Heterogeneity and the effects of cell mixing on the 450K array.

<p>The 450K array provides methylation measurements from a mixed-up sample of multiple cells. (a) An example of a methylation pattern which is highly variable, in a similar way across cells. This leads to low cross-sample heterogeneity, and high IGV, as in cluster hyper 2. (b) An example of a methylation pattern which is highly variable, but in a heterogenous way across cells. This leads to high cross-sample heterogeneity, however the net effect of averaging the methylation profiles across the mixed up sample of many cells gives a measurement with low IGV, as in cluster hypo 1. (c) A measure of CpG-CpG methylation variability, calculated as the mean derivative, or the mean absolute difference in methylation level between adjacent CpGs. (d) The variability of the mean-derivative measure across samples quantifies the heterogeneity of the CpG-CpG methylation variability. Cluster hyper 2 is low according to (d), and hence corresponds to a pattern such as (a). Cluster hypo 1 is high according to (d), and hence corresponds to a pattern such as (b).