This gene-set analysis also uses a regression structure to allow generalization to analysis of continuous properties of genes and simultaneous analysis of multiple gene sets and other gene properties.

The results show that MAGMA has significantly more power than other tools for both the gene and the gene-set analysis, identifying more genes and gene sets associated with Crohn’s Disease while maintaining a correct type 1 error rate.

As such, using this variable Z a very simple intercept-only linear regression model can now be formulated for each gene set 5 of the form Z5 2 flOT —|— 55, where Z5 is the subvector of Z corresponding to the genes in 5.

with elements 5g is then defined, with 5g 2 1 for each gene g in gene set 5 and 0 otherwise.

The parameter A in this model reflects the difference in association between genes in the gene set and genes outside the gene set , and consequently testing the null hypothesis fis = 0 against the one-sided alternative A > 0 provides a competitive test.

Gene-set analysis methods can be subdivided into self-contained and competitive analysis, with the self-con-tained type testing whether the gene set contains any association at all, and the competitive type testing whether the association in the gene set is greater than in other genes [7].

However, one concern with most existing methods is that they first summarize associations per marker before aggregating them to genes or gene sets .

This makes it more difficult to determine the properties of the analysis such as how the significance of a gene set relates to the significance of its constituent genes or whether the analysis corrects for a polygenic architecture.

Finally, we observed an enrichment for low off-target siRNAs in this pathway when performing a gene set enrichment analysis [32] (see supplementary S9 Fig).

This selection step helps to achieve reasonably unbiased results with our model, but it also limits the gene sets we can analyze.

To see if KEGG pathways are affected differently by off-tar-geting siRNAs, we performed a gene set enrichment analysis [32] on the siRNA scores, using 810 Fig.