Computational protocol: Urinary biomarkers predict advanced acute kidney injury after cardiovascular surgery

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Protocol publication

[…] All analyses were performed using SPSS software, version 20 (IBM, Armonk, NY, USA), R software, version 3.2.2 (Free Software Foundation, Inc., Boston, MA, USA), and MedCalc Statistical Software, version 15.11.3 (MedCalc Software bvba, Ostend, Belgium;; 2015). The two-sample t test or Mann–Whitney rank sum test was used as appropriate to compare continuous variables; for categorical variables, the chi-square (χ2) or Fisher’s exact test was applied. Friedman two-way analysis of variance (ANOVA) was used to assess the overall difference in HJV, KIM-1, NGAL, α-GST and π-GST between the “no AKI or stage 1 AKI” and the “stage 2 or 3 AKI” groups at 0, 3, 6, 12 and 24 h after cardiovascular surgery []. We normalized biomarker levels with urine creatinine concentrations and analyzed them at each time point []. We fitted logistic regression models to examine the association between each marker (urinary NGAL, HJV, KIM-1, α-GST and π-GST) and advanced AKI, and generated an area under the receiver-operating characteristic (ROC) curve to assess the predictive accuracy of each marker. Power analysis was conducted based on the prior knowledge that the ratio of cases to controls was 4:1. We required 105 patients (21 with severe AKI and 84 without severe AKI) to achieve power of 0.8, with type I error of 0.05. This was based on the preliminary knowledge that the discriminatory power of urinary HJV to predict severe AKI was 0.7 []. We used a generalized additive model (GAM) (with spline) incorporating the subject-specific (longitudinal) random effects and adjusted for other clinical parameters to predict the outcomes [, ]. Simple and multiple generalized additive models (GAMs) were fitted to detect nonlinear effects of continuous covariates and identify appropriate cutoff point(s) for discretizing continuous covariates, if necessary, during the stepwise variable selection procedure. We defined the optimal cutoff value as odd equals to zero [].To assess the additive prediction ability of each biomarker compared with traditional clinical predictors, we identified clinical risk prediction models (including Liano’s score, CCF ARF score and SOFA score) that were based on area under the curve (AUC) analysis and then added each biomarker individually to this clinical model. We estimated the risk score function using a logistic regression model including clinical and biomarker variables as covariates. The Hosmer-Lemeshow logistic regression model test for goodness of fit was used to assess the calibration between the current model and the expected model. Finally, we calculated the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) to estimate overall improvement in reclassification with urinary biomarkers adding to clinical variables []. We reclassified the patients who developed advanced AKI using 0–12%, 12–30% and > 30% for the risk categories. A p value <0.05 was considered significant.Hierarchical clustering analysis was performed using the cluster program and the results were visualized using the Treeview program []. The biomarkers were arranged in such a way that the most similar expression profiles were placed next to each other. In the color scheme, strong positive staining is indicated as a red cube, weak positive staining as a black cube and negative staining as a green cube. Absence of staining data is indicated with a grey cube. […]

Pipeline specifications

Software tools MedCalc, TreeViewX
Applications Miscellaneous, Phylogenetics
Organisms Homo sapiens
Diseases Kidney Diseases, Acute Kidney Injury
Chemicals Creatinine