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PubMed2003

[Individualization of the frail elderly people and use of health care services].

The challenge of identifying frail elderly subjects is important to optimize the management of care for the old patients. The recognition of frailty allows clinicians to detect subjects whose autonomy is precarious in relation to decreased physical performances and\or vulnerability of their psychosocial stability. A better distinction of healthy old people from frail elderly in an emergency ward makes possible to target the medical care toward the individuals who are more likely to benefit from it and to work out the best strategies of prevention. However, assessment of frailty is time-consuming and there is no consensus on the diagnostic measures. Brief tools to assess the principal components of frailty, which could be included in the routine clinical examination of people over 75 years of age, are currently in progress of validation.

Aged↗

PubMed2005

Multi-target models and their application to data analysis of cellular mortality due to radiation exposure.

We consider multi-target models for use in analyzing data of the dose-response relationship. The target sizes we are concerned with here are both homogeneous, as assumed in the classical model, and heterogeneous, as simplified using geometric progression. We apply two models for establishing the multi-target models: a Poisson regression model constructed by assuming that the response variable Y follows Poisson distribution, and a gamma-frailty model as a Poisson mixture model derived by adding random common risks having a gamma distribution. Applying these models to experimental data relating the effects of miso fermentation-stages on the survival rate of cells of intestinal crypts of mice exposed to radiation yielded the result that there were substantial frailties associated with all miso fermentation-stages. Short-term and medium-term fermented miso provided similar effects, whereas long-term fermentation had the lowest-relative risk value, indicating a significant protection of the crypts against exposure effects. A gamma-frailty model based on heterogeneous target size was more suitably applied when there were at least 3 dead stem cells having 10 target genes.

Animals↗

PubMed1991

Are cohort mortality rates autocorrelated?

In this paper the author examines the proposition that heterogeneity in individual frailty leads to autocorrelation in cohort mortality rates. A simple model is used to construct analytic expressions for the covariance of cohort mortality rates at different ages under a number of alternative assumptions about the stochastic process generating shocks in mortality. The model then is used to construct a procedure that uses correlations in cohort mortality rates to estimate the extent of heterogeneity in a population without relying on strong assumptions about the distribution of frailty or the shape of the underlying hazard. The procedure then is used to show that cohort mortality data from France are consistent with a generalized random-effects model in which frailty is gamma-distributed.

Age Factors↗

PubMed2002

Recruitment of older participants in frailty/injury prevention studies.

Despite the lifelong health benefits of physical activity, frailer older adults have typically been excluded from studies promoting more active lifestyles. This study documents the recruitment process and costs from a multisite study to identify effective strategies for recruiting older adults in frailty/injury prevention research. Randomized controlled clinical trials were conducted at 7 sites; an 8th site was a compliance study. Interventions reflected center- and home-based health promotion programs. Site objectives, eligibility criteria, and contact and screening methods were obtained from manuals of operation. Recruitment results (number screened, eligibility rates, randomized to screened ratios) were ascertained from recruitment data. Sites furnished estimated recruitment costs (nonlabor expenses, investigator and staff time, fringe benefits) up to signing the consent form. The sites targeted diverse populations and sample sizes. The majority revised recruitment methods to meet their recruitment goals. Most sites estimated costs of recruitment at over $300 per participant randomized. Recruitment costs were affected by staff time spent alleviating concerns about participants' health, essential interactions with family members, and arranging for transportation. Neither frailty nor intervention intensity was found to be a major predictor of recruitment outcomes. Recruitment expense was associated with selection criteria and frailty status of the target population. Older people can be successfully recruited into beneficial health promotion programs, but it is often challenging. In planning health promotion studies, investigators need to be aware of the numbers of older people they may need to screen and different strategies for increasing recruitment success.

Accidental Falls↗

PubMed2004

Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: a consensus report.

The discovery of effective interventions to prevent or delay disability in older persons is a public health priority. Most likely to benefit from such interventions are frail individuals who are not yet disabled and those with early disability who are at high risk of progression. In spite of this frail older persons have often been excluded from research on the assumption that they would not tolerate testing or benefit from treatment. The Interventions on Frailty Working Group developed recommendations to screen, recruit, evaluate, and retain frail older persons in clinical trials. Specific recommendations are: Eligibility screening should include a multistage process, to quickly exclude those who are too well and those who are too sick. Inclusion criteria should target those most likely to benefit, be meaningful to clinicians, and reflect advancements in the frailty research area. Disability outcome measures should include self-reported, objective, and proxy measures. Strategies to improve retention and compliance and to monitor their effectiveness should be an integral part of the study design. Estimation of cost and sample size should contemplate high dropout rates and interference by competing outcomes. Additional research is needed to refine criteria for screening frail older persons, identify objective measures of disability that are reliable and valid in frail older persons, and improve the informed consent process for high-risk participants, recognizing that research in this subgroup is essential to improving their health outcomes.

Activities of Daily Living↗

PubMed1997

Regression analysis of discrete time survival data under heterogeneity.

This paper concerns the regression analysis of discrete time survival data for heterogeneous populations by means of frailty models. We express the survival time for each individual as a sequence of binary variables that indicate if the individual survived at each time point. The main result is that the likelihood for these indicators can be factored into contributions that involve the conditional survival probabilities integrated over the frailty distribution of the risk set (population-averaged). We then model these population-averaged conditional probabilities as a function of covariates. The result justifies the practice of treating the failure indicators as independent Bernoulli trials and fitting binary regression models for the conditional failure probabilities at each time point. However, we must interpret the regression coefficients as population-averaged rather than subject-specific parameters. We apply the method to the Framingham Heart Study on risk factors for cardiovascular disease.

Algorithms↗

PubMedDate not supplied

Counts and times to events.

A common response recorded in medical statistics involves the occurrence of events. Often this is summarized as a count for each patient. Reasons are given for disaggregating the data as much as possible and instead studying the time to each event. Global counts may hide evolution of the state of the patient over time. This will appear as overdispersion which may wrongly be interpreted as differential frailty among patients. Interval censoring is only important if the rate of events is very high as compared to the time unit of observation chosen. Repeated times to events on the same patient will be interrelated and so should be appropriately treated, as for any repeated measure. Both serial dependence among successive times to events on the same patient and frailty among patients may be present.

Analysis of Variance↗

PubMed1999

Interval-censored survival data with informative examination times: parametric models and approximate inference.

We develop parametric methods for analysing interval-censored data when examination and survival times are not independent. The hazard function is modelled by introducing individual frailties related to the frequency of examinations. Model parameters may be obtained by direct maximization of the marginal log-likelihood. We develop a simpler approximate method in which the frailties are estimated by empirical Bayes. The two approaches are equivalent asymptotically as the number of examinations on each individual increases. Simulations suggest that the approximate method is adequate for estimating regression parameters even when the number of examinations on each individual is small. The methods are used to estimate age and period effects on HIV incidence in a cohort of repeat attenders at genito-urinary clinics in London, U.K.

Adult↗

PubMed1999

Recurrent injury event-time analysis.

Public health decision making based on data sources that are characterized by a lack of independence and other complicating factors requires the development of innovative statistical techniques. Studies of injuries in occupational cohorts require methods to account for recurrent injuries to workers over time and the temporary removal of workers from the 'risk set' while recuperating. In this study, the times until injury events are modelled in an occupational cohort of employees in a large power utility company where employees are susceptible to recurrent events. The injury history over a ten-year period is used to compare the hazards of specific jobs, adjusted for age when first hired, and race/ethnicity differences. Subject-specific random effects and multiple event-times are accommodated through the application of frailty models which characterize the dependence of recurrent events over time. The counting process formulation of the proportional hazards regression model is used to estimate the effects of covariates for subjects with discontinuous intervals of risk. In this application, subjects are not at risk of injury during recovery periods or other illness, changes in jobs, or other reasons. Previous applications of proportional hazards regression in frailty models have not needed to account for the changing composition of the risk set which is required to adequately model occupational injury data. Published in 1999 by John Wiley & Sons, Ltd. This article is a US Government work and is in the public domain in the United States.

Adolescent↗

PubMed2000

The male climacterium: clinical signs and symptoms of a changing endocrine environment.

Frailty is characterized by generalized weakness, impaired mobility and balance, and poor endurance. Loss of muscle strength is an important factor in the process of frailty, and is the limiting factor for an individual's chances of living an independent life until death. In men, several hormonal systems show a decline in activity during aging. Serum bioavailable testosterone (T) and estradiol (E2), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), and growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations all decrease during aging in men. Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to this decline in hormonal activity. In a cross-sectional study performed among 403 independently living elderly men, positive independent associations were observed between serum bioavailable T and muscle strength and bone mineral density (BMD). Serum T was negatively associated with fat mass. Serum luteinizing hormone (LH) increased with age and was inversely associated with T. Independent of T, LH was negatively related with muscle strength and positively with the number of problems in activities of daily living. Further, a positive relation was present between serum E2 and BMD. A positive association between DHEAS and BMD was dependent on T and E2 concentrations. Finally, in the same study, men with the highest E2 concentrations were significantly more satisfied with life, measured with a questionnaire developed by Herschbach and Huber, compared to men with the lowest E2 concentrations. In conclusion, these findings are in agreement with other studies, which suggest that the maintenance of a good physical functional ability and quality of life is related to serum T, E2, and DHEA(S) concentrations.

Aging↗

PubMed2001

Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable).

BACKGROUND: In general, surgery is believed to offer the best prospects for cure for early stage non-small cell lung cancer (NSCLC). In spite of the intention to consider all patients with stage I-II disease for surgery, there are those who, although technically operable, either refuse surgery or are considered inoperable because of insufficient respiratory reserve, cardiovascular disease or general frailty. This group may therefore be considered "medically inoperable". Some respiratory physicians refer these patients for radical radiotherapy whilst others believe that radiotherapy has little to offer and adopt a watch policy, referring patients for palliative radiotherapy only when they become symptomatic. Although there is little evidence from randomised trials to support the use of radical radiotherapy for stage I/II NSCLC, it is the perception of most clinical oncologists (radiotherapists) that patients should receive radical, as opposed to palliative, treatment (COIN 1999). OBJECTIVES: To determine the effectiveness and the morbidity of radical radiotherapy for medically inoperable NSCLC. SEARCH STRATEGY: Randomised trials were sought by electronic searching the Cochrane Clinical Trials Register and both randomised and non-randomised trials sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching. SELECTION CRITERIA: Studies of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose greater than 40Gy in 20 fractions over four weeks or its radiobiological equivalent. DATA COLLECTION AND ANALYSIS: Two randomised and thirty-five non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria and were not included in the review. MAIN RESULTS: In the randomised trial comparing two radiotherapy schedules, two-year survival was superior following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) compared to 60Gy in 30 fractions over six weeks (24%). There were 26 non-randomised retrospective studies including an estimated 2003 patients, in which overall survival results varied between 33-72% at two years, 17-55% at three years and 0-42% at five years. The proportion of deaths not due to cancer was 11-43%. Cancer-specific survival was between 54-93% at two years, 22-56% at three years and 13-39% at five years. Complete response rates were 33-61% and local failure rates between 6-70%. Distant metastases developed in approximately 25% of patients. Better response rates and survival were seen in those with smaller tumours and in those receiving higher doses though the reasons for prescribing higher doses were not clearly stated. Worse outcome was seen in those with prior weight loss or poor performance status. Assessment of treatment-related morbidity and effects on quality of life and symptom control were inconclusive because of the lack of prospective evaluation and paucity of data. REVIEWER'S CONCLUSIONS: There were no randomised trials that compared a policy of immediate radical radiotherapy with palliative radiotherapy given when patients develop symptoms. In the absence of such trials, radical radiotherapy appears to result in a better survival than might be expected had treatment not been given. A substantial, though variable, proportion of patients died during follow-up from causes other than cancer. The optimal radiation dose and treatment technique (particularly with respect to mediastinal irradiation) remain uncertain.

Carcinoma, Non-Small-Cell Lung↗

PubMed2006

Urban and rural differences in mortality and causes of death in historical Poland.

The purpose of this paper is to document and interpret urban-rural differences in mortality in the past. To this end, we used data on mortality in Wielkopolska, Poland, in the 19th century and at the beginning of the 20th century. The data on mortality in rural areas (N = 1,173,910 deceased), small towns (N = 573,903 deceased), and Poznań, the capital of the Wielkopolska region (N = 86,352 deceased), were gathered from original Prussian statistical yearbooks (Preussische Statistik). Causes of death were also analyzed (rural areas, N = 449,576 deceased; small towns, N = 238,365 deceased; Poznań, N = 61,512 deceased). Mortality measures such as crude death rate (CDR), infant death rate (IDR), and neonatal and postneonatal death rates were calculated. Life tables were constructed for both stationary and stable population models and measures of the opportunity for natural selection calculated (Crow's index I(m), potential gross reproduction rate R(pot), and biological state index I(bs)). Relative frequencies of leading causes of death were computed. Stratification depending on the place of residence was evident in all mortality measures as well as in the values of the life tables and the measures of the opportunity for natural selection, but it was reverse of what is observed today in developed countries. In Poznań (a large industrial city), the mortality situation was the least favorable. It was caused by large population density, lack of water supply and sewage systems (up to 1896), and bad working conditions. The values of CDR ranged between 26.89-31.46, and IDR between 190.6-280.5. Newborn life expectancy (for a stable population model) was 31.6 years, I(m) = 0.79, R(pot) = 0.85, and I(bs) = 0.47. The most common causes of death were tuberculosis, other diseases of the respiratory and circulatory systems, dysentery and diarrhea, and cancer. These diseases were less common in rural areas, so they had the most favorable values of mortality measures (CDR between 22.87-27.32, IDR between 181.8-219.4, life expectancy of newborn e(0) = 42.12, I(m) = 0.55, R(pot) = 0.93, I(bs) = 0.60). Infectious diseases (other than tuberculosis), frailty at birth, and frailty in old age were the most frequent causes of death in rural areas. Small towns (population <20,000) had a mortality intermediate between city and rural areas.

Cause of Death↗

PubMed2007

Early childhood stress and adult age mortality--a study of dental enamel hypoplasia in the medieval Danish village of Tirup.

This study explores how linear enamel hypoplasia (LEH) affects mortality in the village of Tirup (A.D. 1150-1350), Denmark. Data consist of information on 583 skeletons aged 1 year or more. Three partly overlapping subsamples were defined. (1) 104 skeletons of young children aged 1-6 years and 120 skeletons of adults giving information on LEH. (2) 458 skeletons aged 6 years or more. (3) 109 adult skeletons (aged 20 years or more) that provided transition analysis age estimates, sex assessments, and LEH information. Of the 109 skeletons in Subsample 3, 60 had no and 49 had at least one LEH. In Subsample 1, it was found that the case fatality rate for episodes potentially leading to LEH dropped from over 0.5 in 1-year olds to around 0.1 in 3-5-year olds. Only models with heterogeneity of frailty could describe late childhood and adolescent mortality. Further, it was shown that only a model with continuously varying frailty preserved heterogeneity to adulthood. Among young adult females and males in all adult ages, people with LEH experienced a higher mortality than people without it. Among males, the mortality rate ratio (MRR) was 2.28. The analyses indicate that the MRR gives an unbiased estimate for the extra risk of dying for adult males with LEH. The values of the case fatality rates for young children might be slightly biased upward because of a higher than average number of older children and adolescents dying with LEH.

Adolescent↗

PubMed2004

Time-dependent effects on survival in breast carcinoma: results of 20 years of follow-up from the Swedish Two-County Study.

BACKGROUND: Tumor size, lymph node status, and histologic grade are reported to be important predictors of survival in the first 5 years after the diagnosis of invasive breast carcinoma. However, to the authors' knowledge, the effect of these factors in the longer term (>10 years after diagnosis) is not yet clear. METHODS: It is now >20 years since the Swedish Two-County Trial of breast carcinoma screening with mammography was instigated and long-term follow-up is now available to December 1998. In the current study, the authors analyzed the effects of tumor size, lymph node status, and tumor grade on survival to death from breast carcinoma using Cox regression and frailty models that allow the baseline hazard and/or effect of a covariate to vary with time. RESULTS: The effects of tumor size, lymph node status, and tumor grade were shown to progressively diminish with time from diagnosis. The Cox regression model with time-varying coefficients and a dampening parameter then was fitted to allow for the attenuation of prognostic effects; tumor size, lymph node status, and tumor grade were all found to be highly significant (P<0.001). CONCLUSIONS: The results of the current study suggest that long-term survival in women with invasive breast carcinoma could be modelled satisfactorily using either frailty models or Cox regression models with time-varying coefficients. The results also suggest that the value of tumor grade, lymph node status, and tumor size at the time of diagnosis have a lasting influence on subsequent survival, albeit attenuated in later years. The long-term effects of these prognostic factors may explain the fact that the impact of mass screening programs on breast carcinoma mortality rates is still apparent many years later.

Breast Neoplasms↗

PubMed1994

Survival models for developmental genetic data: age of onset of puberty and antisocial behavior in twins.

The use of survival analysis for developmental genetic data is discussed. The main requirements for models based on the decomposition of frailty distributions into shared and unshared components are outlined for the simple case of twins. Extending the earlier work of Clayton, Oakes, and Hougaard, among others, three forms of hazard model are presented, all of which can be applied to pedigree data with flexible baseline hazards without the use of numerical integration. The first two models use an additive decomposition of frailty, with either gamma or positive stable law distributed (PSL) components. The third model previously described by Hougaard involves a multiplicative PSL decomposition. The models are applied to data on the onset of puberty in male twins and illustrate the importance of correct specification of the baseline hazard for correct inference about genetic effects. The difficulty of assessing model specification using information only on the margins is also noted. Overall, the new model with additive PSL components appeared to fit these data best. A second application illustrates the use of a time-varying covariate in examining the impact of puberty on the onset of conduct disorder symptomotology.

Adolescent↗

PubMed2006

Analysing multicentre competing risks data with a mixed proportional hazards model for the subdistribution.

In the competing-risks setting, to test the effect of a covariate on the probability of one particular cause of failure, the Fine and Gray model for the subdistribution hazard can be used. However, sometimes, competing risks data cannot be considered as independent because of a clustered design, for instance in registry cohorts or multicentre clinical trials. Frailty models have been shown useful to analyse such clustered data in a classical survival setting, where only one risk acts on the population. Inclusion of random effects in the subdistribution hazard has not been assessed yet. In this work, we propose a frailty model for the subdistribution hazard. This allows first to assess the heterogeneity across clusters, then to incorporate such an effect when testing the effect of a covariate of interest. Based on simulation study, the effect of the presence of heterogeneity on testing for covariate effects was studied. Finally, the model was illustrated on a data set from a registry cohort of patients with acute myeloid leukaemia who underwent bone marrow transplantation.

Bone Marrow Transplantation↗

PubMed2006

A randomized, controlled trial of disability prevention in frail older patients screened in primary care: the FRASI study. Design and baseline evaluation.

BACKGROUND AND AIMS: We describe the enrollment and intervention phases of FRASI (FRAilty, Screening and Intervention), a randomized controlled trial aimed at preventing ADL disability in frail older persons screened in primary care. METHODS: Patients, 70-85 years old, non-disabled and noncognitively impaired, were screened for frailty (score < or = 9 on the Short Physical Performance Battery, SPPB) during primary care visits. Of 447 eligible persons, 410 came to the study clinic and 251 were randomized into treatment (n=126) and control groups (n=125). The active group received an intensive medical intervention, and sixteen 90-minute supervised exercise sessions over 8 weeks. The primary outcome was time to ADL disability onset or death in the 12-month period after study enrollment. RESULTS: The two study arms were similar for demographics, cognitive function, physical function and health status. Compared with a population-based sample selected according to FRASI inclusion criteria except SPPB score, FRASI participants had significantly worse health and functional status. Restricting the comparison to persons with SPPB < or = 9, all differences disappeared. The 99 participants (78.6% of 126) who completed the intervention participated in a mean of 15.3+/-1.6 exercise sessions. CONCLUSIONS: Screening in primary care for non-disabled, older persons with SPPB < or = 9 yields individuals with substantial morbidity, impairments and functional limitations that can be successfully involved in an intensive medical and exercise intervention. Whether such an intervention effectively prevents new disability remains to be confirmed.

Aged↗

PubMed2004

Decreased cell proliferation and altered cytokine production in frail older adults.

BACKGROUND AND AIMS: Frailty is a geriatric syndrome that predicts increased morbidity and mortality. In order to investigate specific immune system modulations that may contribute to frailty, eleven age- and sex-matched pairs of community-dwelling frail and non-frail older adults were identified. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated and PBMC proliferation and production of IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 in the presence and absence of lipopolysaccharide (LPS) were examined. RESULTS: We found that frail subjects had a significantly lower LPS-induced PBMC proliferation ratio compared with non-frail subjects (2.1+/-0.9 vs 3.11+/-1.9, p<0.03). In addition, frail subjects had higher IL-6 production by PBMC at 48 hours after LPS stimulation (35678+/-15637 vs 25178+/-6342 pg/mL, p<0.03). No significant differences were observed in TNF-alpha, and IL-10 production between groups. CONCLUSIONS: These results suggest that, compared with non-frail controls, frail older adults have both decreased LPS-induced proliferation and increased IL-6 production by PBMC.

Aged↗