Polygenic Score for the Prediction of Postoperative Nausea and Vomiting: A Retrospective Derivation and Validation Cohort Study.

BACKGROUND

Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction following surgery. Because traditional risk factors do not completely explain variability in risk, we hypothesize that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV.

METHODS

Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine and Vanderbilt University Medical Center were studied. PONV was defined as nausea or emesis occurring and documented in the PACU. In the Discovery Phase, genome-wide association studies were performed on each genetic cohort and the results were meta-analyzed. Next, in the Polygenic Phase, we assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (C-statistic) and net reclassification index.

RESULTS

Of 64,523 total patients, 5,703 developed PONV (8.8%). We identified 46 genetic variants exceeding P<1x10-5 threshold, occurring with minor allele frequency > 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex, (aOR 1.027 per standard deviation increase in overall genetic risk, 95% CI 1.001-1.053, P=0.044), a model based on known clinical risks (aOR 1.029, 95% CI 1.003-1.055, P=0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (aOR 1.029, 95% CI 1.002-1.056, P=0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic: 0.616 compared to 0.613, P=0.028) and improved net reclassification of 4.6% of cases.

CONCLUSION

Standardized polygenic risk was associated with PONV in all three of our models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score > 1 standard deviation above the mean, has 2-3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV/motion sickness (55%), having a history of migraines (17%), or being female (83%), and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful.

Informations de copyright

Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.

Déclaration de conflit d'intérêts

Declarations of Interest: CD is a consultant to Exact Sciences and founder of Belay Diagnostics is compensated with income and equity. Exact Sciences is a molecular diagnostics company specializing in the detection of early-stage cancers. Belay Diagnostic is a platform for the detection of brain and spinal cord cancers using cerebrospinal fluid. The companies named above as well as other companies have licensed previously described technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins in accordance with its conflict-of-interest policies. CD’s involvement with both companies is unrelated to the scope of the research presented in this manuscript. CJW is currently employed by Regeneron Pharmaceuticals Inc and holds stock and options. KHW is currently employed by Regeneron Pharmaceutical Inc. MM received funding paid to the University of Michigan from Chiesi USA for work unrelated to the scope of the research presented in this manuscript.