论文标题

通过数字双胞胎对轻度认知障碍和阿尔茨海默氏病的疾病进展进行建模

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

论文作者

Bertolini, Daniele, Loukianov, Anton D., Smith, Aaron M., Li-Bland, David, Pouliot, Yannick, Walsh, Jonathan R., Fisher, Charles K.

论文摘要

阿尔茨海默氏病(AD)是一种神经退行性疾病,会影响广泛严重程度的受试者,并在具有多种认知和功能仪器的临床试验中评估。随着AD中的临床试验越来越集中于疾病的早期阶段,尤其是轻度认知障碍(MCI),对整个疾病范围的主题结果进行建模的能力非常重要。我们使用无监督的机器学习模型,称为有条件受限的玻尔兹曼机器(CRBMS)来创建广告主题的数字双胞胎。数字双胞胎是模拟的临床记录,可与实际受试者共享基线数据,并在护理标准下全面地对其结果进行建模。 CRBM经过观察研究中的受试者的大量记录和整个AD频谱的临床试验的安慰剂组进行培训。这些数据表现出跨数据集中受试者的测量和缺失观察结果的具有挑战性但常见的拼布,我们提出了一种新颖的模型体系结构,旨在从中有效学习。我们对持有的测试数据集进行了评估的性能,并展示了数字双胞胎如何同时捕获各种疾病严重程度(包括MCI和轻度至中度AD)的临床试验中许多关键终点的进展。

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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