Table 2 Potential approaches to discovery of ‘etiologic field effect’ markers

Genomics

Whole-genome sequencing, exome sequencing, targeted sequencing, microarray-based analyses

Whole-genome sequencing is capable of detecting all germline genetic variants and is increasingly affordable. Recognized susceptibility variants explain only a limited proportion of the heritability of complex traits, and each disease-associated variant usually has minimal impact on individual risk. Alone, personal genome sequence data may poorly predict disease risk.²²⁸ Integration with phenotypic data and other large-scale molecular data may increase utility.²²⁹

Epigenomics

Methylation microarrays, high-throughput sequencing methodologies, microRNA arrays, chromatin mapping technologies

High-resolution epigenome mapping is possible.²³⁰ Epigenetic alterations in peripheral blood leukocytes or target tissues have been described in association with a variety of exposures.^{231, 232, 233} Complicated by variability associated with age, ethnicity, and diversity of cell types even in one organ or tissue.

Transcriptomics

Whole transcriptome sequencing, microarray-based gene expression assays

Global transcriptomics on blood or tissue biopsies can detect dynamic gene-expression responses to altered exposome. Studies have described transcriptional alterations associated with lifestyle, dietary, and environmental exposures.^{234, 235, 236, 237} Gene expression may not reflect protein expression/function. Challenges exist in experimental replication, deciphering alterations attributable to age and gender, as well as interpretation of data from complex tissues exposed to multiple exposures.

Proteomics

Mass spectroscopy, protein microarrays, biosensors, protein–protein interaction mapping

Technologies are well established in biomarker discovery, with promise of identifying protein markers of exposure, and may be combined with metabolomics to generate exposome-wide association studies for investigation of serum or tissue exposome biomarkers.²³⁸ Secretome-wide screens for extracellular protein-protein interactions may provide ability to interrogate extracellular interactome.²³⁹ Protein levels may not correlate with protein function, and may need to combine with kinome or other functional omics analysis. Technical challenges exist in secretome interaction mapping.

Metabolomics

Mass spectroscopy, proton nuclear magnetic resonance

Metabolic profiles are determined by both endogenous and environmental influences. It is applicable to biofluids (eg plasma, urine) or tissue extracts. Metabolomic analysis has a capacity to identify markers of exposure to specific dietary components and environmental toxins, as well as characterize metabolic markers of altered energy balance associated with physical activity and obesity.²²³

Interactomics

Interactome network mapping

Interactomics integrates knowledge from molecular networks (eg protein-protein interaction networks, gene regulatory networks, metabolic networks) that underlie complex biological systems.¹⁷⁹ Interactome network mapping may help identify interactome perturbation resulting from adverse exposures.

Biophysics

Spectroscopic adjuncts to endoscopy (eg backscattering spectroscopy).

Feasibility of biophysical analyses has been demonstrated in pilot studies.^{226, 240, 241} Optical technologies can detect nano/micro-architechtural and microvascular correlates of molecular field effect.²²⁷ At this time, the analysis is only applicable to endoscopically accessible tissues.