Machine learning enabled detection of COVID-19 pneumonia using exhaled breath analysis: a proof-of-concept study.

Detection of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) relies on real-time-reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. The false-negative rate of RT-PCR can be high when viral burden and infection is localized distally in the lower airways and lung parenchyma. An alternate safe, simple and accessible method for sampling the lower airways is needed to aid in the early and rapid diagnosis of COVID-19 pneumonia. In a prospective unblinded observational study, patients admitted with a positive RT-PCR and symptoms of SARS-CoV-2 infection were enrolled from three hospitals in Ontario, Canada. Healthy individuals or hospitalized patients with negative RT-PCR and without respiratory symptoms were enrolled into the control group. Breath samples were collected and analyzed by laser absorption spectroscopy (LAS) for volatile organic compounds (VOCs) and classified by machine learning (ML) approaches to identify unique LAS-spectra patterns (breathprints) for SARS-CoV-2. Of the 135 patients enrolled, 115 patients provided analyzable breath samples. Using LAS-breathprints to train ML classifier models resulted in an accuracy of 72.2%-81.7% in differentiating between SARS-CoV2 positive and negative groups. The performance was consistent across subgroups of different age, sex, body mass index, SARS-CoV-2 variants, time of disease onset and oxygen requirement. The overall performance was higher than compared to VOC-trained classifier model, which had an accuracy of 63%-74.7%. This study demonstrates that a ML-based breathprint model using LAS analysis of exhaled breath may be a valuable non-invasive method for studying the lower airways and detecting SARS-CoV-2 and other respiratory pathogens. The technology and the ML approach can be easily deployed in any setting with minimal training. This will greatly improve access and scalability to meet surge capacity; allow early and rapid detection to inform therapy; and offers great versatility in developing new classifier models quickly for future outbreaks.

Infrared cavity ring-down spectroscopy for detecting non-small cell lung cancer in exhaled breath.

Early diagnosis of lung cancer greatly improves the likelihood of survival and remission, but limitations in existing technologies like low-dose computed tomography have prevented the implementation of widespread screening programs. Breath-based solutions that seek disease biomarkers in exhaled volatile organic compound (VOC) profiles show promise as affordable, accessible and non-invasive alternatives to traditional imaging. In this pilot work, we present a lung cancer detection framework using cavity ring-down spectroscopy (CRDS), an effective and practical laser absorption spectroscopy technique that has the ability to advance breath screening into clinical reality. The main aims of this work were to (1) test the utility of infrared CRDS breath profiles for discriminating non-small cell lung cancer (NSCLC) patients from controls, (2) compare models with VOCs as predictors to those with patterns from the CRDS spectra (breathprints) as predictors, and (3) present a robust approach for identifying relevant disease biomarkers. First, based on a proposed learning curve technique that estimated the limits of a model's performance at multiple sample sizes (10-158), the CRDS-based models developed in this work were found to achieve classification performance comparable or superior to like mass spectroscopy and sensor-based systems. Second, using 158 collected samples (62 NSCLC subjects and 96 controls), the accuracy range for the VOC-based model was 65.19%-85.44% (51.61%-66.13% sensitivity and 73.96%-97.92% specificity), depending on the employed cross-validation technique. The model based on breathprint predictors generally performed better, with accuracy ranging from 71.52%-86.08% (58.06%-82.26% sensitivity and 80.21%-88.54% specificity). Lastly, using a protocol based on consensus feature selection, three VOCs (isopropanol, dimethyl sulfide, and butyric acid) and two breathprint features (from a local binary pattern transformation of the spectra) were identified as possible NSCLC biomarkers. This research demonstrates the potential of infrared CRDS breath profiles and the developed early-stage classification techniques for lung cancer biomarker detection and screening.

Data Pre-Processing of Infrared Spectral Breathprints for Lung Cancer Detection.

Though breath analysis shows promise as a noninvasive and cost-effective approach to lung cancer screening, biomarkers in exhaled breath samples can be overwhelmed by irrelevant internal and environmental volatile organic compounds (VOCs). These extraneous VOCs can obscure the disease signature in a spectral breathprint, hindering the performance of pattern recognition models. In this work, pre-processing pipelines consisting of missing value replacement, detrending, and normalization techniques were evaluated to reduce these effects and enhance the features of interest in infrared cavity ring-down spectra. The best performing pipeline consisted of moving average detrending, linear interpolation for missing values, and vector normalization. This model achieved an average accuracy of 73.04% across five types of classifiers, exhibiting an 8.36% improvement compared to a baseline model (p < 0.05). A linear support vector machine classifier yielded the best performance (79.75% accuracy, 67.74% sensitivity, 87.50% specificity). This work can serve to guide pre-processing in future lung cancer breath research and, more broadly, in infrared laser absorption spectroscopy in general.

Machine Learning Model Validation for Early Stage Studies with Small Sample Sizes.

In early stage biomedical studies, small datasets are common due to the high cost and difficulty of sample collection with human subjects. This complicates the validation of machine learning models, which are best suited for large datasets. In this work, we examined feature selection techniques, validation frameworks, and learning curve fitting for small simulated datasets with known underlying discriminability, with the aim of identifying a protocol for estimating and interpreting early stage model performance and for planning future studies. Of a variety of examined validation configurations, a nested cross-validation framework provided the most accurate reflection of the selected features' discriminability, but the relevant features were often not properly identified during the feature selection stage for datasets with small sample sizes. Ultimately, we recommend that: (1) filter-based feature selection methods should be used to minimize overfitting to noise-based features, (2) statistical exploration should be conducted on datasets as a whole to estimate the level of discriminability and the feasibility of the classification problems, and (3) learning curves should be employed using nested cross-validation performance estimates for forecasting accuracy at larger sample sizes and estimating the required number of samples to converge towards best performance. This work should serve as a guideline for researchers incorporating machine learning in small-scale pilot studies.

Fractal Analysis of Human Gait Variability via Stride Interval Time Series.

Fractal analysis of stride interval time series is a useful tool in human gait research which could be used as a marker for gait adaptability, gait disorder, and fall risk among patients with movement disorders. This study is designed to systematically and comprehensively investigate two practical aspects of fractal analysis which significantly affect the outcome: the series length and the parameters used in the algorithm. The Hurst exponent, scaling exponent, and/or fractal dimension are computed from both simulated and experimental data using three fractal methods, namely detrended fluctuation analysis, box-counting dimension, and Higuchi's fractal dimension. The advantages and drawbacks of each method are discussed, in terms of biases and variability. The results demonstrate that a careful selection of fractal analysis methods and their parameters is required, which is dependent on the aim of study (either analyzing differences between experimental groups or estimating an accurate determination of fractal features). A set of guidelines for the selection of the fractal methods and the length of stride interval time series is provided, along with the optimal parameters for a robust implementation for each method.