Abstract
In this work, we propose methods to examine how the complex interrelationships between clinical symptoms and, separately, brain imaging biomarkers change over time leading up to the diagnosis of a disease in subjects with a known genetic near-certainty of disease. We propose a time-dependent undirected graphical model that ensures temporal and structural smoothness across time-specific networks to examine the trajectories of interactions between markers aligned at the time of disease onset. Specifically, we anchor subjects relative to the time of disease diagnosis (anchoring time) as in a revival process, and we estimate networks at each time point of interest relative to the anchoring time. To use all available data, we apply kernel weights to borrow information across observations that are close to the time of interest. Adaptive lasso weights are introduced to encourage temporal smoothness in edge strength, while a novel elastic fused- l0 penalty removes spurious edges and encourages temporal smoothness in network structure. Our approach can handle practical complications such as unbalanced visit times. We conduct simulation studies to compare our approach with existing methods. We then apply our method to data from PREDICT-HD, a large prospective observational study of pre-manifest Huntington's disease (HD) patients, to identify symptom and imaging network changes that precede clinical diagnosis of HD.