Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification

Xinan Wang, Ziwei Zhang, Yi Ding, Tony Chen, Lorelei Mucci, Demetrios Albanes, Maria Teresa Landi, Neil E. Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H. Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D. McKayJohn K. Field, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angie Cox, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Rayjean J. Hung, Christopher I. Amos, Xihong Lin, David C. Christiani*

*Corresponding author af dette arbejde

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Abstract

Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

OriginalsprogEngelsk
Artikelnummer22
TidsskriftGenome Medicine
Vol/bind16
Udgave nummer1
Antal sider11
ISSN1756-994X
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
M. C. Aldrich reports funding from NIH and GO2 foundation, and she serves an advisor to Guardant Health. While M. Johansson and J. D. McKay are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The remaining authors declare that they have no competing interests.

Funding Information:
XW, ZZ, and DCC are supported by 5U01CA209414 from the National Cancer Institute. XL is supported by R35-CA197449 and U19-CA203654 from the National Cancer Institute, and U01-HG009088 and U01HG012064 from NHGRI.

Funding Information:
We thank all the participants from the International Lung Cancer Consortium for sharing their data.

Publisher Copyright:
© The Author(s) 2024.

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