Cellular mechanism-of-action is of fundamental concern in many biological studies. It is of particular interest for identifying the cause of disease and learning the way in which treatments act against disease. However, pinpointing such mechanisms is difficult, due to the fact that small perturbations to the cell can have wide-ranging downstream effects. Given a snapshot of cellular activity, it can be challenging to tell where a disturbance originated. The presence of an ever-greater variety of high-throughput biological data offers an opportunity to examine cellular behavior from multiple angles, but also presents the statistical challenge of how to effectively analyze data from multiple sources. In this setting, we propose a method for mechanism-of-action inference by extending network filtering to multi-attribute data. We first estimate a joint Gaussian graphical model across multiple data types using penalized regression and filter for network effects. We then apply a set of likelihood ratio tests to identify the most likely site of the original perturbation. In addition, we propose a conditional testing procedure to allow for detection of multiple perturbations. We demonstrate this methodology on paired gene expression and methylation data from The Cancer Genome Atlas (TCGA).
Keywords: Biological networks; Data integration; Drug targeting; Gaussian graphical model; Network filtering.
© 2018, The International Biometric Society.