Limits...
Validity of the family-based association test for copy number variant data in the case of non-linear intensity-genotype relationship.

Zanda M, Onengut S, Walker N, Todd JA, Clayton DG, Rich SS, Hurles ME, Plagnol V - Genet. Epidemiol. (2012)

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

: Ionita-Laza and colleagues have proposed a family-based association test (FBAT) based on raw intensity data from copy number variant (CNV) assays rather than genotype calls [... This work is motivated by the difficulty of obtaining reliable discrete CNV calls owing to the limited resolution of CNV assays, especially for complex and multi-allelic CNVs... If this is not the case then the expected CNV data of the affected offspring (Xi) will differ from the midparent intensity, under the hypothesis of no association and for some pairs of parental genotypes... In this non-linear case, the contribution of each trio to the score statistic U does not have zero expectation conditional on the genotype of the parents... The result shown in 3 also shows that any population structure in the parental population that disrupts HWE also leads to a non-zero expectation for Ui in the non-linear case... Hence, the robustness to population structure does not extend from the linear to non-linear case... The trio design as developed in the FBAT CNV test can alleviate these concerns by comparing raw intensity data within families, rather than comparisons across cases and controls... In the non-linear intensity case, if the batch effect can be modelled using a family-specific covariate that acts on the raw intensity data in an additive manner, this covariate will have the same effect on the parental and offspring intensities... Therefore, the effect of this covariate will vanish in the computation of the score statistic... Thus, even in the case of a non-linear effect, the FBAT CNV statistic is expected to be robust to a range of technical artefacts... Approximately 250 of these 372 CNVs are deletions for which the intensity is typically non-linear with copy number... A small subset of CNVs showed significant association (Fig... In this case, the FBAT CNV test is appropriate and the initially proposed estimate of the score variance estimator V is consistent... Moreover, in a non-linear genotype-intensity context, the FBAT CNV test is robust to family-specific technical covariates.

Show MeSH

Related in: MedlinePlus

Distribution of the FBAT CNV statistic in 372 common and well-clustered CNVs computed in 2,159 multiplex T1D families (3,854 transmissions from parents to affected offsprings). The grey shaded area shows the 95% confidence interval. Panel A: All di-allelic CNVs with well-separated classes are shown. Panel B: Same as panel A but CNVs in the HLA locus (known to be T1D associated) are excluded.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3569870&req=5

fig02: Distribution of the FBAT CNV statistic in 372 common and well-clustered CNVs computed in 2,159 multiplex T1D families (3,854 transmissions from parents to affected offsprings). The grey shaded area shows the 95% confidence interval. Panel A: All di-allelic CNVs with well-separated classes are shown. Panel B: Same as panel A but CNVs in the HLA locus (known to be T1D associated) are excluded.

Mentions: To provide an example of the robustness of the FBAT CNV test in a large-scale experiment, we report in Figure 2A the distribution of the FBAT CNV test statistic for 372 common CNVs (selected on the basis of good clustering and minor allele frequency >10%) from a genome-wide CNV association scan in 2,159 T1D multiplex families (3,854 transmissions overall from parents to affected offspring). CNV intensity data were computed from a genome-wide array comparative genomic hybridisation assay (manuscript in preparation). For the association test, we used the FBAT CNV association test suggested in Ionita-Laza et al. [2008, including the robust variance estimate. Approximately 250 of these 372 CNVs are deletions for which the intensity is typically non-linear with copy number. A small subset of CNVs showed significant association (Fig.A). An inspection of these signals showed that these CNVs are all located in the HLA region, known to be T1D associated [Nejentsev et al., 2007. After removing CNVs located in the HLA region, the distribution of the test statistic was consistent with its expectation under the (Fig.B).


Validity of the family-based association test for copy number variant data in the case of non-linear intensity-genotype relationship.

Zanda M, Onengut S, Walker N, Todd JA, Clayton DG, Rich SS, Hurles ME, Plagnol V - Genet. Epidemiol. (2012)

Distribution of the FBAT CNV statistic in 372 common and well-clustered CNVs computed in 2,159 multiplex T1D families (3,854 transmissions from parents to affected offsprings). The grey shaded area shows the 95% confidence interval. Panel A: All di-allelic CNVs with well-separated classes are shown. Panel B: Same as panel A but CNVs in the HLA locus (known to be T1D associated) are excluded.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569870&req=5

fig02: Distribution of the FBAT CNV statistic in 372 common and well-clustered CNVs computed in 2,159 multiplex T1D families (3,854 transmissions from parents to affected offsprings). The grey shaded area shows the 95% confidence interval. Panel A: All di-allelic CNVs with well-separated classes are shown. Panel B: Same as panel A but CNVs in the HLA locus (known to be T1D associated) are excluded.
Mentions: To provide an example of the robustness of the FBAT CNV test in a large-scale experiment, we report in Figure 2A the distribution of the FBAT CNV test statistic for 372 common CNVs (selected on the basis of good clustering and minor allele frequency >10%) from a genome-wide CNV association scan in 2,159 T1D multiplex families (3,854 transmissions overall from parents to affected offspring). CNV intensity data were computed from a genome-wide array comparative genomic hybridisation assay (manuscript in preparation). For the association test, we used the FBAT CNV association test suggested in Ionita-Laza et al. [2008, including the robust variance estimate. Approximately 250 of these 372 CNVs are deletions for which the intensity is typically non-linear with copy number. A small subset of CNVs showed significant association (Fig.A). An inspection of these signals showed that these CNVs are all located in the HLA region, known to be T1D associated [Nejentsev et al., 2007. After removing CNVs located in the HLA region, the distribution of the test statistic was consistent with its expectation under the (Fig.B).

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

: Ionita-Laza and colleagues have proposed a family-based association test (FBAT) based on raw intensity data from copy number variant (CNV) assays rather than genotype calls [... This work is motivated by the difficulty of obtaining reliable discrete CNV calls owing to the limited resolution of CNV assays, especially for complex and multi-allelic CNVs... If this is not the case then the expected CNV data of the affected offspring (Xi) will differ from the midparent intensity, under the hypothesis of no association and for some pairs of parental genotypes... In this non-linear case, the contribution of each trio to the score statistic U does not have zero expectation conditional on the genotype of the parents... The result shown in 3 also shows that any population structure in the parental population that disrupts HWE also leads to a non-zero expectation for Ui in the non-linear case... Hence, the robustness to population structure does not extend from the linear to non-linear case... The trio design as developed in the FBAT CNV test can alleviate these concerns by comparing raw intensity data within families, rather than comparisons across cases and controls... In the non-linear intensity case, if the batch effect can be modelled using a family-specific covariate that acts on the raw intensity data in an additive manner, this covariate will have the same effect on the parental and offspring intensities... Therefore, the effect of this covariate will vanish in the computation of the score statistic... Thus, even in the case of a non-linear effect, the FBAT CNV statistic is expected to be robust to a range of technical artefacts... Approximately 250 of these 372 CNVs are deletions for which the intensity is typically non-linear with copy number... A small subset of CNVs showed significant association (Fig... In this case, the FBAT CNV test is appropriate and the initially proposed estimate of the score variance estimator V is consistent... Moreover, in a non-linear genotype-intensity context, the FBAT CNV test is robust to family-specific technical covariates.

Show MeSH
Related in: MedlinePlus