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Analytical Sensitivity Holds Key to Successful Breath Analysis for Early Disease Detection

Breath testing results reflect current metabolic activities, detecting changes that may occur before symptoms are evident

Dominic Roberts

Dominic Roberts started at Thermo Fisher Scientific as a Senior Applications Specialist and is currently the GC Orbitrap MS Marketing Manager. Dominic is an experienced analytical chemist and mass spectrometrist with more than 20 years of experience using state-of-the-art analytical systems. He has worked in both a regulatory and industrial environment with GC–MS and LC–MS systems to investigate a variety of chemicals in food, biological, and environmental samples.

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Published:Sep 14, 2021
|2 min read
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Using the composition of exhaled breath to accurately determine an individual’s health status is a long-held ambition in diagnostic medicine. Breath testing delivers a noninvasive examination technique, with potential applications in the early detection of disease, exposure to hazardous substances, and the implementation of precision medicine. Of particular interest, is how the volatile organic compounds (VOCs) in exhaled breath can signal changes in biology and health. 

Breath testing results reflect current metabolic activities, detecting changes that may occur long before any damage or phenotypic symptoms are evident. However, the extent to which this is possible relies on the sensitivity of the VOC detection method used. Today, advanced gas chromatography high-resolution accurate mass (HRAM GC-MS) techniques are proving especially valuable. GC-MS linked to breath sample collection enables sensitive detection and quantification of VOCs together with fast, confident compound identification, and is being used in academic and clinical research applications. 

The value of VOCs

Gaseous VOC molecules are often the end product of metabolic processes. Since disease drives metabolic change, particular disease-characteristic VOC patterns can emerge and are often the earliest signs of illness.

VOCs produced in the body enter the bloodstream. When they reach the lungs, they pass from blood into breath, providing a source of biomarkers linked directly to metabolic processes. Since it takes around a minute for blood to flow through the entire circulatory system, sampling breath for 60 seconds or longer enables the collection—then concentration and analysis—of even low levels of VOC biomarkers. This delivers a snapshot of the metabolome.

Developing new workflows

Recent advances in breath collection means “breath biopsy” can now be carried out using devices that ensure reliable, reproducible, and standardized collection and pre-concentration of a wide range of VOCs. These are captured on thermal desorption cartridges for analysis by GC-MS to determine their profile. Software solutions pinpoint VOCs of interest—the identified biomarkers—during discovery work. Subsequently, specific analysis software enables targeted qualitative or quantitative screening of known compounds in more routine applications. 

The HRAM GC-MS advantage

The wide dynamic range, high mass resolving power, and mass accuracy of advanced GC-MS enable confident detection and identification of compounds in a breath sample, ensuring a comprehensive VOC profile. In contrast, the sensor-based systems frequently used in diagnostic applications only detect specific compounds.

Breath analysis is often limited by the number of samples available, making it imperative to collect both quantitative and qualitative information in a single analysis. Parallel targeted and untargeted/discovery analysis using GC-MS allows the study of known and potential novel biomarkers. 

A complexity of breath analysis is that a single sample contains biomarkers present at very high concentrations alongside those at ultra-trace (femtogram) levels as shown in Figure 1. Therefore, access to high quality data across a wide abundance range is critical. Modern GC-MS techniques solve this issue by offering a dynamic range of more than six orders of magnitude.

Figure 1. A total ion chromatogram (TIC) of multiple breath samples demonstrating the wide range in concentrations encountered in breath analysis. Compounds are present across five orders of magnitude.
thermo fisher scientific

Retrospective data analysis with GC-MS provides further opportunities to interrogate the data, compare results, or target specific compounds. This allows researchers to understand what is normal or different in a sample and to identify associated biomarkers.

The road ahead

As work on breath analysis gathers pace, advanced GC-MS workflows bring new levels of security and confidence to the data generated, helping accelerate moves from the research environment into the diagnostic arena.