Fig. 2: Simulation process generates patients with multiple phenotype terms and candidate genes.
From: Simulation of undiagnosed patients with novel genetic conditions
a Patients are first assigned a true disease and initialized with a gene known to cause that disease (blue circle) as well as with positive and negative phenotypes associated with that disease (gray diamonds). Phenotype terms are then randomly removed through phenotype dropout, randomly altered to be less specific according to their position in an ontology relating phenotype terms, and augmented with terms randomly selected by prevalence in a medical claims database. Finally, strong distractor candidate genes and relevant additional phenotypes are generated based on six distractor gene modules. b The six distractor gene modules are inspired by genes that are frequently considered in current clinical genomic workflows and are designed to generate highly plausible, yet ultimately non-causal, genes for each patient. Four of the distractor gene modules are defined by the overlap—or lack thereof—between the phenotypes associated with the distractor gene and the phenotypes associated with the patient’s causal gene. The remaining two modules are defined by their similar tissue expression as the true disease gene or solely by their frequent erroneous prioritization in computational pipelines.
