Extraction and Detection of Fetal Electrocardiograms from Abdominal Recordings

The non-invasive fetal ECG (NIFECG), derived from abdominal surface electrodes, offers novel diagnostic possibilities for prenatal medicine. Despite its straightforward applicability, NIFECG signals are usually corrupted by many interfering sources. Most significantly, by the maternal ECG (MECG), whose amplitude usually exceeds that of the fetal ECG (FECG) by multiple times. The presence of additional noise sources (e.g. muscular/uterine noise, electrode motion, etc.) further affects the signal-to-noise ratio (SNR) of the FECG. These interfering sources, which typically show a strong non-stationary behavior, render the FECG extraction and fetal QRS (FQRS) detection demanding signal processing tasks. In this thesis, several of the challenges regarding NIFECG signal analysis were addressed. In order to improve NIFECG extraction, the dynamic model of a Kalman filter approach was extended, thus, providing a more adequate representation of the mixture of FECG, MECG, and noise. In addition, aiming at the FECG signal quality assessment, novel metrics were proposed and evaluated. Further, these quality metrics were applied in improving FQRS detection and fetal heart rate estimation based on an innovative evolutionary algorithm and Kalman filtering signal fusion, respectively. The elaborated methods were characterized in depth using both simulated and clinical data, produced throughout this thesis. To stress-test extraction algorithms under ideal circumstances, a comprehensive benchmark protocol was created and contributed to an extensively improved NIFECG simulation toolbox. The developed toolbox and a large simulated dataset were released under an open-source license, allowing researchers to compare results in a reproducible manner. Furthermore, to validate the developed approaches under more realistic and challenging situations, a clinical trial was performed in collaboration with the University Hospital of Leipzig. Aside from serving as a test set for the developed algorithms, the clinical trial enabled an exploratory research. This enables a better understanding about the pathophysiological variables and measurement setup configurations that lead to changes in the abdominal signal's SNR. With such broad scope, this dissertation addresses many of the current aspects of NIFECG analysis and provides future suggestions to establish NIFECG in clinical settings.:Abstract Acknowledgment Contents List of Figures List of Tables List of Abbreviations List of Symbols (1)Introduction 1.1)Background and Motivation 1.2)Aim of this Work 1.3)Dissertation Outline 1.4)Collaborators and Conflicts of Interest (2)Clinical Background 2.1)Physiology 2.1.1)Changes in the maternal circulatory system 2.1.2)Intrauterine structures and feto-maternal connection 2.1.3)Fetal growth and presentation 2.1.4)Fetal circulatory system 2.1.5)Fetal autonomic nervous system 2.1.6)Fetal heart activity and underlying factors 2.2)Pathology 2.2.1)Premature rupture of membrane 2.2.2)Intrauterine growth restriction 2.2.3)Fetal anemia 2.3)Interpretation of Fetal Heart Activity 2.3.1)Summary of clinical studies on FHR/FHRV 2.3.2)Summary of studies on heart conduction 2.4)Chapter Summary (3)Technical State of the Art 3.1)Prenatal Diagnostic and Measuring Technique 3.1.1)Fetal heart monitoring 3.1.2)Related metrics 3.2)Non-Invasive Fetal ECG Acquisition 3.2.1)Overview 3.2.2)Commercial equipment 3.2.3)Electrode configurations 3.2.4)Available NIFECG databases 3.2.5)Validity and usability of the non-invasive fetal ECG 3.3)Non-Invasive Fetal ECG Extraction Methods 3.3.1)Overview on the non-invasive fetal ECG extraction methods 3.3.2)Kalman filtering basics 3.3.3)Nonlinear Kalman filtering 3.3.4)Extended Kalman filter for FECG estimation 3.4)Fetal QRS Detection 3.4.1)Merging multichannel fetal QRS detections 3.4.2)Detection performance 3.5)Fetal Heart Rate Estimation 3.5.1)Preprocessing the fetal heart rate 3.5.2)Fetal heart rate statistics 3.6)Fetal ECG Morphological Analysis 3.7)Problem Description 3.8)Chapter Summary (4)Novel Approaches for Fetal ECG Analysis 4.1)Preliminary Considerations 4.2)Fetal ECG Extraction by means of Kalman Filtering 4.2.1)Optimized Gaussian approximation 4.2.2)Time-varying covariance matrices 4.2.3)Extended Kalman filter with unknown inputs 4.2.4)Filter calibration 4.3)Accurate Fetal QRS and Heart Rate Detection 4.3.1)Multichannel evolutionary QRS correction 4.3.2)Multichannel fetal heart rate estimation using Kalman filters 4.4)Chapter Summary (5)Data Material 5.1)Simulated Data 5.1.1)The FECG Synthetic Generator (FECGSYN) 5.1.2)The FECG Synthetic Database (FECGSYNDB) 5.2)Clinical Data 5.2.1)Clinical NIFECG recording 5.2.2)Scope and limitations of this study 5.2.3)Data annotation: signal quality and fetal amplitude 5.2.4)Data annotation: fetal QRS annotation 5.3)Chapter Summary (6)Results for Data Analysis 6.1)Simulated Data 6.1.1)Fetal QRS detection 6.1.2)Morphological analysis 6.2)Own Clinical Data 6.2.1)FQRS correction using the evolutionary algorithm 6.2.2)FHR correction by means of Kalman filtering (7)Discussion and Prospective 7.1)Data Availability 7.1.1)New measurement protocol 7.2)Signal Quality 7.3)Extraction Methods 7.4)FQRS and FHR Correction Algorithms (8)Conclusion References (A)Appendix A - Signal Quality Annotation (B)Appendix B - Fetal QRS Annotation (C)Appendix C - Data Recording GU

Detection of REM Sleep Behaviour Disorder by Automated Polysomnography Analysis

Evidence suggests Rapid-Eye-Movement (REM) Sleep Behaviour Disorder (RBD) is an early predictor of Parkinson's disease. This study proposes a fully-automated framework for RBD detection consisting of automated sleep staging followed by RBD identification. Analysis was assessed using a limited polysomnography montage from 53 participants with RBD and 53 age-matched healthy controls. Sleep stage classification was achieved using a Random Forest (RF) classifier and 156 features extracted from electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) channels. For RBD detection, a RF classifier was trained combining established techniques to quantify muscle atonia with additional features that incorporate sleep architecture and the EMG fractal exponent. Automated multi-state sleep staging achieved a 0.62 Cohen's Kappa score. RBD detection accuracy improved by 10% to 96% (compared to individual established metrics) when using manually annotated sleep staging. Accuracy remained high (92%) when using automated sleep staging. This study outperforms established metrics and demonstrates that incorporating sleep architecture and sleep stage transitions can benefit RBD detection. This study also achieved automated sleep staging with a level of accuracy comparable to manual annotation. This study validates a tractable, fully-automated, and sensitive pipeline for RBD identification that could be translated to wearable take-home technology.Comment: 20 pages, 3 figure

Visualising Convolutional Neural Network Decisions in Automatic Sleep Scoring

Current sleep medicine relies on the supervised analysis of polysomnographic recordings, which comprise amongst others electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) signals. Convolutional neural networks (CNN) provide an interesting framework for automated sleep classification, however, the lack of interpretability of its results has hampered CNN's further use in medicine. In this study, we train a CNN using as input Continuous Wavelet transformed EEG, EOG and EMG recordings from a publicly available dataset. The network achieved a 10-fold cross-validation Cohen's Kappa score of $\kappa = 0.71 \pm 0.01$. Further, we provide insights on how this network classifies individual epochs of sleep using Guided Gradient-weighted Class Activation Maps (Guided Grad-CAM). The proposed approach is able to produce fine-grained activation maps on time-frequency domain for each signal providing a useful tool for identifying relevant features in CNNs

Designing personalised cancer treatments

The concept of personalised medicine for cancer is not new. It arguably began with the attempts by Salmon and Hamburger to produce a viable cellular chemosensitivity assay in the 1970s, and continues to this day. While clonogenic assays soon fell out of favour due to their high failure rate, other cellular assays fared better and although they have not entered widespread clinical practice, they have proved to be very useful research tools. For instance, the ATP-based chemosensitivity assay was developed in the early 1990s and is highly standardised. It has proved useful for evaluating new drugs and combinations, and in recent years has been used to understand the molecular basis of drug resistance and sensitivity to anti-cancer drugs. Recent developments allow unparalleled genotyping and phenotyping of tumours, providing a plethora of targets for the development of new cancer treatments. However, validation of such targets and new agents to permit translation to the clinic remains difficult. There has been one major disappointment in that cell lines, though useful, do not often reflect the behaviour of their parent cancers with sufficient fidelity to be useful. Low passage cell lines — either in culture or xenografts are being used to overcome some of these issues, but have several problems of their own. Primary cell culture remains useful, but large tumours are likely to receive neo-adjuvant treatment before removal and that limits the tumour types that can be studied. The development of new treatments remains difficult and prediction of the clinical efficacy of new treatments from pre-clinical data is as hard as ever. One lesson has certainly been that one cannot buck the biology — and that understanding the genome alone is not sufficient to guarantee success. Nowhere has this been more evident than in the development of EGFR inhibitors. Despite overexpression of EGFR by many tumour types, only those with activating EGFR mutations and an inability to circumvent EGFR blockade have proved susceptible to treatment. The challenge is how to use advanced molecular understanding with limited cellular assay information to improve both drug development and the design of companion diagnostics to guide their use. This has the capacity to remove much of the guesswork from the process and should improve success rates

Designing personalised cancer treatments

The concept of personalised medicine for cancer is not new. It arguably began with the attempts by Salmon and Hamburger to produce a viable cellular chemosensitivity assay in the 1970s, and continues to this day. While clonogenic assays soon fell out of favour due to their high failure rate, other cellular assays fared better and although they have not entered widespread clinical practice, they have proved to be very useful research tools. For instance, the ATP-based chemosensitivity assay was developed in the early 1990s and is highly standardised. It has proved useful for evaluating new drugs and combinations, and in recent years has been used to understand the molecular basis of drug resistance and sensitivity to anti-cancer drugs. Recent developments allow unparalleled genotyping and phenotyping of tumours, providing a plethora of targets for the development of new cancer treatments. However, validation of such targets and new agents to permit translation to the clinic remains difficult. There has been one major disappointment in that cell lines, though useful, do not often reflect the behaviour of their parent cancers with sufficient fidelity to be useful. Low passage cell lines — either in culture or xenografts are being used to overcome some of these issues, but have several problems of their own. Primary cell culture remains useful, but large tumours are likely to receive neo-adjuvant treatment before removal and that limits the tumour types that can be studied. The development of new treatments remains difficult and prediction of the clinical efficacy of new treatments from pre-clinical data is as hard as ever. One lesson has certainly been that one cannot buck the biology — and that understanding the genome alone is not sufficient to guarantee success. Nowhere has this been more evident than in the development of EGFR inhibitors. Despite overexpression of EGFR by many tumour types, only those with activating EGFR mutations and an inability to circumvent EGFR blockade have proved susceptible to treatment. The challenge is how to use advanced molecular understanding with limited cellular assay information to improve both drug development and the design of companion diagnostics to guide their use. This has the capacity to remove much of the guesswork from the process and should improve success rates

SeqSleepNet: End-to-End Hierarchical Recurrent Neural Network for Sequence-to-Sequence Automatic Sleep Staging

Automatic sleep staging has been often treated as a simple classification problem that aims at determining the label of individual target polysomnography (PSG) epochs one at a time. In this work, we tackle the task as a sequence-to-sequence classification problem that receives a sequence of multiple epochs as input and classifies all of their labels at once. For this purpose, we propose a hierarchical recurrent neural network named SeqSleepNet. At the epoch processing level, the network consists of a filterbank layer tailored to learn frequency-domain filters for preprocessing and an attention-based recurrent layer designed for short-term sequential modelling. At the sequence processing level, a recurrent layer placed on top of the learned epoch-wise features for long-term modelling of sequential epochs. The classification is then carried out on the output vectors at every time step of the top recurrent layer to produce the sequence of output labels. Despite being hierarchical, we present a strategy to train the network in an end-to-end fashion. We show that the proposed network outperforms state-of-the-art approaches, achieving an overall accuracy, macro F1-score, and Cohen's kappa of 87.1%, 83.3%, and 0.815 on a publicly available dataset with 200 subjects

Automatic Sleep Stage Classification Using Single-Channel EEG: Learning Sequential Features with Attention-Based Recurrent Neural Networks

We propose in this work a feature learning approach using deep bidirectional recurrent neural networks (RNNs) with attention mechanism for single-channel automatic sleep stage classification. We firstly decompose an EEG epoch into multiple small frames and subsequently transform them into a sequence of frame-wise feature vectors. Given the training sequences, the attention-based RNN is trained in a sequence-to-label fashion for sleep stage classification. Due to discriminative training, the network is expected to encode information of an input sequence into a high-level feature vector after the attention layer. We, therefore, treat the trained network as a feature extractor and extract these feature vectors for classification which is accomplished by a linear SVM classifier. We also propose a discriminative method to learn a filter bank with a DNN for preprocessing purpose. Filtering the frame-wise feature vectors with the learned filter bank beforehand leads to further improvement on the classification performance. The proposed approach demonstrates good performance on the Sleep-EDF dataset