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WIREs Syst Biol Med
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Using systems approaches to address challenges for clinical implementation of pharmacogenomics

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Many genetic variants have been shown to affect drug response through changes in drug efficacy and likelihood of adverse effects. Much of pharmacogenomic science has focused on discovering and clinically implementing single gene variants with large effect sizes. Given the increasing complexities of drug responses and their variability, a systems approach may be enabling for discovery of new biology in this area. Further, systems approaches may be useful in addressing challenges in moving these data to clinical implementation, including creation of predictive models of drug response phenotypes, improved clinical decision‐making through complex biological models, improving strategies for integrating genomics into clinical practice, and evaluating the impact of implementation programs on public health. WIREs Syst Biol Med 2014, 6:125–135. doi: 10.1002/wsbm.1255 This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine

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Two views of drug action. In the top row (panels 1A and 2A), the healthy individual is modeled as a system of interacting nodes, each of represents a molecular entity or set of molecules. In panel 1B, disease is represented by over‐activity (dark green) of a single molecule. In panel 1C, a targeted drug returns activity to normal and restores health. However, disease may also result from changes in interactions (shown in red/blue) that may result in increased (γ2) or decreased (light green, α1) molecular abundance or activity (panel 2B). Administration of a drug corrects some of these perturbations, returning the system toward health (panel 2C). However, the system as a whole still manifests abnormal activity. Thus, in situations in which a single molecular lesion causes a disease, drug may be curative. In situations of complex disease or coexisting pathophysiology, this outcome is less likely.
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Operational aspects of genotyping for pharmacogenomic variants from point of drug prescription to genotype‐guided drug or dose.
[ Normal View | Magnified View ]

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