High-Throughput Breath Volatile Organic Compound Analysis Using

Article Cite This: Anal. Chem. XXXX, XXX, XXX−XXX

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High-Throughput Breath Volatile Organic Compound Analysis Using Thermal Desorption Proton Transfer Reaction Time-of-Flight Mass Spectrometry Andrea Romano,* Sophie Doran, Ilaria Belluomo, and George Bushra Hanna Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Building, St. Mary’s Hospital, South Wharf Road, London W2 1NY, United Kingdom

Anal. Chem. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 08/18/18. For personal use only.

S Supporting Information *

ABSTRACT: Breath analysis is highly acceptable to patients and health care professionals, but its implementation in clinical practice remains challenging. Clinical trials and routine practice require a robust system for collection, storage, and processing of large numbers of samples. This work describes a platform based upon the hyphenation of thermal desorption (TD) with proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS), coupled by means of an original modification of the TD interface. The performance of TD-PTR-ToF-MS was tested against seven oxygenated volatile organic compounds (VOCs), belonging to three chemical classes (i.e., fatty acids, aldehydes, and phenols), previously identified as possible biomarkers of colorectal and esophago-gastric adenocarcinoma. Limits of detection and quantification were on the order of 0.2−0.9 and 0.3−1.5 parts per billion by volume (ppbV), respectively. Analytical recoveries from TD tubes were 80% or higher, linear response was in the low- to mid-ppbV range (R2 = 0.98− 0.99), and coefficients of variation were within 20% of mean values. The usability of the platform was evaluated in the analysis of a set of breath samples of clinical origin, allowing for a throughput of nearly 100 TD tubes for 24 h of continuous operation. All of these characteristics enhance the implementation of TD-PTR-ToF-MS for large-scale clinical studies.

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lites or the direct comparison with data obtained from different biological matrixes (e.g., breath, blood, urine) in the framework of pharmacokinetic modeling studies.5−7 Another potential clinical advantage of SIFT-MS and PTRMS over GC−MS is represented by their reduced analytical times. Both quadrupole-based SIFT-MS and PTR-MS have already been coupled to commercial, two-stage desorption TD systems.8,9 In two-stage TD, VOCs are first transferred from the TD tube to a cold trap, which is generally filled with the same sorbent as the TD tube. The cold trap material is then desorbed by applying a very steep temperature ramp (40 °C s−1 or higher), which ultimately results in the transfer of VOCs to the analyzer by means of a short pulse (typically a few seconds). This is to comply with the requirements of GC−MS, where a quick transfer of VOCs onto the column is essential to optimal chromatographic resolution.10 This constitutes a limitation for the reported TD-SIFT-MS and TD-PTR-MS, as quadrupole mass analyzers are poorly suited to the monitoring of multiple mass-to-charge signals over restricted periods of time. The introduction of proton transfer reaction time-of-flight mass spectrometry,11 with its high time resolution, represents a considerable step forward in terms of performance with respect to coupling to TD. Hyphenated

lterations in the volatile organic compound (VOC) profile of exhaled breath have been reported for different types of cancer types and benign diseases.1,2 The perspective of using breath analysis for diagnostic purposes is very appealing in healthcare systems as breath tests are noninvasive, risk-free, and have very good patient acceptability. The necessity to translate laboratory findings and single-center studies to large scale and multicenter level poses several challenges in the collection, transport, and analysis of large numbers of breath samples.3 Thermal desorption (TD) is a well-established technological standard in the fields of environmental analysis and occupational health,4 where it is usually coupled to gas chromatography−mass spectrometry (GC−MS). TD tubes represent a robust solution for sample collection, transport, and storage, and TD-GC−MS provides a reliable means to perform breath VOC analysis, but the time required for the chromatographic separation often results in low analytical throughput. Selected ion flow tube mass spectrometry (SIFT-MS), as well as proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS), allow for direct VOC quantitation in the gas phase, provided all reagent and product ions and reaction rate constants are known.2 The elucidation of analyte fragmentation patterns also supports structural identification. The direct quantitation of breath metabolites also increases the potential impact of the findings, facilitating the direct establishment of threshold concentrations for target metabo© XXXX American Chemical Society

Received: March 7, 2018 Accepted: July 31, 2018

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DOI: 10.1021/acs.analchem.8b01045 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

connected to the PTR-MS inlet by means of a custom-made adapter (Figures S-1 and S-2). This allowed the collection of VOCs directly from the tube, entirely bypassing the cold trap and achieving one-stage desorption. This reduces the number of tube processing steps and thus results in a shorter TD cycle, also minimizing the potential risk of carry-over effects thanks to the reduction of the TD flow path length. In the final optimized TD method, TD tubes were desorbed for 10 min at 280 °C and 130 sccm using zero-grade nitrogen purified by means of a Supelpure HC hydrocarbon trap (Sigma-Aldrich, St. Louis, MO). For the calculation of breath VOC concentrations ([VOC]breath) based on TD-PTR data, we employed the following equation:

systems have been developed, based on the coupling of PTRToF-MS to collection-thermal-desorption (CTD) traps.12,13 CTD is based on a single, custom-made collection cell, which undergoes a continuous adsorption/desorption cycle. These systems are particularly suited to atmospheric analysis, with a focus on sample concentration and in situ automated measurement, but they do not allow for sample transportability. Similarly to TD-PTR-ToF-MS, multibed needle trap desorption coupled to GC−MS14,15 and TD coupled to electron spray ionization ion mobility MS16,17 address the issue of sample transport and storage and high-throughput analysis from a similar perspective, but these platforms, unlike PTR-MS or SIFT-MS, do not allow for direct VOC quantification. As hundreds of individual breath samples can be collected onto TD tubes every week in the framework of a multicenter clinical trial, the absence of a commercially available technology for wide scale analytical trials represents a major bottleneck in the analytical workflow. The aim of this work is to develop and validate a TD-PTR-ToF-MS platform suitable for large-scale breath clinical studies.

[VOC]breath = ([VOC]TD × t D × φ)/Vb

where [VOC]TD is the measured concentration, tD and φ are desorption time and flow, respectively, and Vb is the collected breath volume or the standard volume loaded onto the tube. The equation corrects for the fact that the total desorption volume is not equal to the volume of breath collected onto each tube. The same approach was used to compare loaded and desorbed VOC amounts when working with authentic standards. We employed stainless steel TD tubes containing a mixed sorbent bed consisting of Tenax TA/Carbograph 5TD (BioMonitoring C4-C30, Markes Ltd.). TD tubes were conditioned using a TC 20 conditioning station (Markes Ltd.) and following the manufacturer’s recommendations. Authentic standards (Sigma-Aldrich) were loaded into TD tubes by means of custom-made permeation tubes. The permeation tubes consisted of PTFE tubing, sealed at both ends. Permeation tubes were maintained at 30 °C at a constant flow rate using a permeation unit (ES 4050P, Eco Scientific, Stroud, Gloucestershire, UK). Clean air was supplied using a membrane pump (KNF Neubeger UK, Witney, Oxfordshire), connected to a hydrocarbon trap. Before tube loading, the permeation unit was connected to the PTR-ToF-MS by means of a PEEK union connection, and measurement was conducted for 3 min; the union was then switched by a TD tube placed between the permeation unit and the mass analyzer. Immediately upon switching, a drop in VOC signals down to baseline levels was observed. Standard loading was conducted at a flow of 200 sccm for 2.5 min, during which no increase in the signals of the VOCs of interest was observed. This showed that sample VOC loading could be carried out without detectable breakthrough. After loading, the TD tube was removed and the device was connected back to the PTR-ToFMS and left to equilibrate for 2 min. The choice of compounds used was based upon previous studies on diagnosis of esophago-gastric cancer and colorectal cancer by means of SIFT-MS.19−21 We selected three aldehydes (propanal, butanal, decanal), three fatty acids (butanoic acid, pentanoic acid, hexanoic acid), and phenol. Clinically relevant concentrations for these compounds range from the low-ppbV level to a few hundreds of ppbV. To optimize desorption time on the one-stage system, VOCs were loaded onto the TD tubes at a fixed reference concentration. For this experiment, in addition to the previously mentioned seven oxygenated VOCs, acetone was also loaded onto the TD tubes. Loading concentrations were as follows: acetone 283.5 ppbV, butanoic acid 21.0 ppbV, pentanoic acid 7.1 ppbV, hexanoic acid 8.8 ppbV, phenol

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EXPERIMENTAL SECTION Development of One-Stage TD-PTR-TOF-MS. Measurements were conducted using a PTR-TOF 1000 instrument equipped with a commercial SRI feature (Ionicon Analytik GmbH, Innsbruck, Austria). Optimal conditions for VOC identification and quantification were defined according to a previously described experimental workflow,18 dedicated to method optimization under breath-relevant conditions. Briefly, the workflow consisted of (i) screening of reduced drift field conditions using different reagent ions, (ii) evaluating the impact of a change in humidity on branching ratios, and (iii) gravimetric calibration using permeation or diffusion tubes. Optimal conditions for the drift tube were: temperature 110 °C, pressure 2.30 mbar, and voltage 350 V, resulting in an E/N of 84 Td (1 Townsend = 10−17 V cm2). Reagent and analyte ions used in VOC determination throughout this Article are summarized in Table 1. Sample inlet consisted of a PEEK Table 1. Mass Peaks Monitored in Breath and Standards with Respective Identifications analyte ion (m/z) 57.03 59.05 71.05 89.06 94.05 103.07 117.09 155.14

reagent ion +

NO H3O+ NO+ H3O+ NO+ H3O+ H3O+ NO+

reaction channel

identification

hydride abstraction proton transfer hydride abstraction proton transfer electron transfer proton transfer proton transfer hydride abstraction

propanal acetone butanal butanoic acid phenol pentanoic acid hexanoic acid decanal

heated line (temperature 110 °C, length 1.2 m, inner diameter 0.04”). Inlet flow rate was set to 200 and 130 sccm for direct injection and thermal desorption analysis, respectively. We employed a TD autosampler (TD100-xr, Markes International Ltd., Llantrisant, UK), adapted for PTR-MS analysis. The original configuration for TD analysis is shown in Figure S-1. In the original configuration, the split line is normally left closed or used to remove excess sample or recollect VOCs onto a second TD tube for repeated analysis. In our configuration, the split filter was replaced by a custommade adapter, consisting of an inert-coated steel tube, B


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Figure 1. Online monitoring of desorption using H3O+ (top) and NO+ (bottom) reagent ions. Average profile and recoveries of replicate measurements of TD tubes loaded with standards (continuous and dashed lines, respectively). Shaded areas represent 95% confidence limits (n = 11 and n = 9 for H3O+ and NO+, respectively).

88.7 ppbV, propanal 12.5 ppbV, butanal 4.9 ppbV, and decanal 2.3 ppbV. Tubes were then analyzed by TD-PTR-ToF-MS, prolonging the desorption time up to 20 min. The performance parameters for method validation and the techniques to evaluate them were chosen adopting the guidelines established by the European Respiratory Society technical standard for the analysis of exhaled biomarkers in lung disease,22 which recommend evaluating method performance with respect to linearity, limit of quantification (LOQ), limit of detection (LOD), and repeatability. Calibration curves were established on the basis of comparison between loaded and desorbed amounts of the authentic standards. Different loading concentrations were achieved by changing the flow rate applied to the permeation oven. At least 10 TD tubes were prepared for each compound, corresponding to five concentration levels, each in duplicate. Breath Collection and Analysis. The findings obtained on authentic standards were corroborated by means of experiments conducted on breath samples. Multiple breath samples (n = 10) were collected within a limited time span from a healthy volunteer. We employed a breath collection device (ReCIVA, Owlstone Ltd., Cambridge UK), using optimized sampling parameters, as determined in a previous study.23 The device allowed for direct breath collection onto TD tubes. The tubes were then immediately analyzed by TDPTR-ToF-MS. In this experiment, a desorption step of 20 min was employed. To assess the usability of the TD-PTR-ToF-MS analytical platform in the high throughput analysis of clinical samples, breath samples were collected from patients attending St Mary’s Hospital for upper gastrointestinal endoscopy or surgery. The use of the ReCIVA breath collection device allowed the simultaneous sampling of up to four TD tubes

from each patient. Ethical approval was obtained through the NHS Health Research Authority (NRES Committee London − Camden and Islington, approval granted on 16th July 2014, REC reference 14/LO/1136). Quality Control. PTR-ToF-MS was submitted to a series of quality checks on a daily basis. Quality control procedures are described in the Supporting Information. Data Analysis. Data were extracted using PTRMS viewer version 3.2.2.2 (Ionicon Analytik). Additional data analysis was conducted using in-house generated scripts written using R programming language.24

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RESULTS AND DISCUSSION Optimization of TD Cycle Duration. Rapidity of analysis is a highly desirable characteristic for a method intended for large-scale clinical studies: for TD-PTR-ToF-MS, the main limiting factor is the duration of the TD analytical cycle. The transition from two-stage to one-stage desorption allows for a first reduction in the TD cycle. Another step affecting TD cycle length is desorption time: the goal is to minimize its duration without compromising analyte (VOC) recovery. Using the permeation unit, eight VOCs (acetone, butanoic acid, pentanoic acid, hexanoic acid, phenol, propanal, butanal, and decanal) were loaded onto the TD tubes at fixed concentrations. Concentrations ranged from a few ppbV to a few hundred ppbV, aiming to simulate a breath-relevant concentration for each of the compounds. The possibility to monitor VOC release online throughout desorption allowed an optimal time to be selected by means of a single experiment, without the need to test different desorption times separately. Experiments were conducted using H3O+ and NO+ as reagent ions (11 and 9 replicates, respectively). The mean release C


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Table 2. Limit of Detection (LOD), Limit of Quantification (LOQ), Calibration Curve Parameters, and Linearity Assessed on Seven Selected Compounds Using TD-PTR-ToF-MS compound

LODa (ppbV)

LOQa (ppbV)

intercept (ppbV)

slope

linear range (ppbV)

R2

n

butanoic acid pentanoic acid hexanoic acid propanal butanal phenol decanal

0.6 0.2 0.2 0.8 0.9 0.5 0.3

0.9 0.3 0.4 1.3 1.5 0.9 0.5

−0.49 −0.10 0.54 −0.80 −0.67 0.44 −1.24

0.98 1.02 0.80 0.99 0.98 0.94 1.25

7−533 3−83 2−17 2−109 2−95 3−41 2−21

0.995 0.995 0.988 0.999 0.999 0.997 0.999

12 12 10 12 12 10 10

a

LOD and LOQ expressed as 3- and 5-fold standard deviations of the blank tube signal, respectively.

profiles (Figure 1) show a compound-dependent behavior, with acetone displaying the fastest kinetics, followed by phenol, aldehydes, and fatty acids. The slow desorption kinetics observed for fatty acids could be related to condensation within the transfer line. This could possibly be obviated by using an inlet line temperature similar to that employed in TDGC-MS (e.g., 140 °C). Interestingly, some of the desorption curves (e.g., acetone) are showing a split profile. This is probably because some compounds are absorbed onto both types of sorbent contained in the TD tube. By comparing loading and desorbed concentrations, it was possible to estimate recoveries. Optimal desorption time was set at 10 min, which allowed one to attain 80% recovery or higher for all of the analytes evaluated. The fact that after 10 min of desorption quantitative recovery is not attained for all analytes could be due to a moderate level of transfer line activation. This could be obviated by the employment of inert materials, such as PEEK or inertised steel, over the whole length of the flow path. It is also worth mentioning that for some compounds, and especially at desorption times >10 min, recovery percentages higher than 100% are obtained. This is probably due to residual VOC amounts remaining on TD tubes after conditioning, which lead to an overestimation of recoveries. Analytical Performance of TD-PTR-TOF-MS. Calibration curves allowed the assessment of linearity (R2 = 0.98− 0.99) within a realistic concentration range for each of the VOCs of interest (Table 2). Slopes were reasonably close to unity (0.8−1.2), indicating that quantitative or nearquantitative VOC recovery was achieved. Limits of detection (LOD) and quantification (LOQ) were established by measuring blank TD tubes (n = 45 for each of the primary ions). LOD and LOQ were fixed at 3-fold and 5-fold the background standard deviation and were in the order of 0.2− 0.9 and 0.3−1.5 ppbV, respectively. As an alternative to the previous method, we calculated LOD and LOQ at 3 and 5 times the standard deviation on the calibration curve intercept: this afforded similar values, comprised between 0.3 and 1.4 ppbV. Repeatability was assessed by applying the same methodology: TD tubes were loaded at 3−4 different concentration levels for all compounds, repeating the procedure in duplicate on five different days. Coefficients of variation of repeated measurements were in the range 7−20%, and recoveries remained higher than 80% for all tested VOCs (Table 3). Previous studies conducted using SIFT-MS20,21 have shown that the VOCs of interest displayed an increase higher than 20% in the disease state with respect to noncancer controls: the analytical performance of TD-PTR-ToF-MS appears therefore to be adequate to clinical application. VOC recoveries from TD tubes are 80% or higher: this shows that

Table 3. Repeatability and Mean Recovery Assessed on Seven Selected Compounds (n = 10) at Four Concentration Levels, Labeled from A (Highest) to D (Lowest) compound butyric acid

pentanoic acid

hexanoic acid

propanal

butanal

phenol

decanal

concentration level A B C D A B C D A B C D A B C D A B C D A B C A B C D

mean ± SD (ppbV)

recovery (%)

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

92 97 89 97 91 94 87 112 100 89 92 94 94 110 85 91 95 110 83 90 104 128 94 122 96 90 80

559 377 54 4 97 46 12 3 19 11 5 2 116 79 13 2 99 44 10 2 34 19 4 20 5 3 1.5

77 62 4 0.4 10 6 1 0.6 4 1 1 0.3 22 14 1 0.4 17 6 1 0.3 5 1 0.5 0.4 0.1 0.6 0.3

the transition from direct analysis to TD is possible with an acceptable loss in quantitation accuracy. LODs are higher than the nominal values reported for this PTR-ToF-MS model used in direct analysis mode. This is likely due to an increase in baseline observed when analyzing TD tubes (Figure S-3). Further optimization of the TD tube conditioning program could lead to lower LOD and LOQ values. Previous studies presenting analytical platforms similar to TD-PTR-ToF-MS, such as those based upon multibed needle trap desorption coupled to GC−MS14,15 or TD coupled to electron spray ionization ion mobility MS,16,17 show similar performance (LOD in the low-ppbV range, %RSD 1.5−28%, R2 = 0.98− 0.99) while necessarily relying on external calibration for VOC quantitation. The overall analytical conditions chosen for TD-PTR-ToFMS guaranteed a relatively uniform analytical response: for all tested compounds, the ratio between signal levels (in counts D


Article


Figure 2. Online monitoring of desorption using H3O+ (top) and NO+ (bottom). Average profile and recoveries of breath sample replicates after blank TD tube subtraction (continuous and dotted lines, respectively).

operation, thus corroborating the usability of the platform for large-scale clinical studies. The visual inspection of selected VOC profiles obtained at the beginning and end of the sequence did not show any analytical artifacts due to carry-over effects (Figure S-3). Table 4 shows concentration ranges for

per second) and measured concentrations was in the range 100 ± 20 cps/ppbV. This highlights the versatility of TD-PTRToF-MS, which allowed for the quantification of oxygenated VOCs from three different classes with similar performance by means of a single analytical method. Breath Analysis by TD-PTR-ToF-MS. The findings obtained on authentic standards were compared to the results obtained by the analysis of breath samples obtained from a healthy volunteer. Tentative identifications were based on accurate mass determination (within ±0.01 mass-to-charge ratio). The perusal of online desorption profiles confirms that, for all considered compounds, the first 10 min of desorption encompass at least 90% of the total VOC release (Figure 2). For the most low-boiling VOCs (e.g., acetone or propanal), release seems to proceed very rapidly, and a first peak in released concentrations is reached within 5 s. This shows how having a high time resolution mass analyzer offers the best chances to fully characterize such a complex analytical matrix as breath. The optimized TD cycle has an overall duration of 15 min (10 min desorption + 5 min between tube loading and unloading and leak test). This results in an expected throughput of nearly 100 samples for 24 h of continuous operation. This was eventually confirmed by means of a platform usability study. Breath was sampled onto TD tubes using a breath collection device (Experimental Section) from 46 patients attending St. Mary’s Hospital (Paddington, London) for upper gastrointestinal endoscopy or surgery. Two TD tubes were collected for each patient, and each tube was analyzed by TD-PTR-ToF-MS, employing either H3O+ or NO+ as the reagent ion. The 92 tubes were processed by the analytical platform over 24 h of continuous, unattended

Table 4. Platform Usability: Detection and Quantification of Eight VOCs in 46 Patients compound acetone butanoic acid pentanoic acid hexanoic acid phenol propanal butanal decanal a

minimum (ppbV)

first quartile (ppbV)

median (ppbV)

third quartile (ppbV)

maximum (ppbV)

33.6 1.4

161.0 2.7

274.8 3.8

523.5 4.9

1760.3 74.4

0.7

1.5

2.0

2.4

3.5

0.4

0.8

1.1

1.7

10.6

2.2 2.9 1.4 0.5a

5.9 3.9 1.9 0.7

7.6 4.9 2.6 0.8

10.2 7.3 3.5 0.9

21.4 9.9 5.4 1.9

For decanal, three samples were below LOQ.

the seven target VOCs. In addition to that, breath acetone was quantified to evaluate the platform performance on an abundant, well-characterized breath VOC. Aldehydes, fatty acids, and phenol remained well above the limit of quantification, with the exception of decanal, with three samples out of 46 lower than LOQ. The range of concentration established for acetone was similar to the values reported for adult volunteers using SIFT-MS.25,26 The number E


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Research Council and the Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, within the framework of Imperial Confidence in Concept.

and distribution of patient samples does not allow for disease diagnosis, which exceeds the scope of this Article.

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CONCLUSION This research work addresses the development of a new analytical platform, based on TD-PTR-ToF-MS, and its applicability to breath analysis. This platform displays high throughput and sensitivity. The high analytical throughput also reduces lead times between breath collection and analysis, even though storage times of 2−6 weeks have been reported for breath collected onto TD tubes.27,28 These characteristics make it highly suitable to large-scale VOC analysis in the clinical setting. According to our vision, breath would be collected from multiple GP practices or clinical hubs, in a way similar to what is already done for blood samples today. Samples would then be analyzed in a regional lab by means of TD-PTR-ToF-MS. The platform is based on a new coupling strategy that permits one-stage desorption. This appears to be better suited for coupling to a direct-injection MS instrument, such as PTR-ToF-MS or SIFT-MS. It must be noted that this coupling, however unprecedented, is easily reproducible using commercial instrumentation and readily available materials. The main limitation of direct injection MS resides in the absence of a chromatographic separation step: hence, unambiguous VOC identification within complex matrixes is not always possible. Possible solutions could be represented by the simultaneous analysis of a subset of the samples by means of TD-GC−MS for cross-platform comparison and robust identification or the integration of a FastGC separation step within the instrumental setup.29 Finally, TD-PTR-ToF-MS offers the possibility to check for VOC breakthrough during adsorption and to monitor directly VOC release kinetics during desorption. The present work, even though limited to seven compounds, presents a validation workflow that is potentially applicable to most breath VOCs.

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(1) Amann, A.; Miekisch, W.; Schubert, J.; Buszewski, B.; Ligor, T.; Jezierski, T.; Pleil, J.; Risby, T. Annu. Rev. Anal. Chem. 2014, 7, 455− 482. (2) Smith, D.; Š paněl, P.; Herbig, J.; Beauchamp, J. J. Breath Res. 2014, 8 (2), 027101. (3) Markar, S. R.; Lagergren, J.; Hanna, G. B. BMJ. Open 2016, 6 (1), No. e009139. (4) Chow, J. C.; Yu, J. Z.; Watson, J. G.; Hang Ho, S. S.; Bohannan, T. L.; Hays, M. D.; Fung, K. K. J. Environ. Sci. Health, Part A: Toxic/ Hazard. Subst. Environ. Eng. 2007, 42 (11), 1521−1541. (5) Smith, D.; Š paněl, P. Journal of Breath Research 2017, 11 (4), 047106. (6) Ross, B. M.; Babgi, R. Journal of Breath Research 2017, 11 (4), 046001. (7) Volatile Biomarkers: Non-Invasive Diagnosis in Physiology and Medicine, 1st ed.; Amann, A., Smith, D., Eds.; Elsevier: Amsterdam; Boston, 2013. (8) Crespo, E.; Devasena, S.; Sikkens, C.; Centeno, R.; Cristescu, S. M.; Harren, F. J. M. Rapid Commun. Mass Spectrom. 2012, 26 (8), 990−996. (9) Hryniuk, A.; Ross, B. M. Int. J. Mass Spectrom. 2009, 285 (1−2), 26−30. (10) Price, J. A.; Saunders, K. J. Analyst 1984, 109 (7), 829−834. (11) Jordan, A.; Haidacher, S.; Hanel, G.; Hartungen, E.; Märk, L.; Seehauser, H.; Schottkowsky, R.; Sulzer, P.; Märk, T. D. Int. J. Mass Spectrom. 2009, 286 (2−3), 122−128. (12) Erickson, M. H.; Gueneron, M.; Jobson, B. T. Atmos. Meas. Tech. 2014, 7 (1), 225−239. (13) Holzinger, R.; Williams, J.; Herrmann, F.; Lelieveld, J.; Donahue, N. M.; Röckmann, T. Atmos. Chem. Phys. 2010, 10 (5), 2257−2267. (14) Mieth, M.; Kischkel, S.; Schubert, J. K.; Hein, D.; Miekisch, W. Anal. Chem. 2009, 81 (14), 5851−5857. (15) Trefz, P.; Rösner, L.; Hein, D.; Schubert, J. K.; Miekisch, W. Anal. Bioanal. Chem. 2013, 405 (10), 3105−3115. (16) Reynolds, J. C.; Blackburn, G. J.; Guallar-Hoyas, C.; Moll, V. H.; Bocos-Bintintan, V.; Kaur-Atwal, G.; Howdle, M. D.; Harry, E. L.; Brown, L. J.; Creaser, C. S.; et al. Anal. Chem. 2010, 82 (5), 2139− 2144. (17) Reynolds, J. C.; Jimoh, M. A.; Guallar-Hoyas, C.; Creaser, C. S.; Siddiqui, S.; Paul Thomas, C. L. J. Breath Res. 2014, 8 (3), 037105. (18) Romano, A.; Hanna, G. B. J. Mass Spectrom. 2018, 53 (4), 287− 295. (19) Kumar, S.; Huang, J.; Abbassi-Ghadi, N.; Š paněl, P.; Smith, D.; Hanna, G. B. Anal. Chem. 2013, 85 (12), 6121−6128. (20) Kumar, S.; Huang, J.; Abbassi-Ghadi, N.; Mackenzie, H. A.; Veselkov, K. A.; Hoare, J. M.; Lovat, L. B.; Š paněl, P.; Smith, D.; Hanna, G. B. Ann. Surg. 2015, 262 (6), 981−990. (21) Markar, S. R.; Chin, S.-T.; Romano, A.; Wiggins, T.; Antonowicz, S.; Paraskeva, P.; Ziprin, P.; Darzi, A.; Hanna, G. B. Ann. Surg. 2018, 1, 1. (22) Horváth, I.; Barnes, P. J.; Loukides, S.; Sterk, P. J.; Högman, M.; Olin, A.-C.; Amann, A.; Antus, B.; Baraldi, E.; Bikov, A.; Boots, A. W.; Bos, L. D.; Brinkman, P.; Bucca, C.; Carpagnano, G. E.; Corradi, M.; Cristescu, S.; de Jongste, J. C.; Dinh-Xuan, A.-T.; Dompeling, E.; Fens, N.; Fowler, S.; Hohlfeld, J. M.; Holz, O.; Jöbsis, Q.; Van De Kant, K.; Knobel, H. H.; Kostikas, K.; Lehtimäki, L.; Lundberg, J. O.; Montuschi, P.; Van Muylem, A.; Pennazza, G.; Reinhold, P.; Ricciardolo, F. L. M.; Rosias, P.; Santonico, M.; van der Schee, M. P.; van Schooten, F.-J.; Spanevello, A.; Tonia, T.; Vink, T. J. Eur. Respir. J. 2017, 49 (4), 1600965.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.8b01045. Figure S-1, schematic representation of the TD instrument; Figure S-2, picture of the TD-PTR-ToF-MS interface; page S-4, quality control; and Figure S-3, assessment of artifacts and background signal (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Tel.: +44 (0)207 886 2125. Fax: +44 (0)207 8862125. Email: [email protected]. ORCID

Andrea Romano: 0000-0003-2392-2705 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are extremely grateful to Prof. David Smith, FRS, and Prof. Patrik Š paněl for providing insightful comments during the final revision of the manuscript. We wish to thank Eco Scientific and Mr. Stephen Durrant for the kind loan of a permeation unit. This work was funded by the Medical F


Article

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High-Throughput Breath Volatile Organic Compound Analysis Using

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