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Sampling strategies for rare variant tests in case-control studies.

ABSTRACT: Advances in sequencing technology allow assessing the impact of rare variation on common disorders. For this purpose, methods combine rare variants across a gene and compare an aggregate statistic between cases and controls. However, sequencing many individuals is costly. Hence, it is necessary to identify case samples that are most likely to result in powerful tests under realistic model assumptions. Power can be increased by selecting cases that are highly likely to carry risk variants. As rare variants that contribute to the heritability of a disease co-segregate among affected family members, selecting cases that have affected family members may increase the power of rare variant tests considerably. Here I compare sequencing random cases to cases ascertained to have affected family members. I quantify the power of the different approaches and provide criteria for sample selection under different models of inheritance. Under a model of multiplicative gene-gene interaction, a sample of random cases has to be 2-16-fold larger to achieve the same power as a sample of cases ascertained to have affected family members. However, in traits with high heritability this power gain can be reduced or even reversed under models of additive gene-gene interaction. Hence study designs should depend on the studied disease's heritability and on the available sample size. I also show that selecting cases that share both chromosomes identical by descent with an affected sibling at candidate regions can result in a further power gain.

SUBMITTER: Zollner S

PROVIDER: S-EPMC3449077 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Sampling strategies for rare variant tests in case-control studies.

Zöllner Sebastian S

European journal of human genetics : EJHG 20120418 10

Advances in sequencing technology allow assessing the impact of rare variation on common disorders. For this purpose, methods combine rare variants across a gene and compare an aggregate statistic between cases and controls. However, sequencing many individuals is costly. Hence, it is necessary to identify case samples that are most likely to result in powerful tests under realistic model assumptions. Power can be increased by selecting cases that are highly likely to carry risk variants. As rar ...[more]

PMID: 22510851

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Project description:A properly designed distance-based measure can capture informative genetic differences among individuals with different phenotypes and can be used to detect variants responsible for the phenotypes. To detect associated variants, various tests have been designed to contrast genetic dissimilarity or similarity scores of certain subject groups in different ways, among which the most widely used strategy is to quantify the difference between the within-group genetic dissimilarity/similarity (i.e., case-case and control-control similarities) and the between-group dissimilarity/similarity (i.e., case-control similarities). While it has been noted that for common variants, the within-group and the between-group measures should all be included; in this work, we show that for rare variants, comparison based on the two within-group measures can more effectively quantify the genetic difference between cases and controls. The between-group measure tends to overlap with one of the two within-group measures for rare variants, although such overlap is not present for common variants. Consequently, a dissimilarity or similarity test that includes the between-group information tends to attenuate the association signals and leads to power loss. Based on these findings, we propose a dissimilarity test that compares the degree of SNP dissimilarity within cases to that within controls to better characterize the difference between two disease phenotypes. We provide the statistical properties, asymptotic distribution, and computation details for a small sample size of the proposed test. We use simulated and real sequence data to assess the performance of the proposed test, comparing it with other rare-variant methods including those similarity-based tests that use both within-group and between-group information. As similarity-based approaches serve as one of the dominating approaches in rare-variant analysis, our results provide some insight for the effective detection of rare variants.

Dataset Information

Sampling strategies for rare variant tests in case-control studies.

Publications

Sampling strategies for rare variant tests in case-control studies.

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