An Improved Model for Disease Progression in Patients From the Alzheimer's Disease Neuroimaging Initiative
Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA. The Journal of Clinical Pharmacology
(Impact Factor: 2.48).
06/2011; 52(5):629-44. DOI: 10.1177/0091270011405497
The objective of this analysis was to develop a semi-mechanistic nonlinear disease progression model using an expanded set of covariates that captures the longitudinal change of Alzheimer's Disease Assessment Scale (ADAS-cog) scores from the Alzheimer's Disease Neuroimaging Initiative study that consisted of 191 Alzheimer disease patients who were followed for 2 years. The model describes the rate of progression and baseline disease severity as a function of influential covariates. The covariates that were tested fell into 4 categories: (1) imaging volumetric measures, (2) serum biomarkers, (3) demographic and genetic factors, and (4) baseline cognitive tests. Covariates found to affect baseline disease status were years since disease onset, hippocampal volume, and ventricular volume. Disease progression rate in the model was influenced by age, total cholesterol, APOE ε4 genotype, Trail Making Test (part B) score, and current levels of impairment as measured by ADAS-cog. Rate of progression was slower for mild and severe Alzheimer patients compared with moderate Alzheimer patients who exhibited faster rates of deterioration. In conclusion, this model describes disease progression in Alzheimer patients using novel covariates that are important for understanding the worsening of ADAS-cog scores over time and may be useful in the future for optimizing study designs through clinical trial simulations.
Available from: sciencedirect.com
- "The absence of this variable might have affected the result because men have higher education than women. However, a recent analysishas shown that it is difficult to detect the influence of education on cognitive performance in clinical trials because clinical trial participants have higher levels of education i.e., the models are not able to describe this effect , likely because of the narrow distribution of years of education in the trial participants. "
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ABSTRACT: To estimate longitudinal changes in disease progression (measured by Alzheimer's disease assessment scale-cognitive 11-item [ADAS-cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status.
Available from: Chuanpu Hu
- "To date, covariates affecting progression of DAD scores remain unknown because of the knowledge gap in the published literature. Previously known ADAS-Cog score models   have identified age, APOE ε4 carrier status, AD concomitant medications (cholinesterase inhibitors or/ and memantine), sex, and years since disease onset (YSO) as potential factors influencing disease progression. Thus, we preselected these covariates to be tested on both intercept and slope of the beta regression model for the DAD scores (Eq. "
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ABSTRACT: Objective Disability assessment for dementia (DAD) measurements from two phase-3 studies of bapineuzumab in APOE ε4 noncarrier and carrier Alzheimer's disease (AD) patients were integrated to develop a disease progression model. Methods We evaluated longitudinal changes in DAD scores, baseline factors affecting disease progression, and bapineuzumab effect on disease progression. Results A beta regression model best described DAD disease progression. The estimated treatment effect of bapineuzumab was not significant, consistent with lack of clinical efficacy observed in the primary analysis. The model suggested that progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was similar regardless of APOE ε4 status but more pronounced in patients with mild AD. Baseline disease status, age, memantine use, and years since onset (YSO) had significant effects on baseline DAD scores. AD concomitant medication use, baseline disease status, and YSO had significant effects on disease progression rate, measured by DAD score. Conclusions The beta regression model is a sensible modeling approach to characterize functional decline in AD patients. This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further evaluation may be warranted in future studies. Trial Registration ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.
Available from: Stuart Maudsley
- "Doody et al.  performed mixed effects regression modeling to predict longitudinal performance on standard clinical measures of AD. A sigmoidal model of the longitudinal changes in AD assessment cognitive sub-scale (ADAScog) was developed by Samtani et al. . Yet, the main contributors in their predictive model were demographic factors and clinical assessment. "
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