Deeper, longer phenotyping to accelerate the discovery of the genetic architectures of diseases

摘要

A recent National Academy of Sciences report entitle'Precision Medicine' [1] made the point that, in this era ocommodity-priced genome-scale measurements, we cannow envisage a systematic reclassification of human pathobiology on a population scale. These high-throughpumeasurement modalities promise greater precision and accuracy to provide patients with individualized diagnoseand therapies. Indeed, we have already seen remarkablsuccess in this regard in improved prognostics and therapeutics for breast cancer [2], non-small-cell lung carcinomas [3] and the leukemias [4] through molecular-basesubtype profiling. By contrast, many have written abouthe artificiality of current organ-based phenotypes anoften clinical-department-based diagnoses [5,6] that dnot correspond to the underlying pathotypes that crosconventional clinical categorizations. This inadequacy othe current and often-arbitrary clinical classificationscoupled with encouraging results from molecular medicine, has led to a swing of the pendulum to the oppositextreme of where it was in the pre-genomic era. Genotypivariation is often but a small slice of relevant pathotypivariation [7], and the recent call for a sequencing-first approach [8] for molecular-driven classification could resulin expensive and frustrating delays in discovering the trugenetic architecture of much of human disease. In mancases, taking a more detailed data-driven look at the clinical characterization of individual patients, particularly arevealed by their distinct trajectories over time, might rescue a large number of otherwise-misdirected genomiinvestigations.