CNet: A multi-omics approach to detecting clinically associated, combinatory genomic signatures

Genome-wide multi-omics profiling of complex diseases provides valuable resources and opportunities to discover associations between various measures of genes and diseases. Currently, a pressing challenge is how to effectively detect functional genes associated with or causing phenotypic outcomes. We developed CNet to identify groups of genomic signatures whose combinatory effect is significantly associated with clinical and phenotypical outcomes. Results: CNet builds on a generalized sequential feedforward method, augmented by a down-sampling bootstrap strategy to reduce random hitchhiking signatures. It further applies a dynamic trimming procedure to remove relatively less informative signatures at every step. CNet can manage heterogeneous genomic signature profiles simultaneously and select the best signature to represent a specific gene. To deal with various forms of clinical and phenotypical measurements, we introduced four models to deal with continuous, categorical and censored data. We tested CNet using drug-response data, multidimensional cancer genomics data and genome-wide association study data for multiple traits. Our results demonstrated that in various scenarios, CNet could effectively identify signatures that are associated with the outcomes. In addition, we applied CNet to identify likely disease-causing chains involving somatic mutations, pathway activities and patient outcomes. With appropriate setting, CNet can be applied in many biological conditions.