Systems biology approaches to precision medicine

This dissertation reviews the development and implementation of two systems biology meth- ods: ADVOCATE and hpARACNE. ADVOCATE was designed to deconvolve epithelium and stroma compartments fractions and virtual expression profiles from bulk gene expression profiles from human patients. We used laser capture microdissection and RNA sequencing to disentangle the transcriptional programs active in the malignant epithelium and stroma of pancreatic ductal adenocarcinoma (PDA), an aggressive malignancy with a prominent stromal component. We learned that distinct molecular subtypes are present in both the epithelium and the stroma of pancreatic cancer, and that the subtype identity of these two compartments are independent of one another. Critically, we discovered that specific com- binations of epithelial and stromal subtypes are strongly associated with patient survival across multiple external datasets, exhibiting both an effect-size and a level of reproducibility that was absent from previous efforts. These analyses were made possible by a new proba- bilistic algorithm (Adaptive DeconVolution Of CAncer Tissue Expression - ADVOCATE) that can extract compartment-specific gene expression