Positive predictive value highlights four novel candidates for actionable genetic screening from analysis of 220,000 clinicogenomic records

Kelly M Schiabor Barrett,Alexandre Bolze,Yunyun Ni,Simon White,Magnus Isaksson,Lavania Sharma,Elissa Levin,William Lee,Joseph J Grzymski,James T Lu,Nicole L Washington,Elizabeth T Cirulli

doi:10.1038/s41436-021-01293-9

Kelly M Schiabor Barrett, Alexandre Bolze + Show 10 more

Open Access

https://doi.org/10.1038/s41436-021-01293-9

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Abstract

PurposeTo identify conditions that are candidates for population genetic screening based on population prevalence, penetrance of rare variants, and actionability.MethodsWe analyzed exome and medical record data from >220,000 participants across two large population health cohorts with different demographics. We performed a gene-based collapsing analysis of rare variants to identify genes significantly associated with disease status.ResultsWe identify 74 statistically significant gene–disease associations across 27 genes. Seven of these conditions have a positive predictive value (PPV) of at least 30% in both cohorts. Three are already used in population screening programs (BRCA1, BRCA2, LDLR), and we also identify four new candidates for population screening: GCK with diabetes mellitus, HBB with β-thalassemia minor and intermedia, PKD1 with cystic kidney disease, and MIP with cataracts. Importantly, the associations are actionable in that early genetic screening of each of these conditions is expected to improve outcomes.ConclusionWe identify seven genetic conditions where rare variation appears appropriate to assess in population screening, four of which are not yet used in screening programs. The addition of GCK, HBB, PKD1, and MIP rare variants into genetic screening programs would reach an additional 0.21% of participants with actionable disease risk, depending on the population.

Highlights

Genetic conditions that are appropriate for population screening in US health programs are recommended to meet multiple criteria as proposed in guidelines by the CDC and/or American College of Medical Genetics and Genomics (ACMG) [1, 2]
In health systems currently offering population genetic screening based on CDC Tier 1 conditions, roughly 1% of an unselected patient population harbors a pathogenic/likely pathogenic (P/LP) variant, and as many as 80% of these individuals are unaware of their elevated risk status [4, 5]
The ethnic makeup of the two cohorts was quite different despite each being predominantly of European ancestry, and our analysis results were similar whether restricting to European ancestry or analyzing across ethnicities (Table S1), consistent with our previous study showing that collapsed rare variant signals tend to be consistent across ancestries [9]

Summary

Introduction

Genetic conditions that are appropriate for population screening in US health programs are recommended to meet multiple criteria as proposed in guidelines by the CDC and/or American College of Medical Genetics and Genomics (ACMG) [1, 2] They must be conditions that affect a large number of people, have a genetic component with high penetrance in unselected populations, benefit from identifying at-risk individuals before they have fully developed the condition, have clear actionability for a change in clinical care upon genetic identification, and have the utility of screening confirmed by appropriate health economic analyses. This means that there is a high positive predictive value (PPV), generally >30%, when identifying individuals with P/LP variants

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