Measuring Alzheimer's disease progression with transition probabilities: estimates from CERAD.

OBJECTIVES: To estimate annual transition probabilities (i.e., the likelihood that a patient will move from one disease stage to another in a given time period) for AD progression. Transition probabilities are estimated by disease stages (mild, moderate, severe) and settings of care (community, nursing home), accounting for differences in age, gender, and behavioral symptoms as well as the length of time a patient has been in a disease stage. METHODS: Using data from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the authors employed a modified survival analysis to estimate stage-to-stage and stage-to-nursing home transition probabilities. To account for individual variability, a Cox proportional hazards model was fit to the CERAD data to estimate hazard ratios for gender, age (50 to 64, 65 to 74, and more than 75 years), and level of behavioral symptoms (low/high, according to responses to the Behavioral Rating Scale for Dementia) for each of the key stage-to-stage and stage-to-nursing home transitions. RESULTS: The transition probabilities underscore the rapid progression of patients into more severe disease stages and into nursing homes and the differences among population subgroups. In general, male gender, age under 65, and high level of behavioral symptoms were associated with higher transition probabilities to more severe disease stages. Disease progression is roughly constant as a function of the time a patient has spent in a particular stage. CONCLUSIONS: Transition probabilities provide a useful means of characterizing AD progression. Economic models of interventions for AD should consider the varied course of progression for different population subgroups, particularly those defined by high levels of behavioral symptoms.

The association between caregiver burden and caregiver health-related quality of life in Alzheimer disease.

The burden experienced by family caregivers of individuals with Alzheimer disease (AD) affects the caregivers' overall health-related quality of life (HRQOL). Assessing the influence on HRQOL is an integral part of determining the efficacy and economic attractiveness of interventions for AD. Generic preference-weighted instruments such as the Health Utilities Index Mark 2 (HUI2) are recommended for measuring HRQOL for cost-effectiveness studies. However, these instruments focus on physical attributes and have not been tested in an AD caregiver population. We administered the HUI2 to a population of 679 caregivers to people with AD at 13 community and institutional sites in the United States. We also administered the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), a caregiver time questionnaire, and a caregiver burden instrument. The mean global HUI2 utility score for caregivers was 0.87 and varied little by the affected person's setting of care and AD stage (range, 0.86-0.89; p > 0.2). The caregiver burden scales all varied by the affected person's setting of care, and some also varied by disease severity. The mental health component summary score of the SF-36 for caregivers varied across both disease stage and setting. Caregiver time increased for caregivers of AD-affected persons with more severe cognitive impairment. Generic preference-weighted instruments may not adequately capture differences in the burden of caregivers of those with AD. The development of condition-specific preference-weighted instruments may provide the means to better estimate HRQOL in AD caregivers.

The use of proxy respondents in studies of older adults: lessons, challenges, and opportunities.

OBJECTIVE: Proxies play a critical role as sources of health information for older persons with cognitive impairment and other chronic debilitating conditions. This paper reviews the validity of proxy responses for people older than age 60 in the following areas: functioning, physical and mental health, cognition, medical care utilization, and preferences for types of care and health states. DESIGN: A Medline review identified 24 clinical studies from 1990 to 1999 that use proxy data as a source of information about older adults. RESULTS: In general, studies report fairly good agreement between subjects and proxies in assessments of functioning, physical health, and cognitive status, and fair-to-poor agreement in assessments of psychological well-being. Proxies tend to describe more impairment in functioning and emotional well-being, relative to subjects, a pattern that is particularly marked among persons with cognitive impairment. In addition, proxies who report more caregiver responsibilities and subjective stress from caregiver duties provide more negative assessments of subjects' health and well-being. CONCLUSIONS: Findings tend to support the use of proxy ratings among older adults in many areas but not all when self-reports are not feasible. There is a need for more evaluation of proxy data in relation to other measures, such as performance assessments, medical records, and claims data, which may be less subject to respondent biases.

A comparison of HUI2 and HUI3 utility scores in Alzheimer's disease.

PURPOSE: The Health Utilities Index (HUI) is a generic, multiattribute, preference-based health-status classification system. The HUI Mark 3 (HUI3) differs from the earlier HUI2 by modifying attributes and allowing more flexibility for capturing high levels of impairment. The authors compared HUI2 and HUI3 scores of patients with Alzheimer's disease (AD) and caregivers, and contrasted results of a cost-effectiveness analysis of new drugs for AD using the two systems. METHODS: In a cross-sectional study of 679 AD patient/caregiver pairs, stratified by patient's disease stage (questionable/mild/moderate/severe/profound/terminal) and setting (community/assisted living/nursing home), caregivers completed the combined HUI2/HUI3 questionnaire as proxy respondents for patients and for themselves. RESULTS: Mean (SD) global utility scores for patients were lower on the HUI3 (0.22[0.26]) than on the HUI2 (0.53 [0.21]). Patient HUI3 utility scores ranged from 0.47(0.24) for questionable AD to -0.23 (0.08) for terminal AD, compared with a range of 0.73 (0.15) to 0.14 (0.07) for the HUI2. Among the 203 patients in the severe, profound, and terminal stages, 96 (48%) had negative global HUI3 utility scores, while none had a negative HUI2 score. The utility scores for caregivers were similar on the HUI3 (0.87 [0.14]) and HUI2 (0.87 [0.11]). Cost-effectiveness analysis of a new medication to treat AD showed somewhat more favorable results using the HUI3. CONCLUSIONS: The HUI2 and HUI3 discriminate well across AD stages. Compared with the HUI2, the HUI3 yields lower global utility scores for patients with AD, and more scores for states judged worse than dead. The HUI3 may yield substantially different results from the HUI2, particularly for persons who have serious cognitive impairments such as AD.

Cost-effectiveness of functional imaging tests in the diagnosis of Alzheimer disease.

PURPOSE: To evaluate the cost-effectiveness of functional neuroimaging in the work-up of patients at specialized Alzheimer disease clinics. MATERIALS AND METHODS: A decision model was used to calculate costs and benefits (in quality-adjusted life-years [QALYs]) that accrued to hypothetical cohorts of patients at presentation to an Alzheimer disease center. Sensitivity analysis was performed to examine the effects of diagnostic test characteristics, therapeutic efficacy, disease severity, and costs on cost-effectiveness. RESULTS: The incremental cost-effectiveness ratio of dynamic susceptibility contrast material-enhanced magnetic resonance (MR) imaging was $479,500 per QALY (compared with the usual diagnostic work-up), while visual or quantitative single photon emission computed tomography (SPECT) was dominated (higher costs, lower effectiveness) by the usual diagnostic work-up. These results depend critically on the sensitivity and specificity of the standard diagnostic work-up, the effectiveness of drug treatment, and the disease severity. Varying these parameters resulted in estimates of incremental cost-effectiveness for dynamic susceptibility contrast-enhanced MR imaging of $24,680 to $8.6 million per QALY. SPECT either was dominated by the usual diagnostic work-up or had cost-effectiveness ratios of $180,200 to $6 million per QALY. CONCLUSION: The addition of functional neuroimaging to the usual diagnostic regimen at Alzheimer disease clinics is not cost-effective given the effectiveness of currently available therapies.

Health utilities in Alzheimer's disease: a cross-sectional study of patients and caregivers.

OBJECTIVES: Although the broad impacts of Alzheimer's disease (AD) are increasingly recognized, little work has focused on the overall health-related quality of life experienced by Alzheimer's disease patients and their caregivers. The study had two main objectives: (1) to test the feasibility of measuring health utilities in Alzheimer's disease with a generic preference-weighted instrument using proxy respondents and (2) to assess the utility scores of Alzheimer's disease patients (and their caregivers) in different disease stages and care setting. METHODS: A cross-sectional study of 679 Alzheimer's disease patient/caregiver pairs was conducted at 13 sites in the United States: four academic medical centers, four managed care plans, two assisted living facilities, and three nursing homes. The Health Utilities Index Mark II (HUI:2) questionnaire was administered to caregivers of patients who responded both as proxies for patients and for themselves. Responses to the questionnaire were converted into a global utility score, between 0 and 1, using the HUI:2 multi-attribute utility function. RESULTS: Global utility scores varied considerably across patients' Alzheimer's disease stage: for the six stages assessed (questionable, mild, moderate, severe, profound, and terminal), mean utility scores were 0.73, 0.69, 0.53, 0.38, 0.27, and 0.14, respectively. In multiple regression analyses, Alzheimer's disease stage was a negative and significant predictor of utility scores for patients; setting did not exert an independent effect. Utility scores for the caregivers were insensitive to patients' Alzheimer's disease stage and setting. CONCLUSIONS: Patients' Alzheimer's disease stage had a substantial influence on health utilities, as measured by the HUI:2. More research is needed to assess the validity of using proxy respondents.

Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.

OBJECTIVE: To demonstrate the use of cost-effectiveness analysis to assess the economic impact of donepezil in the treatment of mild or moderate AD. BACKGROUND: Cost-effectiveness analyses show the relationship between resources used (costs) and health benefits achieved (effects) for an intervention compared with an alternative strategy. METHODS: We developed a model to estimate the incremental cost-effectiveness of donepezil compared with no treatment. We determined costs per quality-adjusted life-years gained, a measurement that enhances the comparability of diverse studies. The model projects the progression of AD patients into more severe disease stages and into nursing homes. Data from a randomized clinical trial of donepezil were used to assess the drug's impact on the 6-week probabilities of progression. Data on the costs and health-related quality of life associated with different disease stages and settings were taken from published estimates and our companion cross-sectional study, respectively. RESULTS: Donepezil costs are partially offset by a reduction in the costs of care due to enhancement in cognitive functioning and the delay to more costly disease stages and settings. The magnitude of this cost offset and of the effect of donepezil on health-related quality of life depends on the model's assumptions about the duration of the drug effect, where controlled data are lacking. If the drug effect exceeds 2 years, the model predicts that for mild AD the drug would pay for itself in terms of cost offsets. CONCLUSIONS: The results of the cost-effectiveness model presented here suggest that donepezil may be cost-effective but additional controlled data on long-term drug efficacy are needed.