Machine Learning for Prediction and Identification of Genetic Variants and Biomarkers in Autism Spectrum Disorder: A Systematic Review

Autism spectrum disorder (ASD) is a diverse neurodevelopmental condition with a significant genetic basis. Machine learning (ML) and deep learning (DL) models are emerging as powerful tools for identifying potential ASD risk genes and biomarkers to improve diagnostic accuracy. This narrative systematic review synthesizes evidence on the use of ML and DL models for ASD prediction and diagnosis, focusing on studies that utilized genetic variants and biomarkers. We conducted a systematic search across six databases [Web of Science, PubMed, Science Direct, Semantic Scholar, Institute of Electrical and Electronics Engineers (IEEE Xplore), and Association for Computing Machinery Digital Library (ACM-DL)] for articles published between 2009 and 2024, yielding 483 initial records. Multiple inclusion criteria were applied, and only peer-reviewed articles that used artificial intelligence, ML, or DL to predict ASD based on genetic biomarkers were included. After deduplication and applying inclusion and exclusion criteria, 14 studies were included in this review. These studies focused on genetic variants based on whole-genome sequencing, whole-exome sequencing, RNA sequencing, single-nucleus RNA sequencing, mRNA expression, long non-coding RNA, or single nucleotide polymorphism data. Our findings indicate that various ML models achieved robust performance, while DL architectures such as DeepASDPred outperformed ML models, with an accuracy of 93.8%. Most of the studies used datasets such as the Simons Foundation Autism Research Initiative (SFARI), the Simons Simplex Collection (SSC), the Autism Genetic Resource Exchange (AGRE), Atlas of the Developing Human Brain (BrainSpan), and the Simons Foundation Powering Autism Research for Knowledge (SPARK). The reviewed studies demonstrate that ML can help identify genetic risk factors and biomarkers that contribute to ASD. However, challenges remain, including data heterogeneity, small sample sizes, and the need for greater model interpretability. Addressing these challenges is crucial for translating ML models into clinically useful tools. In conclusion, DL substantially enhances ASD prediction, leveraging genetic data to identify novel candidate genes and support biological discovery of cell type-specific gene expression and roles of non-coding mutations in ASD.