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PubMed2006

A revolution for aging research.

In the year 1992, two publications on age-specific mortality rates revealed a cessation of demographic aging at later ages in very large cohorts of two dipteran species reared under a variety of conditions. Despite some initial concerns about possible artifacts, these findings have now been amply corroborated in the experimental literature. The eventual cessation of aging undermines the credibility of simple Gompertzian aging models based on a protracted acceleration in age-specific mortality during adulthood. The first attempt to explain the apparent cessation of aging was extreme lifelong heterogeneity among groups with respect to frailty. This lifelong heterogeneity theory assumes an underlying Gompertzian aging affecting every member of an adult cohort, with a merely apparent cessation of aging explained in terms of the increasing domination of a slowly aging group among the survivors to late ages. This theory has received several experimental refutations. The second attempt to explain the cessation of aging applied force of natural selection theory. This explanation of the cessation of aging has been corroborated in several Drosophila experiments. In particular, this theory requires that both age-specific survival and age-specific fecundity cease declining in late life, which has now been experimentally established. This theory also predicts that the timing of the cessation of aging should depend on the last age of reproduction in a population's evolutionary history, a prediction that has been corroborated. While lifelong heterogeneity should reduce average age-specific mortality in late life whenever it is pronounced, the cessation of aging in late life can be explained by plateaus in the forces of natural selection whether lifelong heterogeneity is present or not. The discovery that aging ceases is one of the most significant discoveries in recent aging research, with potentially revolutionary scientific implications.

Age Factors↗

PubMed2005

A diagnostic for association in bivariate survival models.

We propose exploratory, easily implemented methods for diagnosing the appropriateness of an underlying copula model for bivariate failure time data, allowing censoring in either or both failure times. It is found that the proposed approach effectively distinguishes gamma from positive stable copula models when the sample is moderately large or the association is strong. Data from the Women's Health and Aging Study (WHAS, Guralnik et al., The Womens's Health and Aging Study: Health and Social Characterisitics of Older Women with Disability. National Institute on Aging: Bethesda, Mayland, 1995) are analyzed to demonstrate the proposed diagnostic methodology. The positive stable model gives a better overall fit to these data than the gamma frailty model, but it tends to underestimate association at the later time points. The finding is consistent with recent theory differentiating 'catastrophic' from 'progressive' disability onset in older adults. The proposed methods supply an interpretable quantity for copula diagnosis. We hope that they will usefully inform practitioners as to the reasonableness of their modeling choices.

Aged↗

PubMed2005

Multivariate parametric spatiotemporal models for county level breast cancer survival data.

In clustered survival settings where the clusters correspond to geographic regions, biostatisticians are increasingly turning to models with spatially distributed random effects. These models begin with spatially oriented frailty terms, but may also include further region-level terms in the parametrization of the baseline hazards or various covariate effects (as in a spatially-varying coefficients model). In this paper, we propose a multivariate conditionally autoregressive (MCAR) model as a mixing distribution for these random effects, as a way of capturing correlation across both the regions and the elements of the random effect vector for any particular region. We then extend this model to permit analysis of temporal cohort effects, where we use the term "temporal cohort" to mean a group of subjects all of whom were diagnosed with the disease of interest (and thus, entered the study) during the same time period (say, calendar year). We show how our spatiotemporal model may be efficiently fit in a hierarchical Bayesian framework implemented using Markov chain Monte Carlo (MCMC) computational techniques. We illustrate our approach in the context of county-level breast cancer data from 22 annual cohorts of women living in the state of Iowa, as recorded by the Surveillance, Epidemiology, and End Results (SEER) database. Hierarchical model comparison using the Deviance Information Criterion (DIC), as well as maps of the fitted county-level effects, reveal the benefit of our approach.

Adult↗

PubMed2005

Marginal analysis for clustered failure time data.

Clustered failure time data are commonly encountered in biomedical research where the study subjects from the same cluster (e.g., family) share the common genetic and/or environmental factors such that the failure times within the same cluster are correlated. Two approaches that are commonly used to account for the intra-cluster association are frailty models and marginal models. In this paper, we study the marginal proportional hazards model, where the structure of dependence between individuals within a cluster is unspecified. An estimation procedure is developed based on a pseudo-likelihood approach, and a risk set sampling method is proposed for the formulation of the pseudo-likelihood. The asymptotic properties of the proposed estimators are studied, and the related issues regarding the statistical efficiencies are discussed. The performances of the proposed estimator are demonstrated by the simulation studies. A data example from a child vitamin A supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or NNIPS) is used to illustrate this methodology.

Cluster Analysis↗

PubMed2005

Multilevel mixed linear models for survival data.

For the analysis of correlated survival data mixed linear models are useful alternatives to frailty models. By their use the survival times can be directly modelled, so that the interpretation of the fixed and random effects is straightforward. However, because of intractable integration involved with the use of marginal likelihood the class of models in use has been severely restricted. Such a difficulty can be avoided by using hierarchical-likelihood, which provides a statistically efficient and fast fitting algorithm for multilevel models. The proposed method is illustrated using the chronic granulomatous disease data. A simulation study is carried out to evaluate the performance.

Case-Control Studies↗

PubMed2005

A baseline-free procedure for transformation models under interval censorship.

An important property of Cox regression model is that the estimation of regression parameters using the partial likelihood procedure does not depend on its baseline survival function. We call such a procedure baseline-free. Using marginal likelihood, we show that an baseline-free procedure can be derived for a class of general transformation models under interval censoring framework. The baseline-free procedure results a simplified and stable computation algorithm for some complicated and important semiparametric models, such as frailty models and heteroscedastic hazard/rank regression models, where the estimation procedures so far available involve estimation of the infinite dimensional baseline function. A detailed computational algorithm using Markov Chain Monte Carlo stochastic approximation is presented. The proposed procedure is demonstrated through extensive simulation studies, showing the validity of asymptotic consistency and normality. We also illustrate the procedure with a real data set from a study of breast cancer. A heuristic argument showing that the score function is a mean zero martingale is provided.

Algorithms↗

PubMed2007

Bayesian analysis of paired survival data using a bivariate exponential distribution.

We consider a Bayesian analysis method of paired survival data using a bivariate exponential model proposed by Moran (1967, Biometrika 54:385-394). Important features of Moran's model include that the marginal distributions are exponential and the range of the correlation coefficient is between 0 and 1. These contrast with the popular exponential model with gamma frailty. Despite these nice properties, statistical analysis with Moran's model has been hampered by lack of a closed form likelihood function. In this paper, we introduce a latent variable to circumvent the difficulty in the Bayesian computation. We also consider a model checking procedure using the predictive Bayesian P-value.

Bayes Theorem↗

PubMed2006

A comparative study of tests for paired lifetime data.

In this paper, we investigate different procedures for testing the equality of two mean survival times in paired lifetime studies. We consider Owen's M-test and Q-test, a likelihood ratio test, the paired t-test, the Wilcoxon signed rank test and a permutation test based on log-transformed survival times in the comparative study. We also consider the paired t-test, the Wilcoxon signed rank test and a permutation test based on original survival times for the sake of comparison. The size and power characteristics of these tests are studied by means of Monte Carlo simulations under a frailty Weibull model. For less skewed marginal distributions, the Wilcoxon signed rank test based on original survival times is found to be desirable. Otherwise, the M-test and the likelihood ratio test are the best choices in terms of power. In general, one can choose a test procedure based on information about the correlation between the two survival times and the skewness of the marginal survival distributions.

Biometry↗

PubMed2006

Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands.

Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators.

Androgen Antagonists↗

PubMed2005

Prevalence of falls among seniors maintained on hemodialysis.

BACKGROUND: Increasing numbers of seniors are starting renal replacement therapy. Many may experience a loss of functional independence including mobility impairment. Seniors on dialysis commonly have multiple comorbidities that are associated with an increased risk for falls in the general population. Falls lead to serious injury, loss of independence, hospitalization and institutionalization. Despite such morbidity, little attention has been directed toward this marker of frailty in the dialysis population. In this brief preliminary report, we set out to determine the prevalence of falls among seniors on dialysis. METHODS: A cross-sectional interview based survey was used to determine one year fall prevalence in patients aged 65 years and older receiving in center hemodialysis therapy. RESULTS: A total of 135 ambulatory seniors were interviewed. Thirty-seven (27%) people reported having fallen in the past 12 months. An additional 21(16%) reported a fall prior to the past year. Four percent recalled a fall associated fracture or head injury requiring treatment. CONCLUSIONS: Falls are very common amongst seniors on hemodialysis. Further prospective study of the incidence and risk factors for falls in this population is needed to allow targeted interventions.

Accidental Falls↗

PubMed1987

Complexity and contradiction in clinical trial research.

Randomized clinical trials have become the accepted scientific standard for evaluating therapeutic efficacy. Contradictory results from multiple randomized clinical trials on the same topic have been attributed either to methodologic deficiencies in the design of one of the trials or to small sample sizes that did not provide assurance that a meaningful therapeutic difference would be detected. When 36 topics with conflicting results that included over 200 randomized clinical trials in cardiology and gastroenterology were reviewed, it was discovered that results of randomized clinical trials often disagree because the complexity of the randomized clinical trial design and the clinical setting creates inconsistencies and variation in the therapeutic evaluation. Nine methodologic sources of this variation were identified, including six items concerned with the design of the trials, and three items concerned with interpretation. The design issues include eligibility criteria and the selection of study groups, baseline differences in the available population, variability in indications for the principal and concomitant therapies, protocol requirements of the randomized clinical trial, and management of intermediate outcomes. The issues in interpreting the trials include the regulatory effects of treatments, the frailty of double-blinding, and the occurrence of unexpected trial outcomes. The results of this review suggest that pooled analyses of conflicting results of randomized clinical trials (meta-analyses) may be misleading by obscuring important distinctions among trials, and that enhanced flexibility in strategies for data analysis will be needed to ensure the clinical applicability of randomized clinical trial results.

Clinical Trials as Topic↗

PubMed1991

Thoracotomy in the octogenarian.

Octogenarians are rarely referred for thoracic operations, presumably owing to the perceived morbidity of thoracotomy and the presumed frailty and limited life span of the 80-year-old patient. To determine if these concerns are valid, we reviewed our operative experience in 50 patients 80 years of age or older (mean age, 82.7 years; range, 80 to 91 years; 29 men, 21 women) undergoing thoracotomy between Nov 1, 1980, and May 1, 1990, for cancer (39 patients) and benign disease (11 patients). Procedures included 25 lobectomies (24 cancer, 1 abscess), 4 pneumonectomies (all cancer), 3 esophagectomies (1 perforation, 2 cancer), 3 explorations for cancer, 2 bullectomies, 12 wedge or segmental resections (5 open lung biopsies, 5 cancer, and 1 each for benign nodule and hemoptysis), and 1 thymectomy. Five patients (10%) were operated on emergently for massive hemoptysis (1), Boerhaave's syndrome (1), or rapidly progressive respiratory insufficiency (3) with an operative mortality of 80%. Mortality for elective cases was significantly lower (13%, p less than 0.01). Major complications occurred in 19 patients (38%). Univariate analysis performed to identify predictors of operative mortality demonstrated no significant relationship between operative death and patient age, sex, type of operation, diagnosis of malignancy, or the presence of either cardiac disease or chronic obstructive lung disease. Twenty-three patients are alive 2 months to 5 years after thoracotomy. Actuarial survival for the 45 elective patients was 56% and 44% at 1 and 2 years, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1993

Does functional reach improve with rehabilitation?

Functional reach (FR, maximal safe standing forward reach) is a precise, reliable, clinically accessible, age-sensitive measure of balance that approximates center of pressure excursion and validly estimates physical frailty. We now test its ability to detect improvement in balance over time. Twenty-eight inpatient male veterans (age 40 to 105, mean, 67.3) undergoing physical rehabilitation and 13 nonrehabilitation controls were evaluated at baseline and every 4 weeks using FR (yardstick method), 10-foot walking time (WT), the Duke hierarchical mobility skills protocol (HMS) and a portion of the Functional Independence Measure (FIM). Their sensitivity to change was determined using the responsiveness index (RI). FR as well as the other physical performance instruments tested were found to be sensitive to change (RI for FR = 0.97, WT = 11.26, HMS = 4.63, FIM = 4.93) and therefore, appropriate measures for use in prospective clinical trials.

Activities of Daily Living↗

PubMed1986

Structural properties of spinal nerve roots: protein composition.

The protein compositions of dorsal and ventral spinal nerve roots were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Protein readily soluble in sodium dodecyl sulfate (SDS) sample buffer made up 8.1% of the wet weight of dorsal and ventral roots. Spinal root protein samples consisted predominantly (60%) of myelin-associated proteins. Other major proteins including those tentatively identified as tubulin, actin, nuclear histones, and others accounted for the remainder of recovered protein. The protein constituents of nerve roots were similar to those of peripheral nerve but differed from those of spinal cord. Nerve roots and peripheral nerve were characterized by fewer major protein bands but greater concentrations of myelin proteins. Collagen which did not readily solubilize in SDS sample buffer was estimated by assaying for hydroxyproline. Nerve roots consisted of approximately 0.4% collagen by weight which was only one-fifth the amount estimated for nerve but six times more than spinal cord. It was apparent that the biomechanical frailty of roots compared with peripheral nerve might be explained by differences in the relative collagen contents of these tissues. The protein constituents of nerve roots after unilateral nerve crush were relatively stable compared with the profound changes seen in ipsilateral nerve and modest changes seen in contralateral uninjured nerve.

Animals↗

PubMedDate not supplied

Future health care technology and the hospital.

The past decades have been a time of rapid technological change in health care, but technological change will probably accelerate during the next decade or so. This will bring problems, but it will also present certain opportunities. In particular, the health care system is faced with the need to spend its limited resources more effectively. The number of hospital beds is being reduced, and lengths of stay are falling. In the future, the health care system will have to care for an increasing number of elderly people, both with chronic disease and also with dependency because of frailty and functional problems. The hospital of the future will probably be smaller and more intensive in the nature of its care. In part, this is because many present and future clinical technologies can be delivered outside of the hospital setting. And communication technologies offer the possibility of tying the various parts of the health care system into one true system. This would mean that the future hospital would have a more active role in supervising technical care outside of the hospital, and in making specialized knowledge accessible in all parts of the health system.

Computer Systems↗

PubMed1991

Aging and disability in China: cultural issues in measurement and interpretation.

Aging is no longer an issue of concern only to industrialized countries. Recent estimates project that by the year 2000 there will be 590 million people aged 60 or older worldwide. Of these 590 million approximately 61% will be living in lesser developed countries. Thus, these countries will shortly face critical decisions concerning the impact of these aging populations on state plans for economic development. China, the country with the largest anticipated number of elderly in the world, provides an instructive case of how one developing country is attempting to balance the needs of the elderly with those of the nation as a whole. In particular the rapid aging of the Chinese population has prompted official concern about the financial implications of providing health care to increasing numbers of disabled or frail elderly. This paper reports the efforts of one study to determine the extent of disability and frailty among the urban elderly and the strategies they and their family members have developed to cope with it. The research was conducted between June 1987 and January 1988 in two neighborhoods of Canton, the capital of Guangdong Province. Two hundred households, each containing at least one member 70 years of age or older, were randomly selected from household registration lists. In each household a 1-2 hr interview was conducted with the elder (or, in the case of those too disabled to participate, a proxy) on the following topics: personal background, proximity and contact with kin, household composition and organization, health and functionality, use of medical services, work history, income sources, daily activities, and attitudes regarding intergenerational relations. The paper is divided into five parts addressing the following topics: (1) China and research on aging, (2) comparative data--problematic aspects, (3) methodological issues to consider when investigating disability, (4) the findings of the study, and (5) the significance of ideological, environmental, and political factors in mediating the experience of age-associated disability in China.

Aged↗

PubMed1992

Responses to the institution among elderly patients in hospital long-stay care.

The theory of the 'total institution' argues that institutions deliberately create dependency in individuals who would otherwise be self-determining. We examine the significance of this concept for patients in long-stay geriatric wards. All such patients in the South West Thames Region (808) were located and assessed for levels of physical dependency and mental confusion. 87% were profoundly disabled, 53% were severely confused and 23% were seriously ill or unable to communicate. Those capable of responding (291) were interviewed. Three quarters or more were satisfied with 'staff relations', 'autonomy', 'amenities' and 'privacy' and three fifths were satisfied with the 'social environment'. Results suggest that: (a) patients in long-stay geriatric wards who were not severely confused were able to make realistic assessments of their situation and (b) the majority were not passively institutionalized. In terms of institutionalization theory, it is their physical frailty that appears to differentiate this group from other categories of 'inmates'. We conclude that appropriate policy for the long-term ill necessitates consideration of the actual as well as the attributed needs of patients.

Adaptation, Psychological↗

PubMed1993

Commission of the European Communities "Europe Against Cancer" Programme. European school of oncology advisory report. Cancer treatment in the elderly.

Within the EC approximately one million cases of cancer are diagnosed every year. At present, more than 55% of cancers occur in subjects aged over 65 years. There has been little clinical attention to the problem of neoplasia in the elderly. They are not receiving the same standard of specialised oncological care as younger patients. Other diseases (co-morbidity conditions) associated with cancer, and influencing its treatment and outcomes are not being properly considered. Information on surgery, radiotherapy and chemotherapy in younger patients exists for all cancers and could be adapted for the elderly. Controversial aspects of neoplasia in the elderly concern the intensity of chemotherapy, extent of surgery and the relative roles of specialised cancer centres, community hospitals and primary care providers. Future research should aim to replace subjective opinions on presence of frailty with objective instruments such as the multidimensional geriatric assessment scale. New trials could then seek to improve treatment in well-defined populations in terms of both efficacy and quality of life. Funding priorities should firstly consider that clinical trials for tumours in the elderly must be organised from cancer institutes and specialised referral centres in collaboration with geriatricians, primary care and community hospital physicians. Continuing education of doctors should be reported. A document such as this with appropriate modifications might be used as an initial message on neoplasia in the elderly to be published for information to clinicians and the public throughout Europe. Specific measures of quality assurance need financial support to evaluate the improvements in patterns of care. The 10 points of the 'Europe Against Cancer Guidelines' need reemphasising.

Aged↗