Abstract
The early, accurate diagnosis and risk stratification of sepsis remains an important challenge in the critically ill. Since traditional biomarker strategies have not yielded a gold standard marker for sepsis, focus is shifting towards novel strategies that improve assessment capabilities. The combination of technological advancements and information generated through the human genome project positions systems biology at the forefront of biomarker discovery. While previously available, developments in the technologies focusing on DNA, gene expression, gene regulatory mechanisms, protein and metabolite discovery have made these tools more feasible to implement and less costly, and they have taken on an enhanced capacity such that they are ripe for utilization as tools to advance our knowledge and clinical research. Medicine is in a genome-level era that can leverage the assessment of thousands of molecular signals beyond simply measuring selected circulating proteins. Genomics is the study of the entire complement of genetic material of an individual. Epigenetics is the regulation of gene activity by reversible modifications of the DNA. Transcriptomics is the quantification of the relative levels of messenger RNA for a large number of genes in specific cells or tissues to measure differences in the expression levels of different genes, and the utilization of patterns of differential gene expression to characterize different biological states of a tissue. Proteomics is the large-scale study of proteins. Metabolomics is the study of the small molecule profiles that are the terminal downstream products of the genome and consists of the total complement of all low-molecular-weight molecules that cellular processes leave behind. Taken together, these individual fields of study may be linked during a systems biology approach. There remains a valuable opportunity to deploy these technologies further in human research. The techniques described in this paper not only have the potential to increase the spectrum of diagnostic and prognostic biomarkers in sepsis, but they may also enable the discovery of new disease pathways. This may in turn lead us to improved therapeutic targets. The objective of this paper is to provide an overview and basic framework for clinicians and clinical researchers to better understand the 'omics technologies' to enhance further use of these valuable tools.
Highlights
The early, accurate diagnosis and risk stratification of sepsis remains an important challenge in the critically ill
Systems biology refers to the integration and analysis of complex datasets derived from multiple facets of the body’s signaling and response pathways
Proteomics is considered the step in the study of biological systems downstream from genomics and transcriptomics. mRNA expression levels do not necessarily correlate with protein content [73,74]
Summary
The early, accurate diagnosis and risk stratification of sepsis remains an important challenge in the critically ill. Technological advancements, along with the information generated through the human genome project, have positioned systems biology at the forefront of biomarker discovery. This has facilitated approaches that may yield an improved insight into complicated sepsis pathophysiology, but may identify unexplored pathways [7,8]. GWAS have far uncovered >800 SNP associations for more than 150 disease and other traits [28] For these hypothesis-generating studies, DNA microarrays or whole genome sequencing are often used because high throughput is feasible, and a priori selection of specific SNPs is not required. The association between gene polymorphisms and mortality awaits large-scale validation but there is a strong support for the inclusion of genotyping when designing sepsis trials [19,39,40]
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