The component-specific to total IgE ratios do not improve peanut and hazelnut allergy diagnoses  Linus Grabenhenrich, MD, MPH, Lars Lange, MD, Magdalena Härtl, MD, Birgit Kalb, MD, Mandy Ziegert, Antje Finger, MD, Neda Harandi, MD, Ruppert Schlags, MD, Monika Gappa, MD, Letizia Puzzo, MD, Volker Stephan, MD, Thomas Heigele, MD, Susanne Büsing, MD, Hagen Ott, MD, Bodo Niggemann, MD, Kirsten Beyer, MD  Journal of Allergy and Clinical Immunology  Volume 137, Issue 6, Pages 1751-1760.e8 (June 2016) DOI: 10.1016/j.jaci.2016.01.043 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Component-specific IgE levels versus component-specific to total IgE ratio distributions by food challenge outcome. Left, Ara h 2–specific IgE and peanut challenge outcomes. Right, Cor a 14–specific IgE and hazelnut challenge outcomes. Red solid circles, Positive challenge outcome; green open circles, negative challenge outcome. The raw component axis (x-axis) is log-scaled, and the proportional axis (y-axis) is scaled to the fifth root. The corresponding percentiles are interpolated with a gray line and penalized spline-smoothed to the second degree (isopercentile). Marginal box-and-whisker plots by challenge outcome are shown, with labeled group medians. In each panel/group 2 cases with a component-specific IgE level of 0 kU/L but a positive challenge outcome are shown (lower left corner, red solid circle). Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Receiver operating characteristic curves predicting positive challenge outcomes for peanut (left) and hazelnut (right) food allergies (n = 191 peanut allergies and n = 130 hazelnut allergies in the model). Complete models (multivariate, gray lines, and shaded areas) are comprised of the 3 listed IgE ratio measures. Solid blue line, Component/total IgE ratio; dashed blue line, component/specific; black line, and specific/total ratio. Raw component measures were included as a comparison (orange line). In the tables areas under curve (AUC), including 95% CIs, are shown. *Significance tests for equal AUCs of the complete logistic model (reference category) and single ratio measures. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Predicted probabilities for positive peanut (upper panel) and hazelnut (lower panel) challenge outcomes (blue line and confidence bands) at component-specific/total IgE ratios. Upward-pointing arrows, Estimated component/total IgE ratios that yielded prespecified prediction probabilities (10%, 20%, 80%, and 90%) from the univariate logistic models. Continuous modeling of the positive predictive value (PPV; red) and negative predictive value (NPV; green) is shown. Gray circles indicate actual cases. Plus signs in the top panels represent actual children by challenge outcomes. A-I indicate exceptions that are further detailed in Table III. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Predicted probabilities for a positive peanut (upper panel) or hazelnut (lower panel) challenge outcome with Ara h 2– or Cor a 14–specific IgE levels by strata of low, medium, and high total IgE levels (approximate tertiles). Number of peanut challenges in the low, medium, and high total IgE strata were 53, 86, and 68, respectively. Number of hazelnut challenges in the low, medium, and high total IgE strata were 44, 61, and 37, respectively. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Component/peanut-specific IgE levels in approximate total IgE tertiles by food challenge outcome. Red solid circles, Positive challenge outcomes; green open circles, negative challenge outcomes. Horizontal lines and shaded areas represent the median and interquartile range in total IgE tertiles, respectively. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Component/hazelnut-specific IgE levels in approximate total IgE tertiles by food challenge outcome. Red solid circles, Positive challenge outcomes; green open circles, negative challenge outcomes. Horizontal lines and shaded areas represent the median and interquartile range in total IgE tertiles, respectively. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Sensitivities and specificities of Ara h 2–specific/total IgE (upper panel) and Cor a 14–specific/total IgE (lower panel) ratios in predicting peanut/hazelnut food challenge outcomes. Actual positive (solid gray dots) and negative (gray circles) challenge results are shown. The logistic fit is highlighted at predefined levels (colored line and markers), and the pointwise binomial 95% CIs are also shown (colored band and error bars). Estimated sensitivities and specificities at predefined cutoffs are shown in the table. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Interdependencies between baseline characteristics (upper half), immunoglobulins (lower half), and challenge outcome. Arrows/solid lines indicate directed links or associations, and dashed lines indicate no association. Reported P values are from Tables E2 and E3. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Predicted probability for a positive peanut (upper panel) or hazelnut (lower panel) challenge outcome according to the Ara h 2– or Cor a 14–specific IgE levels by age strata at food challenge (approximate tertiles). Number of peanut challenges in the age strata of 0 to 1, 2 to 5, and 6 or more years were 42, 93, and 72, respectively. Number of hazelnut challenges in the age strata of 0 to 1, 2 to 5, and 6 or more years were 27, 67, and 48, respectively. Journal of Allergy and Clinical Immunology 2016 137, 1751-1760.e8DOI: (10.1016/j.jaci.2016.01.043) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions