Identification and prediction of Parkinson’s disease subtypes and progression using machine learning in two cohorts

Background The clinical manifestations of Parkinson’s disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. The emergence of machine learning to detect hidden patterns in complex, multi-dimensional datasets provides unparalleled opportunities to address this critical need.

Methods and Findings We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson’s Disease Progression Marker Initiative (PPMI) (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson’s Disease Biomarker Program (PDBP) (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression five years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01 for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast progressing group (PDvec3). We identified serum neurofilament light (Nfl) as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent validation cohort, released the analytical code, and developed models in an open science manner.

Conclusions Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes that might have been masked by cohort heterogeneity. We anticipate that machine learning models will improve patient counseling, clinical trial design, allocation of healthcare resources, and ultimately individualized patient care.