Closing the 'phenotype gap' in precision medicine: improving what we measure to understand complex disease mechanisms.

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The central concept underlying precision medicine is a mechanistic understanding of each disease and its response to therapy sufficient to direct a specific intervention. To execute on this vision requires parsing incompletely defined disease syndromes into discrete mechanistic subsets and developing interventions to precisely address each of these etiologically distinct entities. This willrequire substantial adjustment of traditional paradigms which have tended to aggregate high-level phenotypes with very different etiologies. In the currentenvironment, where diagnoses are not mechanistic, drug development has become so expensive that it is now impractical to imagine the cost-effective creation of new interventions for many prevalent chronic conditions. The vision of precision medicine also argues for a much more seamless integration of research and development with clinical care, where shared taxonomies willenable every clinical interaction to inform our collective understanding of disease mechanisms and drug responses. Ideally, this would be executed in ways that drive real-time and real-world discovery, innovation, translation, and implementation. Only in oncology, where at least some of the biology is accessible through surgical excision of the diseased tissueor liquid biopsy, has "co-clinical" modeling proven feasible. In most common germline disorders, while genetics often reveal the causal mutations, there still remain substantial barriers to efficient disease modeling. Aggregation of similar disorders under single diagnostic labelshas directly contributed to the paucity of etiologic and mechanistic understanding by directlyreducing the resolution of any subsequent studies. Existing clinical phenotypes are typically anatomic, physiologic, or histologic, and result in a substantial mismatch in information content between the phenomes in humans or in animal 'models' and the variation in the genome. This lack of one-to-one mapping of discrete mechanisms between disease and animalmodels causes a failure of translation and is one form of 'phenotype gap.' In this review, we will focus on the origins of the phenotyping deficit and approaches that may be considered to bridge the gap, creating shared taxonomies between human diseases and relevant models, using cardiovascular examples.