Maxime Verhoeven

67 Validation of a prediction model for insufficient response to MTX Similar results were found for the prediction of non-response at 6 months. An ROC curve was constructed with an AUC of 0.71 (95%CI: 0.60 – 0.82) in U-Act-Early (validation), which is similar to the predictive value of the tREACH model (derivation) at 6 months (AUC 0.75, 95%CI: 0.67 – 0.83), see Supplementary Figure S1. Enhancement of model’s clinical applicability Next, the U-Act-Early and tREACH cohort were combined to increase power and enhance the model’s clinical applicability. In this combined cohort the ORs for all predictors were greater than 1 and all predictors, except for the SNPs were significant, Supplementary Table S1. The combined model reached an AUC of 0.74 (95%CI: 0.68 – 0.80) at 3 months, Supplementary Table S1 and Figure 1. Additionally, in this combined set, we investigated whether all predictors were required to reach 74% predictive power or whether the model could be further simplified. To do so, we analyzed changes in AUC upon sequential addition of predictors to the model. We started with the most readily available clinical predictors DAS28 >5.1 and HAQ >0.6, which generated an ROC with an AUC of 0.67 (95%CI: 0.61 – 0.74), Table 3. Upon addition of smoking to the model, the AUC significantly increased (p=0.01) to 0.70 (95%CI: 0.64 – 0.76), followed by BMI, upon which the AUC further improved to 0.72 (95%CI: 0.66 – 0.78, p=0.02). Upon addition of erythrocyte folate to the model the AUC reached 0.73 (95%CI: 0.67 – 0.79, p=0.02). Addition of ABCB1 and ABCC3 genotypes did not significantly improve the model (AUC=0.74, 95%CI: 0.68 – 0.80, p=0.12), Table 3. Hence, the model could be simplified to a model where SNP genotypes were excluded resulting in a model with predictive power of 73%. To fine-tune the model, all two-way interaction terms between predictors were tested. An interaction term between HAQ and BMI (OR= 3.68, 95%CI: 1.07 – 13.14) significantly contributed to the model. This means that a BMI >25kg/m 2 was associated with worse disease activity when HAQ values were >0.6. Furthermore, an interaction term between HAQ and erythrocyte folate (OR= 0.23, 95%CI 0.06 – 0.86) also significantly contributed to the model, indicating that low erythrocyte folate concentrations (<750 nmol/L) significantly predicted insufficient response when HAQ values were <0.6. Hence, interaction terms for HAQ and BMI and HAQ and erythrocyte folate were added to the model. Upon addition of these interaction terms to the model, the AUC of the final model, shown in Table 4, increased to 0.75 (95%CI: 0.69 – 0.81). As mentioned in the method section, we generated new cut-off values for erythrocyte folate and the BMI in the U-Act-Early cohort which, when included, did not result in higher AUCs. 4