A comparative analysis of current phasing and imputation software.

Abstract

Whole-genome data has become significantly more accessible over the last two decades. This can largely be attributed to both reduced sequencing costs and imputation models which make it possible to obtain nearly whole-genome data from less expensive genotyping methods, such as microarray chips. Although there are many different approaches to imputation, the Hidden Markov Model (HMM) remains the most widely used. In this study, we compared the latest versions of the most popular HMM-based tools for phasing and imputation: Beagle5.4, Eagle2.4.1, Shapeit4, Impute5 and Minimac4. We benchmarked them on four input datasets with three levels of chip density. We assessed each imputation software on the basis of accuracy, speed and memory usage, and showed how the choice of imputation accuracy metric can result in different interpretations. The highest average concordance rate was achieved by Beagle5.4, followed by Impute5 and Minimac4, using a reference-based approach during phasing and the highest density chip. IQS and R2 metrics revealed that Impute5 and Minimac4 obtained better results for low frequency markers, while Beagle5.4 remained more accurate for common markers (MAF>5%). Computational load as measured by run time was lower for Beagle5.4 than Minimac4 and Impute5, while Minimac4 utilized the least memory of the imputation tools we compared. ShapeIT4, used the least memory of the phasing tools examined with genotype chip data, while Eagle2.4.1 used the least memory phasing WGS data. Finally, we determined the combination of phasing software, imputation software, and reference panel, best suited for different situations and analysis needs and created an automated pipeline that provides a way for users to create customized chips designed to optimize their imputation results.