Higher criticism approach to detect rare variants using whole genome sequencing data
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Updated: Sep 21, 2026

Detection of Rare Genomic Variants from Pooled Sequencing Using SPLINTER
Published on: June 22, 2012
Jing Xuan1, Li Yang1, Zheyang Wu1
1Department of Mathematical Science, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA 01609-2280, USA.
Abstract:
Because of low statistical power of single-variant tests for whole genome sequencing (WGS) data, the association test for variant groups is a key approach for genetic mapping. To address the features of sparse and weak genetic effects to be detected, the higher criticism (HC) approach has been proposed and theoretically has proven optimal for detecting sparse and weak genetic effects. Here we develop a strategy to apply the HC approach to WGS data that contains rare variants as the majority. By using Genetic Analysis Workshop 18 "dose" genetic data with simulated phenotypes, we assess the performance of HC under a variety of strategies for grouping variants and collapsing rare variants. The HC approach is compared with the minimal p-value method and the sequence kernel association test. The results show that the HC approach is preferred for detecting weak genetic effects.
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