Probabilistic Clustering using Shared Latent Variable Model for Assessing Alzheimers Disease Biomarkers

Abstract

The preclinical stage of many neurodegenerative diseases can span decades before symptoms become apparent. Understanding the sequence of preclinical biomarker changes provides a critical opportunity for early diagnosis and effective intervention prior to significant loss of patients' brain functions. The main challenge to early detection lies in the absence of direct observation of the disease state and the considerable variability in both biomarkers and disease dynamics among individuals. Recent research hypothesized the existence of subgroups with distinct biomarker patterns due to co-morbidities and degrees of brain resilience. Our ability to early diagnose and intervene during the preclinical stage of neurodegenerative diseases will be enhanced by further insights into heterogeneity in the biomarker-disease relationship. In this paper, we focus on Alzheimer's disease (AD) and attempt to identify the systematic patterns within the heterogeneous AD biomarker-disease cascade. Specifically, we quantify the disease progression using a dynamic latent variable whose mixture distribution represents patient subgroups. Model estimation uses Hamiltonian Monte Carlo with the number of clusters determined by the Bayesian Information Criterion (BIC). We report simulation studies that investigate the performance of the proposed model in finite sample settings that are similar to our motivating application. We apply the proposed model to the BIOCARD data, a longitudinal study that was conducted over two decades among individuals who were initially cognitively normal. Our application yields evidence consistent with the hypothetical model of biomarker dynamics presented in Jack et al. (2013). In addition, our analysis identified two subgroups with distinct disease-onset patterns. Finally, we develop a dynamic prediction approach to improve the precision of prognoses.