Figure 4. Mediation Analysis of Inflammation Principal Components/Clusters as Mediators of the Association Between Comorbidity Burden and Mitral E Velocity in PROMIS-HFpEF.

Mediation modeling including testing of underlying assumptions. Mitral E velocity was used as an example outcome measure. Values adjacent to the arrows in (A) and (B) depict standardized β-coefficients (95% CIs) and P-values from linear regression models adjusted for age, gender, glomerular filtration rate, study site, and atrial fibrillation. (A) Total effect of the association of comorbidity burden with mitral E velocity on linear regression analysis, a prerequisite for mediation analysis. (B) Investigating the assumptions that comorbidity burden is associated with increased inflammation (reflected by protein PCs/clusters) and that inflammation is associated with increased mitral E velocity in HFpEF. Mediators in light blue do not fulfill the assumptions for mediation analysis because there is no statistically significant effect between predictor and mediator and/or between mediator and outcome. (C) Mediated effect in mediation analysis of parameters fulfilling the underlying assumptions, indicating that 19–35% of the association of comorbidity burden with increased mitral E velocity is mediated by systemic inflammation. *P>0.05 after false discovery rate correction. **Percent mediated = mediated effect / total effect × 100.