A Novel 5-Cytokine Panel Outperforms Conventional Predictive Markers of Persistent Organ Failure in Acute Pancreatitis

Abstract

Introduction: Existing laboratory markers and clinical scoring systems have shown suboptimal accuracies for early prediction of persistent organ failure (POF) in acute pancreatitis (AP). We used information theory and machine learning to select the best-performing panel of circulating cytokines for predicting POF early in the disease course and performed verification of the cytokine panel's prognostic accuracy in an independent AP cohort.

Methods: The derivation cohort included 60 subjects with AP with early serum samples collected between 2007 and 2010. Twenty-five cytokines associated with an acute inflammatory response were ranked by computing the mutual information between their levels and the outcome of POF; 5 high-ranking cytokines were selected. These cytokines were subsequently measured in early serum samples of an independent prospective verification cohort of 133 patients (2012-2016), and the results were trained in a Random Forest classifier. Cross-validated performance metrics were compared with the predictive accuracies of conventional laboratory tests and clinical scores.

Results: Angiopoietin 2, hepatocyte growth factor, interleukin 8, resistin, and soluble tumor necrosis factor receptor 1A were the highest-ranking cytokines in the derivation cohort; each reflects a pathologic process relevant to POF. A Random Forest classifier trained the cytokine panel in the verification cohort and achieved a 10-fold cross-validated accuracy of 0.89 (area under the curve 0.91, positive predictive value 0.89, and negative predictive value 0.90), which outperformed individual cytokines, laboratory tests, and clinical scores (all P ≤ 0.006).

Discussion: We developed a 5-cytokine panel, which accurately predicts POF early in the disease process and significantly outperforms the prognostic accuracy of existing laboratory tests and clinical scores.

Trial registration: ClinicalTrials.gov NCT03075605.

Conflict of interest statement

Guarantor of the article: Georgios I. Papachristou, MD, PhD.

Specific author contributions: Christopher Langmead, PhD, and Peter J. Lee, MBChB are first co-authors. Christopher Langmead, PhD, and Peter J. Lee, MBChB, contributed equally to this work. David C. Whitcomb, MD, PhD, and Georgios I. Papachristou, MD, PhD, codirected this project. C.L.: planning statistical methodology, statistical analysis, interpretation of data, and manuscript review. P.J.L.: interpretation of data and manuscript drafting. P.P.: data collection and manuscript review. P.G.: execution of the experiments, data collection, interpretation of data, and manuscript review. K.S.: execution of the experiments and data collection. P.A.H.: interpretation of data and manuscript review. D.C.W. conception of the study, interpretation of data, and manuscript review. G.I.P.: conception of the study, interpretation of data, manuscript drafting, and direct supervision of the manuscript.

Financial support: This research was funded by the Department of Veterans Affairs Merit Review I01CX000272 (G.I.P.), the U.S. Department of Defense Congressionally Directed Medical Research Programs (CDMRP) Awards W81XWH-14-1-0376 (D.C.W.) and W81XWH-17-1-0502 (D.C.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Potential competing interests: The authors report no conflicts of interest directly related to this research.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.

Figures

Figure 1.

Comparisons of cytokine levels between the mild/moderately severe group (i.e., no POF; green) and the severe group (i.e., POF present; red) in the verification cohort. All P values were <0.001 when comparing cytokine levels between groups. Ang-2, angiopoietin 2; HGF, hepatocyte growth factor; IL-8, interleukin 8; POF, persistent organ failure; TNF-R1, tumor necrosis factor alpha receptor superfamily 1A.

Figure 2.

Receiver operating characteristic (ROC) curves comparing the cytokine panel (blue) to the clinical panel (black), BISAP (red), and BUN (green) in the verification cohort. AUC, area under the curve; BISAP, Bedside Index of Severity of Acute Pancreatitis; BUN, blood urea nitrogen.

Figure 3.

Proposed conceptual model for prediction of severe acute pancreatitis. The figure was constructed to aid discussion of the results and is not meant to exhaustively represent all cytokines and biomarkers associated with acute pancreatitis. IL, interleukin; HGF, hepatocyte growth factor; TNF-α, tumor necrosis factor alpha.