Using population-specific add-on polymorphisms to improve genotype imputation in underrepresented populations

Genome-wide association studies rely on the statistical inference of untyped variants, called imputation, to increase the coverage of genotyping arrays. However, the results are often suboptimal in populations underrepresented in existing reference panels and array designs, since the selected single nucleotide polymorphisms (SNPs) may fail to capture population-specific haplotype structures, hence the full extent of common genetic variation. Here, we propose to sequence the full genomes of a small subset of an underrepresented study cohort to inform the selection of population-specific add-on tag SNPs and to generate an internal population-specific imputation reference panel, such that the remaining array-genotyped cohort could be more accurately imputed. Using a Tanzania-based cohort as a proof-of-concept, we demonstrate the validity of our approach by showing improvements in imputation accuracy after the addition of our designed add-on tags to the base H3Africa array.

EagleImp: Fast and Accurate Genome-wide Phasing and Imputation in a Single Tool

Background: Reference-based phasing and genotype imputation algorithms have been developed with sublinear theoretical runtime behaviour, but runtimes are still high in practice when large genome-wide reference datasets are used. Methods: We developed EagleImp, a software with algorithmic and technical improvements and new features for accurate and accelerated phasing and imputation in a single tool. Results: We compared accuracy and runtime of EagleImp with Eagle2, PBWT and prominent imputation servers using whole-genome sequencing data from the 1000 Genomes Project, the Haplotype Reference Consortium and simulated data with more than 1 million reference genomes. EagleImp is 2 to 10 times faster (depending on the single or multiprocessor configuration selected) than Eagle2/PBWT, with the same or better phasing and imputation quality in all tested scenarios. For common variants investigated in typical GWAS studies, EagleImp provides same or higher imputation accuracy than the Sanger Imputation Service, Michigan Imputation Server and the newly developed TOPMed Imputation Server, despite larger (not publicly available) reference panels. It has many new features, including automated chromosome splitting and memory management at runtime to avoid job aborts, fast reading and writing of large files, and various user-configurable algorithm and output options. Conclusions: Due to the technical optimisations, EagleImp can perform fast and accurate reference-based phasing and imputation for future very large reference panels with more than 1 million genomes. EagleImp is freely available for download from https://github.com/ikmb/eagleimp.

Comparison of Genotype Imputation for SNP Array and Low-Coverage Whole-Genome Sequencing Data

Genotype imputation is the term used to describe the process of inferring unobserved genotypes in a sample of individuals. It is a key step prior to a genome-wide association study (GWAS) or genomic prediction. The imputation accuracy will directly influence the results from subsequent analyses. In this simulation-based study, we investigate the accuracy of genotype imputation in relation to some factors characterizing SNP chip or low-coverage whole-genome sequencing (LCWGS) data. The factors included the imputation reference population size, the proportion of target markers /SNP density, the genetic relationship (distance) between the target population and the reference population, and the imputation method. Simulations of genotypes were based on coalescence theory accounting for the demographic history of pigs. A population of simulated founders diverged to produce four separate but related populations of descendants. The genomic data of 20,000 individuals were simulated for a 10-Mb chromosome fragment. Our results showed that the proportion of target markers or SNP density was the most critical factor affecting imputation accuracy under all imputation situations. Compared with Minimac4, Beagle5.1 reproduced higher-accuracy imputed data in most cases, more notably when imputing from the LCWGS data. Compared with SNP chip data, LCWGS provided more accurate genotype imputation. Our findings provided a relatively comprehensive insight into the accuracy of genotype imputation in a realistic population of domestic animals.

Reconstruction of Missing Segments in Well Data History Using Data Analytics

The problem of missing data is a frequent occurrence in well production history records. Due to network outage, facility maintenance or equipment failure, the time series production data measured from surface and downhole gauges can be intermittent. The fragmentary data are an obstacle for reservoir management. The incomplete dataset is commonly simplified by omitting all observations with missing values, which will lead to significant information loss. Thus, to fill the missing data gaps, in this study, we developed and tested several missing data imputation approaches using machine learning and deep learning methods. Traditional data imputation methods such as interpolation and counting most frequent values can introduce bias to the data as the correlations between features are not considered. Thus, in this study, we investigated several multivariate imputation algorithms that use the entire set of available data streams to estimate the missing values. The methods use a full suite of well measurements, including wellhead and downhole pressures, oil, water and gas flow rates, surface and downhole temperatures, choke settings, etc. Any parameter that has gaps in its recorded history can be imputed from the other available data streams. The models were tested on both synthetic and real datasets from operating Norwegian and Abu Dhabi reservoirs. Based on the characteristics of the field data, we introduced different types of continuous missing distributions, which are the combinations of single-multiple missing sections in a long-short time span, to the complete dataset. We observed that as the missing time span expands, the stability of the more successful methods can be kept to a threshold of 30% of the entire dataset. In addition, for a single missing section over a shorter period, which could represent a weather perturbation, most methods we tried were able to achieve high imputation accuracy. In the case of multiple missing sections over a longer time span, which is typical of gauge failures, other methods were better candidates to capture the overall correlation in the multivariate dataset. Most missing data problems addressed in our industry focus on single feature imputation. In this study, we developed an efficient procedure that enables fast reconstruction of the entire production dataset with multiple missing sections in different variables. Ultimately, the complete information can support the reservoir history matching process, production allocation, and develop models for reservoir performance prediction.

Rapid, Reference-Free Human Genotype Imputation with Denoising Autoencoders

Genotype imputation is a foundational tool for population genetics. Standard statistical imputation approaches rely on the co-location of large whole-genome sequencing-based reference panels, powerful computing environments, and potentially sensitive genetic study data. This results in computational resource and privacy-risk barriers to access to cutting-edge imputation techniques. Moreover, the accuracy of current statistical approaches is known to degrade in regions of low and complex linkage disequilibrium.Artificial neural network-based imputation approaches may overcome these limitations by encoding complex genotype relationships in easily portable inference models. Here we demonstrate an autoencoder-based approach for genotype imputation, using a large, commonly-used reference panel, and spanning the entirety of human chromosome 22. Our autoencoder-based genotype imputation strategy achieved superior imputation accuracy across the allele-frequency spectrum and across genomes of diverse ancestry, while delivering at least 4-fold faster inference run time relative to standard imputation tools.

Development of the Wheat Practical Haplotype Graph Database as a Resource for Genotyping Data Storage and Genotype Imputation

To improve the efficiency of high-density genotype data storage and imputation in bread wheat (Triticum aestivum L.), we applied the Practical Haplotype Graph (PHG) tool. The wheat PHG database was built using whole-exome capture sequencing data from a diverse set of 65 wheat accessions. Population haplotypes were inferred for the reference genome intervals defined by the boundaries of the high-quality gene models. Missing genotypes in the inference panels, composed of wheat cultivars or recombinant inbred lines genotyped by exome capture, genotyping-by-sequencing (GBS), or whole-genome skim-seq sequencing approaches, were imputed using the wheat PHG database. Though imputation accuracy varied depending on the method of sequencing and coverage depth, we found 92% imputation accuracy with 0.01x sequence coverage, which was slightly lower than the accuracy obtained using the 0.5x sequence coverage (96.6%). Compared to Beagle, on average, PHG imputation was ∼3.5% (p-value < 2 x 10−14) more accurate, and showed 27% higher accuracy at imputing a rare haplotype introgressed from a wild relative into wheat. We found reduced accuracy of imputation with independent 2x GBS data (88.6%), which increases to 89.2% with the inclusion of parental haplotypes in the database. The accuracy reduction with GBS is likely associated with the small overlap between GBS markers and the exome capture dataset, which was used for constructing PHG. The highest imputation accuracy was obtained with exome capture for the wheat D genome, which also showed the highest levels of linkage disequlibrium and proportion of identity-by-descent regions among accessions in the PHG database. We demonstrate that genetic mapping based on genotypes imputed using PHG identifies SNPs with a broader range of effect sizes that together explain a higher proportion of genetic variance for heading date and meiotic crossover rate compared to previous studies.

Genome-wide Imputation Using the Practical Haplotype Graph in the Heterozygous Crop Cassava

Genomic applications such as genomic selection and genome-wide association have become increasingly common since the advent of genome sequencing. The cost of sequencing has decreased in the past two decades, however genotyping costs are still prohibitive to gathering large datasets for these genomic applications, especially in non-model species where resources are less abundant. Genotype imputation makes it possible to infer whole genome information from limited input data, making large sampling for genomic applications more feasible. Imputation becomes increasingly difficult in heterozygous species where haplotypes must be phased. The Practical Haplotype Graph is a recently developed tool that can accurately impute genotypes, using a reference panel of haplotypes. We showcase the ability of the Practical Haplotype Graph to impute genomic information in the highly heterozygous crop cassava (Manihot esculenta). Accurately phased haplotypes were sampled from runs of homozygosity across a diverse panel of individuals to populate PHG, which proved more accurate than relying on computational phasing methods. The Practical Haplotype Graph achieved high imputation accuracy, using sparse skim-sequencing input, which translated to substantial genomic prediction accuracy in cross validation testing. The Practical Haplotype Graph showed improved imputation accuracy, compared to a standard imputation tool Beagle, especially in predicting rare alleles.

BiLSTM-I: A Deep Learning-Based Long Interval Gap-Filling Method for Meteorological Observation Data

Complete and high-resolution temperature observation data are important input parameters for agrometeorological disaster monitoring and ecosystem modelling. Due to the limitation of field meteorological observation conditions, observation data are commonly missing, and an appropriate data imputation method is necessary in meteorological data applications. In this paper, we focus on filling long gaps in meteorological observation data at field sites. A deep learning-based model, BiLSTM-I, is proposed to impute missing half-hourly temperature observations with high accuracy by considering temperature observations obtained manually at a low frequency. An encoder-decoder structure is adopted by BiLSTM-I, which is conducive to fully learning the potential distribution pattern of data. In addition, the BiLSTM-I model error function incorporates the difference between the final estimates and true observations. Therefore, the error function evaluates the imputation results more directly, and the model convergence error and the imputation accuracy are directly related, thus ensuring that the imputation error can be minimized at the time the model converges. The experimental analysis results show that the BiLSTM-I model designed in this paper is superior to other methods. For a test set with a time interval gap of 30 days, or a time interval gap of 60 days, the root mean square errors (RMSEs) remain stable, indicating the model’s excellent generalization ability for different missing value gaps. Although the model is only applied to temperature data imputation in this study, it also has the potential to be applied to other meteorological dataset-filling scenarios.

Evaluation of Vicinity-based Hidden Markov Models for Genotype Imputation

The decreasing cost of DNA sequencing has led to a great increase in our knowledge about genetic variation. While population-scale projects bring important insight into genotype-phenotype relationships, the cost of performing whole-genome sequencing on large samples is still prohibitive. In-silico genotype imputation coupled with genotyping-by-arrays is a cost-effective and accurate alternative for genotyping of common and uncommon variants. Imputation methods compare the genotypes of the typed variants with the large population-specific reference panels and estimate the genotypes of untyped variants by making use of the linkage disequilibrium patterns. Most accurate imputation methods are based on the Li-Stephens hidden Markov model, HMM, that treats the sequence of each chromosome as a mosaic of the haplotypes from the reference panel. Here we assess the accuracy of local-HMMs, where each untyped variant is imputed using the typed variants in a small window around itself (as small as 1 centimorgan). Locality-based imputation is used recently by machine learning-based genotype imputation approaches. We assess how the parameters of the local-HMMs impact the imputation accuracy in a comprehensive set of benchmarks and show that local-HMMs can accurately impute common and uncommon variants and can be relaxed to impute rare variants as well. The source code for the local HMM implementations is publicly available at https://github.com/harmancilab/LoHaMMer.

Assessment of Imputation Quality: Comparison of Phasing and Imputation Algorithms in Real Data

Despite the widespread use of genotype imputation tools and the availability of different approaches, late developments of currently used programs have not been compared comprehensively. We therefore assessed the performance of 35 combinations of phasing and imputation programs, including versions of SHAPEIT, Eagle, Beagle, minimac, PBWT, and IMPUTE, for genetic imputation of completely missing SNPs with a HRC reference panel regarding quality and speed. We used a data set comprising 1,149 fully sequenced individuals from the German population, subsetting the SNPs to approximate the Illumina Infinium-Omni5 array. Five hundred fifty-three thousand two hundred and thirty-four SNPs across two selected chromosomes were utilized for comparison between imputed and sequenced genotypes. We found that all tested programs with the exception of PBWT impute genotypes with very high accuracy (mean error rate < 0.005). PBTW hardly ever imputes the less frequent allele correctly (mean concordance for genotypes including the minor allele <0.0002). For all programs, imputation accuracy drops for rare alleles with a frequency <0.05. Even though overall concordance is high, concordance drops with genotype probability, indicating that low genotype probabilities are rare. The mean concordance of SNPs with a genotype probability <95% drops below 0.9, at which point disregarding imputed genotypes might prove favorable. For fast and accurate imputation, a combination of Eagle2.4.1 using a reference panel for phasing and Beagle5.1 for imputation performs best. Replacing Beagle5.1 with minimac3, minimac4, Beagle4.1, or IMPUTE4 results in a small gain in accuracy at a high cost of speed.