Dependency on background cells

[NoahMottelson]

Dependency on background cells

[martinjzhang]

Hi,

Thank you for your interest in our work! This is indeed an expected behavior.

Specifically, the scDRS results of a given cell depend on other cells in the data set through both the estimation of technical noise levels and the selection of matched control genes (expression mean and variance are evaluated across all cells in the data). In a way, scDRS assesses if a given cell has excess disease enrichment compared to an "average cell", and this "average cell" is defined by other cells in the data set. As a result, including only causal cells will likely yield non-significant results.

To see this, consider the case where MSN is the causal cell type and all putative disease genes are highly expressed in MSNs (and lowly expressed in other cells). If we include only MSNs, the mean expression of the disease genes will be very high. As a result, the matched control genes will also have high expression, producing high control scores and making the disease scores non-significant. However, such a situation would not appear if we include all cells in the TMS data, where the mean expression of the putative disease genes, averaged across both the causal MSNs and other non-causal cells, will not be very high.

Please see also the discussion points 6 and 7 in the manuscript (lines 472-481; https://www.biorxiv.org/content/10.1101/2021.09.24.461597v1.full.pdf).

We recommend including all cells in your scRNA-seq data set. In general, to run scDRS for a given disease gene set, the scRNA-seq data should ideally contain a good proportion of non-causal cells to provide enough contrast to the causal cell population.

Let me know if you have more questions.

Best,
Martin

[NoahMottelson]

Thanks a lot for the detailed answer!

[NoahMottelson]

In the 7th discussion point of the manuscript you mention the possibility of choosing the control gene sets based on a different data set than the one you're analyzing. Is this implemented as an option in the software yet?