S-EBM: Generalising event-based modelling of disease progression for simultaneous events

Abstract

This study introduces the parsimonious event-based model of disease progression (P-EBM). The P-EBM generalises the event-based model of disease progression (EBM) to allow inference of fewer disease progression stages than the number of input biomarkers. The original EBM is designed to estimate a single distinct biomarker abnormality, termed an event, at each model stage. By allowing multiple events within a common stage, the P-EBM prevents redundant complexity to permit discovery of parsimonious sequences of disease progression - those that contain purely serial events, as in the original EBM, as well as those containing one or more sets of simultaneous events. This study describes P-EBM theory, evaluates its sequence estimation and staging performance and demonstrates its application to derive a parsimonious sequence of disease progression in sporadic Alzheimers disease (AD). Results show that the P-EBM can accurately recover a wider range of sequences than EBM under a range of realistic experimental scenarios, including different numbers of simultaneous events, biomarker disease signals and dataset sizes. The P-EBM sequence successfully highlights redundant biomarkers and stages subjects using fewer biomarkers. In sporadic AD, the P-EBM estimates a shorter sequence than the EBM with substantially higher likelihood which plausibly suggests that some biomarker events appear simultaneously. The P-EBM has potential application for generating new insights into disease evolution and for suggesting efficient biomarker collection strategies for patient staging.