\textsc{Background} Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. Currently, a major problem in biology is to cherry pick the combinations based on expert advice, literature survey or guesses for investigation. The search and wet lab testing of these combinations costs a lot in terms of time, investment and energy. In a recent development of the PORCN-WNT inhibitor ETC-1922159 for colorectal cancer, a list of down-regulated genes were recorded in a time buffer after the administration of the drug. The regulation of the genes were recorded individually but for a majority, it is still not known which higher ($\geq 2$) order combinations might be playing a greater role in the pathway. \textsc{Results} The pipeline provides a prioritised list of important $2^{nd}$ order combinations of a range of family of genes involved in the Wnt pathway. More specifically, it reveals the various unexplored FZD-WNT combinations that have been untested till now in the pathway. In relation to ETC-1922159 affected combinations, the down-regulation of LGR-RNF family after the drug treatment is evident in these rankings as it takes bottom priorities for LGR5-RNF43 combination. The LGR6-RNF43 takes higher ranking than LGR5-RNF43, indicating that it might not be playing a greater role as LGR5 during the Wnt enhancing signals. These rankings confirm the efficacy of the proposed search engine design. \textsc{Conclusion} A pipeline has been developed to prioritise an $n^{th}$ order combination of factors that affect a signaling pathway. It takes into account the sensitivity indices computed from variance based (SOBOL) and density-kernel based (HSIC) methods to estimate the influence of each factor or combination of factors. These are then fed as feature vectors into a powerful support vector ranking algorithm that produces a ranked list of the interactions/combinations.
Keywords:
Subject: Biology and Life Sciences - Other
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.