Skip to main content

Conference Program

Subpage Hero

Loading

A Framework To Identify Individuals at Low Risk of Disease In the Population

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Genetics can be used to identify individuals at lower risk of disease. Benefits include (i) reallocating resources to those at increased risk, (ii) avoiding unnecessary screening, and (iii) facilitating discussions with the ‘average’ risk group about the importance of following the standard guidelines. However, few papers focus on the genetics of resistance to disease, and genetic screening programs currently do not return results for low disease risk. Concerns about misclassifying individuals at low risk have hindered implementing a ‘low genetic risk’ program. Our study aims to develop a framework to select conditions and models to identify individuals at lower disease risk.

Methods:
We studied 161,406 individuals from seven US health systems in the Helix Research Network. For a given condition, a person may be classified as low genetic risk if they meet three criteria: (i) do not have a pathogenic or likely pathogenic variant, (ii) do not have a rare variant of potential risk (e.g., a rare VUS high), and (iii) have a low polygenic risk score or a rare protective variant. Analytical validity was measured by testing sensitivity, specificity and accuracy of polygenic risk score models and detection of known protective rare variants. Clinical validity was tested using longitudinal phenotype data from electronic health records. Clinical utility was assessed by estimating potential screening reductions and residual risk in those classified as low risk.

Results:
Breast cancer was the top-ranked condition. Women with a pathogenic variant in BRCA1, BRCA2, PALB2, ATM, and CHEK2 were considered high risk. Additionally, women with a rare (<0.001%) predicted loss-of-function (pLOF) variant in BARD1, CDH1, MAP3K1, RAD51C, RAD51D and TP53 were excluded from potentially being classified as low risk. Lastly, among those remaining, the ones with a polygenic risk score in the bottom 5% were considered at low genetic risk. USPSTF recommends biennial from age 40 to catch or prevent early cancers. While 0.69% of women had a breast cancer diagnosis by age 45, the rate reached 0.69% at age 51 for women classified as low genetic risk.

Conclusion:
Using a systematic framework and risk-equivalent approach, our results illustrate the potential benefits of identifying individuals at lower disease risk and returning these results. Besides breast cancer, other conditions like coronary artery disease could also qualify. We are currently testing the best way to account for rare protective variants such as rare pLOF variants in APOB and PCSK9, which lead to very low LDL-C levels and protect against coronary artery disease.

Agenda

Sponsors