Sparse Pathway-Induced Dynamic Network Biomarker Discovery for Early Warning Signal Detection in Complex Diseases

In many complex diseases, the transition process from the healthy stage to the catastrophic stage does not occur gradually. Recent studies indicate that the initiation and progression of such diseases are comprised of three steps including healthy stage, pre-disease stage, and disease stage. It has been demonstrated that a certain set of trajectories can be observed in the genetic signatures at the molecular level, which might be used to detect the pre-disease stage and to take necessary medical interventions. In this paper, we propose two optimization-based algorithms for extracting the dynamic network biomarkers responsible for catastrophic transition into the disease stage, and to open new horizons to reverse the disease progression at an early stage through pinpointing molecular signatures provided by high-throughput microarray data. The first algorithm relies on meta-heuristic intelligent search to characterize dynamic network biomarkers represented as a complete graph. The second algorithm induces sparsity on the adjacency matrix of the genes by taking into account the biological signaling and metabolic pathways, since not all the genes in the ineractome are biologically linked. Comprehensive numerical and meta-analytical experiments verify the effectiveness of the results of the proposed approaches in terms of network size, biological meaningfulness, and verifiability.