TY - JOUR
AU - Mirgorodskaya,, Ekaterina
AB - Abstract BACKGROUND Exhaled breath contains nonvolatile substances that are part of aerosol particles of submicrometer size. These particles are formed and exhaled as a result of normal breathing and contain material from distal airways of the respiratory system. Exhaled breath can be used to monitor biomarkers of both endogenous and exogenous origin and constitutes an attractive specimen for medical investigations. CONTENT This review summarizes the present status regarding potential biomarkers of nonvolatile compounds in exhaled breath. The field of exhaled breath condensate is briefly reviewed, together with more recent work on more selective collection procedures for exhaled particles. The relation of these particles to the surfactant in the terminal parts of the respiratory system is described. The literature on potential endogenous low molecular weight compounds as well as protein biomarkers is reviewed. The possibility to measure exposure to therapeutic and abused drugs is demonstrated. Finally, the potential future role and importance of mass spectrometry is discussed. SUMMARY Nonvolatile compounds exit the lung as aerosol particles that can be sampled easily and selectively. The clinical applications of potential biomarkers in exhaled breath comprise diagnosis of disease, monitoring of disease progress, monitoring of drug therapy, and toxicological investigations. Exhaled breath constitutes an attractive specimen for medical investigations. Compared to alternatives, exhaled breath is readily accessible and sampling is convenient for the donor and noninvasive in nature. Considering that exhaled breath may contain as many detectable components as blood and urine (1), it may be underused for clinical testing and represents a field for future developments. Currently, there are 7 breath-related tests approved by the US Food and Drug Administration (FDA)3 (2). Exhaled breath contains both volatile and nonvolatile compounds. Major components of breath are water vapor and inhaled air that has not reached alveoli, both of which contribute to difficulties in estimating the sample size. It might be obvious to direct attention toward smaller volatile compounds in exhaled breath because they are part of the gas phase. But a more recent interest has evolved concerning nonvolatiles present in aerosol particles that are formed from the airway lining fluid during normal breathing (3, 4). This review aims to summarize the present status regarding sampling, analysis, and potential diagnostic use of nonvolatiles in exhaled breath in relation to recent advancements and the potential role of mass spectrometry (MS). MS technology has undergone substantial developments during the last 2 decades following the introduction of the electrospray interface and techniques for measuring large molecules, and will help provide technology for developing biomarkers in exhaled breath into clinical use. Recent reviews focusing on volatiles in breath are available. Exhaled Breath Condensate Interest in exhaled breath condensate (EBC) was originally focused on measuring pH, but EBC has become a specimen and sampling method of pulmonary components in general. EBC has been subject of research and development for over 20 years (5). Commercial instruments as well as more simple home-built devices for sampling EBC are in use. EBC is considered a way to sample and study both semivolatile and nonvolatile components (5). The technique used for EBC formation is cooling. During a sampling time of several minutes the individual providing the sample breathes into a mouthpiece while wearing a nose clip. The exhaled breath is condensed in a precooled component and subsequently collected as a liquid sample of about 1 mL after thawing. The cooling efficiency and protection from saliva contamination may differ between collection procedures. Proposed and studied biomarker candidates in EBC include pH, cytokines, leukotrienes, nitrogen oxides and organic nitro-compounds, hydrogen peroxide, aldehydes, adenosine, and metabolites. For biomarker discovery, metabolomics and proteomics have been used in both MS and nuclear magnetic resonance applications (5, 6). The field of biomarkers in EBC has long been considered to have great potential but has been hampered by lack of standardization, both regarding the sampling procedure and the reporting unit per volume of condensate (5). A considerable and varying dilution of analytes in the condensed water fraction is a circumstance that adds to the uncertainty of measurement. No generally accepted dilution marker exists. Determination of nonvolatiles in EBC represents a bioanalytical challenge from an analytical sensitivity point of view, and this may be one explanation for the low reproducibility of most biomarkers determined in EBC so far. The possibility of saliva contamination adds to the uncertainty. Exhaled Breath Particles The part of EBC that contains the nonvolatile components is the aerosol particles. The microparticle fraction of breath has been of interest in relation to transmission of infectious disease because these particles can be transported over large distances. Sampling techniques for these particles that are more selective than EBC are now available. Papineni and Rosenthal showed in 1997 that particles of sizes of about 1 μm in diameter were always present in human breath, although in variable amounts (3). Most particles were <1 μm in diameter and both the number of particles and size distribution varied between breathing maneuvers. A more detailed investigation on this matter has been reported recently (4). During tidal breathing there is a 100-fold variation between individuals in particle emission and a tendency for the number of particles emitted to increase with age (4). With increased ventilation ratios (tidal volume), the number of exhaled particles (PEx) increases, which may relate to a higher yield of emitted particles at an increased flow rate. A special breathing technique allowing for airway closure and reopening increases the particle emission 10–100-fold (7). This maneuver includes 3 steps: (a) exhalation to residual volume (airway closure), (b) rapid inhalation to vital capacity (airway reopening), and (c) relaxed exhalation for sampling of the material generated by the airway reopening. Similar to tidal breathing, the amount of PEx produced with airway reopening maneuvers increase with age. These particles are formed during inhalation, when small airways reopen and the lining fluid burst. The particles follow the airstream into the very distal airways (7). How particles are formed during tidal breathing is not yet established, but it is likely that some of them are also formed during airway closure and reopening. Particle formation may also occur in other parts of the respiratory system, in more proximal airways, for example during dynamic compression or opening of glottis. In this research, inhalation of filtered air is always used to avoid influence of particles from surrounding air. A reproducible feature is the particle size distribution. This is in agreement with model calculations that predict larger and smaller particles to become deposited and never become part of the exhaled fraction (4, 8). The median particle diameter experimentally determined is 0.3 μm, with a range of about 0.1–2 μm and normal distribution (4). For the airway closure and reopening maneuver, the majority of PEx are distributed as a broad maximum between 0.2 and 0.5 μm (9). The weight of a particle with a diameter of 2 or 0.2 μm, and density of 1 g/mL, would be about 4 pg or 4 fg, respectively. Recently an alternative for collection of the exhaled aerosol particles has been presented (10) and a research instrument in portable size is now available. The instrument uses an impaction principle for aerosol particle collection. Particles of different sizes can be selectively sampled by the impactor, with the current design being optimized for collection of the 0.5–2.0 μm fraction. The size and the number of the PEx are recorded during the sampling procedure. This allows calculation of the amount of collected material, which is crucial for the quantitative analysis of exhaled material. The exhaled material is collected on hydrophilic Teflon filters and is extracted before analysis in a solvent of choice. Analysis of collected material revealed the presence of phospholipids and proteins characteristic of lung surfactant (10, 11). Another recent finding is the use of exhaled breath for drug testing. Drugs of abuse are also transported from the body in the PEx fraction (12, 13). The work with drug testing has resulted in the development of a simple and disposable sampling device based on the use of a microparticle filter (13). Surfactant Surfactant is secreted in the distal airways by the alveolar type II cells and is crucial for lung function (4). The exact surfactant composition is functionally important and complex, and consists of lipids (mainly phospholipids) and proteins (11). Both proteins and lipids are considered important for mechanical and protective functions. Both components may be affected by disease. Thus, surfactant is an interesting source of potential biomarkers. Currently, there is large interest in understanding the involvement of the distal airways in the development and progression of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (14, 15). For a long time the distal airways were not accessible and therefore were often referred to as the “silent zone” of the lungs. Understanding of the physiological variations of lung surfactant and the pathological alteration leading to disease development and progression is important, and the aerosol particles might become a valuable source for surfactant studies. Potential Biomarkers TOXICOLOGY A successful attempt was made in 1983 by Manolis and coworkers to measure tetrahydrocannabinol (THC) in breath after smoking marijuana (16), but the detection time for THC was only 12 min after stopping smoking. In 2010 the detection of amphetamine in exhaled breath at about 24 h after intake was reported (12) and initiated a new set of work aiming to explore drug breath testing further. With a sampling procedure based on using a C18 solid-phase extraction filter, the possibility to detect amphetamine, methamphetamine, methadone, and THC in exhaled breath from drug users was documented (12, 17, 18). Methadone was used as a study compound for further experiments demonstrating that an active filter surface was not needed and that a particle filter worked as well (19). This is consistent with the fact that methadone is a nonvolatile compound and part of the particle fraction. Methadone was also found to be present in EBC. The use of an electret filter for collecting aerosol particles from air was then explored and found to work for collecting methadone from exhaled breath (19). This filter offered the advantage of having a low flow resistance and the support of a pump during sampling was no longer needed. An electrostatic filter made of polypropylene fibers is termed an electret filter and can be used to trap micrometer-sized aerosol particles. They have a large capacity and are used for cleaning of indoor air (20) and also as exhaust filters in respirator systems. A commercial sampling device based on this technology was used in a clinical study of illicit drug users recovering from acute intoxication (13). The results demonstrated that all 12 studied drug substances (Table 1) were detected in the collected exhaled breath sample at the time they were clinically recovered, which was estimated to be 12–24 h after drug intake. Actual drug intake was determined on the basis of self-report and plasma, and urine analysis. For example, methadone was detected in 12 out of 47 participants. In 11 of these 12 participants, a methadone intake was supported by plasma, urine, or self-report results. Table 1. List of substances demonstrated to be present in exhaled breath following recovery from intoxication.a Substance . Observed range pg/filterb . Amphetamine 20–4700 Metamphetamine 30–790 THC 8–332 Cocaine 29–13 000 Benzoylecgonine 18–560 Morphine 25–4650 6-Acetylmorphine 42–6080 Diazepam 2–145 Oxazepam 4–84 Alprazolam 4–53 Methadone 58–2420 Buprenorphine 114–567 Substance . Observed range pg/filterb . Amphetamine 20–4700 Metamphetamine 30–790 THC 8–332 Cocaine 29–13 000 Benzoylecgonine 18–560 Morphine 25–4650 6-Acetylmorphine 42–6080 Diazepam 2–145 Oxazepam 4–84 Alprazolam 4–53 Methadone 58–2420 Buprenorphine 114–567 a Data from Beck et al. (13). b The sampling procedure collects particles from about 30 L of breath on a filter surface. Analyses were done with LC–MS/MS. Open in new tab Table 1. List of substances demonstrated to be present in exhaled breath following recovery from intoxication.a Substance . Observed range pg/filterb . Amphetamine 20–4700 Metamphetamine 30–790 THC 8–332 Cocaine 29–13 000 Benzoylecgonine 18–560 Morphine 25–4650 6-Acetylmorphine 42–6080 Diazepam 2–145 Oxazepam 4–84 Alprazolam 4–53 Methadone 58–2420 Buprenorphine 114–567 Substance . Observed range pg/filterb . Amphetamine 20–4700 Metamphetamine 30–790 THC 8–332 Cocaine 29–13 000 Benzoylecgonine 18–560 Morphine 25–4650 6-Acetylmorphine 42–6080 Diazepam 2–145 Oxazepam 4–84 Alprazolam 4–53 Methadone 58–2420 Buprenorphine 114–567 a Data from Beck et al. (13). b The sampling procedure collects particles from about 30 L of breath on a filter surface. Analyses were done with LC–MS/MS. Open in new tab Cannabis has been the subject of a clinical trial including exhaled breath sampling in which 24 study participants smoked 6.8% THC standard cigarettes. THC was detected in exhaled breath for a few hours' time in all participants but 1 (21). In a previous study, samples were collected 1–2 h after smoking cannabis and all 8 participants were positive for THC (18). Another clinical study was performed on participants in treatment for cannabis abuse (22). All 45 participants provided urine samples positive for the carboxylic acid metabolite THCCOOH in urine drug testing. Fifteen participants had THC detectable in plasma and there was a significant correlation of THC being detected in plasma with a high THCCOOH/creatinine ratio in urine supporting recent intake. Eleven of the 15 participants with THC detectable in plasma also had THC detectable in breath. There were significantly higher THC plasma concentrations in participants with THC detectable in breath. This supports the possibility that breath can be an alternative to blood to disclose very recent drug intake, which is relevant for example in drugged-driving monitoring (21). More recently it was observed that the chronic alcohol exposure marker phosphatidylethanol, which normally is measured in whole blood, is also present in the exhaled breath particle fraction of alcoholics (23). THERAPEUTIC DRUGS Apart from methadone, buprenorphine, amphetamine, and methylphenidate, other therapeutic agents have also been measured in exhaled breath. Propofol is an anesthetic agent that has been of interest to measure in exhaled breath, mainly in real time (24). The initial demonstration over 10 years ago that propofol is detectable in breath using MS has been confirmed by others (24). Propofol concentrations in end tidal exhaled breath highly correlate with plasma concentrations. Subsequent work on propofol in exhaled breath has been focused on finding an MS technology for on-line measurement to provide dosage guidance during anesthesia (24). Another anesthetic agent, fentanyl, has been detected in exhaled breath following intravenous administration. Sampling was done by withdrawing a sample of exhaled breath from the anesthetic system with a syringe. A metabolite of valproic acid was measured in exhaled breath online and found to correlate well with free blood valproic acid concentrations (24). A drug candidate, GS-9411, with molecular weight of about 463, as well as its 2 metabolites, have been measured in EBC from sheep (25). The drug GS9411 has lung tissue as the target and the drug is administered as an inhaled aerosol. ENDOGENOUS BIOMARKERS On the basis of the assumption that the distal airways are involved in disease development, monitoring of lung surfactant composition is of major interest. Recent studies on particle formation suggest that they consist of lung surfactant and therefore are a potential source of the biomarkers. However, no such clinically significant marker is yet established. Immunoassay of a number of known proinflammatory cytokines has been reported for EBC (26), but studies often lack the reproducibility needed for clinical application. An immunoassay of surfactant protein A, a major locally produced protein involved in both surfactant and host-defense functions, was established for PEx (27). In explorative studies, surfactant protein A in PEx was shown to be reduced in connection with chronic rejection in lung-transplanted patients (28) and with increased COPD stage (29). As an alternative to immunoassay, MS-based proteomics may facilitate discovery of new biomarkers in PEx. Several groups have investigated the feasibility of MS-based proteomics in EBC. These efforts resulted in identification of cytokeratins, raising the question of their origin in exhaled breath (30). The major keratin species present in EBC were shown to have exogenous origin by 2 independent groups (31). Later reports on the EBC proteome based on the analysis of pooled samples documented detection of proteins other than cytokeratins (32). Recently, detection of 167 proteins has been reported in pooled EBC samples collected from healthy nonsmoking individuals (33). Detection of lung surfactant proteins, known to be abundant in bronchoalveolar lavage fluid (BALF), has been reported (32). The proteomics analysis of PEx using a combination of 1-dimensional gel and liquid chromatography-tandem MS (GeLC-MS/MS) approach has been reported (11). The major difference between reported exhaled proteomes of EBC and PEx is that no cytokeratins were reported for PEx. To exclude false identification of the exogenous proteins, 2 separate controls were included, i.e., room air to exclude ambient contamination as well as analysis of a gel spot from an empty lane to exclude technical contamination. All proteins observed in the technical control and room-air control were excluded from further evaluation for PEx samples, because of their potentially external origin. Together with the rule that an identified protein must have at least 1 unique peptide that is different from other identified homologs in the protein family, the result was the removal of all cytokeratins from the reported PEx proteins identified. The observed proteins were compared to those previously reported in BAL and were shown to have a good agreement between them, with >80% of the identified PEx proteins being previously reported in BAL and with both local surfactant proteins and major blood protein being detected in PEx. A number of endogenous and nonvolatile low molecular weight compounds have been detected in EBC. Several leukotrienes, leukotriene B4 and cysteinyl leukotrienes, have been measured in EBC by immunoassay and MS. Increased concentrations of these inflammation mediators are associated with asthma, COPD, and cystic fibrosis (5). The prostanoids PGE2 and TxB2 have also been measured in EBC. Isoprostane-8 has repeatedly been subject to study in EBC as a marker of oxidative stress. Recent applications of isoprostane-8 as a biomarker of oxidative stress comprise demonstration of its response to air pollution (34). Other eicosanoids, as well as adenosine, aldehydes, nitrotyrosine, and S-nitrosothiols, are among studied biomarker candidates. Finally, the surfactant lipid composition has been studied in BALF. The compositions of phoshatidylcholines, lysophoshatidylcholines, and phosphatidylglycerols are all considered potential biomarkers of pulmonary disease (35). TOF secondary ion MS of PEx revealed the presence of phospholipids characteristic of lung surfactant (10). The pilot study carried out using TOF secondary ion MS of PEx samples collected from patients with asthma and healthy controls showed that the observed phospholipid signals could separate the groups by orthogonal partial least-square analysis (36). Role of MS Measurement of nonvolatiles in exhaled breath poses an analytical challenge regarding sensitivity because of the limited amount of sample. The unique combination of sensitivity and selectivity offered by MS is therefore likely to be instrumental in the future development of biomarkers in exhaled breath. For quantitative determination of low molecular weight compounds LC-MS/MS is preferred and already applied for most low molecular analytes discussed above. Because phospholipids are major components of the PEx, the influence from the matrix must carefully be taken into account in method design and validation. For determination of phospholipids, methods without chromatographic separation can be used (10). MS analysis without chromatographic separation offers fast profiling and analysis of major phospholipid species in PEx (Fig. 1). However, this might not be optimal for quantification of individual and low-abundance lipid compounds. An example of chromatograms from the routine application of exhaled breath drug testing using selected reaction monitoring LC-MS/MS is shown in Fig. 2. In this case analytical evidence of amphetamine and heroin intake is provided by the detection of amphetamine, morphine, and 6-acetylmorphine in the collected breath sample. MS analysis without chromatographic separation of major phospholipid species in PEx. Fig. 1. Open in new tabDownload slide PC, phosphatidylcholine (number of carbons in the 2 fatty acids: number of unsaturations); IS, internal standard; DPPC, dipalmitoylphosphatidylcholine. Fig. 1. Open in new tabDownload slide PC, phosphatidylcholine (number of carbons in the 2 fatty acids: number of unsaturations); IS, internal standard; DPPC, dipalmitoylphosphatidylcholine. Sample chromatograms from the routine application of exhaled breath drug testing using selected reaction monitoring LC-MS/MS. Fig. 2. Open in new tabDownload slide RT, retention time; AA, peak area count; AH, peak height count; SN, signal-to-noise ratio. Amphetamine, 340 pg/filter (A); morphine, 9 pg/filter (B); 6-monoacetylmorphine, 21 pg/filter (C). Fig. 2. Open in new tabDownload slide RT, retention time; AA, peak area count; AH, peak height count; SN, signal-to-noise ratio. Amphetamine, 340 pg/filter (A); morphine, 9 pg/filter (B); 6-monoacetylmorphine, 21 pg/filter (C). It is accepted that not a single marker but a panel of markers are likely to be of clinical relevance. MS and nuclear magnetic resonance are key analytical techniques used in omics platforms, i.e., metabolomics, lipidomics, and proteomics. MS-based omics platforms allow for large-scale detection of all class-related molecules in a single sample, offering the unique possibility for unbiased analysis in biomarker discovery. The application of MS-based omics platforms to nonvolatiles in exhaled air is so far very limited and is limited to proteomic studies only. The application of MS to exhaled proteome is in its early stage, with initial cataloging of the present compounds being performed and the collection techniques being harmonized with the downstream MS analysis. When these steps have been completed, it will be essential to move toward quantitative analysis for clinical application. Because of long analysis time, MS-based proteomics has suffered from low sample throughput. This is now changing because of the possibility of performing simultaneous analysis of multiple samples when using an isobaric-tag labeling approach (37, 38), improving sample throughput by 10 times in case of a 10-plex isobaric reagent set. Alternatively, a targeted proteomics approach can be used for protein quantification (39, 40). Application of MS in targeted proteomics studies is relatively recent, although it is based on the single reaction–monitoring assays that are commonly used for quantitative analysis of small molecules. Similar to immunoassays, targeted MS requires a prior knowledge of the proteins of interest. MS analysis is performed at the peptide instead of the protein level. Selection of several peptides, all belonging to the same protein, ensures accurate quantification even when posttranslational protein processing occurs. In contrast to large proteins, peptide standards are readily produced by peptide synthesis. Targeted MS offers reproducible protein quantification, an alternative to antibody-based assays, with detection limits similar to those for the existing immunoassays. Although not yet applied to exhaled breath analysis, the method is likely to be of interest after initial identification of the exhaled proteome composition. One challenging application of MS is online in real-time analysis of exhaled air samples. An example of such an application is measurement of propofol online in real time to help adjust doses during anesthesia. For this determination, systems based on direct infusion of exhaled air into the MS analyzer have been explored (24). A major challenge is to achieve ionization of the exhaled breath components. The best ionization techniques for nonvolatile components are considered to be atmospheric pressure chemical ionization and secondary electrospray ionization (24). Ion mobility may be used to provide a dimension of separation power and can be used together with these ionization techniques. A new challenging solution for effecting the ionization of analytes is to let the sample donor be at a high potential using a van der Graaff electrostatic generator and breathe directly into the MS system (41) (Fig. 3). A van der Graaff generator is a cheap and simple instrument, and it has been used to detect menthol in the breath of a human study participant. Further success in developing this MS application may provide a powerful detector for both volatile and nonvolatile compounds in breath. A sample donor touching a van der Graaff electrostatic generator and breathing directly into an MS system. Fig. 3. Open in new tabDownload slide Fig. 3. Open in new tabDownload slide Concluding Remarks For diagnosis, exhaled breath offers the unique possibility of noninvasive collection of material from the airways. In combination with modern MS instrumentation that is compatible with offline as well as online real-time analysis, exhaled breath sampling could offer analysis of a broad range of biomarkers. For exhaled breath analysis, MS offers both the unique combination of analytical sensitivity and selectivity for targeted analyte detection as well as an unbiased screening methodology for new candidate marker discovery, i.e., omics platforms. Omics approaches are hypothesis-generating platforms that are analytically and resource demanding and thus are often performed on relatively small sample sets. This is especially true for samples other than blood or urine, for which sample collection and availability of samples can be a limitation on its own. Being noninvasive, exhaled breath collection can be easily performed on large groups of healthy individuals and respiratory patients, thus providing enough power for case control omics studies designed for discovery for new biomarker candidates. Furthermore, exhaled breath sampling is well compatible with repeated sampling, bringing possibilities for unbiased hypothesis-generating longitudinal studies in respiratory research as well as follow-up targeted studies. Although currently performing at the lower end of detection levels of present MS instrumentation, exhaled breath analysis offers the unique possibility of noninvasive sample collection for drug detection and monitoring as well as biomarker research and discovery. With fast development in MS instrumentation, the current detection limitation is likely to be overcome, bringing MS as an important technique in the future development of biomarkers in exhaled breath. 3 Nonstandard abbreviations FDA US Food and Drug Administration MS mass spectrometry EBC exhaled breath condensate PEx exhaled particles COPD chronic obstructive pulmonary disease THC tetrahydrocannabinol THCCOOH carboxylic acid THC metabolite BALF bronchoalveolar lavage fluid GeLC-MS/MS 1-dimensional gel and liquid chromatography-tandem MS. " Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. " Authors' Disclosures or Potential Conflicts of Interest:Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: " Employment or Leadership: A.C. Olin, PExA AB. " Consultant or Advisory Role: None declared. " Stock Ownership: O.M.L. Beck, Sensabues AB; A.C. Olin, PExA AB; E. Mirgorodskaya, PExA AB. " Honoraria: None declared. " Research Funding: None declared. " Expert Testimony: None declared. " Patents: O.M.L. Beck, patent number: US 8,368,883; A.C. Olin, patent numbers: P1758SE00 and P1414SE00. References 1. Popov TA . Human exhaled breath analysis . Ann Allergy Asthma Immunol 2011 ; 106 : 451 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Amann A , Miekisch W, Schubert J, Buszewski B, Ligor T, Jezierski T , et al. Analysis of exhaled breath for disease detection . Ann Rev Anal Chem 2014 ; 7 : 455 – 82 . Google Scholar Crossref Search ADS WorldCat 3. Papineni RS , Rosenthal FS . 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Google Scholar Crossref Search ADS PubMed WorldCat © 2016 The American Association for Clinical Chemistry This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath
JO - Clinical Chemistry
DO - 10.1373/clinchem.2015.239285
DA - 2016-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/potential-of-mass-spectrometry-in-developing-clinical-laboratory-uwJ0mxCT90
SP - 84
VL - 62
IS - 1
DP - DeepDyve
ER -