‘Deep phenotyping’: characterizing populations in the era of genomics and systems biology

Abstract

Large-scale genomic studies establish genotype-phenotype associations, but they use phenotypes that represent current views of disease. There is an opportunity to enhance our understanding of genotype-phenotype associations by extending phenotypes into much greater detail ('deep phenotyping'). We should engage in deep phenotyping for the following reasons. First, the current emphasis on clinical outcomes, although necessary for the advancement of clinical medicine, is not sufficient. Second, analytical and biological variance embedded in traditional phenotypes dilutes statistical power and strength of association. Finally, even relatively precise phenotypes may vary in terms of underlying pathophysiology across an individual's life history. Deep phenotyping focuses on the biological relevance of pathways and metabolic flux, increasing the 'granularity' of phenotypes. Focus on medical phenotypes is critical, but long-term interests require additional studies that illuminate underlying biology. Deep phenotyping is less likely to yield dramatic changes in current medical practice but it offers an opportunity to gain scientific insight in an incremental manner and to make progress in redefining clinical outcomes with greater precision. It is expensive, and debate is needed to determine when and how it should be applied.