Modeling Disease Progression in Mild Cognitive Impairment and Alzheimer's Disease with Digital Twins

Alzheimer's Disease (AD) is a neurodegenerative disease that affects subjects in a broad range of severity and is assessed in clinical trials with multiple cognitive and functional instruments. As clinical trials in AD increasingly focus on earlier stages of the disease, especially Mild Cognitive Impairment (MCI), the ability to model subject outcomes across the disease spectrum is extremely important. We use unsupervised machine learning models called Conditional Restricted Boltzmann Machines (CRBMs) to create Digital Twins of AD subjects. Digital Twins are simulated clinical records that share baseline data with actual subjects and comprehensively model their outcomes under standard-of-care. The CRBMs are trained on a large set of records from subjects in observational studies and the placebo arms of clinical trials across the AD spectrum. These data exhibit a challenging, but common, patchwork of measured and missing observations across subjects in the dataset, and we present a novel model architecture designed to learn effectively from it. We evaluate performance against a held-out test dataset and show how Digital Twins simultaneously capture the progression of a number of key endpoints in clinical trials across a broad spectrum of disease severity, including MCI and mild-to-moderate AD.

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Bayesian prognostic covariate adjustment


Using Digital Twins to Decrease Enrollment and Increase Statistical Power in Alzheimer's Disease Trials (CTAD 2020)


Increasing the efficiency of randomized trial estimates via linear adjustment for a prognostic score

Linear adjustment for a prognostic score is an effective and safe method for leveraging historical data to reduce uncertainty in randomized trials.
We showed that digital twins could reduce the number of control subjects required in the analysis to achieve equivalent results to an analysis of the actual subjects.
Our novel method - Bayesian prognostic covariate adjustment - is a Bayesian analysis that draws on the strengths of the prognostic model approach.