A genome-by-environment interaction classifier for precision medicine: personal transcriptome response to rhinovirus identifies children prone to asthma exacerbations

Abstract: 
Objective: To introduce a disease prognosis framework enabled by a robust classification scheme derived from patient-specific transcriptomic response to stimulation. Materials and Methods: Within an illustrative case study to predict asthma exacerbation, we designed a stimulation assay that reveals individualized transcriptomic response to human rhinovirus. Gene expression from peripheral blood mononuclear cells was quantified from 23 pediatric asthmatic patients and stimulated in vitro with human rhinovirus. Responses were obtained via the single-subject gene set testing methodology "N-of-1-pathways." The classifier was trained on a related independent training dataset (n = 19). Novel visualizations of personal transcriptomic responses are provided. Results: Of the 23 pediatric asthmatic patients, 12 experienced recurrent exacerbations. Our classifier, using individualized responses and trained on an independent dataset, obtained 74% accuracy (area under the receiver operating curve of 71%; 2-sided P = .039). Conventional classifiers using messenger RNA (mRNA) expression within the viral-exposed samples were unsuccessful (all patients predicted to have recurrent exacerbations; accuracy of 52%). Discussion: Prognosis based on single time point, static mRNA expression alone neglects the importance of dynamic genome-by-environment interplay in phenotypic presentation. Individualized transcriptomic response quantified at the pathway (gene sets) level reveals interpretable signals related to clinical outcomes. Conclusion: The proposed framework provides an innovative approach to precision medicine. We show that quantifying personal pathway-level transcriptomic response to a disease-relevant environmental challenge predicts disease progression. This genome-by-environment interaction assay offers a noninvasive opportunity to translate omics data to clinical practice by improving the ability to predict disease exacerbation and increasing the potential to produce more effective treatment decisions.