Dataset Information

Adaptive clustering and adaptive weighting methods to detect disease associated rare variants.

ABSTRACT: Current statistical methods to test association between rare variants and phenotypes are essentially the group-wise methods that collapse or aggregate all variants in a predefined group into a single variant. Comparing with the variant-by-variant methods, the group-wise methods have their advantages. However, two factors may affect the power of these methods. One is that some of the causal variants may be protective. When both risk and protective variants are presented, it will lose power by collapsing or aggregating all variants because the effects of risk and protective variants will counteract each other. The other is that not all variants in the group are causal; rather, a large proportion is believed to be neutral. When a large proportion of variants are neutral, collapsing or aggregating all variants may not be an optimal solution. We propose two alternative methods, adaptive clustering (AC) method and adaptive weighting (AW) method, aiming to test rare variant association in the presence of neutral and/or protective variants. Both of AC and AW are applicable to quantitative traits as well as qualitative traits. Results of extensive simulation studies show that AC and AW have similar power and both of them have clear advantages from power to computational efficiency comparing with existing group-wise methods and existing data-driven methods that allow neutral and protective variants. We recommend AW method because AW method is computationally more efficient than AC method.

SUBMITTER: Sha Q

PROVIDER: S-EPMC3573192 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Adaptive clustering and adaptive weighting methods to detect disease associated rare variants.

Sha Qiuying Q Wang Shuaicheng S Zhang Shuanglin S

European journal of human genetics : EJHG 20120711 3

Current statistical methods to test association between rare variants and phenotypes are essentially the group-wise methods that collapse or aggregate all variants in a predefined group into a single variant. Comparing with the variant-by-variant methods, the group-wise methods have their advantages. However, two factors may affect the power of these methods. One is that some of the causal variants may be protective. When both risk and protective variants are presented, it will lose power by col ...[more]

PMID: 22781093

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Project description:BACKGROUND: Along with the improvement of high throughput sequencing technologies, the genetics community is showing marked interest for the rare variants/common diseases hypothesis. While sequencing can still be prohibitive for large studies, commercially available genotyping arrays targeting rare variants prove to be a reasonable alternative. A technical challenge of array based methods is the task of deriving genotype classes (homozygous or heterozygous) by clustering intensity data points. The performance of clustering tools for common polymorphisms is well established, while their performance when conducted with a large proportion of rare variants (where data points are sparse for genotypes containing the rare allele) is less known. We have compared the performance of four clustering tools (GenCall, GenoSNP, optiCall and zCall) for the genotyping of over 10,000 samples using the Illumina's HumanExome BeadChip, which includes 247,870 variants, 90% of which have a minor allele frequency below 5% in a population of European ancestry. Different reference parameters for GenCall and different initial parameters for GenoSNP were tested. Genotyping accuracy was assessed using data from the 1000 Genomes Project as a gold standard, and agreement between tools was measured. RESULTS: Concordance of GenoSNP's calls with the gold standard was below expectations and was increased by changing the tool's initial parameters. While the four tools provided concordance with the gold standard above 99% for common alleles, some of them performed poorly for rare alleles. The reproducibility of genotype calls for each tool was assessed using experimental duplicates which provided concordance rates above 99%. The inter-tool agreement of genotype calls was high for approximately 95% of variants. Most tools yielded similar error rates (approximately 0.02), except for zCall which performed better with a 0.00164 mean error rate. CONCLUSIONS: The GenoSNP clustering tool could not be run straight "out of the box" with the HumanExome BeadChip, as modification of hard coded parameters was necessary to achieve optimal performance. Overall, GenCall marginally outperformed the other tools for the HumanExome BeadChip. The use of experimental replicates provided a valuable quality control tool for genotyping projects with rare variants.

Dataset Information

Adaptive clustering and adaptive weighting methods to detect disease associated rare variants.

Publications

Adaptive clustering and adaptive weighting methods to detect disease associated rare variants.

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