Machine learning approaches in microbiome research: challenges and best practices.

Microbiome data predictive analysis within a machine learning (ML) workflow presents numerous domain-specific challenges involving preprocessing, feature selection, predictive modeling, performance estimation, model interpretation, and the extraction of biological information from the results. To assist decision-making, we offer a set of recommendations on algorithm selection, pipeline creation and evaluation, stemming from the COST Action ML4Microbiome. We compared the suggested approaches on a multi-cohort shotgun metagenomics dataset of colorectal cancer patients, focusing on their performance in disease diagnosis and biomarker discovery. It is demonstrated that the use of compositional transformations and filtering methods as part of data preprocessing does not always improve the predictive performance of a model. In contrast, the multivariate feature selection, such as the Statistically Equivalent Signatures algorithm, was effective in reducing the classification error. When validated on a separate test dataset, this algorithm in combination with random forest modeling, provided the most accurate performance estimates. Lastly, we showed how linear modeling by logistic regression coupled with visualization techniques such as Individual Conditional Expectation (ICE) plots can yield interpretable results and offer biological insights. These findings are significant for clinicians and non-experts alike in translational applications.

Advancing microbiome research with machine learning: key findings from the ML4Microbiome COST action.

The rapid development of machine learning (ML) techniques has opened up the data-dense field of microbiome research for novel therapeutic, diagnostic, and prognostic applications targeting a wide range of disorders, which could substantially improve healthcare practices in the era of precision medicine. However, several challenges must be addressed to exploit the benefits of ML in this field fully. In particular, there is a need to establish "gold standard" protocols for conducting ML analysis experiments and improve interactions between microbiome researchers and ML experts. The Machine Learning Techniques in Human Microbiome Studies (ML4Microbiome) COST Action CA18131 is a European network established in 2019 to promote collaboration between discovery-oriented microbiome researchers and data-driven ML experts to optimize and standardize ML approaches for microbiome analysis. This perspective paper presents the key achievements of ML4Microbiome, which include identifying predictive and discriminatory 'omics' features, improving repeatability and comparability, developing automation procedures, and defining priority areas for the novel development of ML methods targeting the microbiome. The insights gained from ML4Microbiome will help to maximize the potential of ML in microbiome research and pave the way for new and improved healthcare practices.

A method for AI assisted human interpretation of neonatal EEG.

The study proposes a novel method to empower healthcare professionals to interact and leverage AI decision support in an intuitive manner using auditory senses. The method's suitability is assessed through acoustic detection of the presence of neonatal seizures in electroencephalography (EEG). Neurophysiologists use EEG recordings to identify seizures visually. However, neurophysiological expertise is expensive and not available 24/7, even in tertiary hospitals. Other neonatal and pediatric medical professionals (nurses, doctors, etc.) can make erroneous interpretations of highly complex EEG signals. While artificial intelligence (AI) has been widely used to provide objective decision support for EEG analysis, AI decisions are not always explainable. This work developed a solution to combine AI algorithms with a human-centric intuitive EEG interpretation method. Specifically, EEG is converted to sound using an AI-driven attention mechanism. The perceptual characteristics of seizure events can be heard using this method, and an hour of EEG can be analysed in five seconds. A survey that has been conducted among targeted end-users on a publicly available dataset has demonstrated that not only does it drastically reduce the burden of reviewing the EEG data, but also the obtained accuracy is on par with experienced neurophysiologists trained to interpret neonatal EEG. It is also shown that the proposed communion of a medical professional and AI outperforms AI alone by empowering the human with little or no experience to leverage AI attention mechanisms to enhance the perceptual characteristics of seizure events.

Automatic segmentation for neonatal phonocardiogram.

This work addresses the automatic segmentation of neonatal phonocardiogram (PCG) to be used in the artificial intelligence-assisted diagnosis of abnormal heart sounds. The proposed novel algorithm has a single free parameter - the maximum heart rate. The algorithm is compared with the baseline algorithm, which was developed for adult PCG segmentation. When evaluated on a large clinical dataset of neonatal PCG with a total duration of over 7h, an F1 score of 0.94 is achieved. The main features relevant for the segmentation of neonatal PCG are identified and discussed. The algorithm is able to increase the number of cardiac cycles by a factor of 5 compared to manual segmentation, potentially allowing to improve the performance of heart abnormality detection algorithms.

An EEG analysis framework through AI and sonification on low power IoT edge devices.

This study explores the feasibility of implementation of an analysis framework of neonatal EEG, including ML, sonification and intuitive visualization, on a low power IoT edge device. Electroencephalography (EEG) analysis is a very important tool to detect brain disorders. Neonatal seizure detection is a known, challenging problem. Under-resourced communities across the globe are particularly affected by the cost associated with EEG analysis and interpretation. Machine learning (ML) techniques have been successfully utilized to automate seizure detection in neonatal EEG, in order to assist a healthcare professional in visual analysis. Several usage scenarios are reviewed in this study. It is shown that both sonification and ML can be efficiently implemented on low-power edge platforms without any loss of accuracy. The developed platform can be easily expanded to address EEG analysis applications in neonatal and adult population.

Towards Deeper Neural Networks for Neonatal Seizure Detection.

Machine learning and more recently deep learning have become valuable tools in clinical decision making for neonatal seizure detection. This work proposes a deep neural network architecture which is capable of extracting information from long segments of EEG. Residual connections as well as data augmentation and a more robust optimizer are efficiently exploited to train a deeper architecture with an increased receptive field and longer EEG input. The proposed system is tested on a large clinical dataset of 4,570 hours of duration and benchmarked on a publicly available Helsinki dataset of 112 hours duration. The performance has improved from an AUC of 95.41% to an AUC of 97.73% when compared to a deep learning baseline.

Deep Learning for EEG Seizure Detection in Preterm Infants.

EEG is the gold standard for seizure detection in the newborn infant, but EEG interpretation in the preterm group is particularly challenging; trained experts are scarce and the task of interpreting EEG in real-time is arduous. Preterm infants are reported to have a higher incidence of seizures compared to term infants. Preterm EEG morphology differs from that of term infants, which implies that seizure detection algorithms trained on term EEG may not be appropriate. The task of developing preterm specific algorithms becomes extra-challenging given the limited amount of annotated preterm EEG data available. This paper explores novel deep learning (DL) architectures for the task of neonatal seizure detection in preterm infants. The study tests and compares several approaches to address the problem: training on data from full-term infants; training on data from preterm infants; training on age-specific preterm data and transfer learning. The system performance is assessed on a large database of continuous EEG recordings of 575[Formula: see text]h in duration. It is shown that the accuracy of a validated term-trained EEG seizure detection algorithm, based on a support vector machine classifier, when tested on preterm infants falls well short of the performance achieved for full-term infants. An AUC of 88.3% was obtained when tested on preterm EEG as compared to 96.6% obtained when tested on term EEG. When re-trained on preterm EEG, the performance marginally increases to 89.7%. An alternative DL approach shows a more stable trend when tested on the preterm cohort, starting with an AUC of 93.3% for the term-trained algorithm and reaching 95.0% by transfer learning from the term model using available preterm data. The proposed DL approach avoids time-consuming explicit feature engineering and leverages the existence of the term seizure detection model, resulting in accurate predictions with a minimum amount of annotated preterm data.

A Framework for AI-Assisted Detection of Patent Ductus Arteriosus from Neonatal Phonocardiogram.

The current diagnosis of Congenital Heart Disease (CHD) in neonates relies on echocardiography. Its limited availability requires alternative screening procedures to prioritise newborns awaiting ultrasound. The routine screening for CHD is performed using a multidimensional clinical examination including (but not limited to) auscultation and pulse oximetry. While auscultation might be subjective with some heart abnormalities not always audible it increases the ability to detect heart defects. This work aims at developing an objective clinical decision support tool based on machine learning (ML) to facilitate differentiation of sounds with signatures of Patent Ductus Arteriosus (PDA)/CHDs, in clinical settings. The heart sounds are pre-processed and segmented, followed by feature extraction. The features are fed into a boosted decision tree classifier to estimate the probability of PDA or CHDs. Several mechanisms to combine information from different auscultation points, as well as consecutive sound cycles, are presented. The system is evaluated on a large clinical dataset of heart sounds from 265 term and late-preterm newborns recorded within the first six days of life. The developed system reaches an area under the curve (AUC) of 78% at detecting CHD and 77% at detecting PDA. The obtained results for PDA detection compare favourably with the level of accuracy achieved by an experienced neonatologist when assessed on the same cohort.

Gut microbiome, big data and machine learning to promote precision medicine for cancer.

The gut microbiome has been implicated in cancer in several ways, as specific microbial signatures are known to promote cancer development and influence safety, tolerability and efficacy of therapies. The 'omics' technologies used for microbiome analysis continuously evolve and, although much of the research is still at an early stage, large-scale datasets of ever increasing size and complexity are being produced. However, there are varying levels of difficulty in realizing the full potential of these new tools, which limit our ability to critically analyse much of the available data. In this Perspective, we provide a brief overview on the role of gut microbiome in cancer and focus on the need, role and limitations of a machine learning-driven approach to analyse large amounts of complex health-care information in the era of big data. We also discuss the potential application of microbiome-based big data aimed at promoting precision medicine in cancer.

Ensembling crowdsourced seizure prediction algorithms using long-term human intracranial EEG.

Seizure prediction is feasible, but greater accuracy is needed to make seizure prediction clinically viable across a large group of patients. Recent work crowdsourced state-of-the-art prediction algorithms in a worldwide competition, yielding improvements in seizure prediction performance for patients whose seizures were previously found hard to anticipate. The aim of the current analysis was to explore potential performance improvements using an ensemble of the top competition algorithms. The results suggest that minor increments in performance may be possible; however, the outcomes of statistical testing limit the confidence in these increments. Our results suggest that for the specific algorithms, evaluation framework, and data considered here, incremental improvements are achievable but there may be upper bounds on machine learning-based seizure prediction performance for some patients whose seizures are challenging to predict. Other more tailored approaches that, for example, take into account a deeper understanding of preictal mechanisms, patient-specific sleep-wake rhythms, or novel measurement approaches, may still offer further gains for these types of patients.

Neonatal seizure detection from raw multi-channel EEG using a fully convolutional architecture.

A deep learning classifier for detecting seizures in neonates is proposed. This architecture is designed to detect seizure events from raw electroencephalogram (EEG) signals as opposed to the state-of-the-art hand engineered feature-based representation employed in traditional machine learning based solutions. The seizure detection system utilises only convolutional layers in order to process the multichannel time domain signal and is designed to exploit the large amount of weakly labelled data in the training stage. The system performance is assessed on a large database of continuous EEG recordings of 834h in duration; this is further validated on a held-out publicly available dataset and compared with two baseline SVM based systems. The developed system achieves a 56% relative improvement with respect to a feature-based state-of-the art baseline, reaching an AUC of 98.5%; this also compares favourably both in terms of performance and run-time. The effect of varying architectural parameters is thoroughly studied. The performance improvement is achieved through novel architecture design which allows more efficient usage of available training data and end-to-end optimisation from the front-end feature extraction to the back-end classification. The proposed architecture opens new avenues for the application of deep learning to neonatal EEG, where the performance becomes a function of the amount of training data with less dependency on the availability of precise clinical labels.

Prediction of short-term health outcomes in preterm neonates from heart-rate variability and blood pressure using boosted decision trees.

BACKGROUND AND OBJECTIVE: Efficient management of low blood pressure (BP) in preterm neonates remains challenging with considerable variability in clinical practice. There is currently no clear consensus on what constitutes a limit for low BP that is a risk to the preterm brain. It is argued that a personalised approach rather than a population based threshold is more appropriate. This work aims to assist healthcare professionals in assessing preterm wellbeing during episodes of low BP in order to decide when and whether hypotension treatment should be initiated. In particular, the study investigates the relationship between heart rate variability (HRV) and BP in preterm infants and its relevance to a short-term health outcome. METHODS: The study is performed on a large clinically collected dataset of 831 h from 23 preterm infants of less than 32 weeks gestational age. The statistical predictive power of common HRV features is first assessed with respect to the outcome. A decision support system, based on boosted decision trees (XGboost), was developed to continuously estimate the probability of neonatal morbidity based on the feature vector of HRV characteristics and the mean arterial blood pressure. RESULTS: It is shown that the predictive power of the extracted features improves when observed during episodes of hypotension. A single best HRV feature achieves an AUC of 0.87. Combining multiple HRV features extracted during hypotensive episodes with the classifier achieves an AUC of 0.97, using a leave-one-patient-out performance assessment. Finally it is shown that good performance can even be achieved using continuous HRV recordings, rather than only focusing on hypotensive events - this had the benefit of not requiring invasive BP monitoring. CONCLUSIONS: The work presents a promising step towards the use of multimodal data in providing objective decision support for the prediction of short-term outcome in preterm infants with hypotensive episodes.

Analysis of a Low-Cost EEG Monitoring System and Dry Electrodes toward Clinical Use in the Neonatal ICU.

Electroencephalography (EEG) is an important clinical tool for monitoring neurological health. However, the required equipment, expertise, and patient preparation inhibits its use outside of tertiary care. Non-experts struggle to obtain high-quality EEG due to its low amplitude and artefact susceptibility. Wet electrodes are currently used, which require abrasive/conductive gels to reduce skin-electrode impedance. Advances in dry electrodes, which do not require gels, have simplified this process. However, the assessment of dry electrodes on neonates is limited due to health and safety barriers. This study presents a simulation framework for assessing the quality of EEG systems using a neonatal EEG database, without the use of human participants. The framework is used to evaluate a low-cost EEG acquisition system and compare performance of wet and dry (Micro Transdermal Interface Platforms (MicroTIPs), g.tec-g.SAHARA) electrodes using accurately acquired impedance models. A separate experiment assessing the electrodes on adult participants was conducted to verify the simulation framework's efficacy. Dry electrodes have higher impedance than wet electrodes, causing a reduction in signal quality. However, MicroTIPs perform comparably to wet electrodes at the frontal region and g.tec-g.SAHARA performs well at the occipital region. Using the simulation framework, a 25dB signal-to-noise ratio (SNR) was obtained for the low-cost EEG system. The tests on adults closely matched the simulated results.

System Level Framework for Assessing the Accuracy of Neonatal EEG Acquisition.

Significant research has been conducted in recent years to design low-cost alternatives to the current EEG monitoring systems used in healthcare facilities. Testing such systems on a vulnerable population such as newborns is complicated due to ethical and regulatory considerations that slow down the technical development. This paper presents and validates a method for quantifying the accuracy of neonatal EEG acquisition systems and electrode technologies via clinical data simulations that do not require neonatal participants. The proposed method uses an extensive neonatal EEG database to simulate analogue signals, which are subsequently passed through electrical models of the skin-electrode interface, which are developed using wet and dry EEG electrode designs. The signal losses in the system are quantified at each stage of the acquisition process for electrode and acquisition board losses. SNR, correlation and noise values were calculated. The results verify that low-cost EEG acquisition systems are capable of obtaining clinical grade EEG. Although dry electrodes result in a significant increase in the skin-electrode impedance, accurate EEG recordings are still achievable.

Neonatal EEG Interpretation and Decision Support Framework for Mobile Platforms.

This paper proposes and implements an intuitive and pervasive solution for neonatal EEG monitoring assisted by sonification and deep learning AI that provides information about neonatal brain health to all neonatal healthcare professionals, particularly those without EEG interpretation expertise. The system aims to increase the demographic of clinicians capable of diagnosing abnormalities in neonatal EEG. The proposed system uses a low-cost and low-power EEG acquisition system. An Android app provides single-channel EEG visualization, traffic-light indication of the presence of neonatal seizures provided by a trained, deep convolutional neural network and an algorithm for EEG sonification, designed to facilitate the perception of changes in EEG morphology specific to neonatal seizures. The multifaceted EEG interpretation framework is presented and the implemented mobile platform architecture is analyzed with respect to its power consumption and accuracy.

Heart Rate Variability during Periods of Low Blood Pressure as a Predictor of Short-Term Outcome in Preterms.

Efficient management of low blood pressure (BP) in preterm neonates remains challenging with a considerable variability in clinical practice. The ability to assess preterm wellbeing during episodes of low BP will help to decide when and whether hypotension treatment should be initiated. This work aims to investigate the relationship between heart rate variability (HRV), BP and the short-term neurological outcome in preterm infants less than 32 weeks gestational age (GA). The predictive power of common HRV features with respect to the outcome is assessed and shown to improve when HRV is observed during episodes of low mean arterial pressure (MAP) - with a single best feature leading to an AUC of 0.87. Combining multiple features with a boosted decision tree classifier achieves an AUC of 0.97. The work presents a promising step towards the use of multimodal data in building an objective decision support tool for clinical prediction of short-term outcome in preterms who suffer episodes of low BP.

Investigating the Impact of CNN Depth on Neonatal Seizure Detection Performance.

This study presents a novel, deep, fully convolutional architecture which is optimized for the task of EEG-based neonatal seizure detection. Architectures of different depths were designed and tested; varying network depth impacts convolutional receptive fields and the corresponding learned feature complexity. Two deep convolutional networks are compared with a shallow SVMbased neonatal seizure detector, which relies on the extraction of hand-crafted features. On a large clinical dataset, of over 800 hours of multichannel unedited EEG, containing 1389 seizure events, the deep 11-layer architecture significantly outperforms the shallower architectures, improving the AUC90 from 82.6% to 86.8%. Combining the end-to-end deep architecture with the feature-based shallow SVM further improves the AUC90 to 87.6%. The fusion of classifiers of different depths gives greatly improved performance and reduced variability, making the combined classifier more clinically reliable.

Epilepsyecosystem.org: crowd-sourcing reproducible seizure prediction with long-term human intracranial EEG.

Accurate seizure prediction will transform epilepsy management by offering warnings to patients or triggering interventions. However, state-of-the-art algorithm design relies on accessing adequate long-term data. Crowd-sourcing ecosystems leverage quality data to enable cost-effective, rapid development of predictive algorithms. A crowd-sourcing ecosystem for seizure prediction is presented involving an international competition, a follow-up held-out data evaluation, and an online platform, Epilepsyecosystem.org, for yielding further improvements in prediction performance. Crowd-sourced algorithms were obtained via the 'Melbourne-University AES-MathWorks-NIH Seizure Prediction Challenge' conducted at kaggle.com. Long-term continuous intracranial electroencephalography (iEEG) data (442 days of recordings and 211 lead seizures per patient) from prediction-resistant patients who had the lowest seizure prediction performances from the NeuroVista Seizure Advisory System clinical trial were analysed. Contestants (646 individuals in 478 teams) from around the world developed algorithms to distinguish between 10-min inter-seizure versus pre-seizure data clips. Over 10 000 algorithms were submitted. The top algorithms as determined by using the contest data were evaluated on a much larger held-out dataset. The data and top algorithms are available online for further investigation and development. The top performing contest entry scored 0.81 area under the classification curve. The performance reduced by only 6.7% on held-out data. Many other teams also showed high prediction reproducibility. Pseudo-prospective evaluation demonstrated that many algorithms, when used alone or weighted by circadian information, performed better than the benchmarks, including an average increase in sensitivity of 1.9 times the original clinical trial sensitivity for matched time in warning. These results indicate that clinically-relevant seizure prediction is possible in a wider range of patients than previously thought possible. Moreover, different algorithms performed best for different patients, supporting the use of patient-specific algorithms and long-term monitoring. The crowd-sourcing ecosystem for seizure prediction will enable further worldwide community study of the data to yield greater improvements in prediction performance by way of competition, collaboration and synergism.10.1093/brain/awy210_video1awy210media15817489051001.

Coupling between mean blood pressure and EEG in preterm neonates is associated with reduced illness severity scores.

Hypotension or low blood pressure (BP) is a common problem in preterm neonates and has been associated with adverse short and long-term neurological outcomes. Deciding when and whether to treat hypotension relies on an understanding of the relationship between BP and brain functioning. This study aims to investigate the interaction (coupling) between BP and continuous multichannel unedited EEG recordings in preterm infants less than 32 weeks of gestational age. The EEG was represented by spectral power in four frequency sub-bands: 0.3-3 Hz, 3-8 Hz, 8-15 Hz and 15-30 Hz. BP was represented as mean arterial pressure (MAP). The level of coupling between the two physiological systems was estimated using linear and nonlinear methods such as correlation, coherence and mutual information. Causality of interaction was measured using transfer entropy. The illness severity was represented by the clinical risk index for babies (CRIB II score) and contrasted to the computed level of interaction. It is shown here that correlation and coherence, which are linear measures of the coupling between EEG and MAP, do not correlate with CRIB values, whereas adjusted mutual information, a nonlinear measure, is associated with CRIB scores (r = -0.57, p = 0.003). Mutual information is independent of the absolute values of MAP and EEG powers and quantifies the level of coupling between the short-term dynamics in both signals. The analysis indicated that the dominant causality is from changes in EEG producing changes in MAP. Transfer entropy (EEG to MAP) is associated with the CRIB score (0.3-3 Hz: r = 0.428, p = 0.033, 3-8 Hz: r = 0.44, p = 0.028, 8-15 Hz: r = 0.416, p = 0.038) and indicates that a higher level of directed coupling from brain activity to blood pressure is associated with increased illness in preterm infants. This is the first study to present the nonlinear measure of interaction between brain activity and blood pressure and to demonstrate its relation to the initial illness severity in the preterm infant. The obtained results allow us to hypothesise that the normal wellbeing of a preterm neonate can be characterised by a nonlinear coupling between brain activity and MAP, whereas the presence of weak coupling with distinctive directionality of information flow is associated with an increased mortality rate in preterms.

Portable neonatal EEG monitoring and sonification on an Android device.

Clinical evaluation of electroencephalogram (EEG) is important for understanding and monitoring the electrical activity present in the brain. In collusion with engineering advances, the movement towards portable, rapid and low-cost EEG monitoring is growing. This will allow a greater availability of monitoring technologies for assessing brain function and health in disadvantaged communities. This paper presents an alternative method for interpreting neonatal brain health in real-time via the sonification of EEG on a smartphone. The paper discusses the implementation of the real-time EEG sonification using a phase vocoder and shows how the method is achievable using low-cost smartphone technologies with energy efficient algorithms.