Enhancing diagnosis of benign lesions and lung cancer through ensemble text and breath analysis: a retrospective cohort study.

Early diagnosis of lung cancer (LC) can significantly reduce its mortality rate. Considering the limitations of the high false positive rate and reliance on radiologists' experience in computed tomography (CT)-based diagnosis, a multi-modal early LC screening model that combines radiology with other non-invasive, rapid detection methods is warranted. A high-resolution, multi-modal, and low-differentiation LC screening strategy named ensemble text and breath analysis (ETBA) is proposed that ensembles radiology report text analysis and breath analysis. In total, 231 samples (140 LC patients and 91 benign lesions [BL] patients) were screened using proton transfer reaction-time of flight-mass spectrometry and CT screening. Participants were randomly assigned to a training set and a validation set (4:1) with stratification. The report section of the radiology reports was used to train a text analysis (TA) model with a natural language processing algorithm. Twenty-two volatile organic compounds (VOCs) in the exhaled breath and the prediction results of the TA model were used as predictors to develop the ETBA model using an extreme gradient boosting algorithm. A breath analysis model was developed based on the 22 VOCs. The BA and TA models were compared with the ETBA model. The ETBA model achieved a sensitivity of 94.3%, a specificity of 77.3%, and an accuracy of 87.7% with the validation set. The radiologist diagnosis performance with the validation set had a sensitivity of 74.3%, a specificity of 59.1%, and an accuracy of 68.1%. High sensitivity and specificity were obtained by the ETBA model compared with radiologist diagnosis. The ETBA model has the potential to provide sensitivity and specificity in CT screening of LC. This approach is rapid, non-invasive, multi-dimensional, and accurate for LC and BL diagnosis.

A combined screening study for evaluating the potential of exhaled acetone, isoprene, and nitric oxide as biomarkers of lung cancer.

Background: the early lung cancer (LC) screening strategy significantly reduces LC mortality. According to previous studies, lung cancer can be effectively diagnosed by analyzing the concentration of volatile organic compounds (VOCs) in human exhaled breath and establishing a diagnosis model based on the different VOCs. This method, called breath analysis, has the advantage of being rapid and non-invasive. To develop a non-invasive, portable breath detection instrument based on cavity ring-down spectroscopy (CRDS), we explored the feasibility of establishing a model with acetone, isoprene, and nitric oxide (NO) exhaled through human breath, which can be detected on the CRDS instrument. Methods: a total of 511 participants were recruited from the Cancer Institute and Hospital, Tianjin Medical University as the discovery set and randomly split (2 : 1) into training set and internal validation set with stratification. For external validation, 51 participants were recruited from the General Hospital, Tianjin Medical University. Acetone and isoprene from exhaled breath were detected by proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS), and NO was measured using CRDS. The model was constructed using the ensemble learning method that set eXtreme gradient boosting and logistic regression as the basis model and logistic regression as the senior model. The model was evaluated based on accuracy, sensitivity, and specificity. Results: the model achieved an accuracy of 78.8%, sensitivity of 81.0%, specificity of 70.0%, and area under the receiver operating curve (ROC, AUC) of 0.8341 (95% CI from 0.8055 to 0.8852) in the internal validation set. Furthermore, it attained an accuracy of 66.7%, sensitivity of 68.2%, specificity of 65.5%, and AUC of 0.6834 (95% CI from 0.5259 to 0.7956) in the external validation set. Conclusion: the model, established with acetone, isoprene, and NO as predictors, possesses the ability to identify LC patients from healthy control (HC) participants. The CRDS instrument, which simultaneously detects acetone, isoprene, and NO, is expected to be a non-invasive, rapid, portable, and accurate device for early screening of LC.

Development and validation of a screening model for lung cancer using machine learning: A large-scale, multi-center study of biomarkers in breath.

Objectives: Lung cancer (LC) is the largest single cause of death from cancer worldwide, and the lack of effective screening methods for early detection currently results in unsatisfactory curative treatments. We herein aimed to use breath analysis, a noninvasive and very simple method, to identify and validate biomarkers in breath for the screening of lung cancer. Materials and methods: We enrolled a total of 2308 participants from two centers for online breath analyses using proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS). The derivation cohort included 1007 patients with primary LC and 1036 healthy controls, and the external validation cohort included 158 LC patients and 107 healthy controls. We used eXtreme Gradient Boosting (XGBoost) to create a panel of predictive features and derived a prediction model to identify LC. The optimal number of features was determined by the greatest area under the receiver-operating characteristic (ROC) curve (AUC). Results: Six features were defined as a breath-biomarkers panel for the detection of LC. In the training dataset, the model had an AUC of 0.963 (95% CI, 0.941-0.982), and a sensitivity of 87.1% and specificity of 93.5% at a positivity threshold of 0.5. Our model was tested on the independent validation dataset and achieved an AUC of 0.771 (0.718-0.823), and sensitivity of 67.7% and specificity of 73.0%. Conclusion: Our results suggested that breath analysis may serve as a valid method in screening lung cancer in a borderline population prior to hospital visits. Although our breath-biomarker panel is noninvasive, quick, and simple to use, it will require further calibration and validation in a prospective study within a primary care setting.

Facile Fabrication of Multi-Hydrogen Bond Self-Assembly Poly(MAAc-co-MAAm) Hydrogel Modified PVDF Ultrafiltration Membrane to Enhance Anti-Fouling Property.

In this work, a facile preparation method was proposed to reduce natural organics fouling of hydrophobic membrane via UV grafting polymerization with methacrylic acid (MAAc) and methyl acrylamide (MAAm) as hydrophilic monomers, followed by multihydrogen bond self-assembly. The resulting poly(vinylidene fluoride)-membranes were characterized with respect to monomer ratio, chemical structure and morphology, surface potential, and water contact angle, as well as water flux and organic foulants ultrafiltration property. The results indicated that the optimal membrane modified with a poly(MAAc-co-MAAm) polymer gel layer derived from a 1:1 monomer ratio exhibited superior hydrophilicity and excellent gel layer stability, even after ultrasonic treatment or soaking in acid or alkaline aqueous solution. The initial water contact angle of modified membranes was only 36.6° ± 2.9, and dropped to 0° within 13 s. Moreover, flux recovery rates (FRR) of modified membranes tested by bovine serum albumin (BSA), humic acid (HA), and sodium alginate (SA) solution, respectively, were all above 90% after one-cycle filtration (2 h), significantly higher than that of the pure membrane (70-76%). The total fouling rates (Rt) of the pure membrane for three foulants were as high as 47.8-56.2%, while the Rt values for modified membranes were less than 30.8%. Where Rt of BSA dynamic filtration was merely 10.7%. The membrane designed through grafting a thin-layer hydrophilic hydrogel possessed a robust antifouling property and stability, which offers new insights for applications in pure water treatment or protein purification.

Measurement of Exhaled Nitric Oxide in 456 Lung Cancer Patients Using a Ringdown FENO Analyzer.

The objective of this study was to investigate the clinical value of exhaled nitric oxide (NO) for diagnosing lung cancer patients by using a relatively large sample. An online and near-real-time ringdown exhaled NO analyzer calibrated by an electrochemical sensor at clinical was used for breath analysis. A total of 740 breath samples from 284 healthy control subjects (H) and 456 lung cancer patients (LC) were collected. The recorded data included exhaled NO, medications taken within the last half month, demographics, fasting status and smoking status. The LC had a significantly higher level of exhaled NO than the H (H: 21.0 ± 12.1 ppb vs. LC: 34.1 ± 17.2 ppb). The area under the receiver operating characteristic curve for exhaled NO predicting LC and H was 0.728 (sensitivity was 0.798; specificity was 0.55). There was no significant difference in exhaled NO level between groups divided by different types of LC, tumor node metastasis (TNM) stage, sex, smoking status, age, body mass index (BMI) or fasting status. Exhaled NO level alone is not a useful clinical tool for identifying lung cancer, but it should be considered when developing a diagnosis model of lung cancer by using breath analysis.

An exploratory study on online quantification of isoprene in human breath using cavity ringdown spectroscopy in the ultraviolet.

Breath analysis offers a promising method of noninvasive analyses of volatile metabolites and xenobiotics present in human body. Isoprene is one of the highest abundant volatile organic compounds (VOCs) present in human exhaled breath. Breath isoprene (50-200 part per billion by volume (ppbv) or higher) can be analyzed by using mass spectroscopy-based methods, yet laser absorption spectral detection of breath isoprene has not been much reported, partially due to its ultraviolet (UV) absorption wavelength and the spectral overlap with other breath VOCs such as acetone in the same wavelength region. These facts make it challenging to develop a spectroscopy-based breath isoprene analyzer for a potential portable instrument. Here we report on the development of a cavity ringdown spectroscopy (CRDS) system for detection of breath isoprene in the UV region near 226 nm. First, we investigated spectral absorption interferences near 226 nm and selected an optimal detection wavelength at 226.56 nm with minimum to no spectral interference. We then measured absorption cross-sections of isoprene at 225.5-227.4 nm under controlled cavity pressures, and the measured absorption cross-section 1.93 × 10-17 cm2/molecule at 226.56 nm was used to quantify isoprene in different cases including human breath gas samples. Finally, we validated the CRDS system by measuring breath gas samples from 19 human subjects using proton transfer reaction mass spectrometry (PTR-MS). The CRDS system shows good linear response (R2 = 0.999), high stability (0.2%), and high accuracy (R2 = 0.906 with PTR-MS). The limit of detection of the system was 0.47 ppbv, with average over 100 ringdown events (equivalent to 5 s). This work represents the first exploratory study of the detection of breath isoprene using CRDS. The results demonstrate the potential of developing a CRDS-based breath analyzer for online, near-real time, sensitive analysis of breath isoprene for further research that would help to elucidate its physiological and clinical significance.

Cavity ringdown spectroscopy of nitric oxide in the ultraviolet region for human breath test.

We report the spectrum of nitric oxide (NO) in the ultraviolet (UV) (225.4-227.0 nm) region based on cavity ringdown spectroscopy (CRDS). A cavity ringdown system, which consisted of a tunable UV laser source and a vacuum-pumped ringdown cavity, was constructed to measure NO at room temperature and atmospheric or reduced pressure. The measured spectra were validated using LIFBase simulations. The absorption cross-section of NO at the strongest absorption peak at 226.255 nm was measured to be 7.64 × 10-18 cm2 molecule-1. Using the measured mirror reflectivity of 99.55% at 226.255 nm, the detection limit of NO was determined to be 7.4 ppb (parts per billion) based on the standard 3-σ criteria. The stability and reproducibility of this CRDS system were also tested. Furthermore, exhaled gas samples from 203 human subjects (105 healthy people and 98 lung cancer patients) were measured using the system. Results demonstrated that the cavity ringdown spectroscopy in the deep-UV region has potential for breath NO test.

A Portable Real-Time Ringdown Breath Acetone Analyzer: Toward Potential Diabetic Screening and Management.

Breath analysis has been considered a suitable tool to evaluate diseases of the respiratory system and those that involve metabolic changes, such as diabetes. Breath acetone has long been known as a biomarker for diabetes. However, the results from published data by far have been inconclusive regarding whether breath acetone is a reliable index of diabetic screening. Large variations exist among the results of different studies because there has been no "best-practice method" for breath-acetone measurements as a result of technical problems of sampling and analysis. In this mini-review, we update the current status of our development of a laser-based breath acetone analyzer toward real-time, one-line diabetic screening and a point-of-care instrument for diabetic management. An integrated standalone breath acetone analyzer based on the cavity ringdown spectroscopy technique has been developed. The instrument was validated by using the certificated gas chromatography-mass spectrometry. The linear fittings suggest that the obtained acetone concentrations via both methods are consistent. Breath samples from each individual subject under various conditions in total, 1257 breath samples were taken from 22 Type 1 diabetic (T1D) patients, 312 Type 2 diabetic (T2D) patients, which is one of the largest numbers of T2D subjects ever used in a single study, and 52 non-diabetic healthy subjects. Simultaneous blood glucose (BG) levels were also tested using a standard diabetic management BG meter. The mean breath acetone concentrations were determined to be 4.9 ± 16 ppm (22 T1D), and 1.5 ± 1.3 ppm (312 T2D), which are about 4.5 and 1.4 times of the one in the 42 non-diabetic healthy subjects, 1.1 ± 0.5 ppm, respectively. A preliminary quantitative correlation (R = 0.56, p < 0.05) between the mean individual breath acetone concentration and the mean individual BG levels does exist in 20 T1D subjects with no ketoacidosis. No direct correlation is observed in T1D subjects, T2D subjects, and healthy subjects. The results from a relatively large number of subjects tested indicate that an elevated mean breath acetone concentration exists in diabetic patients in general. Although many physiological parameters affect breath acetone, under a specifically controlled condition fast (<1 min) and portable breath acetone measurement can be used for screening abnormal metabolic status including diabetes, for point-of-care monitoring status of ketone bodies which have the signature smell of breath acetone, and for breath acetone related clinical studies requiring a large number of tests.

Detection of Melanoma Cancer Biomarker Dimethyl Disulfide Using Cavity Ringdown Spectroscopy at 266 nm.

Skin cells emit volatile organic compounds (VOCs), and some of them can be used as biomarkers for screening specific diseases. Dimethyl disulfide (DMDS) has been recently reported as a biomarker of melanoma skin cancer (Kwak et al. "Volatile Biomarkers from Human Melanoma Cells". J. Chromatogr. B. 2013. 931: 90-96.). With the motivation of diagnosing melanoma using DMDS as its biomarker, we explore the potential of measuring DMDS using an advanced laser spectroscopic technique as an alternative method. We report on the first DMDS measurements using an experimental system based on cavity ringdown spectroscopy (CRDS). The test samples were mixtures of DMDS vapor and nitrogen in different concentrations. Two sampling methods were investigated to dilute the DMDS sample to low concentrations for ringdown measurements. The results showed that the ringdown system responded to various DMDS concentrations linearly and a theoretical detection limit of sub-ppb (parts per billion) could be achieved at the absorption wavelength of 266 nm. This ringdown system exhibited a high dynamic range for DMDS measurements, from ppm (parts per million) to ppt (parts per trillion) levels, given different laser wavelengths used. The feasibility of developing a portable melanoma screening sensor using the CRDS technique was also demonstrated in this study.

A fully integrated standalone portable cavity ringdown breath acetone analyzer.

Breath analysis is a promising new technique for nonintrusive disease diagnosis and metabolic status monitoring. One challenging issue in using a breath biomarker for potential particular disease screening is to find a quantitative relationship between the concentration of the breath biomarker and clinical diagnostic parameters of the specific disease. In order to address this issue, we need a new instrument that is capable of conducting real-time, online breath analysis with high data throughput, so that a large scale of clinical test (more subjects) can be achieved in a short period of time. In this work, we report a fully integrated, standalone, portable analyzer based on the cavity ringdown spectroscopy technique for near-real time, online breath acetone measurements. The performance of the portable analyzer in measurements of breath acetone was interrogated and validated by using the certificated gas chromatography-mass spectrometry. The results show that this new analyzer is useful for reliable online (online introduction of a breath sample without pre-treatment) breath acetone analysis with high sensitivity (57 ppb) and high data throughput (one data per second). Subsequently, the validated breath analyzer was employed for acetone measurements in 119 human subjects under various situations. The instrument design, packaging, specifications, and future improvements were also described. From an optical ringdown cavity operated by the lab-set electronics reported previously to this fully integrated standalone new instrument, we have enabled a new scientific tool suited for large scales of breath acetone analysis and created an instrument platform that can even be adopted for study of other breath biomarkers by using different lasers and ringdown mirrors covering corresponding spectral fingerprints.

Determination of breath acetone in 149 type 2 diabetic patients using a ringdown breath-acetone analyzer.

Over 90% of diabetic patients have Type 2 diabetes. Although an elevated mean breath acetone concentration has been found to exist in Type 1 diabetes (T1D), information on breath acetone in Type 2 diabetes (T2D) has yet to be obtained. In this study, we first used gas chromatography-mass spectrometry (GC-MS) to validate a ringdown breath-acetone analyzer based on the cavity-ringdown-spectroscopy technique, through comparing breath acetone concentrations in the range 0.5-2.5 ppm measured using both methods. The linear fitting of R = 0.99 suggests that the acetone concentrations obtained using both methods are consistent with a largest standard deviation of ±0.4 ppm in the lowest concentration of the range. Next, 620 breath samples from 149 T2D patients and 42 healthy subjects were collected and tested using the breath analyzer. Four breath samples were taken from each subject under each of four different conditions: fasting, 2 h post-breakfast, 2 h post-lunch, and 2 h post-dinner. Simultaneous blood glucose levels were also measured using a standard diabetic-management blood-glucose meter. For the 149 T2D subjects, their exhaled breath acetone concentrations ranged from 0.1 to 19.8 ppm; four different ranges of breath acetone concentration, 0.1-19.8, 0.1-7.1, 0.1-6.3, and 0.1-9.5 ppm, were obtained for the subjects under the four different conditions, respectively. For the 42 healthy subjects, their breath acetone concentration ranged from 0.1 to 2.6 ppm; four different ranges of breath acetone concentration, 0.3-2.6, 0.1-2.6, 0.1-1.7, and 0.3-1.6 ppm, were obtained for the four different conditions. The mean breath acetone concentration of the 149 T2D subjects was determined to be 1.5 ± 1.5 ppm, which was 1.5 times that of 1.0 ± 0.6 ppm for the 42 healthy subjects. No correlation was found between the breath acetone concentration and the blood glucose level of the T2D subjects and the healthy volunteers. This study using a relatively large number of subjects provides new data regarding breath acetone in diabetes (T1D and T2D) and suggests that an elevated mean breath acetone concentration also exists in T2D.

[The noninvasive measurement research of human blood parameters under flow control of time gate].

In order to further improve the noninvasive measurement precision of human blood components and achieve clinical requirements, we propose a new measurement method based on the dynamic dual wavelength time-resolved transmittance measurement, combined with the advanced time gate technology and Laplasse transform to detect human blood components noninvasively in the blocked blood flow conditions. Simulation results show that when p>0, emphasizing the importance of early arriving photons contribution can enhance the detection sensitivity of human body blood parameters.

Effect of surface roughness on determination of tissue optical properties obtained by diffusion approximation.

A nylon bar with different surface roughness is used as a simulation sample of biological tissue for the determination of optical properties by using the spatially resolved steady-state diffuse reflection technique. The results obtained indicate that surface roughness has some effects on the determination of the optical properties of the nylon bar. The determined reduced scattering coefficient decreases with the decrease of the surface roughness of the nylon bar and goes to a constant for the lower surface roughness, and the determined absorption coefficient increases with the decrease of the surface roughness of the nylon bar. Consequently, the optical properties of the tissues obtained by the spatially resolved steady-state diffuse reflection technique should be modified.