Ultrasensitive multispecies spectroscopic breath analysis for real-time health monitoring and diagnostics

Abstract

Breath analysis enables rapid, noninvasive diagnostics, as well as long-term monitoring of human health, through the identification and quantification of exhaled biomarkers. Here, we demonstrate the remarkable capabilities of mid-infrared (mid-IR) cavity-enhanced direct-frequency comb spectroscopy (CE-DFCS) applied to breath analysis. We simultaneously detect and monitor as a function of time four breath biomarkers—CH3OH, CH4, H2O, and HDO—as well as illustrate the feasibility of detecting at least six more (H2CO, C2H6, OCS, C2H4, CS2, and NH3) without modifications to the experimental apparatus. We achieve ultrahigh detection sensitivity at the parts-per-trillion level. This is made possible by the combination of the broadband spectral coverage of a frequency comb, the high spectral resolution afforded by the individual comb teeth, and the sensitivity enhancement resulting from a high-finesse cavity. Exploiting recent advances in frequency comb, optical coating, and photodetector technologies, we can access a large variety of biomarkers with strong carbon–hydrogen-bond spectral signatures in the mid-IR.

Breath analysis by ultra-sensitive broadband laser spectroscopy detects SARS-CoV-2 infection

“…Inspired by the DOME recommendations calling for a standard to enable improved cross-study diagnostic comparisons 14 , we analyze this large sample group and use 10,000 cross-validation runs based on stratified random sampling to obtain converging indicators required for medical diagnostic studies. Excellent cross-validated prediction performance for COVID-19 is achieved with an area under the Receiver-Operating-Characteristic (ROC) curve of 0.849 (4). Interestingly, this combmachine learning breath analysis also identifies significant differences based on a number of variables collected in tandem for this study including male vs. female and smoker vs. nonsmoker.…”

“…The availability of tens of thousands of molecular spectral features for rigorous machine learning and classification provides a powerful new medical capability that promises to surpass traditional techniques of breath analysis including the use of animals, and highlights methodologies for diagnosing a diverse set of disease states, including breast cancer, asthma, and intestinal problems 4 . With an optical frequency comb serving as a massively parallel data generator, analyzer, and processor, we anticipate other exciting and important applications in the modern scientific era of big data with increased size and complexity 29,30 .…”

“…The application of CE-DFCS to breath analysis was initially demonstrated in the near-infrared spectral region 3 . In 2021, a more than 2-orders-of-magnitude improvement in sensitivity was achieved by extending this technology to the mid-infrared molecular fingerprint region, where strong fundamental vibrational transitions are accessed and detection sensitivities as high as parts-pertrillion (10 −12 ) were achieved 4 . We have thus finally reached the full sensitivity requirement for breath analysis where most trace species are present at the 10 −9 to 10 −12 levels 1 .…”

Dual-comb cavity ring-down spectroscopy

“…Potential applications include the accurate measurement of critical reference data to enable the identification of natural gas leaks 45 and precision radiative transfer and climate change models 46 – 49 , as well as the evolution of methane and oxygen line shapes relevant to the search for exoplanet companion biosignatures 50 , 51 . Other potential applications of DC-CRDS include non-invasive optical sensors to probe complex gas matrices such as breath 6 , 52 , as well as agile multispecies trace gases analyzers for atmospheric composition monitoring 53 – 55 , characterization of broadband mirror loss and dispersion 37 , 56 , chemical reaction kinetics 8 and collisional processes in gases 57 . Finally, DC-CRDS could bring all the advantages of CRDS to the frontier of research on high-resolution broadband spectroscopy of cold large organic molecules 58 and other complex molecular systems 59 .…”

“…Although these methods do not exhibit the intrinsic laser noise-immunity of CRDS, they do provide simultaneous detection of many species. Applications include trace gas detection in complex gas matrices like human breath 5 , 6 and the Earth's atmosphere 7 , 8 , and observations of complex chemical kinetics 9 – 11 . Various schemes to read out cavity transmission probed by an optical frequency comb have been demonstrated, including use of an optical-Vernier coupling approach 12 , a swept cavity 13 , and cross-dispersive methods 5 .…”