Development of Biomarker Models to Predict Outcomes in Lupus Nephritis

Abstract

Objective: The American College of Rheumatology guidelines for the treatment of lupus nephritis recommend change in induction therapy when response to therapy has not occurred within 6 months. Response is not defined, and renal fibrosis can occur while waiting for this end point. Therefore, a decision support tool to better define response is needed to guide clinicians when starting patients on therapy. This study was undertaken to identify biomarker models with sufficient predictive power to develop such a tool.

Methods: Urine samples from 140 patients with biopsy-proven lupus nephritis who had not yet started induction therapy were analyzed for a panel of urinary biomarkers. Univariate receiver operating characteristic (ROC) curves were generated for each individual biomarker and compared to the ROC area under the curve values from machine learning models developed using random forest algorithms. Biomarker models of outcome developed with novel markers in addition to clinical markers were compared to those developed with traditional clinical markers alone.

Results: Models developed with the combined traditional and novel biomarker panels demonstrated clinically meaningful predictive power. Markers most predictive of response were chemokines, cytokines, and markers of cellular damage.

Conclusion: This is the first study to demonstrate the power of low-abundance biomarker panels and machine learning algorithms for predicting lupus nephritis outcomes. This is a critical first step in research to develop clinically meaningful decision support tools.

Trial registration: ClinicalTrials.gov NCT00282347 NCT00430677.

© 2016, American College of Rheumatology.

Figures

Figure 1

Effect of varying threshold on the sensitivity (Sens) and specificity (Spec) of random forest models of response to therapy that included traditional clinical markers alone or clinical markers plus novel biomarkers. Random forest models were created for the prediction of complete response to therapy for lupus nephritis at 1 year.

Figure 2

Importance plot for individual biomarkers in the random forest model. A random forest model for prediction of complete response to therapy for lupus nephritis at 1 year was developed using standard clinical markers and clinical markers plus novel urinary biomarkers. The importance of each individual biomarker in the model is plotted as mean decrease in Gini Index (a measure of prediction purity). OPG = osteoprotegerin; IL-2Rα = interleukin-2 receptor α; urine prot/creat = urinary protein-to-creatinine ratio; MCP-1 = monocyte chemotactic protein 1; IP-10 = interferon-inducible protein 10; EGFR = estimated glomerular filtration rate; CysC = cystatin C; GM-CSF = granulocyte–macrophage colony-stimulating factor; NGAL = neutrophil gelatinase–associated lipocalin; MIP-1β = macrophage inflammatory protein 1β; PDGF-BB = platelet-derived growth factor BB; NAG = N-acetyl-β-d-glucosaminidase; IFNγ = interferon-γ; dsDNA = doublestranded DNA; MMF = mycophenolate mofetil.