Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterised by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalised medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilises an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signalling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.