Sensitivity to detect and differential bias. Detection
of CNVs from array data is sensitive to the
detailed noise properties of each hybridization,
which in turn arise from sample and hybridization
quality. (A survey of the supplementary data sets
underlying many CNV-discovery approaches
indicates that the number of CNVs detected per
sample can vary 4-fold from sample to sample.)
As the DNA from affected and unaffected individuals
in GWAS often originates at different clinical
sites, is extracted at different times, or is analyzed
in different experimental plates or batches,
‘differential bias’ —the confounding of
detection sensitivity with Case/Control status—is
pervasive. The problem is particularly severe
in analyses of the ‘genomic burden’ of CNVs
across the genome, since such analyses aggregate
the effects of confounds at thousands of loci. It is
therefore important to carefully dissect the
sample- and batch-specific influences on detection
sensitivity, and to develop carefully controlled
analyses. Algorithmic approaches for this are an
urgent need in the field.
Rare CNVs that are shared by unrelated individuals are frequently present on a long
shared haplotype (blue); the possibility that some other feature of this haplotype might be the causal feature needs to be evaluated in an integrated analysis of
CNV and SNP haplotypes.
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