Using an onset-anchored Bayesian hierarchical model to improve predictions for amyotrophic lateral sclerosis disease progression

Abstract Background Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a rare disease with extreme between-subject variability, especially with respect to rate of disease progression. This makes modelling a subject’s disease progression, which is measured by the ALS Functional Rating Scale (ALSFRS), very difficult. Consider the problem of predicting a subject’s ALSFRS score at 9 or 12 months after a given time-point. Methods We obtained ALS subject data from the Pooled Resource Open-Access ALS Clinical Trials Database, a collection of data from various ALS clinical trials. Due to the typical linearity of the ALSFRS, we consider several Bayesian hierarchical linear models. These include a mixture model (to account for the two potential classes of “fast” and “slow” ALS progressors) as well as an onset-anchored model, in which an additional artificial data-point, using time of disease onset, is utilized to improve predictive performance. Results The onset-anchored model had a drastically reduced posterior predictive mean-square-error distributions, when compared to the Bayesian hierarchical linear model or the mixture model under a cross-validation approach. No covariates, other than time of disease onset, consistently improved predictive performance in either the Bayesian hierarchical linear model or the onset-anchored model. Conclusions Augmenting patient data with an additional artificial data-point, or onset anchor, can drastically improve predictive modelling in ALS by reducing the variability of estimated parameters at the cost of a slight increase in bias. This onset-anchored model is extremely useful if predictions are desired directly after a single baseline measure (such as at the first day of a clinical trial), a feat that would be very difficult without the onset-anchor. This approach could be useful in modelling other diseases that have bounded progression scales (e.g. Parkinson’s disease, Huntington’s disease, or inclusion-body myositis). It is our hope that this model can be used by clinicians and statisticians to improve the efficacy of clinical trials and aid in finding treatments for ALS