The difference between A-optimal and D-optimal designs becomes more apparent for the largest cluster, 𝑑 1 (Supplemental Fig. ). For 𝑑 1 , the A-optimal design has 30 more edges than the Doptimal design to the reference ligand. However, the edges exclusive to the D-optimal design are overall higher weight with a gain in the average weight from 0.30 ± 0.09 for A-optimal to 0.5 ± 0.1 for D-optimal (Supplemental Fig. ). The increased connections to the reference reduce the theoretical MSE of A-optimal designs compared to D-optimal designs (Fig. ). But, the overall transformations that one must perform in A-optimal designs could be more challenging.