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PubMed2006

Possible acceleration of aging by adjuvant chemotherapy: a cause of early onset frailty?

Cancer chemotherapy has three main applications. It is curative for a small number of malignancies including childhood leukemia, Hodgkin's and non-Hodgkin's lymphoma, and germ cell malignancies. It has a palliative role for most metastatic epithelial malignancies. Finally, it has an adjuvant role in several types of resected epithelial malignancies particularly breast cancer. First successfully employed in the mid 1970s, adjuvant chemotherapy is associated with up to a 30% relative improvement in long-term overall survival in high risk breast cancer but demonstrates significantly less absolute improvement. Now that adjuvant chemotherapy is being used in lower risk disease, both the relative and absolute improvement in overall survival is even less impressive. With a growing number of long-term survivors, we are only now able to define the delayed implications of adjuvant chemotherapy. These long-term side effects include acceleration of neurocognitive decline, musculoskeletal complications such as early onset osteoporosis, premature skin and ocular changes and the most common long-term complaint; mild to profound fatigue. This complex of problems is suggestive of early onset frailty. This paper explores various potential mechanisms of aging including accumulation of free-radical damage, accumulation of DNA damage, telomere shortening with accompanying decline in telomerase activity and finally a decline in neuroendocrine/immune function. The impact of chemotherapy, particularly those agents used in the adjuvant setting, in relationship to these aging mechanisms is explored. There is good evidence that chemotherapy can effect all these aging mechanisms leading to early onset frailty. The implications of this hypothesis are quite profound. Whereas short-term toxicity of chemotherapy can usually be considered acceptable even for a small improvement in survival, long-term toxicity such as early onset frailty can have an impact on quality of life that could last for years. This possible effect on aging could have implications on the decision to take adjuvant chemo, what agents to use, means to minimize the aging effect and the need to monitor for early onset frailty.

Aging, Premature↗

PubMed2002

The mortality rate as a function of accumulated deficits in a frailty index.

In a representative Canadian population survey (n=66589) the proportion of accumulated deficits in a frailty index showed a linear relationship with mortality in a log-log plot, such that the mortality rate was a power-law function of the frailty index. Represented in this way, the frailty index readily summarizes individual differences in health status. The exponent and amplitude parameters of the power function are gender specific, reflecting that while, on average, women accumulate more deficits than men of the same age, their risk of mortality is lower. The dependence of the mortality rate on the frailty index points to the merit of the index as a simple and accessible tool for estimating individual risks of mortality.

Adolescent↗

PubMed2000

[Falls, frailty and osteoporosis in the elderly: a public health problem].

INTRODUCTION: Elderly people can be subdivided into three groups: healthy elderly persons (65-70% of the population), elderly subjects with diseases (about 5%) and frail old people. Frailty represents "age-related physiologic vulnerability resulting from impaired homeotasic stock and a reduced capacity of the organism to withstand stress". It could lead elderly subjects to pathological, barely reversible, ageing. CURRENT KNOWLEDGE AND KEY POINTS: One of the main objective of geriatricians is to develop useful screening tools to identify people at high risk, thus allowing them to benefit from preventive interventions as early as possible. It has been suggested that the decline in homeostatic stock involves numerous physiological systems. Those at the core of frailty would be neuromuscular changes resulting in sarcopenia, neuroendocrine dysregulation, and immune disorders. A recent study has shown that increased levels of interleukin 6 is a risk factor for frailty. FUTURE PROSPECTS AND PROJECTS: Work in progress aimed at identification of at-risk patients should: lead to early detection; draw attention on underestimated fields such as the nutritional status, sarcopenia, or gait disorders; promote the development of the standardized gerontological evaluation in order to identify the different components of frailty; and promote the development of non-pharmacological programmes including physical training, nutritional managing, and optimal social life.

Accidental Falls↗

PubMed1999

Frailty bias in comorbidity risk adjustments of community-dwelling elderly populations.

Our objective was to describe distortion in outcome studies due to "frailty bias" or differential susceptibility to adverse health outcomes due to frailties but attributed to other factors. We linked an administrative database to survey data (n = 5934) containing functional, condition, and outcome measures. The disease classification scheme of an empirically derived mortality model was used to categorize 7500 ICD-9-CM codes into five risk levels. Cox and logistic regressions were used to compare outcomes. Commonly employed measures differ in their sensitivity to detect and control frailty bias across a spectrum of major chronic diseases. Survival is inversely related to increasing functional impairment after adjusting for age, race, gender, education, number of comorbid conditions, and highest disease risk occurring during follow-up. Functional status appears to be a superior and essential element for control of the frailty bias that threatens comparability of outcome measures across community-dwelling populations containing chronically-ill disabled elderly.

Activities of Daily Living↗

PubMed1999

Analyzing incidence of testis cancer by means of a frailty model.

There are two striking epidemiological features of testicular cancer. First, the incidence has increased strongly over the past few decades. Secondly, the incidence is greatest among younger men, and then declines from a certain age. We have constructed a statistical model to fit these observations. The idea of the model is that a subgroup of men is particularly susceptible to testicular cancer. In statistical terminology this is called a frailty model, since it focuses on varying frailty of the individuals. The frailty, or susceptibility, is considered as being established by birth, and due to a mixture of genetic and environmental effects. The strong increase in incidence over calendar time points to strong environmental effects, which are thought to operate in fetal life, causing damage to the fetus. Based on data from the Norwegian Cancer Registry we fit a frailty model to incidence data collected during 1953-93. The model gives a good fit and we discuss the interpretations of our findings.

Adolescent↗

PubMed2000

Fisher information for two gamma frailty bivariate Weibull models.

The asymptotic properties of frailty models for multivariate survival data are not well understood. To study this aspect, the Fisher information is derived in the standard bivariate gamma frailty model, where the survival distribution is of Weibull form conditional on the frailty. For comparison, the Fisher information is also derived in the bivariate gamma frailty model, where the marginal distribution is of Weibull form.

Bacterial Infections↗

PubMed2002

An additive genetic gamma frailty model for linkage analysis of diseases with variable age of onset using nuclear families.

Many late-onset complex diseases exhibit variable age of onset. Efficiently incorporating age of onset information into linkage analysis can potentially increase the power of dissecting complex diseases. In this paper, we treat age of onset as a genetic trait with censored observations. We use multiple markers to infer the inheritance vector at the disease susceptibility (DS) locus in order to extract information about the inheritance pattern of the disease allele in a pedigree. Given the inheritance distribution at the DS locus, we define the genetic frailty for each individual within a nuclear family as the sum of frailties due to a putative major disease gene and a polygenic effect due to any remaining DS loci. Conditioning on these frailties we use the proportional hazards model for the risk of developing disease. We show that a test of linkage can be formulated as a test of zero variance due to a specific locus of the additive gamma frailties. Maximum likelihood estimation, using the EM algorithm, and likelihood ratio tests are employed for parameter estimation and tests of linkage. A simulation study presented indicates that the proposed method is well behaved and can be more powerful than the currently available allele-sharing based linkage methods. A breast cancer data example is used for illustration.

Adult↗

PubMed2003

Maximum penalized likelihood estimation in a gamma-frailty model.

The shared frailty models allow for unobserved heterogeneity or for statistical dependence between observed survival data. The most commonly used estimation procedure in frailty models is the EM algorithm, but this approach yields a discrete estimator of the distribution and consequently does not allow direct estimation of the hazard function. We show how maximum penalized likelihood estimation can be applied to nonparametric estimation of a continuous hazard function in a shared gamma-frailty model withright-censored and left-truncated data. We examine the problem of obtaining variance estimators for regression coefficients, the frailty parameter and baseline hazard functions. Some simulations for the proposed estimation procedure are presented. A prospective cohort (Paquid) with grouped survival data serves to illustrate the method which was used to analyze the relationship between environmental factors and the risk of dementia.

Algorithms↗

PubMed2004

Physical frailty and body composition in obese elderly men and women.

OBJECTIVE: To evaluate the prevalence of frailty and interrelationships among body composition, physical function, and quality of life in community-dwelling obese elderly (OE) persons. RESEARCH METHODS AND PROCEDURES: Fifty-two OE, 52 nonobese frail, and 52 nonobese nonfrail subjects, matched for age and sex, were studied. Subjective and objective measures of functional status were evaluated by using the physical performance test, exercise stress test, lower extremity (LE) strength, gait speed, static and dynamic balance, functional status questionnaires, and health-related quality-of-life questionnaire (Medical Outcomes Short Form). Body composition was evaluated by using DXA, and muscle quality was evaluated by determining the ratio of LE strength to LE lean mass. RESULTS: Among OE subjects, 96% met our standard criteria for mild to moderate frailty. Compared with the nonobese nonfrail group, the OE and nonobese frail groups had lower and similar scores in physical performance test, peak aerobic power, and functional status questionnaire, and exhibited similar impairments in strength, walking speed, balance, and health-related quality of life. Although absolute fat-free mass (FFM) was greater, the percentage body weight as FFM and muscle quality was lower in the OE group than in the other two groups. DISCUSSION: Physical frailty, which predisposes to loss of independence, is common in community-living OE men and women. Physical frailty in OE subjects was associated with low percentage FFM, poor muscle quality, and decreased quality of life. These findings suggest that weight loss therapy may be particularly important in OE persons to improve physical function, in addition to improving the medical complications associated with obesity.

Aged↗

PubMed1999

The additive genetic gamma frailty model for linkage analysis of age-of-onset variation.

Age of onset is a key factor in the linkage analysis of many complex diseases. Current methods in nonparametric linkage analysis are mainly concentrated on the affected relative pairs or affected family members with age of onset information either ignored or taken into account by specifying age-dependent penetrances for liability classes. On the other hand, gamma frailty models were developed in the biostatistics literature to model familial aggregation of age of onset. However, these frailty models cannot be used directly for linkage analysis. This paper extends the gamma frailty model by incorporating inheritance vector information and provides a semiparametric approach for linkage testing. For a given inheritance vector at the putative disease locus, we construct an additive genetic gamma frailty for each individual within a nuclear family and use the Cox proportional hazard model to model age of onset. We derive the conditional hazard ratio parameter for sib pairs and define a likelihood ratio based LOD score statistic under our model. The EM algorithm is used for estimating the parameters and the maximum likelihood functions. Simulated data sets are used to illustrate these new statistical methods.

Age Factors↗

PubMed2002

Effects of exercise training on frailty in community-dwelling older adults: results of a randomized, controlled trial.

OBJECTIVES: Although deficits in skeletal muscle strength, gait, balance, and oxygen uptake are potentially reversible causes of frailty, the efficacy of exercise in reversing frailty in community-dwelling older adults has not been proven. The aim of this study was to determine the effects of intensive exercise training (ET) on measures of physical frailty in older community-dwelling men and women. DESIGN: Randomized controlled trial. SETTING: Medical school research center. PARTICIPANTS: One hundred fifteen sedentary men and women (mean age +/- standard deviation = 83 +/- 4) with mild to moderate physical frailty, as defined by two of the following three criteria: Modified Physical Performance Test (modified PPT) score between 18 and 32, peak oxygen uptake (VO2 peak) between 10 and 18 mL/kg/min, and self-report of difficulty or assistance with one basic activity of daily living (ADL), or two instrumental ADLs. INTERVENTION: Participants were randomly assigned to a control group that performed a 9-month low-intensity home exercise program (control) or an exercise-training program (ET). The control intervention primarily consisted of flexibility exercises. ET began with 3 months of flexibility, light-resistance, and balance training. During the next 3 months, resistance training was added, and, during the next 3 months, endurance training was added. MEASUREMENTS: Modified PPT score, VO2 peak, performance of ADLs as measured by the Older Americans Resources and Services instrument, and the Functional Status Questionnaire (FSQ). RESULTS: ET resulted in significantly greater improvements than home exercise in three of the four primary outcome measures. Adjusted 95% confidence bounds on the magnitude of improvement in the ET group compared with the control group were 1.0 to 5.2 points for the modified PPT score, 0.9 to 3.6 mL/kg/min for VO2 peak, and 1.6 to 4.9 points for the FSQ score. CONCLUSIONS: Our results show that intensive ET can improve measures of physical function and preclinical disability in older adults who have impairments in physical performance and oxygen uptake and are not taking hormone replacement therapy better than a low-intensity home exercise program.

Activities of Daily Living↗

PubMedDate not supplied

Frailty and the aging male.

Frailty occurs in aging males for a variety of reasons. It is less common in males than females. Diseases which are particularly associated with frailty are diabetes mellitus, atherosclerosis, anemia and chronic obstructive pulmonary disease. Insulin resistance syndrome plays a pathogenetic role in the "fat-frail" syndrome. Sarcopenia occurs predominantly because of hormone deficiency and cytokine excess. Pain and anorexia are also associated with frailty. Stem cell research represents a potential promise for the treatment of frailty.

Age Factors↗

PubMed2000

Physical and performance measures for the identification of mild to moderate frailty.

BACKGROUND: The relative importance and association of factors contributing to physical frailty in elderly persons are unclear. METHODS: Physical measures of upper and lower extremity strength, range of motion, balance, coordination, sensation, and gait were evaluated in relation to scores obtained on a 36-point physical performance test (PPT) in 107 elderly subjects. RESULTS: Scores on the PPT were significantly associated with the measures of strength and balance, gait, several range of motion values, and sensation. Subjects were also grouped according to score on the PPT as not frail (32-36 points), mildly frail (25-31 points), or moderately frail (17-24 points). ANOVA followed by Bonferroni post hoc analyses were used to examine the relationships of physical measures to this index of frailty. Balance measures, an obstacle course, the Berg scale, the full tandem portion of the Romberg test, and fast gait speed were significantly different among the three groups. Multiple stepwise regression analyses indicated that the strongest combination of variables, explaining 73% of all the variance in the PPT, included obstacle course performance, hip abduction strength, the semitandem portion of the Romberg test, and coordination (pegboard). CONCLUSIONS: Results provide further insight into the relative importance of factors that contribute to frailty and factors that should be considered in treatment planning for the remediation of physical frailty in old adults.

Aged↗

PubMed2006

Low serum micronutrient concentrations predict frailty among older women living in the community.

BACKGROUND: Micronutrient deficiencies are common among older adults. We hypothesized that low serum micronutrient concentrations were predictive of frailty among older disabled women living in the community. METHODS: We studied 766 women, aged 65 and older, from the Women's Health and Aging Study I, a population-based study of moderately to severely disabled community-dwelling women in Baltimore, Maryland. Serum vitamins A, D, E, B(6), and B(12), carotenoids, folate, zinc, and selenium were measured at baseline. Frailty status was determined at baseline and during annual visits for 3 years of follow-up. RESULTS: At baseline, 250 women were frail and 516 women were not frail. Of 463 nonfrail women who had at least one follow-up visit, 205 (31.9%) became frail, with an overall incidence rate of 19.1 per 100 person-years. Compared with women in the upper three quartiles, women in the lowest quartile of serum carotenoids (hazard ratio [HR] 1.39; 95% confidence interval [CI], 1.01-1.92), alpha-tocopherol (HR 1.39; 95% CI, 1.02-1.92), and 25-hydroxyvitamin D (HR 1.34; 95% CI, 0.94-1.90) had an increased risk of becoming frail. The number of nutritional deficiencies (HR 1.10; 95% CI, 1.01-1.20) was associated with an increased risk of becoming frail, after adjusting for age, smoking status, and chronic pulmonary disease. Adjusting for potential confounders, we found that women in the lowest quartile of serum carotenoids had a higher risk of becoming frail (HR 1.54; 95% CI, 1.11-2.13). CONCLUSIONS: Low serum micronutrient concentrations are an independent risk factor for frailty among disabled older women, and the risk of frailty increases with the number of micronutrient deficiencies.

Aged↗

PubMed2006

Vitamin and carotenoid status in older women: associations with the frailty syndrome.

OBJECTIVE: We investigated the relationship of micronutrient deficiencies with the frailty syndrome in older women living in the community. METHODS: Frailty status and serum micronutrients were assessed in a cross-sectional study of 754 women, 70-80 years old, from the Women's Health and Aging Studies I and II. RESULTS: Among nonfrail, prefrail, and frail women, respectively, geometric mean serum concentrations were 1.842, 1.593, and 1.376 micromol/L for total carotenoids (p <.001); 2.66, 2.51, and 2.43 micromol/L for retinol (p =.04); 50.9, 47.4, and 43.8 nmol/L for 25-hydroxyvitamin D (p =.019); 43.0, 35.8, and 30.9 nmol/L for vitamin B(6) (p =.002); and 10.2, 9.3, and 8.7 ng/mL for folate (p =.03). Frail women were more likely to have at least two or more micronutrient deficiencies (p =.05). The age-adjusted odds ratios of being frail were significantly higher for those participants whose micronutrient concentrations were in the lowest quartile compared to the top three quartiles for total carotenoids, alpha-tocopherol, 25-hydroxyvitamin D, and vitamin B(6). The association between nutrients and frailty was strongest for beta-carotene, lutein/zeaxanthin, and total carotenoids (odds ratio ranging from 1.82 to 2.45, p =.05), after adjusting for age, sociodemographic status, smoking status, and body mass index. CONCLUSION: Frail women are more likely to have relatively low serum carotenoid and micronutrient concentrations and are more likely to have multiple micronutrient deficiencies. Future longitudinal studies are needed to examine the relationships between micronutrient concentrations and frailty in older women.

Aged↗

PubMed1999

Recurrence in affective disorder: analyses with frailty models.

The risk of recurrence in affective disorder is influenced by the number of prior episodes and by a person's tendency toward recurrence. Newly developed frailty models were used to estimate the effect of the number of episodes on the rate of recurrence, taking into account individual frailty toward recurrence. The study base was the Danish psychiatric case register of all hospital admissions for primary affective disorder in Denmark during 1971-1993. A total of 20,350 first-admission patients were discharged with a diagnosis of major affective disorder. For women with unipolar disorder and for all kinds of patients with bipolar disorder, the rate of recurrence was affected by the number of prior episodes even when the effect was adjusted for individual frailty toward recurrence. No effect of episodes but a large effect of the frailty parameter was found for unipolar men. The authors concluded that the risk of recurrence seems to increase with the number of episodes of bipolar affective disorder in general and for women with unipolar disorder.

Age Distribution↗

PubMed2004

Clinical Global Impression of Change in Physical Frailty: development of a measure based on clinical judgment.

OBJECTIVES: To expand the ability to assess physical frailty by developing a Clinical Global Impression of Change in Physical Frailty (CGIC-PF) instrument. DESIGN: Qualitative and quantitative instrument development. SETTING: Academic centers. PARTICIPANT: s Six expert panel members, 46 clinicians, 24 patients, and 12 caregivers. MEASUREMENTS: Literature review and structured group processes with experts, clinicians, and consumers were used to generate an initial list of domains and indicators. Structured interviews with clinical experts in the area of frailty were used to establish relevance and feasibility of measurement of domains. Interrater reliability was assessed through a Web-based study. Geriatricians pilot tested the feasibility of the baseline CGIC-PF with 10 patients. RESULTS: The CGIC-PF includes six intrinsic domains (mobility, balance, strength, endurance, nutrition, and neuromotor performance) and seven consequences domains (medical complexity, healthcare utilization, appearance, self-perceived health, activities of daily living, emotional status, and social status). Each domain has two to four clinical indicators. Change is scored on a 7-point scale from markedly worse to markedly improved. Average interrater reliability of the CGIC-PF for the Web-based cases was 0.97. Geriatricians completed a baseline CGIC-PF on their own patients in 10 minutes or less. CONCLUSION: The CGIC-PF is a structured assessment of change in physical frailty with defined content and process. It has strong face validity, reliability, and feasibility for use in clinical research. It may be useful as one criterion of change and as an anchor for change in other measures.

Activities of Daily Living↗

PubMed2000

Genetic nature of individual frailty: comparison of two approaches.

The traditional frailty models used in genetic analysis of bivariate survival data assume that individual frailty (and longevity) is influenced by thousands of genes, and that the contribution of each separate gene is small. This assumption, however, does not have a solid biological basis. It may just happen that one or a small number of genes makes a major contribution to determining the human life span. To answer the questions about the nature of the genetic influence on life span using survival data, models are needed that specify the influence of major genes on individual frailty and longevity. The goal of this paper is to test the nature of genetic influences on individual frailty and longevity using survival data on Danish twins. We use a new bivariate survival model with one major gene influencing life span to analyse survival data on MZ (monozygotic) and DZ (dizygotic) twins. The analysis shows that two radically different classes of model provide an equally good fit to the data. However, the asymptotic behaviour of some conditional statistics is different in models from different classes. Because of the limited sample size of bivariate survival data we cannot draw reliable conclusions about the nature of genetic effects on life span. Additional information about tails of bivariate distribution or risk factors may help to solve this problem.

Alleles↗