Browsing by Subject "Alzheimer’s disease"
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Item Predicting the course of Alzheimer’s progression(SpringerOpen, 2019-06-17) Iddi, S.; Li, D.; Aisen, P.S.; Rafii, M.S.; Thompson, W.K.; Donohue, M.C.Alzheimer’s disease is the most common neurodegenerative disease and is characterized by the accumulation of amyloid-beta peptides leading to the formation of plaques and tau protein tangles in brain. These neuropathological features precede cognitive impairment and Alzheimer’s dementia by many years. To better understand and predict the course of disease from early-stage asymptomatic to late-stage dementia, it is critical to study the patterns of progression of multiple markers. In particular, we aim to predict the likely future course of progression for individuals given only a single observation of their markers. Improved individual-level prediction may lead to improved clinical care and clinical trials. We propose a two-stage approach to modeling and predicting measures of cognition, function, brain imaging, fluid biomarkers, and diagnosis of individuals using multiple domains simultaneously. In the first stage, joint (or multivariate) mixed-effects models are used to simultaneously model multiple markers over time. In the second stage, random forests are used to predict categorical diagnoses (cognitively normal, mild cognitive impairment, or dementia) from predictions of continuous markers based on the first-stage model. The combination of the two models allows one to leverage their key strengths in order to obtain improved accuracy. We characterize the predictive accuracy of this two-stage approach using data from the Alzheimer’s Disease Neuroimaging Initiative. The two-stage approach using a single joint mixed-effects model for all continuous outcomes yields better diagnostic classification accuracy compared to using separate univariate mixed-effects models for each of the continuous outcomes. Overall prediction accuracy above 80% was achieved over a period of 2.5 years. The results further indicate that overall accuracy is improved when markers from multiple assessment domains, such as cognition, function, and brain imaging, are used in the prediction algorithm as compared to the use of markers from a single domain only.Item The relative efficiency of time-to-progression and continuous measures of cognition in presymptomatic Alzheimer’s disease(Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2019-07-18) Iddi, S.; Li, D.; Aisen, P.S.; Thompson, W.K.; Donohue, M.C.Introduction: Clinical trials on preclinical Alzheimer’s disease are challenging because of the slow rate of disease progression.We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently than models of time to progression. Methods: Multivariate continuous data are simulated from a Bayesian joint mixed-effects model fit to data from the Alzheimer’s Disease Neuroimaging Initiative. Simulated progression events are algorithmically derived from the continuous assessments using a random forest model fit to the same data. Results: We find that power is approximately doubled with models of repeated continuous outcomes compared with the time-to-progression analysis. The simulations also demonstrate that a plausible informative missing data pattern can induce a bias that inflates treatment effects, yet 5% type I error is maintained. Discussion: Given the relative inefficiency of time to progression, it should be avoided as a primary analysis approach in clinical trials of preclinical Alzheimer’s disease.