Flowchart for threshold determination.

1) Define at least two distinct groups of genes expected to be similar. 2) Compute the intra- and inter-group similarities and compile the results into S and N distributions. If these two distributions are significantly different, the groups of genes are relevant. 3) If S and N do not overlap, define threshold τ_sim using any value between τ_S (the lowest value of S) and τ_N (the highest value of N). Else, considering every value under the threshold as FN and every value above the threshold as FP, compute the FN proportion in the S distribution (3a) and the FP proportion in the N distribution (3b) for all samples of the similarity threshold between τ_N to τ_S. 3c) For each possible threshold value, sum the FN and FP proportions obtained in steps 3a and 3b. The similarity threshold τ_sim is the one that minimizes this sum.