Instrumental drift removal in GC-MS data for breath analysis: the short-term and long-term temporal validation of putative biomarkers for COPD.

Breath analysis holds the promise of a non-invasive technique for the diagnosis of diverse respiratory conditions including chronic obstructive pulmonary disease (COPD) and lung cancer. Breath contains small metabolites that may be putative biomarkers of these conditions. However, the discovery of reliable biomarkers is a considerable challenge in the presence of both clinical and instrumental confounding factors. Among the latter, instrumental time drifts are highly relevant, as since question the short and long-term validity of predictive models. In this work we present a methodology to counter instrumental drifts using information from interleaved blanks for a case study of GC-MS data from breath samples. The proposed method includes feature filtering, and additive, multiplicative and multivariate drift corrections, the latter being based on component correction. Biomarker discovery was based on genetic algorithms in a filter configuration using Fisher's ratio computed in the partial least squares-discriminant analysis subspace as a figure of merit. Using our protocol, we have been able to find nine peaks that provide a statistically significant area under the ROC curve of 0.75 for COPD discrimination. The method developed has been successfully validated using blind samples in short-term temporal validation. However, the attempt to use this model for patient screening six months later was not successful. This negative result highlights the importance of increasing validation rigor when reporting biomarker discovery results.

Comparison of the performance of three ion mobility spectrometers for measurement of biogenic amines.

The performance of three different types of ion mobility spectrometer (IMS) devices: GDA2 with a radioactive ion source (Airsense, Germany), UV-IMS with a photo-ionization source (G.A.S. Germany) and VG-Test with a corona discharge source (3QBD, Israel) was studied. The gas-phase ion chemistry in the IMS devices affected the species formed and their measured reduced mobility values. The sensitivity and limit of detection for trimethylamine (TMA), putrescine and cadaverine were compared by continuous monitoring of a stream of air with a given concentration of the analyte and by measurement of headspace vapors of TMA in a sealed vial. Preprocessing of the mobility spectra and the effectiveness of multivariate curve resolution techniques (MCR-LASSO) improved the accuracy of the measurements by correcting baseline effects and adjusting for variations in drift time as well as enhancing the signal to noise ratio and deconvolution of the complex data matrix to their pure components. The limit of detection for measurement of the biogenic amines by the three IMS devices was between 0.1 and 1.2ppm (for TMA with the VG-Test and GDA, respectively) and between 0.2 and 0.7ppm for putrescine and cadaverine with all three devices. Considering the uncertainty in the LOD determination there is almost no statistically significant difference between the three devices although they differ in their operating temperature, ionization method, drift tube design and dopant chemistry. This finding may have general implications on the achievable performance of classic IMS devices.

The potential of ion mobility spectrometry (IMS) for detection of 2,4,6-trichloroanisole (2,4,6-TCA) in wine.

The off-flavor of "tainted wine" is attributed mainly to the presence of 2,4,6-trichloroanisole (2,4,6-TCA) in the wine. In the present study the atmospheric pressure gas-phase ion chemistry, pertaining to ion mobility spectrometry, of 2,4,6-trichloroanisole was investigated. In positive ion mode the dominant species is a monomer ion with a lower intensity dimer species with reduced mobility values (K(0)) of 1.58 and 1.20 cm(2)V(-1) s(-1), respectively. In negative mode the ion with K(0) =1.64 cm(2)V(-1)s(-1) is ascribed to a trichlorophenoxide species while the ions with K(0) =1.48 and 1.13 cm(2)V(-1)s(-1) are attributed to chloride attachment adducts of a TCA monomer and dimer, respectively. The limit of detection of the system for 2,4,6-TCA dissolved in dichloromethane deposited on a filter paper was 2.1 µg and 1.7 ppm in the gas phase. In ethanol and in wine the limit of detection is higher implying that pre-concentration and pre-separation are required before IMS can be used to monitor the level of TCA in wine.

Rapid detection of sepsis in rats through volatile organic compounds in breath.

BACKGROUND: Sepsis is one of the main causes of death in adult intensive care units. The major drawbacks of the different methods used for its diagnosis and monitoring are their inability to provide fast responses and unsuitability for bedside use. In this study, performed using a rat sepsis model, we evaluate breath analysis with Ion Mobility Spectrometry (IMS) as a fast, portable and non-invasive strategy. METHODS: This study was carried out on 20 Sprague-Dawley rats. Ten rats were injected with lipopolysaccharide from Escherichia coli and ten rats were IP injected with regular saline. After a 24-h period, the rats were anaesthetized and their exhaled breaths were collected and measured with IMS and SPME-gas chromatography/mass spectrometry (SPME-GC/MS) and the data were analyzed with multivariate data processing techniques. RESULTS: The SPME-GC/MS dataset processing showed 92% accuracy in the discrimination between the two groups, with a confidence interval of between 90.9% and 92.9%. Percentages for sensitivity and specificity were 98% (97.5-98.5%) and 85% (84.6-87.6%), respectively. The IMS database processing generated an accuracy of 99.8% (99.7-99.9%), a specificity of 99.6% (99.5-99.7%) and a sensitivity of 99.9% (99.8-100%). CONCLUSIONS: IMS involving fast analysis times, minimum sample handling and portable instrumentation can be an alternative for continuous bedside monitoring. IMS spectra require data processing with proper statistical models for the technique to be used as an alternative to other methods. These animal model results suggest that exhaled breath can be used as a point-of-care tool for the diagnosis and monitoring of sepsis.