Gene-gene interaction: the curse of dimensionality.

Identified genetic variants from genome wide association studies frequently show only modest effects on the disease risk, leading to the "missing heritability" problem. An avenue, to account for a part of this "missingness" is to evaluate gene-gene interactions (epistasis) thereby elucidating their effect on complex diseases. This can potentially help with identifying gene functions, pathways, and drug targets. However, the exhaustive evaluation of all possible genetic interactions among millions of single nucleotide polymorphisms (SNPs) raises several issues, otherwise known as the "curse of dimensionality". The dimensionality involved in the epistatic analysis of such exponentially growing SNPs diminishes the usefulness of traditional, parametric statistical methods. With the immense popularity of multifactor dimensionality reduction (MDR), a non-parametric method, proposed in 2001, that classifies multi-dimensional genotypes into one- dimensional binary approaches, led to the emergence of a fast-growing collection of methods that were based on the MDR approach. Moreover, machine-learning (ML) methods such as random forests and neural networks (NNs), deep-learning (DL) approaches, and hybrid approaches have also been applied profusely, in the recent years, to tackle this dimensionality issue associated with whole genome gene-gene interaction studies. However, exhaustive searching in MDR based approaches or variable selection in ML methods, still pose the risk of missing out on relevant SNPs. Furthermore, interpretability issues are a major hindrance for DL methods. To minimize this loss of information, Python based tools such as PySpark can potentially take advantage of distributed computing resources in the cloud, to bring back smaller subsets of data for further local analysis. Parallel computing can be a powerful resource that stands to fight this "curse". PySpark supports all standard Python libraries and C extensions thus making it convenient to write codes to deliver dramatic improvements in processing speed for extraordinarily large sets of data. 2019 Annals of Translational Medicine. All rights reserved.