. in scientific features between main nonresponders and responders. Eight alleles were associated with PNR. A combined clinical-genetic model (AUROC, 0.87) more accurately predicted PNR compared with a clinical-only model (AUROC, 0.57; 0.0001). In an external cohort of 131 patients, increasing tertiles of PNR genetic risk score correlated with increased risk of PNR (= 0.052). Twelve candidate loci were associated with DR. Rabbit Polyclonal to C1QB Genetic risk score quartiles for DR exhibited a strong dose-response relationship in predicting treatment period. Genetic risk scores for PNR and DR were not associated with infliximab levels or antibody formation. Conclusion Genetic polymorphisms enhance prediction of Oxibendazole PNR and DR to anti-TNF therapy in patients with UC. 0.001, genotyping call rate 99%, and genotyping success rate 80% were included in analysis. For the 201 IBD-associated alleles, a genetic association for inclusion in PNR or DR genetic risk scores was set as significant if 0.05. For other Immunochip loci, in this hypothesis-generating study, a threshold of 1 10C6 was used. Using significant alleles from each genetic association analysis, separate weighted genetic risk scores for PNR and DR were calculated as a the cumulative sum of the product of the log-odds ratio and allele burden for each of the risk SNPs. Genetic risk scores for PNR and DR were then joined into multivariable logistic regression models, with relevant clinical covariates determined using a priori knowledge. Discrimination of the Genetic and Combined Models Calibration of the combined genetic/clinical models was tested using logistic regression with the Hosmer and Lemeshow goodness-of-fit test. To test discrimination, each combined genetic/clinical multivariable model was compared with the clinical predictive model and the genetic risk score using area under the receiver operating characteristic (AUROC) curves and likelihood ratio tests. External Validation of the Primary Nonresponse Genetic Risk Score External validation of the primary nonresponse genetic risk score was then performed in an impartial cohort of 131 Caucasian adult patients (age 18 years) with UC recruited at the IBD Center at Cedars-Sinai Medical Center who underwent genotyping with the same Illumina Immunochip-v1 platform.29 Primary nonresponse was defined in this cohort as lack of response after 8 weeks of initiation of anti-TNF therapy. Logistic Oxibendazole regression was utilized to determine the association of PNR genetic risk score tertile derived in the primary cohort, with main nonresponse in the validation cohort. Internal Validation of the Durable Response Genetic Risk Score External validation of the durable response genetic risk score was not performed due to significant differences in the definition for durable response between the primary and external cohorts. Consequently, we performed internal validation by bootstrapping with 10 000-fold replications. We separately performed internal validation in our cohort through a Kaplan-Meier analysis, with time to cessation of anti-TNF therapy as a time-to-event analysis. Assessment of the Association Between Genetic Risk Score and Infliximab Trough Levels and Antibodies Among the 190 individuals who were exposed to infliximab, 84 (44%) underwent infliximab level and antibody screening, of which 79 were confirmed to have levels drawn at trough. Oxibendazole We performed univariate and multivariable logistic regression to determine the association of genetic risk scores for PNR and DR with therapeutic trough level and antibodies. All statistical analyses were performed using SAS Studio (Cary, NC, USA). Ethical Considerations The study was approved by the Institutional Review Table of Partners Healthcare. RESULTS Study Cohort Five-hundred thirty-nine patients with an enrollment diagnosis of ulcerative colitis underwent genotyping around the Illumina Immunochip at our center. After excluding those with no exposure to anti-TNF therapy (n = 229), those with a diagnosis of CD or inflammatory bowel disease C unclassified (n = 41), those who were postcolectomy at anti-TNF initiation (n = 14), or those with insufficient follow-up paperwork (n = 24), we had a.