Plain-language medical vocabulary for “precision diagnosis”

Following up on the most recent GEITP email about “precision medicine” or “personalized medicine,” this brief letter [see attached] concerns “precision diagnosis.” Often discussed in these GEITP pages have been genome-wide association studies (GWAS) in which one or more genes (genotype) is identified as “being associated with” a particular trait (phenotype). If one has a study population (cohort) of 10,000 having Trait A, compared with a control cohort of 10,000 without Trait A –– this is what is called a “genotype-phenotype association study”.

For a simple example, let’s say we have chosen to study a cohort with “blue eyes”, i.e. what gene(s) are associated with this trait? (And the control cohort is “brown eyes.”) If, within the 10,000 individuals purported to have blue eyes, there are 10 subjects misdiagnosed because they have green eyes. The results of this study would therefore be “fuzzy,” or “tainted,” by this “lack of precision diagnosis,” or “increased noise.” Many genomicists refer to this as an equivocal phenotype. Everyone would prefer to have a study cohort having only an unequivocal phenotype. The same can be said about any trait –– type-2 diabetes, schizophrenia, breast cancer, autism spectrum disorder –– if some in the study cohort are misdiagnosed, then the results of the study are plagued with decreased statistical power.

Perhaps especially for patients not yet diagnosed, and those with rare diseases, the affected individuals themselves are an especially critical source of phenotyping information. These patients live with their condition, and develop explicit and implicit knowledge about it –– whether from multiple-clinician evaluations or from other families and patients experiencing diagnosis for similar conditions. Many web sites have been set up, over the past three decades, for those with a common ailment to share their grief/concern/advice/comments/questions. From these interactions, they develop a lexicon of relevant terms; these terms are frequently in plain layman language, but can also include clinical terms.

Human genetics and precision medicine therefore aim to understand the relationship between genetic variants and diseases. Whole-exome seuencing (WES) and whole-genome sequencing (WGS) have transformed the ability comprehensively to characterize genetic variants. Although WES and WGS have led to the discovery of many novel disease-associated genes, the diagnostic yield in patients without a clear clinical diagnosis has been 11% to 25%. The Human Phenotype Ontology (HPO) was created [Am J Hum Genet 2oo8; 83: 610] to enable ‘deep phenotyping’, i.e. capture of symptoms and phenotypic findings using a logically-constructed hierarchy of phenotypic terms. The HPO has become the de facto standard for representing clinical phenotype data to inform diagnoses for rare genetic diseases by the 100,000 Genomes Project, the NIH Undiagnosed Diseases Program (UDP), and Undiagnosed Diseases Network (UDN), as well as thousands of other clinics, laboratories, tools, and databases. Further details are described in the attached letter. 🙂


Nature Genetics Apr 2o18; 50: 474–476

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