External Validation of a Breath-Based Prediction Model for Malignant Pleural Mesothelioma

SIMPLE SUMMARY: Malignant pleural mesothelioma (MPM) is an incurable asbestos-related thoracic cancer for which early-stage diagnosis remains a major challenge. Volatile organic compounds (VOCs), which are metabolites present in exhaled breath, have proven to be promising non-invasive biomarkers for MPM. However, without the necessary validation in an independent group of individuals, clinical implementation is hampered. Therefore, we performed external validation of a VOC-based prediction model for MPM, which initially revealed a poor performance and thus poor generalisability of the model. However, subsequent updating of the model improved its performance in the validation cohort, resulting in a more generalisable model with a screening potential, which could significantly impact MPM management. ABSTRACT: During the past decade, volatile organic compounds (VOCs) in exhaled breath have emerged as promising biomarkers for malignant pleural mesothelioma (MPM). However, as these biomarkers lack external validation, no breath test for MPM has been implemented in clinical practice. To address this issue, we performed the first external validation of a VOC-based prediction model for MPM. The external validation cohort was prospectively recruited, consisting of 47 MPM patients and 76 asbestos-exposed (AEx) controls. The predictive performance of the previously developed model was assessed by determining the degree of agreement between the predicted and actual outcome of the participants (patient/control). Additionally, to optimise the performance, the model was updated by refitting it to the validation cohort. External validation revealed a poor performance of the original model as the accuracy was estimated at only 41%, indicating poor generalisability. However, subsequent updating of the model improved the differentiation between MPM patients and AEx controls significantly (73% accuracy, 92% sensitivity, and 92% negative predictive value), substantiating the validity of the original predictors. This updated model will be more generalisable to the target population and exhibits key characteristics of a potential screening test for MPM, which could significantly impact MPM management.