Identification of Discriminating Biomarkers for Human Disease Using Integrative Network Biology

There is a strong clinical imperative to identify discerning molecular biomarkers of disease to inform diagnosis, prognosis, and treatment. Ideally, such biomarkers would be drawn from peripheral sources non-invasively to reduce costs and lower potential for complication. Advances in high-throughput genomics and proteomics have vastly increased the space of prospective molecular biomarkers. Consequently, the elucidation of molecular biomarkers of clinical importance often entails a genome- or proteome-wide search for candidates. Here we present a novel framework for the identification of disease-specific protein biomarkers through the integration of biofluid proteomes and inter-disease genomic relationships using a network paradigm. We created a blood plasma biomarker network by linking expression-based genomic profiles from 136 diseases to 1,028 detectable blood plasma proteins. We also created a urine biomarker network by linking genomic profiles from 127 diseases to 577 proteins detectable in urine. Through analysis of these molecular biomarker networks, we find that the majority (> 80%) of putative protein biomarkers are linked to multiple disease conditions. Thus, prospective disease-specific protein biomarkers are found in only a small subset of the biofluids proteomes. These findings illustrate the importance of considering shared molecular pathology across diseases when evaluating biomarker specificity. The proposed framework is amenable to integration with complimentary network models of biology, which could further constrain the biomarker candidate space, and establish a role for the understanding of multi-scale, inter-disease genomic relationships in biomarker discovery.