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Shared frailty models for recurrent events and a terminal event.

There has been an increasing interest in the analysis of recurrent event data (Cook and Lawless, 2002, Statistical Methods in Medical Research 11, 141-166). In many situations, a terminating event such as death can happen during the follow-up period to preclude further occurrence of the recurrent events. Furthermore, the death time may be dependent on the recurrent event history. In this article we consider frailty proportional hazards models for the recurrent and terminal event processes. The dependence is modeled by conditioning on a shared frailty that is included in both hazard functions. Covariate effects can be taken into account in the model as well. Maximum likelihood estimation and inference are carried out through a Monte Carlo EM algorithm with Metropolis-Hastings sampler in the E-step. An analysis of hospitalization and death data for waitlisted dialysis patients is presented to illustrate the proposed methods. Methods to check the validity of the proposed model are also demonstrated. This model avoids the difficulties encountered in alternative approaches which attempt to specify a dependent joint distribution with marginal proportional hazards and yields an estimate of the degree of dependence.

Algorithms↗

Joint modeling of longitudinal and survival data via a common frailty.

We develop a joint model for the analysis of longitudinal and survival data in the presence of data clustering. We use a mixed effects model for the repeated measures that incorporates both subject- and cluster-level random effects, with subjects nested within clusters. A Cox frailty model is used for the survival model in order to accommodate the clustering. We then link the two responses via the common cluster-level random effects, or frailties. This model allows us to simultaneously evaluate the effect of covariates on the two types of responses, while accounting for both the relationship between the responses and data clustering. The model was motivated by a study of end-stage renal disease patients undergoing hemodialysis, where we wished to evaluate the effect of iron treatment on both the patients' hemoglobin levels and survival times, with the patients clustered by enrollment site.

Algorithms↗

Functional reach: a marker of physical frailty.

OBJECTIVE: To establish the concurrent validity of our new balance instrument, functional reach (FR = maximal safe standing forward reach), as a marker of physical frailty compared with other clinical measures of physical performance. DESIGN, SETTING AND PARTICIPANTS: 45 community-dwelling persons age 66-104 were evaluated at one point in time using (1) FR (yardstick method), (2) Physical and Instrumental Activities of Daily Living (PADL, IADL), (3) Life Space, a 3-point measure of social mobility, (4) 10-item hierarchical mobility skills protocol, (5) 10-foot walking speed, (6) one-footed standing, and (7) tandem walking. Data analysis employed Spearman correlations. Partial r's were also calculated after controlling for age. RESULTS: The FR performance range was broad (4.3-16.5 inches, mean 10.9, SD 3.1). Except for PADL, the association of FR with the other physical performance measures was strong, with r's ranging from 0.64-0.71; the association of FR with PADL was 0.48. After controlling for age in the regression analysis, partial r's ranged from 0.52-0.63. The association of FR with age was -0.50. CONCLUSIONS: Based on cross-sectional data, FR is a practical instrument that correlates with physical frailty even more than with age.

Activities of Daily Living↗

Factors associated with institutionalization of older people in Canada: testing a multifactorial definition of frailty.

OBJECTIVES: To test a model of frailty by examining factors associated with institutionalization of older people in Canada; to assess whether diagnostic data provided information about risk beyond that provided by data on functional capacity and demographic variables. METHODS: Cross-sectional study of 1258 institutional subjects and 9113 community-dwelling older adults from the Canadian Study of Health and Aging. RESULTS: Multiple logistic regression analysis showed that female gender, being unmarried, absence of a caregiver, presence of cognitive impairment (including all types of dementia), functional impairment, diabetes mellitus, stroke, and Parkinson's disease were independently associated with being in a long-term care facility. CONCLUSION: Frailty appears to be a multidimensional construct, and not simply a synonym for dependence in Activities of Daily Living. Studies of health outcomes in older people should include diagnostic data as well as demographic information and data on functional capacity.

Activities of Daily Living↗

Attention, frailty, and falls: the effect of a manual task on basic mobility.

OBJECTIVE: To investigate the effect of a second task on balance and gait maneuvers used in everyday life. Our hypothesis was that those who were more distracted by a familiar manual task performed concurrently with functional maneuvers were more frail and more prone to falls. DESIGN: A cross-sectional design with prospective follow-up for falls. SETTING: Sheltered accommodation in Umeå, Sweden. PARTICIPANTS: Forty-two residents (30 women, 12 men; mean age +/- SD = 79.7 +/- 6.1 years), ambulant with or without a walking aid, able to follow simple instructions and able to carry a tumbler. MEASUREMENTS: Timed Up & Go (TUG), i.e., the time taken to rise from an armchair, walk 3 meters, turn round, and sit down again. TUG was repeated with an added manual task (TUGmanual), which was to carry a glass of water while walking. The Montgomery-Asberg Depression Rating Scale, Barthel Index, Functional Reach, Mini-Mental State Examination, and Line Bisection test were used to assess for frailty. The subjects were followed-up prospectively regarding falls indoors for a period of 6-months. RESULTS: Subjects with a time difference (diffTUG) between TUGmanual and TUG of > or = 4.5 seconds were considered to be distracted by the second task. Ten subjects had a difference in time of > or = 4.5 seconds. These subjects were more frail, and seven of them fell indoors during the follow-up period (odds ratio 4.7, 95%Confidence Interval (CI) 1.5-14.2). CONCLUSION: The time difference between the TUGmanual and the TUG appears to be a valid marker of frailty and a useful tool for identifying older persons prone to falling.

Accidental Falls↗

Frailty approach for the analysis of clustered failure time observations in dental research.

Because dental implant failure patterns tend to cluster within subjects, we hypothesized that the risk of implant failure varies among subjects. To address this hypothesis in the setting of clustered, correlated observations, we considered a retrospective cohort study where we identified a cohort having at least one implant placed. The cohort was composed of 677 patients who had 2349 implants placed. To test the hypothesis, we applied an innovative analytic method, i.e., the Cox proportional hazards model with frailty, to account for correlation within subjects and the heterogeneity of risk, i.e., frailty, among subjects for implant failure. Consistent with our hypothesis, risk for implant failure among subjects varied to a statistically significantly degree (p=0.041). In addition, the risk for implant failure is significantly associated with several factors, including tobacco use, implant length, immediate implant placement, staging, well size, and proximity of adjacent implants or teeth.

Analysis of Variance↗

Sarcopenia: a major modifiable cause of frailty in the elderly.

Sarcopenia is the loss of muscle mass and strength that occurs with aging. It is a consequence of normal aging, and does not require a disease to occur, although muscle loss can be accelerated by chronic illness. Sarcopenia is a major cause of disability and frailty in the elderly. There are many candidate mechanisms leading to sarcopenia, including age-related declines in alpha-motor neurons, growth hormone production, sex steroid levels, and physical activity. In addition, fat gain, increased production of catabolic cytokines, and inadequate intake of dietary energy and protein are also potentially important causes of sarcopenia. The relative contribution of each of these factors is not yet clear. Sarcopenia can be reversed with high-intensity progressive resistance exercise, which can probably also slow its development. A major challenge in preventing an epidemic of sarcopenia-induced frailty in the future is developing public health interventions that deliver an anabolic stimulus to the muscle of elderly adults on a mass scale.

Aged↗

Multivariate frailty model with a major gene: application to genealogical data.

Multivariate survival models are shown to be appropriate for the analysis of the genetic and the environmental nature of a human life-span. Models which involve continuously distributed individual frailty, play an important role in the genetic analysis of an individual's susceptibility to disease and death. These models, however, are not appropriate for the detection of the effects of separate genes on survival. For this purpose we developed a 'major gene' frailty model of multivariate survival and applied it to simulated and real pedigree data. The analysis shows that this model can be used for the detection of the presence of major genes in the population and for the evaluation of the effects of such genes on survival.

Adolescent↗

Determining the effects of patient casemix on length of hospital stay: a proportional hazards frailty model approach.

OBJECTIVES: To identify factors associated with hospital length of stay (LOS) and to model variations in LOS within Diagnosis Related Groups (DRGs). METHODS: A proportional hazards frailty modelling approach is proposed that accounts for patient transfers and the inherent correlation of patients clustered within hospitals. The investigation is based on patient discharge data extracted for a group of obstetrical DRGs. RESULTS: Application of the frailty approach has highlighted several significant factors after adjustment for patient casemix and random hospital effects. In particular, patients admitted for childbirth with private medical insurance coverage have higher risk of prolonged hospitalization compared to public patients. CONCLUSIONS: The determination of pertinent factors provides important information to hospital management and clinicians in assessing the risk of prolonged hospitalization. The analysis also enables the comparison of inter-hospital variations across adjacent DRGs.

Delivery, Obstetric↗

Frailty and survival.

Using data for selected developed countries, the factors affecting an individual's susceptibility to morbidity and mortality are analyzed. "On the basis of empirical data the author concludes that frailty is not unchangeable throughout a person's lifetime but subject to period effects,...which tend to overwhelm the genetic element.... Current external conditions...exert a pervasive influence on the frailty of an individual and the mortality of the population making them responsive to health-related policies and personal choice." (SUMMARY IN FRE AND ITA)

Behavior↗

Biomarkers of frailty in older persons.

Trajectories of health and functioning with age show extreme variability among different individuals. Normal aging implies a progressive decline of physiological reserve and ability to compensate, but it is compatible with autonomy over the entire life span. In frail, older persons the decline in functional reserve is accelerated and compensatory mechanisms start failing, with high risk of homeostasis disruption and consequent negative health outcomes. Frailty is currently conceptualized as an age-related alteration in physiology and pathology that results into a typical constellation of signs and symptoms. Although current attempts to identify frail, older individuals for clinical purposes are based on measures of mobility and motor performance, candidate biological markers that may characterize the frailty syndrome start to emerge in the literature. These potential markers include, but are not limited to, soluble mediators of the inflammatory response, hormones, free radicals, antioxidants and macro- and micro-nutrients. This is a research area undergoing a rapid, dynamic development that may profit from new ways of defining disability outcomes in epidemiological studies of the elderly.

Aged↗

[Demographic evolution, aging and frailty].

The 20th century will be remembered for its technological and scientific discoveries and for the exceptional changes in the demographic structure brought about by these and the improved economic and social conditions; in fact, the reduction in the birth rate and a fall in the death rate have caused an increase in the population of the elderly. Today the elderly population represents about 20% of the total and is much more heterogeneous than in the past, with several classes of the elderly: the young elderly from 64 to 74; the old elderly from 75 to 84, the very old from 85 to 100 and the oldest old who are living around a century. The aging of the population has brought out several problems of the elderly, among the "frailty", the effects of which increase as the years pass and which regards about one half of the very old. Frailty is a reduction of the body's ability to maintaine global homeostasis and is caused by a reduction of the functional reserves of all the organs and apparatus which occurs with aging. Screening the frail elderly with a careful multidimensional assessment is important to prevent health problems and to promote good health and it is a good parameter in evaluating the management of the geriatric assistance network and thus health and social costs.

Adolescent↗

Aging, disability, and frailty: implications for universal design.

Throughout the world all populations are seeing burgeoning numbers of "elders", defined as persons aged 65 year and older. In many countries, including Japan, the United States, Norway, Sweden and the United Kingdom, those aged over 65 are at or approaching 15% of the population. As their numbers have increased, so have their health care expenses, leading to extensive research on the health, well being, and life expectancy of these increasingly older elders. Today this group is further sub-divided: the young-old ages 65-74, the old-old ages 75-84, and the oldest-old ages 85+, for both health care and research purposes. However broad variation still characterizes even these groupings. Rates of frailty and disability increase with increasing age among these elders. For example, inabilities to complete at least one activity of daily living increased from about 5-7% at ages 65-69 years to about 28-36% at ages 85+ in 1987. Death rates continue to decline at all ages past 50 years and rates of disability seem to be doing the same. For the foreseeable future, we may expect increasing numbers of older, frail elders than in previous decades. Thus, people are not only living longer, they generally are healthier at advanced ages than were previous cohorts, thus "old age" disabilities of the 20th century will be put off to even older ages during the 21st century. As yet there is no clear way to assess senescent changes in humans, although activities of daily living, allostatic load, and frailty indices have all been suggested. One future need is greater development and use of universal and accessible design in all aspects of the built environment.

Activities of Daily Living↗

The effects of exercise on falls in elderly patients. A preplanned meta-analysis of the FICSIT Trials. Frailty and Injuries: Cooperative Studies of Intervention Techniques.

OBJECTIVE: To determine if short-term exercise reduces falls and fall-related injuries in the elderly. DESIGN: A preplanned meta-analysis of the seven Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT)--independent, randomized, controlled clinical trials that assessed intervention efficacy in reducing falls and frailty in elderly patients. All included an exercise component for 10 to 36 weeks. Fall and injury follow-up was obtained for up to 2 to 4 years. SETTING: Two nursing home and five community-dwelling (three health maintenance organizations) sites. Six were group and center based; one was conducted at home. PARTICIPANTS: Numbers of participants ranged from 100 to 1323 per study. Subjects were mostly ambulatory and cognitively intact, with minimum ages of 60 to 75 years, although some studies required additional deficits, such as functionally dependent in two or more activities of daily living, balance deficits or lower extremity weakness, or high risk of falling. INTERVENTIONS: Exercise components varied across studies in character, duration, frequency, and intensity. Training was performed in one area or more of endurance, flexibility, balance platform, Tai Chi (dynamic balance), and resistance. Several treatment arms included additional nonexercise components, such as behavioral components, medication changes, education, functional activity, or nutritional supplements. MAIN OUTCOME MEASURES: Time to each fall (fall-related injury) by self-report and/or medical records. RESULTS: Using the Andersen-Gill extension of the Cox model that allows multiple fall outcomes per patient, the adjusted fall incidence ratio for treatment arms including general exercise was 0.90 (95% confidence limits [CL], 0.81, 0.99) and for those including balance was 0.83 (95% CL, 0.70, 0.98). No exercise component was significant for injurious falls, but power was low to detect this outcome. CONCLUSIONS: Treatments including exercise for elderly adults reduce the risk of falls.

Accidental Falls↗

Population-based, genetically informative sample for studies of physical frailty and aging: black elderly twin study.

In this article 1 describe efforts to build a genetically informative, population-based sample of black twins to study physical frailty and aging in the United States. This project involves the use of governmental registries combined with sampling techniques developed to overcome limitations in the registry data. Two analytical approaches to measures of disability are included to illustrate the types of questions that can be addressed with this sample. These results suggest that physical disability in late life has both genetic and environmental determinants. Only with a genetically informative sample can evidence be collected indicating that frailty may be driven by fixed processes (i.e., disability resulting from activation of senescence genes), fluid processes (i.e., disability resulting from changes in the features of the environment), or a combination of both.

Activities of Daily Living↗

An attempt to give nursing home residents a voice in the quality improvement process: the challenge of frailty.

Advanced frailty and confusion of many nursing home residents present a particular conundrum to researchers committed to resident participation. While the research is set in Australia, the challenge of frailty is common to researchers working with compromised older persons. This study was conducted in an Australian 32 bed nursing home. As researchers we took on the roles of facilitators and negotiators within a quality improvement process using the approach of fourth generation evaluation. The overall aim of the project was to provide all stakeholders, including residents and their significant others, with a voice in the negotiations and decisions that impact on their lives. The focus of this paper is our attempt to gain the perspective of residents and significant others.

Aged↗

An additive frailty model for correlated life times.

A frailty model for multivariate correlated life times is considered. The model both extends, in a rather straight-forward way, ordinary survival analysis with its emphasis on hazard modeling and incorporates well-known variance components models to account for the dependence between events of related individuals. Different approaches to estimation and inference are considered. An example from an ongoing study of genetic and environmental influences on premature death in adults serves to motivate and illustrate the model. Multivariate frailty models offer a conceptually simple and promising framework for analysis of correlated event times data, even if current knowledge is too sparse for such models to be tested critically.

Adoption↗

Dehydroepiandrosterone sulfate (DHEA-S) and psychiatric and laboratory measures of frailty in a residential care population.

Previous reports have found low levels of dehydroepiandrosterone sulfate (DHEA-S) in association with frailty in elderly patients. The mechanisms underlying these associations are not known. Therefore, psychiatric symptoms and disorders that are common in frail elderly patients were correlated with DHEA-S levels in a convenience sample selected from a nursing home population. Low DHEA-S levels were associated with high degrees of self-rated disability and insomnia. In women, low DHEA-S levels were also associated with increased numbers of pain sites. However, cognitive impairment was associated with higher DHEA-S levels in women. Thus, in frail elderly patients, there are contradictory relationships between DHEA-S and neuropsychiatric measures of frailty (cognitive impairment, disability, insomnia, and number of pain sites), and there may also be gender differences in these relationships.

Age Factors↗