Harnessing Diversity towards the Reconstructing of Large Scale Gene Regulatory Networks

Elucidating gene regulatory network (GRN) from large scale experimental data remains a central challenge in systems biology. Recently, numerous techniques, particularly consensus driven approaches combining different algorithms, have become a potentially promising strategy to infer accurate GRNs. Here, we develop a novel consensus inference algorithm, TopkNet that can integrate multiple algorithms to infer GRNs. Comprehensive performance benchmarking on a cloud computing framework demonstrated that (i) a simple strategy to combine many algorithms does not always lead to performance improvement compared to the cost of consensus and (ii) TopkNet integrating only high-performance algorithms provide significant performance improvement compared to the best individual algorithms and community prediction. These results suggest that a priori determination of high-performance algorithms is a key to reconstruct an unknown regulatory network. Similarity among gene-expression datasets can be useful to determine potential optimal algorithms for reconstruction of unknown regulatory networks, i.e., if expression-data associated with known regulatory network is similar to that with unknown regulatory network, optimal algorithms determined for the known regulatory network can be repurposed to infer the unknown regulatory network. Based on this observation, we developed a quantitative measure of similarity among gene-expression datasets and demonstrated that, if similarity between the two expression datasets is high, TopkNet integrating algorithms that are optimal for known dataset perform well on the unknown dataset. The consensus framework, TopkNet, together with the similarity measure proposed in this study provides a powerful strategy towards harnessing the wisdom of the crowds in reconstruction of unknown regulatory networks.Author Summary: Elucidating gene regulatory networks is crucial to understand disease mechanisms at the system level. A large number of algorithms have been developed to infer gene regulatory networks from gene-expression datasets. If you remember the success of IBM's Watson in ”Jeopardy!„ quiz show, the critical features of Watson were the use of very large numbers of heterogeneous algorithms generating various hypotheses and to select one of which as the answer. We took similar approach, “TopkNet”, to see if “Wisdom of Crowd” approach can be applied for network reconstruction. We discovered that “Wisdom of Crowd” is a powerful approach where integration of optimal algorithms for a given dataset can achieve better results than the best individual algorithm. However, such an analysis begs the question “How to choose optimal algorithms for a given dataset?” We found that similarity among gene-expression datasets is a key to select optimal algorithms, i.e., if dataset A for which optimal algorithms are known is similar to dataset B, the optimal algorithms for dataset A may be also optimal for dataset B. Thus, our “TopkNet” together with similarity measure among datasets can provide a powerful strategy towards harnessing “Wisdom of Crowd” in high-quality reconstruction of gene regulatory networks.