Fig. 1: Matrix of calculated CI values of additive combinations.
From: Reanalysis of in vivo drug synergy validation study rules out synergy in most cases
Values of the Combination Index (CI) calculated using the same formula as Narayan et al. for 2-drug combinations, assuming only additive effects. For example, when drug A has a T/C of 40% and B has a T/C of 30%, the combination will have a T/C of 12% when additive (40% × 30% = 12%). When we apply these numbers to the formula of Narayan et al.: \({{{\rm{CI}}}}_{(n,{{\rm{drugs}}})}=\frac{{\sum }_{k=0}^{n}\left(\frac{1}{{V}_{n}}\right)-\left(\frac{n-1}{100}\right)}{\left(\frac{1}{{V}_{1..n}}\right)}\)(10) the calculated value of the CI yields (((1/40) + (1/30))−((2−1)/100))/(1/12) = 0.58. A correct formula should have returned a CI of 1, as this is an example of a purely additive combination. The color pattern indicates with red combinations which are automatically considered as synergistic, while they are actually just additive. As shown, the calculated CI threshold value declines when single-agent efficacy increases. Hence, the calculated value is not a bonafide CI and cannot be used to assess synergy. We now refer to the values in the figure as the threshold values for calling synergy. For details and calculations, see SI File 1: Part 2 Combination Index in in vivo models.
