Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data

The 10 Warning Signs (WS) of Primary Immunodeficiency were created 30 years ago to advance recognition of inborn-errors of immunity (IEI). However, no population-level assessment of their utility applied to electronic health record (EHR) data has been conducted.We sought to quantify the value of having 2+ WS towards diagnosing IEI using a highly representative real-world US cohort. A secondary goal was estimating the US prevalence of IEI.In this cohort study, we accessed normalized and de-identified EHR data on 152 million US lives. An IEI cohort (n=41,080) was defined by having at least 1 verifiable IEI diagnosis placed ≥2 times in their record and compared to a matched set of controls (n=250,262). WS were encoded along with relevant diagnoses, relative weights were calculated and the proportion of IEI vs controls with 2+ WS was compared.The proportion of IEI patients with 2+ warning signs significantly differed from controls (0.33 vs. 0.031; p < 0.0005 ChiSq). We also estimated a US IEI prevalence of 6:10,000 individuals (41,080/73,165,655; 0.056%). Warning signs 9 (2+deep-seated infections), 7(fungal infections), 5(failure to thrive) and 4(2+pneumonias in 1 year) were the most heavily weighted among the IEI cohort.From this nationally representative US-based cohort study, we note that WS presence, and associated clinical diagnoses, can facilitate IEI patient identification from EHR data. In addition, we estimate that 6 in 10,000 or approximately 150-200,00 persons are affected by IEI across the US.