Adjusting wheal size measures to correct atopy misclassification

Hongmei Zhang^1,*, Wilfried Karmaus^1,*, Jianjun Gan², Weichao Bao^1,*, Yan D Zhao³, Dewi Rahardja³, John W Holloway⁵, Martha Scott^4,5, Syed Hasan Arshad^4,5
1Department of Epidemiology and Biostatistics, The University of South Carolina, Columbia, SC, USA; ²GlaxoSmithKline, Research Triangle Park, NC, USA; ³Department of Clinical Science and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA; ⁴The David Hide Asthma and Allergy Research Center, St Mary’s Hospital, Newport, Isle of Wight, UK; ⁵School of Medicine, University of Southampton, Southampton, UK
^*These authors contributed equally to this article

Purpose: Skin prick testing (SPT) is fundamental to the practice of clinical allergy identifying relevant allergens and predicting the clinical expression of disease. Wheal sizes on SPT are used to identify atopic cases, and the cut-off value for a positive test is commonly set at 3 mm. However, the measured wheal sizes do not solely reflect the magnitude of skin reaction to allergens, but also skin reactivity (reflected in the size of histamine reaction) and other random or non-random factors. We sought to estimate wheal sizes exclusively due to skin response to allergens and propose gender-specific cutoff points of atopy.
Methods: We developed a Bayesian method to adjust observed wheal sizes by excluding histamine and other factor effects, based on which revised cutoff points are proposed for males and females, respectively. The method is then applied to and intensively evaluated using a study population aged 18, at a location on the Isle of Wight in the United Kingdom. To evaluate the proposed approach, two sample t-tests for population means and proportion tests are applied.
Results: Four common aeroallergens, house dust mite (HDM), grass pollen, dog dander, and alternaria are considered in the study. Based on 3 mm cutoff, males tend to be more atopic than females (P-values are between 0.00087 and 0.062). After applying the proposed methods to adjust wheal sizes, our findings suggest that misclassifications of atopy occur more often in males. Revised allergen-specific cutoff values are proposed for each gender.
Conclusion: To reduce the gender discrepancy, we may have two potentially convenient solutions. One way is to apply allergen-specific and gender-specific cutoff values following the proposed method. Alternatively, we can revise the concentration of allergens in the SPT solutions but keep the cutoff values unchanged, which may be more convenient to clinicians.

Keywords: SPT, atopy, Bayesian method, joint modeling, misclassification