Using Multiple Risk Factors and Generalized Linear Mixed Models with 5-Fold Cross-Validation Strategy for Optimal Carotid Plaque Progression Prediction

Background Cardiovascular diseases are closely linked to atherosclerotic plaque development and rupture.Plaque progression prediction is of fundamental significance to cardiovascular research and disease diagnosis,prevention,and treatment.Generalized linear mixed models(GLMM)is an extension of linear model for categorical responses while considering the correlation among observations.Methods Magnetic resonance image(MRI)data of carotid atheroscleroticplaques were acquired from 20 patients with consent obtained and 3D thin-layer models were constructed to calculate plaque stress and strain for plaque progression prediction.Data for ten morphological and biomechanical risk factors included wall thickness(WT),lipid percent(LP),minimum cap thickness(MinCT),plaque area(PA),plaque burden(PB),lumen area(LA),maximum plaque wall stress(MPWS),maximum plaque wall strain(MPWSn),average plaque wall stress(APWS),and average plaque wall strain(APWSn)were extracted from all slices for analysis.Wall thickness increase(WTI),plaque burden increase(PBI)and plaque area increase(PAI) were chosen as three measures for plaque progression.Generalized linear mixed models(GLMM)with 5-fold cross-validation strategy were used to calculate prediction accuracy for each predictor and identify optimal predictor with the highest prediction accuracy defined as sum of sensitivity and specificity.All 201 MRI slices were randomly divided into 4 training subgroups and 1 verification subgroup.The training subgroups were used for model fitting,and the verification subgroup was used to estimate the model.All combinations(total1023)of 10 risk factors were feed to GLMM and the prediction accuracy of each predictor were selected from the point on the ROC(receiver operating characteristic)curve with the highest sum of specificity and sensitivity.Results LA was the best single predictor for PBI with the highest prediction accuracy(1.360 1),and the area under of the ROC curve(AUC)is0.654 0,followed by APWSn(1.336 3)with AUC=0.6342.The optimal predictor among all possible combinations for PBI was the combination of LA,PA,LP,WT,MPWS and MPWSn with prediction accuracy=1.414 6(AUC=0.715 8).LA was once again the best single predictor for PAI with the highest prediction accuracy(1.184 6)with AUC=0.606 4,followed by MPWSn(1. 183 2)with AUC=0.6084.The combination of PA,PB,WT,MPWS,MPWSn and APWSn gave the best prediction accuracy(1.302 5)for PAI,and the AUC value is 0.6657.PA was the best single predictor for WTI with highest prediction accuracy(1.288 7)with AUC=0.641 5,followed by WT(1.254 0),with AUC=0.6097.The combination of PA,PB,WT,LP,MinCT,MPWS and MPWS was the best predictor for WTI with prediction accuracy as 1.314 0,with AUC=0.6552.This indicated that PBI was a more predictable measure than WTI and PAI. The combinational predictors improved prediction accuracy by 9.95%,4.01%and 1.96%over the best single predictors for PAI,PBI and WTI(AUC values improved by9.78%,9.45%,and 2.14%),respectively.Conclusions The use of GLMM with 5-fold cross-validation strategy combining both morphological and biomechanical risk factors could potentially improve the accuracy of carotid plaque progression prediction.This study suggests that a linear combination of multiple predictors can provide potential improvement to existing plaque assessment schemes.