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PubMed2000

A comparison of frailty and other models for bivariate survival data.

Multivariate survival data arise when each study subject may experience multiple events or when study subjects are clustered into groups. Statistical analyses of such data need to account for the intra-cluster dependence through appropriate modeling. Frailty models are the most popular for such failure time data. However, there are other approaches which model the dependence structure directly. In this article, we compare the frailty models for bivariate data with the models based on bivariate exponential and Weibull distributions. Bayesian methods provide a convenient paradigm for comparing the two sets of models we consider. Our techniques are illustrated using two examples. One simulated example demonstrates model choice methods developed in this paper and the other example, based on a practical data set of onset of blindness among patients with diabetic Retinopathy, considers Bayesian inference using different models.

Bayes Theorem↗

PubMed2002

Maximum likelihood inference for multivariate frailty models using an automated Monte Carlo EM algorithm.

We present a maximum likelihood estimation procedure for the multivariate frailty model. The estimation is based on a Monte Carlo EM algorithm. The expectation step is approximated by averaging over random samples drawn from the posterior distribution of the frailties using rejection sampling. The maximization step reduces to a standard partial likelihood maximization. We also propose a simple rule based on the relative change in the parameter estimates to decide on sample size in each iteration and a stopping time for the algorithm. An important new concept is acquiring absolute convergence of the algorithm through sample size determination and an efficient sampling technique. The method is illustrated using a rat carcinogenesis dataset and data on vase lifetimes of cut roses. The estimation results are compared with approximate inference based on penalized partial likelihood using these two examples. Unlike the penalized partial likelihood estimation, the proposed full maximum likelihood estimation method accounts for all the uncertainty while estimating standard errors for the parameters.

Algorithms↗

PubMed2004

Height, frailty, and the standard of living: modelling the effects of diet and disease on declining mortality and increasing height.

Explanations of historical trends in both mortality and human height differ over the relative contributions of better nutrition and reduced exposure to disease. This paper explores theoretical models in which interactions between diet and disease determine both mortality and height. One model assumes that adult height is directly related to frailty, the relative risk of dying. The second model links frailty to differences between attained and potential height. Diet plays a small role in the transition to low mortality in the first model. The second model assigns a large role to diet in historical mortality trends, but implies that mortality will be unrelated to height in the future.

Anthropometry↗

PubMed1999

Group sequential procedures for repeated events data with frailty.

In this article we consider the design aspects of group sequential trials with recurrent study endpoints, where the subjects are from a heterogeneous population. The usual procedures of sequential analysis based on the "independent increments" property are no longer valid due to the heterogeneity of the study subjects, as pointed out by Cook and Lawless. We focus on the aspect of study planning and consider a special model (Poisson process with frailty) to investigate the effects of frailty (or subject heterogeneity). We prescribe the valid procedures and provide convenient tables for computing stopping boundaries and sample sizes. The methodology is illustrated through an example of an animal experiment with recurrent tumors, using procedures such as group sequential tests and repeated confidence intervals. Minimal cost analysis is considered for determining the optimal combination of study duration and sample size.

Animals↗

PubMed2004

Frailty models for quality of life in oncology.

Quality of life (QOL) and survival data are commonly measured in clinical trials in oncology. Frailty models are an excellent tool to exploit the natural dependence between these domains. We propose a novel application of frailty models, providing a detailed example relating to QOL in advanced prostate cancer patients. We discuss model fitting, estimation, and interpretation and describe available software.

Clinical Trials, Phase III as Topic↗

PubMed1990

The association of age and frailty with paracetamol conjugation in man.

The association of age, physical frailty and liver size upon hepatic conjugation reactions was studied using paracetamol as a model drug. Nineteen fit subjects (mean age 26 years), 20 fit subjects (mean age 73 years), and eight frail, hospitalized subjects (mean age 82 years) were recruited. Paracetamol clearance expressed in terms of body weight was significantly lower in the fit elderly than in the fit young subjects, and was lowest in the frail elderly subjects (p less than 0.01). There was no difference in paracetamol clearance expressed per unit volume of liver between the fit young and fit elderly subjects but it was significantly reduced in the frail subjects. Although the partial metabolic clearance to paracetamol sulphate was preserved per unit volume of liver with ageing and frailty, the partial metabolic clearance to paracetamol glucuronide per unit volume of liver was markedly reduced in the frail elderly (p less than 0.01) when compared with the fit subjects. These results show that age-associated changes in paracetamol clearance are attributable to both changes in liver volume and in general health. The findings underline the important influences of the elderly person's physical state upon drug clearance.

Acetaminophen↗

PubMed1993

The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide.

We have investigated the association of age and frailty with the pharmacokinetics and pharmacodynamics of the conjugated drug, metoclopramide. Six healthy young, six healthy elderly (> 65 years), and six frail elderly (> 65 years) subjects were studied on two occasions, receiving 10 mg metoclopramide by intravenous bolus and orally, in random order. Blood and urine were collected for measurement of pharmacokinetic parameters. Liver volume was measured by ultrasound. Sedation and contentment were self-recorded on visual analogue scales. Liver volume was not significantly different in the three groups, nor was bio-availability of metoclopramide. Clearance was similar in the young and fit elderly but reduced in the frail elderly subjects when compared with the young (p < 0.05), both when expressed in absolute terms and per unit liver volume. There were no differences in percentages cleared as the free drug or as the sulphate or glucuronide metabolite within or between groups, suggesting that frailty can produce a general impairment of conjugation pathways. The frail elderly subjects reported more sedation after intravenous dosage than the other subjects, whilst only young subjects reported akathisia. This did not relate to pharmacokinetic differences and seemed therefore to reflect associated pharmacodynamic changes in specific receptor or target sites.

Administration, Oral↗

PubMed1994

Is low blood pressure in elderly people just a consequence of heart disease and frailty?

Low blood pressure has been associated with increased mortality in older people, but it is unclear whether the hypotension is a risk in its own right or just a marker of disease. In this study we investigated the extent to which those in the lowest decile of systolic and diastolic pressures could be predicted by measures of cardiovascular disease and frailty. We studied 782 people 70 years and over drawn from the only group of general practices in a rural township. Hypotension was defined separately for systolic and diastolic blood pressures as a pressure less than the tenth percentile for the sample as a whole. This was a systolic pressure of < or = 122 mmHg and a diastolic pressure of < or = 68 mmHg. There was a significant relationship between low systolic blood pressure and male sex, history of myocardial infarction by questionnaire and low body mass index (BMI), and between low diastolic pressure and male sex, history of angina and myocardial infarction, use of one or more hypotensive drugs, low BMI, low corrected arm muscle area, low self-maintenance score and the use of two or more home services. There was no association with ECG abnormalities. In the multivariate analysis only 4.2% of those with low diastolic pressure and none of those with low systolic pressure could be correctly classified. Hypotension in old age is only partially explained by established cardiovascular disease and frailty.

Activities of Daily Living↗

PubMed2004

Fear-related avoidance of activities, falls and physical frailty. A prospective community-based cohort study.

OBJECTIVE: to investigate the relationship between fear-related avoidance of activities and physical frailty. SUBJECTS AND METHODS: fear-related avoidance of activities, physical performance, maximal isometric muscle strength and postural control were assessed in 225 community-living elderly (94 men and 131 women), aged between 61 and 92 years of age. RESULTS: bivariate analyses revealed significant correlations between avoidance of activities on the one hand, and physical performance, muscle strength, forward endpoint excursion of the centre of gravity, and previous falls on the other hand. Logistic regression analysis revealed that fear of falling and avoidance of activities in daily life were predictive of falls within a 1-year follow-up, together with general fear of falling, old age and being female. CONCLUSIONS: fear-related avoidance of activities may have negative effects on physical abilities and may also be predictive for future falls. Avoidance of activities is therefore an important additional psychological variable in the development of physical frailty and falling in community-living elderly.

Accidental Falls↗

PubMed2003

Frailty amplifies the effects of aging on protein metabolism: role of protein intake.

BACKGROUND: We previously showed that muscle contributes less to whole-body protein breakdown with healthy aging. OBJECTIVE: We hypothesized that frailty further compromises protein metabolism and that short-term protein supplementation improves protein status. DESIGN: Protein metabolism was studied with the oral, 60-h [(15)N]glycine and N(tau)-methylhistidine methods in 8 frail and 13 healthy elderly women during a 9-d isoenergetic, isonitrogenous formula diet and then after increased protein intakes in the frail women, to match the intakes of healthy subjects, for 12 d. RESULTS: Compared with healthy women, frail women had higher rates of whole-body protein synthesis and breakdown per kg fat-free mass and lower rates of muscle protein breakdown when expressed as total amounts per day but higher rates when expressed per kg muscle. Because muscle mass was lower in frail women, the contribution of muscle to whole-body protein breakdown was lower and that of nonmuscle lean tissues was higher. The protein-enriched diet had no effect on these variables but resulted in an increase in net endogenous protein balance and a positive nitrogen balance at the end of the diet period. CONCLUSIONS: Frailty exacerbates age-related changes in protein metabolism by inducing an increase in muscle protein catabolism and a decrease in muscle mass. At low protein intakes, the increase in muscle catabolism may be a form of protection for both nonmuscle lean tissue mass and function at the expense of muscle mass. Frail women maintained the capacity to retain nitrogen after increased protein intakes, which could convey health benefits if sustained over a long enough period to result in lean tissue accretion.

Aged↗

PubMed2002

Dynamics of stability: the physiologic basis of functional health and frailty.

Under basal resting conditions most healthy physiologic systems demonstrate highly irregular, complex dynamics that represent interacting regulatory processes operating over multiple time scales. These processes prime the organism for an adaptive response, making it ready and able to react to sudden physiologic stresses. When the organism is perturbed or deviates from a given set of boundary conditions, most physiologic systems evoke closed-loop responses that operate over relatively short periods of time to restore the organism to equilibrium. This transiently alters the dynamics to a less complex, dominant response mode, which is denoted "reactive tuning." Aging and disease are associated with a loss of complexity in resting dynamics and maladaptive responses to perturbations. These alterations in the dynamics of physiologic systems lead to functional decline and frailty. Nonlinear mathematical techniques that quantify physiologic dynamics may predict the onset of frailty, and interventions aimed toward restoring healthy dynamics may prevent functional decline.

Aged↗

PubMed1993

Psychosocial and behavioral dimensions of physical frailty.

Findings from a decade of research on physical frailty in diverse elderly populations are summarized and integrated. While much of the literature focuses on the physical and functional consequences of chronic and acute illness, we emphasize the psychosocial and behavioral aspects of physical frailty. The underlying assumption of our approach is that the psychological representation of illness and disability, as well as the social contexts in which they occur, are important determinants of their impact on patients and family members. We focus on both patients and their primary support persons and on the comparative analysis of different disabling conditions. A patient and family caregiver impact model is used to summarize major findings of our research program and to make recommendations for intervention research.

Aged↗

PubMed1998

Predilection for frailty remedial strategies among black and white seniors.

BACKGROUND: Frailty prevention and remedial programs based on exercise, hormone replacement, and vitamin supplementation are becoming available for use with older patients, but success of these programs depends largely on seniors' willingness to participate. METHODS: We evaluated preferences for specific aspects of these programs using a sample of 359 older persons recruited from potential delivery sites. Main effects and subgroup analyses were done. RESULTS: Subjects preferred stretching, chair-based, walking, and dynamic balance exercises over lifting weights, dancing, hormone and vitamin therapy; exercising alone in their own homes over exercising in groups; and vitamins over hormones. Preferences were affected to some extent by sex, race, recruitment site, and functional status. However, subjects' willingness even to consider exercise was rarely as high as the desired levels of participation set forth in Healthy People 2000. CONCLUSIONS: Physicians and public health authorities need to educate older persons about effective methods to prevent or treat frailty.

Accidental Falls↗

PubMed2006

Network frailty and the geometry of herd immunity.

The spread of infectious disease through communities depends fundamentally on the underlying patterns of contacts between individuals. Generally, the more contacts one individual has, the more vulnerable they are to infection during an epidemic. Thus, outbreaks disproportionately impact the most highly connected demographics. Epidemics can then lead, through immunization or removal of individuals, to sparser networks that are more resistant to future transmission of a given disease. Using several classes of contact networks-Poisson, scale-free and small-world-we characterize the structural evolution of a network due to an epidemic in terms of frailty (the degree to which highly connected individuals are more vulnerable to infection) and interference (the extent to which the epidemic cuts off connectivity among the susceptible population that remains following an epidemic). The evolution of the susceptible network over the course of an epidemic differs among the classes of networks; frailty, relative to interference, accounts for an increasing component of network evolution on networks with greater variance in contacts. The result is that immunization due to prior epidemics can provide greater community protection than random vaccination on networks with heterogeneous contact patterns, while the reverse is true for highly structured populations.

Animal Diseases↗

PubMed2000

A frailty model of segregation analysis: understanding the familial transmission of alcoholism.

Coupled with environmental factors, genes contribute to numerous human diseases and traits. While there are many epidemiological methods to assess the familial clustering of traits, few are flexible enough to accommodate interactions between covariates and familial factors. In this paper, we propose and develop a frailty model that establishes an integrated framework to evaluate familial transmission of a disease by controlling for covariate effects and conveniently testing the interactions between covariates and familial factors. We also present a peeling algorithm that dramatically reduces the computational burden. This frailty model is employed to examine the familial transmission of major subtypes of alcoholism, namely, alcohol abuse and dependence. We conclude that alcohol dependence is strongly familial whereas alcohol abuse expresses a marginally significant pattern of familial transmission. Moreover, females manifest alcoholism at a lower threshold, and there is no sex-specific familial transmission of alcoholism after adjustment for the threshold effect.

Alcoholism↗

PubMed2002

Modeling spatial survival data using semiparametric frailty models.

We propose a new class of semiparametric frailty models for spatially correlated survival data. Specifically, we extend the ordinary frailty models by allowing random effects accommodating spatial correlations to enter into the baseline hazard function multiplicatively. We prove identifiability of the models and give sufficient regularity conditions. We propose drawing inference based on a marginal rank likelihood. No parametric forms of the baseline hazard need to be assumed in this semiparametric approach. Monte Carlo simulations and the Laplace approach are used to tackle the intractable integral in the likelihood function. Different spatial covariance structures are explored in simulations and the proposed methods are applied to the East Boston Asthma Study to detect prognostic factors leading to childhood asthma.

Asthma↗

PubMed2002

A frailty model for informative censoring.

To account for the correlation between failure and censoring, we propose a new frailty model for clustered data. In this model, the risk to be censored is affected by the risk of failure. This model allows flexibility in the direction and degree of dependence between failure and censoring. It includes the traditional frailty model as a special case. It allows censoring by some causes to be analyzed as informative while treating censoring by other causes as noninformative. It can also analyze data for competing risks. To fit the model, the EM algorithm is used with Markov chain Monte Carlo simulations in the E-steps. Simulation studies and analysis of data for kidney disease patients are provided. Consequences of incorrectly assuming noninformative censoring are investigated.

Algorithms↗

PubMed2003

The gamma-frailty Poisson model for the nonparametric estimation of panel count data.

In this article, we study nonparametric estimation of the mean function of a counting process with panel observations. We introduce the gamma frailty variable to account for the intracorrelation between the panel counts of the counting process and construct a maximum pseudo-likelihood estimate with the frailty variable. Three simulated examples are given to show that this estimation procedure, while preserving the robustness and simplicity of the computation, improves the efficiency of the nonparametric maximum pseudo-likelihood estimate studied in Wellner and Zhang (2000, Annals of Statistics 28, 779-814). A real example from a bladder tumor study is used to illustrate the method.

Algorithms↗