DOKI: Domain knowledge-driven inference method for reverse-engineering transcriptional regulatory relationships among genes in cancer

Abstract

Efficient reverse-engineering methods are important for identifying transcriptional regulatory relationships among genes in cancer. These methods are becoming increasingly useful in this era where huge volumes of data are generated through the use of high-throughput technologies such as next-generation sequencing technologies and microarrays. However, it is important to improve current methods because of complications involved in modelling complex biological systems. In this paper, we present a novel approach, Domain Knowledge-driven Inference (DOKI), for identification of transcriptional regulatory relationships among genes, given a biological context such as cancer. Combining data normalization, the use of a probability distribution function and Kullback-Leibler Divergence, DOKI incorporates a domain knowledge-driven criterion to make determinations of the existence of regulatory relationships between given transcription factors and given specific gene targets. Characteristics of DOKI enable it to adequately handle complexities inherent in data, and accurately unearth linear and higher-order dependent relationships among genes. DOKI performed equally well with one established high-performing method and better than three other high-performing methods on relatively small data sets. However, it remarkably outperformed these methods on larger data sets to demonstrate its utility. Furthermore, we demonstrate the relevance of such inference algorithms for identifying novel relationships among genes in breast cancer, as some of the consensus results representing novel relationships were confirmed in previously published experimental results. Thus, DOKI will facilitate current efforts to gain etiological insights and help uncover new targeted therapies for various diseases.