Imputing missing genotypic data of single-nucleotide polymorphisms using neural networks

With advances in high-throughput single-nucleotide polymorphism (SNP) genotyping, the amount of genotype data available for genetic studies is steadily increasing, and with it comes new abilities to study multigene interactions as well as to develop higher dimensional genetic models that more closely represent the polygenic nature of common disease risk. The combined impact of even small amounts of missing data on a multi-SNP analysis may be considerable. In this study, we present a neural network method for imputing missing SNP genotype data. We compared its imputation accuracy with fastPHASE and an expectation–maximization algorithm implemented in HelixTree. In a simulation data set of 1000 SNPs and 1000 subjects, 1, 5 and 10% of genotypes were randomly masked. Four levels of linkage disequilibrium (LD), LD R2<0.2, R2<0.5, R2<0.8 and no LD threshold, were examined to evaluate the impact of LD on imputation accuracy. All three methods are capable of imputing most missing genotypes accurately (accuracy >86%). The neural network method accurately predicted 92.0–95.9% of the missing genotypes. In a real data set comparison with 419 subjects and 126 SNPs from chromosome 2, the neural network method achieves the highest imputation accuracies >83.1% with missing rate from 1 to 5%. Using 90 HapMap subjects with 1962 SNPs, fastPHASE had the highest accuracy (∼97%) while the other two methods had >95% accuracy. These results indicate that the neural network model is an accurate and convenient tool, requiring minimal parameter tuning for SNP data recovery, and provides a valuable alternative to usual complete-case analysis.