BETASEQ

BETASEQ controls type-I error inflation in rare variant association testing for next-generation sequencing (NGS) case-control studies with two-stage designs in which a subset of cases is sequenced and discovered variants are subsequently genotyped.

Key Features:

• Type-I Error Control: Corrects for inflation of type-I error in two-stage sequencing–genotyping designs without excluding sequenced cases or altering genotypes of discovered rare variants.
• Pseudo-Variant Supplementation: Introduces pseudo-variants to supplement original sequence and genotype data to mitigate bias from the two-stage design.
• Compatibility with Existing Methods: Integrates with rare variant association methods that accept genotypes or imputed genotypes as input.
• High Testing Power: Demonstrates superior or comparable testing power in simulations and real-data analyses while maintaining controlled or conservative type-I error rates.

Scientific Applications:

• Partially sequenced case-control studies: Applicable to NGS studies that sequence only a subset of cases and then genotype discovered variants across remaining cases and controls.
• Rare variant association studies: Suited for detecting rare variant associations contributing to complex disease genetic architecture using sequence-derived variants and genotypes.

Methodology:

Implements strategic addition of pseudo-variants to the dataset while preserving original sequence and genotype information; compatible with analyses using genotypes or imputed genotypes and validated via simulations and analyses on real datasets.