Automating parameter selection to avoid implausible biological pathway models

A common way to integrate and analyze large amounts of biological "omic" data is through pathway reconstruction: using condition-specific omic data to create a subnetwork of a generic background network that represents some process or cellular state. A challenge in pathway reconstruction is that adjusting pathway reconstruction algorithms' parameters produces pathways with drastically different topological properties and biological interpretations. Due to the exploratory nature of pathway reconstruction, there is no ground truth for direct evaluation, so parameter tuning methods typically used in statistics and machine learning are inapplicable. We developed the pathway parameter advising algorithm to tune pathway reconstruction algorithms to minimize biologically implausible predictions. We leverage background knowledge in pathway databases to select pathways whose high-level structure resembles that of manually curated biological pathways. At the core of this method is a graphlet decomposition metric, which measures topological similarity to curated biological pathways. In order to evaluate pathway parameter advising, we compare its performance in avoiding implausible networks and reconstructing pathways from the NetPath database with other parameter selection methods across four pathway reconstruction algorithms. We also demonstrate how pathway parameter advising can guide reconstruction of an influenza host factor network. Pathway parameter advising is method agnostic; it is applicable to any pathway reconstruction algorithm with tunable parameters.