An in-silico analysis of experimental designs to study ventricular function: A focus on the right ventricle

In-vivo studies of pulmonary vascular disease and pulmonary hypertension (PH) have provided key insight into the progression of right ventricular (RV) dysfunction. Additional in-silico experiments using multiscale computational models have provided further details into biventricular mechanics and hemodynamic function in the presence of PH, yet few have assessed whether model parameters are practically identifiable prior to data collection. Moreover, none have used modeling to devise synergistic experimental designs. To address this knowledge gap, we conduct a practical identifiability analysis of a multiscale cardiovascular model across four simulated experimental designs. We determine a set of parameters using a combination of Morris screening and local sensitivity analysis, and test for practical identifiability using profile likelihood-based confidence intervals. We employ Markov chain Monte Carlo (MCMC) techniques to quantify parameter and model forecast uncertainty in the presence of noise corrupted data. Our results show that model calibration to only RV pressure suffers from practical identifiability issues and suffers from large forecast uncertainty in output space. In contrast, parameter and model forecast uncertainty is substantially reduced once additional left ventricular (LV) pressure and volume data is included. A comparison between single point systolic and diastolic LV data and continuous, time-dependent LV pressure-volume data reveals that any information from the LV substantially reduces parameter and forecast uncertainty, encouraging at least some quantitative data from both ventricles for future experimental studies. Author summary Computational models of cardiac dynamics are becoming increasingly useful in understanding the underlying mechanisms of disease. In-silico analyses are especially insightful in understanding pulmonary vascular disease and eventual RV dysfunction, as these conditions are diagnosed months to years after disease onset. Many researchers couple computational models with in-vivo experimental models of PH, yet few ever assess what data might be necessary or sufficient for parameter inference prior to designing their experiments. Here, we considered a multiscale computational model including sarcomere dynamics, biventricular interactions, and vascular hemodynamics, and assessed whether parameters could be inferred accurately given limited cardiac data. We utilized sensitivity analyses, profile likelihood confidence intervals, and MCMC to quantify parameter influence and uncertainty. We observed that RV pressure alone is not sufficient to infer the influential parameters in the model, whereas combined pressure and volume data in both the RV and LV reduced uncertainty in model parameters and in model forecasts. We conclude that synergistic PH studies utilizing computational modeling include these data to reduce issues with practical parameter identifiability and minimize uncertainty.

Automated summary

This study combines experiments and computational models to analyze the progression of right ventricular dysfunction in the presence of pulmonary hypertension. The researchers assess the feasibility of parameter inference before designing experiments. The results show that calibrating the model with only right ventricular pressure has limitations, while including pressure and volume data from both ventricles reduces parameter identifiability and forecast uncertainty.