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PubMed2005

A version of the EM algorithm for proportional hazard model with random effects.

Proportional hazard models with multivariate random effects (frailties) acting multiplicatively on the baseline hazard have recently become a topic of an intensive research. One of the main practical problems related to the models is the estimation of parameters. To this aim, several approaches based on the EM algorithm have been proposed. The major difference between these approaches is the method of the computation of conditional expectations required at the E-step. In this paper an alternative implementation of the EM algorithm is proposed, in which the expected values are computed with the use of the Laplace approximation. The method is computationally less demanding than the approaches developed previously. Its performance is assessed based on a simulation study and compared to a non-EM based estimation approach proposed by Ripatti and Palmgren (2000).

Algorithms↗

PubMed1986

Management of acute cholangitis and the impact of endoscopic sphincterotomy.

Ninety-four patients admitted to Leicester Hospitals with acute cholangitis since 1977 were reviewed to coincide with the availability of endoscopic sphincterotomy (ES). Thirty-four were men and sixty were women, their mean age was 69.7 years and the median hospital stay was 20 days. There were 15 deaths (16 per cent) by 30 days in patients with significantly lower initial serum albumin levels (P less than 0.005) and significantly higher serum urea levels (P less than 0.05) than survivors. Eighty-two patients had common bile duct (CBD) calculi of whom 71 underwent early decompression of the biliary tree either surgically (28) or by ES(43). Early surgical decompression was associated with a significantly higher 30 day mortality (6/28) than early ES (2/43) (P less than 0.02) despite the fact that patients undergoing early ES were significantly older (P less than 0.02) and had significantly more medical risk factors (P less than 0.05). Of the 43 patients undergoing early ES 7 had had a previous cholecystectomy, 13 underwent subsequent elective cholecystectomy with no mortality and the remaining 23 had the gallbladder left in situ because of advanced age (mean age 79 years) and frailty. Only 2 of the 23 have since required cholecystectomy. We suggest that patients with acute cholangitis who do not rapidly respond to conservative treatment should undergo early ES with early surgery reserved for those who do not improve following ES. Elective cholecystectomy following successful ES can often be avoided in the elderly and frail.

Acute Disease↗

PubMed2003

A mind to blame: new views on involuntary acts.

This article examines the legal implications linked to recent scientific research on human consciousness. The article contends that groundbreaking revelations about consciousness expose the frailties of the criminal law's traditional dual dichotomies of conscious versus unconscious thought processes and voluntary versus involuntary acts. These binary doctrines have no valid scientific foundation and clash with other key criminal law defenses, primarily insanity. As a result, courts may adjudicate like individuals very differently based upon their (often unclear) understanding of these doctrines and the science that underlies them. This article proposes a compromise approach by recommending that the criminal law's concept of voluntariness consist of three parts: (i) voluntary acts, (ii) involuntary acts, and (iii) semi-voluntary acts. The semi-voluntary acts category, which is new, incorporates modern ideas of consciousness and also advances the law. Using some actual criminal cases, this article applies this new three-part grouping and demonstrates how it enhances a more just outcome for defendants, victims, and society.

Adult↗

PubMed2005

Random-effects Cox proportional hazards model: general variance components methods for time-to-event data.

Proportional hazards regression models are commonly used to study factors associated with time-to-event data. Because many complex genetic diseases exhibit variation in age at onset, it is important to have the capability to perform survival analyses on data collected from individuals whose observations are correlated due to shared genes or environment. While there are widely accepted methods for variance components analysis for simple quantitative traits, a parallel methodology for survival data has not been available. This manuscript outlines a method to perform variance component analyses under general random effects proportional hazards models. This method is based on a Laplace approximation, and makes computation for correlated time-to-event data feasible. The correlated frailty models described here can be used to perform genetic analyses, and other analyses with structured random effects, on age-at-onset data in a manner analogous to standard variance components methods for quantitative traits. We illustrate the use of the method by examining the heritability of breast cancer in a large familial cohort study. We also perform variance components linkage analyses on data simulated for the Twelfth Genetic Analysis Workshop (GAW12), and further examine the performance of this method for linkage analysis in a simulation study. The breast cancer analyses support significant heritability of disease age-at-onset that is of moderate size. The variance component linkage analyses successfully identify the location of the disease genes that were simulated to have a direct impact on age-at-onset. The methods outlined here make it possible to perform general variance components analyses on time-to-event endpoints, even on large data sets, in a computationally efficient manner.

Age of Onset↗

PubMed2002

Gait performance in dementia: the effects of a 6-week resistance training program in an adult day-care setting.

BACKGROUND: Age-related declines in balance and muscle power are largely responsible for the changes in the various components of gait performance among elderly people. But these can often be remedied with strength training. People with cognitive impairment frequently demonstrate impaired gait, putting them at increased risks for falls and serious injury. OBJECTIVES: This paper reports on the effects of a six-week pilot study of moderate intensity strength training on the gait of elderly individuals with dementia who attend a day-care center. METHODS: Twenty-six adults (23 female, three male), age = 79.2 +/- 6.6 years, completed the study. Each subject completed a baseline assessment of lower extremity strength and gait. Gait was evaluated using free- and fast-gait speed over a 6-meter course, the Tinetti-Gait Assessment scale, the 'Timed-Up-and-Go', and the Gait Assessment Rating Scale (GARS). The intervention consisted of moderate-intensity progressive resistance lower extremity exercise using Theraband, for two to three sessions per week over the six weeks. Post-intervention assessment of strength and gait was repeated at the completion of the sixth week. Multiple paired t-tests were calculated for each outcome measure. RESULTS: The baseline assessment of gait suggests a high degree of frailty and risk for falls in the sample. Although post-intervention scores reflected improvement on all gait measures, the only statistically significant change observed was in fast-gait time. CONCLUSION: A six-week resistance training program proved to be of insufficient duration, intensity or specificity to produce significant change in gait outcome measures, with the exception of fast speed gait.

Activities of Daily Living↗

PubMed2003

Factors associated with antipsychotic drug use in residential care: changes between 1990 and 1997.

BACKGROUND: There is limited information from population-based studies about the rates of antipsychotic drug use in residential and nursing homes in the UK, and associated adverse effects. OBJECTIVES: To examine the relationship between antipsychotic drug prescription, cognitive impairment and disturbed behaviour in this population over time, and to identify possible adverse consequences of their use. METHODS: Two censuses of the residential and nursing home population aged 65 years and older in Leicestershire, carried out in 1990 and 1997. A questionnaire was completed by care staff for each resident, including information on demographic details, physical functioning, cognitive impairment, behaviour disturbance, urinary incontinence, falls, mobility, daytime alertness (1997 only), and prescribed medication. RESULTS: The prevalence of staff-rated moderate or severe cognitive impairment increased from 38.0% in 1990 to 44.3% in 1997. The prevalence of staff-rated disturbed behaviour decreased from 11.8% in 1990 to 10.4% in 1997. Cognitive impairment was strongly associated with disturbed behaviour in both years. The prescription rate of antipsychotic drugs increased from 17.8% in 1990 to 21.9% in 1997. There was no significant change in the prescription rates to cognitively impaired residents between 1990 and 1997 (29.1% vs 30.7%). In residents without cognitive impairment, the prescription rate rose from 10.7% to 15.0%. Antipsychotic drug use was independently associated with: younger age, type of home (1990 only), cognitive impairment, offensive behaviour, lower ADL dependency (1990 only), antidepressant drug use, reported urinary incontinence and greater mobility. There was no association with increased liability to falls or drowsiness. In the cognitively unimpaired residents, antipsychotic drug use was not associated with urinary incontinence in 1997, and there was an association with increased drowsiness in that year. CONCLUSIONS: The only significant change in antipsychotic drug prescribing practice in this population over the period covered by this study was an increase in the prescription rate in cognitively unimpaired residents in 1997, possibly related to mental hospital closures. Urinary incontinence was the principal adverse effect of antipsychotic drug use observed in the group as a whole. Changes in the adverse effects associated with antipsychotic drug use may be a function of the increasing frailty.

Activities of Daily Living↗

PubMedDate not supplied

Caring for the caregivers: the hidden victims of illness and disability.

As advances in medical care extend the life expectancy of the elderly as well as those with disabling and chronic conditions, new sets of problems often emerge. One such problem is the constantly growing population of those providing care for spouses who, due to a disability, chronic illness, medical condition, or simply the frailty of old age, can no longer totally care for themselves. Well spouses who provide care are at risk for numerous physical, mental, emotional, social, and financial problems of their own. The literature points to several issues that emerge from the caregiving experience, as well as appropriate and effective responses to these issues. Nurses are in a position to identify at-risk caregivers and to advise them of their increased risk of physical and emotional problems. Addressing caregivers' needs helps to ensure that better care will be given to those dealing with or recovering from chronic illness, disability, or medical condition and, thus, that there will be improved results.

Caregivers↗

PubMed2002

Whining, griping, and complaining: positivity in the negativity.

Recent years have seen a surge of interest in the positive psychology movement. The emphasis of positive psychology is on human virtue rather than on human vice, on human strength rather than human frailty. In an effort to focus on what is good about human nature, however, the positive psychology movement has neglected to examine the redeeming features of seemingly aversive behaviors. Thus, the purpose of the present article is to broaden the scope of positive psychology by examining, in addition to its negative facets, the positive features of one particular aversive behavior, complaining. After defining complaining, we address the personal, relational, interpersonal, and material benefits of complaining to show that there is, indeed, positivity in the negativity.

Affect↗

PubMed2002

Multivariate survival analysis with doubly-censored data: application to the assessment of Accutane treatment for fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva is a rare genetic disorder in which the joints of patients become disabled by the formation of heterotopic bone. Data are available on the status of 11 joints of each of 21 patients before, during and after treatment with Accutane. These are compared with data obtained by questionnaire from 40 untreated patients to determine the efficacy of the treatment. Both left- and right-censoring are present in each group, which, together with the multivariate nature of the data and the time-dependent treatment covariate, makes analysis difficult. We consider two alternative parametric models for incorporating within-subject dependence: a marginal model and a frailty model. Both analyses suggest that Accutane treatment is effective. We discuss and illustrate the differences between the two approaches. We also discuss the extent to which the conclusions are compromised by the observational nature of the study.

Humans↗

PubMed2002

Maximum likelihood estimation in the joint analysis of time-to-event and multiple longitudinal variables.

Joint modelling of longitudinal and survival data has received much attention in recent years. Most have concentrated on a single longitudinal variable. This paper considers joint modelling in the presence of multiple longitudinal variables. We explore direct association of time-to-event and multiple longitudinal processes through a frailty model and use a mixed effects model for each of the longitudinal variables. Correlations among the longitudinal variables are induced through correlated random effects. We allow effects of categorical and continuous covariates on both longitudinal and time-to-event responses and explore interactions between the longitudinal variables and other covariates on time-to-event. Estimates of the parameters are obtained by maximizing the joint likelihood for the longitudinal variable processes and the event process. We use a one-step-late EM algorithm to handle the direct dependence of the event process on the modelled longitudinal variables along with the presence of other fixed covariates in both processes. We argue that such a joint analysis with multiple longitudinal variables is advantageous to one with only a single longitudinal variable in revealing interplay among multiple longitudinal variables and the time-to-event.

Head and Neck Neoplasms↗

PubMed2003

A parametric model for long-term follow-up data from phase III breast cancer clinical trials.

We propose a parametric version of a univariate gamma frailty model. The proposed model is shown to be flexible enough to model long-term follow-up survival data from breast cancer clinical trials when the treatment effect diminishes as time progresses, a case for which neither the proportional hazards nor proportional odds assumptions are satisfied. The observed information matrix is computed to evaluate the variances of parameter estimates. A simple parametric test statistic to test proportional odds assumption is also constructed. The model is applied to a data set from a phase III clinical trial on breast cancer.

Antineoplastic Agents, Hormonal↗

PubMed2004

Parametric randomization-based methods for correcting for treatment changes in the assessment of the causal effect of treatment.

We develop parametric maximum likelihood methods to adjust for treatment changes during follow-up in order to assess the causal effect of treatment in clinical trials with time-to-event outcomes. The accelerated failure time model of Robins and Tsiatis relates each observed event time to the underlying event time that would have been observed if the control treatment had been given throughout the trial. We introduce a bivariate parametric frailty model for time to treatment change and time to trial endpoint. Estimating equations which respect the randomization are constructed and compared to maximum likelihood methods in a simulation study. The Concorde trial of immediate versus deferred zidovudine in HIV infection is used as a motivating example and illustration of the methods.

Anti-HIV Agents↗

PubMed2004

A regression shrinkage method tailored to qualitative regressors and clustered data.

We propose a shrinkage method for estimation in linear regression models with qualitative regressors. Due to the nature of the shrinkage constraint, this method tends to give estimates that are exactly zero for some groups of coefficients belonging to the same regressor. The method hence results in concise models, since some of the regressors are entirely eliminated. In conjunction with this estimation method, a model with a fixed cluster effect turns out to be closely related to frailty models. We apply the method for modelling hospital readmissions.

Adolescent↗

PubMed2004

Multiple imputation to estimate the association between eyes in disease progression with interval-censored data.

In many ophthalmologic studies, progression of diseases such as diabetic retinopathy, age-related maculopathy, cataract, and glaucoma is only noted when each eye is examined at intervals that commonly vary between subjects. Such data are often analysed using continuous time survival methods with observed progression assumed to occur at the end of the interval. Tied times of progression can lead to substantial bias in estimation of the association between progression in right and left eyes. We describe a multiple imputation strategy to create multiple data sets without ties, based on drawing interval-censored progression times from a parametric gamma frailty model that accounts for continuous and discrete covariates. We illustrate the method with data from 478 patients with insulin-dependent diabetes mellitus who were followed for progression of diabetic retinopathy in the Sorbinil Retinopathy Trial. Resolution of tied failure times allows for valid estimation of the hazard of progression in one eye given the progression status of the other eye. A simulation study suggests that the method performs well. Results highlight the advantage of multiple imputation that data imputed under one model can be analysed under several alternative models.

Adolescent↗

PubMed2004

A test for informative censoring in clustered survival data.

Frailty models are frequently used to analyse clustered survival data. The assumption of non-informative censoring is commonly used by these models, even though it may not be true in many situations. This article proposes a test for this assumption. It uses the estimated correlation between two types of martingale residuals, one from a model for failure and the other from a model for censoring. It distinguishes two types of censoring, namely withdrawal and the end of the study. Simulation studies show that the proposed test works well under various scenarios. For illustration, the test is applied to a data set for kidney disease patients from multiple dialysis centres.

Cluster Analysis↗

PubMed2004

Analysis of clustered and interval censored data from a community-based study in asthma.

Many authors in recent years have proposed extensions of familiar survival analysis methodologies to apply in dependent data settings, for example, when data are clustered or subject to repeated measures. However, these extensions have been considered largely in the context of right censored data. In this paper, we discuss a parametric frailty model for the analysis of clustered and interval censored failure time data. Details are presented for the specific case where the underlying time to event data follow a Weibull distribution. Maximum likelihood estimates will be obtained using commercially available software and the empirical efficiency of these estimators will be explored via a simulation study. We also discuss a score test to make inferences about the magnitude and significance of over-dispersion in clustered data settings. These methods will be illustrated using data from the East Boston Asthma Study.

Asthma↗

PubMed2006

Rank tests for clustered survival data when dependent subunits are randomized.

In clustered survival data, subunits within each cluster share similar characteristics, so that observations made from them tend to be positively correlated. In clinical trials, the correlated subunits from the same cluster are often randomized to different treatment groups. In this case, the variance formulas of the standard rank tests such as the logrank, Gehan-Wilcoxon or Prentice-Wilcoxon, proposed for independent samples, need to be adjusted for intracluster correlations both within and between treatment groups for testing equality of marginal survival distributions. In this paper we derive a general form of simple variance formulas of the rank tests when subunits from the same cluster are randomized into different treatment groups. Extensive simulation studies are conducted to investigate small sample performance of the variance formulas. We compare our non-parametric rank tests based on the adjusted variances with one from a shared frailty model, which is an optimal semi-parametric testing procedure when the intracluster correlations within and between groups are the same.

Animals↗

PubMed2006

Assessing genetic effects in survival data by correlating martingale residuals with an application to age at onset of Huntington disease.

Genetic models for survival data are hard to formulate and hard to fit. For example, the popular gamma-frailty model for sib-pair data does not generalize easily to extended pedigrees and is not easy to fit. In this paper we show how martingale residuals from a (marginal) Cox model can be employed to estimate the presence of a genetic effect and to estimate genetic correlations depending on the genetic distance (kinship). The methodology is applied to age at onset of Huntington disease (HD) in carriers of the HD gene. The number of CAG repeats in the HD gene is a well-known predictor for age at onset of the disease. However, there is an indication that other genes might be involved as well; leading to unexplained familial clustering. Using our methodology, we found a clearly significant genetic association between the martingale residuals with correlations of about 0.6 for relatives that share 50 per cent of their genes (sib-pairs and parent-child) and about 0.3 for relatives that share 25 per cent of their genes (grandparent-grandchild, uncle/aunt-niece/nephew).

Adolescent↗