Power Calculations for Clinical Trials in Alzheimer's Disease
ABSTRACT The Alzheimer research community is actively pursuing novel biomarker and other biologic measures to characterize disease progression or to use as outcome measures in clinical trials. One product of these efforts has been a large literature reporting power calculations and estimates of sample size for planning future clinical trials and cohort studies with longitudinal rate of change outcome measures. Sample size estimates reported in this literature vary greatly depending on a variety of factors, including the statistical methods and model assumptions used in their calculation. We review this literature and suggest standards for reporting power calculation results. Regardless of the statistical methods used, studies consistently find that volumetric neuroimaging measures of regions of interest, such as hippocampal volume, outperform global cognitive scales traditionally used in clinical treatment trials in terms of the number of subjects required to detect a fixed percentage slowing of the rate of change observed in demented and cognitively impaired populations. However, statistical methods, model assumptions, and parameter estimates used in power calculations are often not reported in sufficient detail to be of maximum utility. We review the factors that influence sample size estimates, and discuss outstanding issues relevant to planning longitudinal studies of Alzheimer's disease.
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ABSTRACT: Introduction: Longitudinal assessment of cognitive decline in amnestic mild cognitive impairment (aMCI) and Alzheimer?s disease (AD) often involves the use of both informant-based and objective cognitive assessments. As efforts have focused on identifying individuals in pre-clinical stages, instruments that are sensitive to subtle cognitive changes are needed. The Alzheimer?s Questionnaire (AQ) has demonstrated high sensitivity and specificity in identifying aMCI and AD; however its ability to measure longitudinal change has not been assessed. The aims of this study are to assess the sensitivity to change of the AQ and to determine whether the AQ predicts change in global cognition and function in cognitively normal (CN), aMCI, and AD subjects. Methods: Data from 202 individuals participating in a brain and body donation program were utilized for this study (101 CN, 62 aMCI, 39?AD). AD and aMCI individuals were matched on age, education, and gender to CN individuals. Sensitivity to change of the AQ was assessed in addition to the AQ?s ability to predict change in global cognition and function. The Mini Mental State Exam (MMSE) and Functional Activities Questionnaire (FAQ) were used as gold standard comparisons of cognition and function. Sample size calculations for a 25% treatment effect were also carried out for all three groups. Results: The AQ demonstrated small sensitivity to change in the aMCI and CN groups (d=0.33, d=0.23, respectively) and moderate sensitivity to change in the AD group (d=0.43). The AQ was associated with increases in the Clinical Dementia Rating Global Score (OR=1.20 (1.09, 1.32), P <0.001). Sample size calculations found that the AQ would require substantially fewer subjects than the MMSE given a 25% treatment effect. Conclusions: Although the AQ demonstrated small sensitivity to change in aMCI and CN individuals in terms of effect size, the AQ may be superior to objective cognitive tests in terms of required sample size for a clinical trial. As clinicians and researchers continue to identify and treat individuals in earlier stages of AD, there is a need for instruments that are sensitive to cognitive changes in these earlier stages.Alzheimer's Research and Therapy 01/2015; 7(1). DOI:10.1186/s13195-014-0092-z · 3.50 Impact Factor
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ABSTRACT: Background Non-pharmacological interventions may improve cognition and quality of life, reduce disruptive behaviors, slow progression from Mild Cognitive Impairment (MCI) to dementia, and delay institutionalization. It is important to look at their trial designs as well as outcomes to understand the state of the evidence supporting non-pharmacological interventions in Alzheimer’s disease (AD). An analysis of trial design strengths and limitations may help researchers clarify treatment effect and design future studies of non-pharmacological interventions for MCI related to AD. Methods A systematic review of the methodology of Randomized Controlled Trials (RCTs) targeting physical activity, cognitive interventions, and socialization among subjects with MCI in AD reported until March 2014 was undertaken. The primary outcome was CONSORT 2010 reporting quality. Secondary outcomes were qualitative assessments of specific methodology problems. Results 23 RCT studies met criteria for this review. Eight focused on physical activity, fourteen on cognitive interventions, and one on the effects of socialization. Most studies found a benefit with the intervention compared to control. CONSORT reporting quality of physical activity interventions was higher than that of cognitive interventions. Reporting quality of recent studies was higher than older studies, particularly with respect to sample size, control characteristics, and methodology of intervention training and delivery. However, the heterogeneity of subjects identified as having MCI and variability in interventions and outcomes continued to limit generalizability. Conclusions The role for non-pharmacological interventions targeting MCI is promising. Future studies of RCTs for non-pharmacological interventions targeting MCI related to AD may benefit by addressing design limitations.The Journal of Nutrition Health and Aging 02/2014; 19(2). DOI:10.1007/s12603-014-0565-6 · 2.66 Impact Factor
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ABSTRACT: Aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.Alzheimer Disease and Associated Disorders 11/2014; 9(4). DOI:10.1097/WAD.0000000000000071 · 2.69 Impact Factor