Volatile Organic Compounds (VOCs) triggering respiratory irritation are implicated in conditions such as Trimethylaminuria (TMAU) and "people are allergic to me" (PATM) which occur in otherwise healthy individuals without clear syndromic associations. Despite the absence of established non-targeted non-challenge-based diagnostic procedures, recent studies have identified discriminatory VOCs associated with PATM using gas chromatography-mass spectrometry. Breath VOCs, originating from the bloodstream, hold promise for non-invasive diagnosis. We conducted breath analysis on 23 individuals exhibiting TMAU-like symptoms and identified a diverse array of volatile organic compounds (VOCs) that discriminate between different subgroups. Using logistic regression, we achieved an accuracy of 88%, with both precision and recall at 88-89%, in distinguishing TMAU-negative individuals from those who tested positive at some point in their lives, solely based on the presence of Propylene Oxide ((2R)-2-Methyloxirane and (2S)-2-Methyloxirane). However, due to the limited subset and missing data, it cannot serve as the sole discriminating biomarker. Inclusion of additional VOCs in the analysis increased accuracy of the model to 85-95%, with precision and recall ranging from 85% to 100%, depending on the combinations of VOCs used. Unsupervised learning algorithms generally grouped positively tested individuals together based on endogenous VOCs, while negatively tested individuals were clustered into two distinct groups. Toluene, previously found to be elevated in PATM individuals, was identified as a discriminatory marker for those previously diagnosed with TMAU, but had since tested negative while still experiencing symptoms. Other PATM biomarkers, such as p-Xylene and Hexanal, were generally higher in TMAU positive individuals and were good predictors of TMAU history when combined with other VOCs. Our analysis revealed that the TMAU-positive group exhibited a greater abundance of biomarkers indicative of advanced oxidative stress in their breath samples and primary oxidative stress in their air samples, likely originating from their skin. Conversely, the TMAU-negative group demonstrated a higher likelihood of biomarkers associated with secondary oxidative stress in their air samples. Our findings highlight the potential of breath analysis as a non-invasive diagnostic tool for idiopathic malodor conditions. They underscore the importance of analyzing exogenous chemicals for insights into metabolism, detoxification, and elimination of toxins. This approach could help eliminate unnecessary challenge tests and emphasize the role of metabolomics in understanding the mechanisms underlying these conditions.

The authors have declared no competing interest.

https://doi.org/10.1101/2021.01.25.21250101

https://classic.clinicaltrials.gov/ct2/show/NCT03451994

This study did not receive any funding

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Ethical review was provided by MEBO Research (Miami, FL, USA) Institutional Review Board. The primary prospective study was approved on February 28, 2012 (MR 2012-01) and the secondary retrospective study was approved on February 15, 2018 (20111001005MEBO). The research was conducted in accordance with the principles embodied in the Declaration of Helsinki and in accordance with local statutory requirements. All relevant ethical guidelines have been followed. All participants gave written informed consent to participate in the study.

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