Extracellular matrix (ECM) remodeling plays important roles in both white adipose tissue (WAT) and the skeletal muscle (SM) metabolism. Excessive adipocyte hypertrophy causes fibrosis, inflammation, and metabolic dysfunction in adipose tissue, as well as impaired adipogenesis. Similarly, disturbed ECM remodeling in SM has metabolic consequences such as decreased insulin sensitivity. Most of described ECM molecular alterations have been associated with DNA sequence variation, alterations in gene expression patterns, and epigenetic modifications. Among others, the most important epigenetic mechanism by which cells are able to modulate their gene expression is DNA methylation. Epigenome-Wide Association Studies (EWAS) have become a powerful approach to identify DNA methylation variation associated with biological traits in humans. Likewise, Genome-Wide Association Studies (GWAS) and gene expression microarrays have allowed the study of whole-genome genetics and transcriptomics patterns in obesity and metabolic diseases. The aim of this review is to explore the molecular basis of ECM in WAT and SM remodeling in obesity and the consequences of metabolic complications. For that purpose, we reviewed scientific literature including all omics approaches reporting genetic, epigenetic, and transcriptomic (GWAS, EWAS, and RNA-seq or cDNA arrays) ECM-related alterations in WAT and SM as associated with metabolic dysfunction and obesity.

The use of machine learning techniques for the construction of predictive models of disease outcomes (based on omics and other types of molecular data) has gained enormous relevance in the last few years in the biomedical field. Nonetheless, the virtuosity of omics studies and machine learning tools are subject to the proper application of algorithms as well as the appropriate pre-processing and management of input omics and molecular data. Currently, many of the available approaches that use machine learning on omics data for predictive purposes make mistakes in several of the following key steps: experimental design, feature selection, data pre-processing, and algorithm selection. For this reason, we propose the current work as a guideline on how to confront the main challenges inherent to multi-omics human data. As such, a series of best practices and recommendations are also presented for each of the steps defined. In particular, the main particularities of each omics data layer, the most suitable preprocessing approaches for each source, and a compilation of best practices and tips for the study of disease development prediction using machine learning are described. Using examples of real data, we show how to address the key problems mentioned in multi-omics research (e.g., biological heterogeneity, technical noise, high dimensionality, presence of missing values, and class imbalance). Finally, we define the proposals for model improvement based on the results found, which serve as the bases for future work.

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