Model-Based and Model-Free Techniques for Amyotrophic Lateral Sclerosis Diagnostic Prediction and Patient Clustering

摘要

Amyotrophic lateral sclerosis (ALS) is a complex progressive neurodegenerative disorder with an estimated prevalence of about 5 per 100,000 people in the United States. In this study, the ALS disease progression is measured by the change of Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score over time. The study aims to provide clinical decision support for timely forecasting of the ALS trajectory as well as accurate and reproducible computable phenotypic clustering of participants. Patient data are extracted from DREAM-Phil Bowen ALS Prediction Prize4Life Challenge data, most of which are from the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) archive. We employed model-based and model-free machine-learning methods to predict the change of the ALSFRS score over time. Using training and testing data we quantified and compared the performance of different techniques. We also used unsupervised machine learning methods to cluster the patients into separate computable phenotypes and interpret the derived subcohorts. Direct prediction of univariate clinical outcomes based on model-based (linear models) or model-free (machine learning based techniques - random forest and Bayesian adaptive regression trees) was only moderately successful. The correlation coefficients between clinically observed changes in ALSFRS scores relative to the model-based/model-free predicted counterparts were 0.427(random forest) and 0.545(BART). The reliability of these results were assessed using internal statistical cross validation and well as external data validation. Unsupervised clustering generated very reliable and consistent partitions of the patient cohort into four computable phenotypic subgroups. These clusters were explicated by identifying specific salient clinical features included in the PRO-ACT archive that discriminate between the derived subcohorts. There are differences between alternative analytical methods in forecasting specific clinical