status, and serum albumin levels, reduced the strength of this association. No clear association was observed between serum fructosamine level and the risk of vertebral fracture. CONCLUSION: Low serum fructosamine levels, which likely reflect frailty or malnutrition, may be a useful clinical tool to identify women at risk for hip fracture.

Aged↗

PubMed2001

Treatment of cancer in old age, shortcomings and challenges.

The burden of cancer in old age is increasing as a result from both the expanding number of older persons in the population and the high and still increasing cancer incidence in this group. The goal of this article is to outline the shortcomings and challenges of the management of cancer in the elderly. Several factors contribute to the complexity of this management, such as the enormous heterogeneity in this population, increased co-morbidity, reduced functional status, increased frailty and different treatment goals from those in younger patients. Other problems include the lack of data on the efficacy and toxicity of cancer treatment in this age group, the lack of awareness of life-expectancy and the lack of an easy applicable and validated frailty scale. Improvement of the quality of oncological care in this age group could be achieved by initiation of clinical trials specifically directed at the elderly, in which a frailty scale is implemented. The results of these trials may lead to more evidence-based decision making in cancer treatment in the elderly.

Activities of Daily Living↗

PubMed2000

Psychological morbidity among informal caregivers of older people: a 2-year follow-up study.

BACKGROUND: It has long been assumed that mental frailty in older care-recipients results in a deterioration in family caregivers' psychological well-being. This hypothesis has not been tested in longitudinal studies. Research about the impact on families of supporting older people in institutions is limited. The present study examined psychological morbidity in informal caregivers of frail older people at home and in institutions. Caregivers were followed up over 2 years. Predictors of psychological morbidity in caregivers and factors related to deterioration in their well-being over time were identified. METHODS: Two-year panel survey of informal caregivers of older care-recipients, using semi-structured interview schedules and the 30-item GHQ. Care-recipients were those defined as physically or mentally frail after screening a stratified random sample of people aged > or = 65. Respondents were 276 caregivers of older people living at home at baseline and 47 visitors of those in long-term care at baseline. RESULTS: There were no differences in GHQ scores between caregivers at home and visitors, and no changes in GHQ score over time. The strongest predictors of psychological morbidity at follow-up, and of change in GHQ scores over time, were baseline GHQ score and indicators of subjective well-being. Characteristics of care-recipients, including frailty type (mental or physical), were not significantly associated with changes in caregivers' psychological morbidity. CONCLUSIONS: Mental frailty in care-recipients was not associated with deterioration over time in caregivers' psychological well-being. Caregiver characteristics were stronger than those of care-recipients in predicting psychological morbidity at follow-up and in predicting deteriorating well-being over time.

Aged↗

PubMed2001

Heating stress patterns in Caenorhabditis elegans longevity and survivorship.

Survival data from Caenorhabditis elegans strain TJ1060 (spe-9; fer-15) following brief exposure to 35 degrees C have been investigated. Three experiments with 3-day-old worms were conducted with heat duration ranging between 0 and 12 hours. A statistically significant increase in life expectancy was observed in the groups heated for less than 2 hours, as compared to the unheated control groups. In different experiments P-values for the observed life spans under the hypothesis that heating has no influence on longevity were P < 0.004 after 0.5 hour heat, P < 0.012 after 1 hour heat and P < 0.055 after 2 hours of heating. A biphasic survival model with Gamma distributed frailty has been constructed to describe the survival of worms after heating. The increase in the remaining life expectancy is determined by more effective protection by heat-induced substances in the ages yanger than 27 days. The unheated control group demonstrated acquired heterogeneity of frailty with chronological age while the heat-induced substances defend the worms in a universal way and protect against the development of frailty.

Animals↗

PubMed2003

The last 2 years of life: functional trajectories of frail older people.

OBJECTIVES: To characterize the functional trajectories during the last 2 years of life of patients with progressive frailty, with and without cognitive impairment, and to assess whether it was possible to identify discrete functional indicators that signal the end of life. DESIGN: A retrospective analysis of functional trajectories during the last 24 months of life. SETTING: Twelve demonstration sites of the Program of All-inclusive Care for the Elderly (PACE). PACE cares for frail older people who meet criteria for nursing home placement, with the goal of keeping the patient at home. PARTICIPANTS: Nine hundred seventeen patients who died while enrolled in PACE. MEASURES: At PACE entry and every 3 months thereafter, data were collected about the degree of dependence (none, partial, or full) in bathing, eating, and walking and the degree of incontinence (none, bladder, or bowel). Cognitive impairment was defined as six or more errors on the Short Portable Mental Status Questionnaire. To describe the end-of-life trajectories of patients, data were analyzed from observational windows of time, beginning with the patients' dates of death and extending backward in time to 24 months before death. Each analytical window was 3 months in duration. For each of the functional measures, the probability of functional deterioration in the last 2 years of life in patients with (64%) and without (36%) cognitive impairment was also compared. RESULTS: The mean age at death was 84; 69% of patients were women. For patients with and without cognitive impairment, a prolonged, steady increase in the rates of functional dependence that were evident at least 1 year before death, rather than sudden increases in functional dependence shortly before death, characterized the functional trajectories. It was not possible for any of the four measures to detect a time point before death at which there was an abrupt decline in function likely to signal impending death. For each measure, patients with cognitive impairment declined earlier, were more likely than patients without cognitive impairment to have the maximal level of dependence in the 0- to 3-month window before death (e.g., 56% vs 30% for mobility, P <.001), and were more likely to decline in the 2 years before death (e.g., 56% vs 36% for mobility, P <.001). CONCLUSION: Patients with advanced frailty, with or without cognitive impairment, have an end-of-life functional course marked by slowly progressive functional deterioration, with only a slight acceleration in the trajectory of functional loss as death approaches. Patients with cognitive impairment have particularly high rates of functional impairment at the time of death. These results suggest that end-of-life care systems that are targeted toward patients with functional trajectories clearly suggesting impending death (such as the Medicare hospice benefit) are poorly suited to older people dying with progressive frailty.

Activities of Daily Living↗