"True" reference interactomes for fly and human were generated by random sampling of interactions from the set of all possible pairs of proteins using the interaction probabilities in the String database46. Protein pairs not included in the String database were sampled using a low background probability, such that the total number of interactions in the sampled interactomes agreed with current estimates of interactome sizes30 (~100,000 fly interactions and ~260,000 human interactions). The detectability of each protein pair was independently sampled for each new assay type (representing a new type of measurement technology or new bait/prey orientation) using a 66% FNR for true interactions and 0.2% FPR for false interactions (corresponding to 82% FDR). Once an interaction was defined as "Detectable/ Undetectable", direct pairwise experiments were assumed to be 100% reproducible for a given protein pair and assay. For pooled assays, each detectable interaction in the sample space of a pool was assumed to be observed in the pool with probability equal to the pooling sensitivity (Table 1) . Pools with at least one observed interaction were declared positive. For each strategy, after every 1000 experiments the mapped interactomes were compared to the "true" interactomes and the coverage and FDR were recorded.