Integrative computational epigenomics to build data-driven gene regulation hypotheses.

Background: Diseases are complex phenotypes often arising as an emergent property of a non-linear network of genetic and epigenetic interactions. To translate this resulting state into a causal relationship with a subset of regulatory features, many experiments deploy an array of laboratory assays from multiple modalities. Often, each of these resulting datasets is large, heterogeneous, and noisy. Thus, it is non-trivial to unify these complex datasets into an interpretable phenotype. Although recent methods address this problem with varying degrees of success, they are constrained by their scopes or limitations. Therefore, an important gap in the field is the lack of a universal data harmonizer with the capability to arbitrarily integrate multi-modal datasets.

Results: In this review, we perform a critical analysis of methods with the explicit aim of harmonizing data, as opposed to case-specific integration. This revealed that matrix factorization, latent variable analysis, and deep learning are potent strategies. Finally, we describe the properties of an ideal universal data harmonization framework.

Conclusions: A sufficiently advanced universal harmonizer has major medical implications, such as (i) identifying dysregulated biological pathways responsible for a disease is a powerful diagnostic tool; (2) investigating these pathways further allows the biological community to better understand a disease's mechanisms; and (3) precision medicine also benefits from developments in this area, particularly in the context of the growing field of selective epigenome editing, which can suppress or induce a desired phenotype.