A genotype imputation method for de-identified haplotype reference information by using recurrent neural network

Abstract

Genotype imputation estimates the genotypes of unobserved variants using the genotype data of other observed variants based on a collection of haplotypes for thousands of individuals, which is known as a haplotype reference panel. In general, more accurate imputation results were obtained using a larger size of haplotype reference panel. Most of the existing genotype imputation methods explicitly require the haplotype reference panel in precise form, but the accessibility of haplotype data is often limited, due to the requirement of agreements from the donors. Since de-identified information such as summary statistics or model parameters can be used publicly, imputation methods using de-identified haplotype reference information might be useful to enhance the quality of imputation results under the condition where the access of the haplotype data is limited. In this study, we proposed a novel imputation method that handles the reference panel as its model parameters by using bidirectional recurrent neural network (RNN). The model parameters are presented in the form of de-identified information from which the restoration of the genotype data at the individual-level is almost impossible. We demonstrated that the proposed method provides comparable imputation accuracy when compared with the existing imputation methods using haplotype datasets from the 1000 Genomes Project (1KGP) and the Haplotype Reference Consortium. We also considered a scenario where a subset of haplotypes is made available only in de-identified form for the haplotype reference panel. In the evaluation using the 1KGP dataset under the scenario, the imputation accuracy of the proposed method is much higher than that of the existing imputation methods. We therefore conclude that our RNN-based method is quite promising to further promote the data-sharing of sensitive genome data under the recent movement for the protection of individuals’ privacy. Author summary Genotype imputation estimates the genotypes of unobserved variants using the genotype data of other observed variants based on a collection of genome data of a large number of individuals called a reference panel. In general, more accurate imputation results are obtained using a larger size of the reference panel. Although most of the existing imputation methods use the reference panel in an explicit form, the accessibility of genome data is often limited due to the requirement of agreements from the donors. We thus proposed a new imputation method that handles the reference panel as its model parameters by using bidirectional recurrent neural network. Since it is almost impossible to restore genome data at the individual-level from the model parameters, they can be shared publicly as the de-identified information even when the accessibility of the original reference panel is limited. We demonstrate that the proposed method provides comparable imputation accuracy with the existing methods. We also considered a scenario where a part of the genome data is made available only in de-identified form for the reference panel and have shown that the imputation accuracy of the proposed method is much higher than that of the existing methods under the scenario.