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<p>Genotype imputation is a powerful tool for inferring missing genotype data in large-scale genetic studies. Over the last two decades, multiple imputation algorithms have been developed, steadily improving in speed and overall accuracy. However, accurate imputation of rare and infrequent variants remains a challenge, largely because existing methods rely on local haplotype matching within genomic windows and do not fully exploit the extended patterns of haplotype sharing that span entire chromosomes. Here we present Selphi, a new genotype imputation algorithm that combines the Positional Burrows-Wheeler Transform (PBWT) with a multi-stage haplotype selection heuristic operating across entire chromosomes. When compared to state-of-the-art methods Beagle 5.4, IMPUTE5, and Minimac4, Selphi showed higher accuracy on the 1000 Genomes Project and TOPMed datasets, across all super-populations and allele frequencies. Similarly, Selphi achieved higher accuracy than Beagle 5.4 on the UK Biobank dataset, which translated into improved concordance with hc-WGS GWAS summary statistics at known trait-associated loci and more accurate polygenic risk scores (PRS). Selphi outputs standard VCF files with genotype dosages (DS), haplotype-specific allele probabilities (AP1, AP2), and a per-variant dosage R-squared quality score (DR2), enabling direct integration with downstream analytical pipelines including standard post-imputation quality filtering.</p>

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Selphi, a tool for improving genotype imputation accuracy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Adriano De Marino,
  • Abdallah Amr Mahmoud,
  • Sandra Bohn,
  • Jon Lerga-Jaso,
  • Biljana Novković,
  • Charlie Manson,
  • Salvatore Loguercio,
  • Andrew Terpolovsky,
  • Mykyta Matushyn,
  • Ali Torkamani,
  • Puya G. Yazdi

摘要

Genotype imputation is a powerful tool for inferring missing genotype data in large-scale genetic studies. Over the last two decades, multiple imputation algorithms have been developed, steadily improving in speed and overall accuracy. However, accurate imputation of rare and infrequent variants remains a challenge, largely because existing methods rely on local haplotype matching within genomic windows and do not fully exploit the extended patterns of haplotype sharing that span entire chromosomes. Here we present Selphi, a new genotype imputation algorithm that combines the Positional Burrows-Wheeler Transform (PBWT) with a multi-stage haplotype selection heuristic operating across entire chromosomes. When compared to state-of-the-art methods Beagle 5.4, IMPUTE5, and Minimac4, Selphi showed higher accuracy on the 1000 Genomes Project and TOPMed datasets, across all super-populations and allele frequencies. Similarly, Selphi achieved higher accuracy than Beagle 5.4 on the UK Biobank dataset, which translated into improved concordance with hc-WGS GWAS summary statistics at known trait-associated loci and more accurate polygenic risk scores (PRS). Selphi outputs standard VCF files with genotype dosages (DS), haplotype-specific allele probabilities (AP1, AP2), and a per-variant dosage R-squared quality score (DR2), enabling direct integration with downstream analytical pipelines including standard post-imputation quality filtering.