Network perturbation analysis of gene transcriptional profiles reveals protein targets and mechanism of action of drugs and influenza A viral infection

Noh, Heeju; Shoemaker, Jason E; Gunawan, Rudiyanto

where z ki denotes the z-score of gene k and s ji denotes the score of the TF/protein j in the drug treatment sample i. The weighting coefficients w kj are set equal to the edge weights a kj divided by the maximum magnitude of a kj across all j. In other words, the weight w kj reflects the fraction of the regulation of gene k expression that could be attributed to protein j. When w kj (or a kj ) and z ki have the same signs, w kj z ki thus takes a positive value. As illustrated in Figure 1C , a positive w kj z ki implies an enhanced regulatory activity of protein j on gene k, since the activation (inhibition) of gene k expression by protein j is stronger in this sample than expected by the PGRN model. In contrast, a negative w kj z ki indicates an attenuation of the regulatory influence of protein j on gene k, since the activation (inhibition) of gene k expression by protein j is weaker than predicted by the PGRN model. Consequently, a highly positive (negative) score s ji is an overall indicator of strongly enhanced (attenuated) regulatory activity of protein j by the drug treatment in sample i (see Figure 1D ). The protein targets in each drug treatment sample are ranked in decreasing magnitude of the scores s ji .