Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage–derived cytokines Allan R. Brasier, MD, Sundar Victor, MS,

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Presentation transcript:

Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage–derived cytokines Allan R. Brasier, MD, Sundar Victor, MS, Gary Boetticher, PhD, Hyunsu Ju, PhD, Chang Lee, MS, Eugene R. Bleecker, MD, Mario Castro, MD, William W. Busse, MD, William J. Calhoun, MD Journal of Allergy and Clinical Immunology Volume 121, Issue 1, Pages 30-37.e6 (January 2008) DOI: 10.1016/j.jaci.2007.10.015 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Hierarchical clustering of 18 cytokines. Shown is a heat map of clustering cytokine values. Each row is an individual patient. Left, Dendogram showing similarity of groups. Right, Four major groups (G) are indicated by vertical bars (G1-G4). RANT, RANTES. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Treatment patterns as a result of glucocorticoid therapy. Patients were separately clustered on the basis of glucocorticoid therapy at the time of BAL. Left, Subjects taking glucocorticoids (inhaled or oral) versus right, subjects not on glucocorticoids. Note similar cytokine patterns are seen in both groups. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Cytokine classifiers for G1. Shown is a rank-ordered list of the 10 cytokines that minimize cross-validation error for G1 patients with asthma. Left, Centroid of G1; right, centroid of combined G2-G4 (threshold of 1.2). X-axis is deviation from the overall class centroid. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Identification of hyperresponder (HR) subjects. Shown is a frequency histogram of the 67 patients in whom PC20 methacholine sensitivity was measured. Patients with PC20 methacholine response of <0.5 mg/mL were classified as HR. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Classification and regression tree classification. C.4.5 decision tree was performed on the z-score normalized cytokine data. Shown is the most accurate model. For each node (rectangles), the classification and number of correctly grouped subjects are indicated. The identity of the hyperresponder (HR) class—A, B, or C—is indicated in the upper right corner of each terminal leaf. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Pairwise comparison of methacholine hyperresponder (HR) classes. Demographic variables of methacholine HR classes A, B, and C were compared by ANOVA. Top, BAL eosinophils; bottom, PC20 methacholine. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Misclassification error for cytokines to group G1 versus G2 (representing G2, G3, and G4 combined). The misclassification error is calculated at each step after reducing the number of cytokines used in the classification with the method of shrunken centroids. Y-axis is the misclassification error and x-axis the threshold. The point where the misclassification error is least is considered the minimal number of cytokines that discriminate G1 versus G2. This occurs at the threshold where the feature reduction from 18 cytokines to 10 cytokines occurs. Above a threshold of value of 1.4, the misclassification error rate rises sharply. The shrunken centroid lists the 10 cytokines identified from the misclassification plot, which is later used for analysis. CV, Crossvalidation. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Cross-validated probabilities for 2 class prediction Cross-validated probabilities for 2 class prediction. Y-axis is the probability of each subject being classified into group G1 or the combined group G2-G4 (termed G2) on the basis of the linear discriminant classifier. X-axis represents each individual subject. The predicted class is the class having the largest probability (G1 or G2) as indicated in the plot. The correct class is indicated in white box for the group. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Comparison of 4 groups (G1, G2, G3, and G4) using 18 cytokines and 10 cytokines identified by feature reduction (the identity of the 10 cytokines is shown in Fig 3). For each subject in the y-axis, grouping into each of 4 groups is compared. Note that the subjects in the 4 groups are largely similar, irrespective of whether 18 or 10 cytokines are used for the groupings. This shows that we are still able to identify clearly the same 4 groups with reduced features (10 cytokines). Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Validation of IL-2 measurements Validation of IL-2 measurements. BAL samples from 10 hyperresponder and 26 LR subjects were measured by using IL-2 ELISA. Shown is the scattergram for each group by the type of assay used. The horizontal bar is the mean value for each group. The measurements for IL-2 are highly similar regardless of the assay used. xMAP, Multiplex bead assay. Journal of Allergy and Clinical Immunology 2008 121, 30-37.e6DOI: (10.1016/j.jaci.2007.10.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions