Publications

Sudden cardiac death (SCD) remains a pressing health issue, affecting hundreds of thousands each year globally. The heterogeneity among SCD victims, ranging from individuals with severe heart failure to seemingly healthy individuals, poses a significant challenge for effective risk assessment. Conventional risk stratification, which primarily relies on left ventricular ejection fraction, has resulted in only modest efficacy of implantable cardioverter-defibrillators for SCD prevention. In response, artificial intelligence (AI) holds promise for personalized SCD risk prediction and tailoring preventive strategies to the unique profiles of individual patients. Machine and deep learning algorithms have the capability to learn intricate nonlinear patterns between complex data and defined end points and leverage these to identify subtle indicators and predictors of SCD that may not be apparent through traditional statistical analysis. However, despite the potential of AI to improve SCD risk stratification, there are important limitations that need to be addressed. We aim to provide an overview of the current state-of-the-art of AI prediction models for SCD, highlight the opportunities for these models in clinical practice, and identify the key challenges hindering widespread adoption.

MZH Kolk, S Ruipérez-Campillo, AAM Wilde, RE Knops, SM Narayan, FVY Tjong

Heart Rhythm

06.09.2024

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Background: Segmenting computed tomography (CT) is crucial in various clinical applications, such as tailoring personalized cardiac ablation for managing cardiac arrhythmias. Automating segmentation through machine learning (ML) is hindered by the necessity for large, labeled training data, which can be challenging to obtain. This article proposes a novel approach for automated, robust labeling using domain knowledge to achieve high-performance segmentation by ML from a small training set. The approach, the domain knowledge-encoding (DOKEN) algorithm, reduces the reliance on large training datasets by encoding cardiac geometry while automatically labeling the training set. The method was validated in a hold-out dataset of CT results from an atrial fibrillation (AF) ablation study. Methods: The DOKEN algorithm parses left atrial (LA) structures, extracts “anatomical knowledge” by leveraging digital LA models (available publicly), and then applies this knowledge to achieve high ML segmentation performance with a small number of training samples. The DOKEN-labeled training set was used to train a nnU-Net deep neural network (DNN) model for segmenting cardiac CT in N = 20 patients. Subsequently, the method was tested in a hold-out set with N = 100 patients (five times larger than training set) who underwent AF ablation. Results: The DOKEN algorithm integrated with the nn-Unet model achieved high segmentation performance with few training samples, with a training to test ratio of 1:5. The Dice score of the DOKEN-enhanced model was 96.7% (IQR: 95.3% to 97.7%), with a median error in surface distance of boundaries of 1.51 mm (IQR: 0.72 to 3.12) and a mean centroid–boundary distance of 1.16 mm (95% CI: −4.57 to 6.89), similar to expert results (r = 0.99; p < 0.001). In digital hearts, the novel DOKEN approach segmented the LA structures with a mean difference for the centroid–boundary distances of −0.27 mm (95% CI: −3.87 to 3.33; r = 0.99; p < 0.0001). Conclusions: The proposed novel domain knowledge-encoding algorithm was able to perform the segmentation of six substructures of the LA, reducing the need for large training data sets. The combination of domain knowledge encoding and a machine learning approach could reduce the dependence of ML on large training datasets and could potentially be applied to AF ablation procedures and extended in the future to other imaging, 3D printing, and data science applications.

P Ganesan^*, R Feng^*, B Deb, FVY Tjong, AJ Rogers, S Ruipérez-Campillo, S Somani, Paul Clopton, T Baykaner, M Rodrigo, J Zou, F Haddad, M Zaharia, SM Narayan
^* denotes shared first authorship

Diagnostics

17.07.2024

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The efficacy of an implantable cardioverter-defibrillator (ICD) in patients with a non-ischaemic cardiomyopathy for primary prevention of sudden cardiac death is increasingly debated. We developed a multimodal deep learning model for arrhythmic risk prediction that integrated late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI), electrocardiography (ECG) and clinical data. Short-axis LGE-MRI scans and 12-lead ECGs were retrospectively collected from a cohort of 289 patients prior to ICD implantation, across two tertiary hospitals. A residual variational autoencoder was developed to extract physiological features from LGE-MRI and ECG, and used as inputs for a machine learning model (DEEP RISK) to predict malignant ventricular arrhythmia onset. In the validation cohort, the multimodal DEEP RISK model predicted malignant ventricular arrhythmias with an area under the receiver operating characteristic curve (AUROC) of 0.84 (95% confidence interval (CI) 0.71–0.96), a sensitivity of 0.98 (95% CI 0.75–1.00) and a specificity of 0.73 (95% CI 0.58–0.97). The models trained on individual modalities exhibited lower AUROC values compared to DEEP RISK [MRI branch: 0.80 (95% CI 0.65–0.94), ECG branch: 0.54 (95% CI 0.26–0.82), Clinical branch: 0.64 (95% CI 0.39–0.87)]. These results suggest that a multimodal model achieves high prognostic accuracy in predicting ventricular arrhythmias in a cohort of patients with non-ischaemic systolic heart failure, using data collected prior to ICD implantation.

MZH Kolk, S Ruipérez-Campillo, CP Allaart, AAM Wilde, RE Knops, SM Narayan, FVY Tjong

Nature Scientific Reports

27.06.2024

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Background and Objectives: The extensive collection of electrocardiogram (ECG) recordings stored in paper format has provided opportunities for numerous digitization studies. However, the traditional 10 s 12-lead ECG printout typically splits the ECG signals into four asynchronous sections of 3 leads and 2.5 s each. Since each lead corresponds to different time instants, developing a synchronization method becomes necessary for applications such as vectorcardiogram (VCG) reconstruction. Methods: A beat-level synchronization method has been developed and validated using a dataset of 21,674 signals. This method effectively addresses synchronization distortions caused by RR interval variations and preserves the time lags between R peaks across different leads for each beat. Results: The results demonstrate that the proposed method successfully synchronizes the ECG, allowing a VCG reconstruction with an average Pearson Correlation Coefficient of 0.9815±0.0426. The Normalized Root Mean Squared Error (NRMSE) and Mean Absolute Error (MAE) values for the reconstructed VCG are 0.0248±0.0214 mV and 0.0133±0.0123 mV, respectively. These metrics indicate the reliability of the VCG reconstruction achieved by means of the proposed synchronization method. Conclusions: The synchronization method has demonstrated its robustness and high performance compared to existing techniques in the field. Its effectiveness has been observed across a wide variety of signals, showcasing its applicability in real clinical environments. Moreover, its ability to handle a large number of signals makes it suitable for various applications, including retrospective studies and the development of machine learning methods.

E Ramírez, S Ruipérez-Campillo, F Castells, R Casado-Arroyo, J Millet

Biomedical Signal Processing and Control

01.05.2024

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High-density multielectrode catheters are becoming increasingly popular in cardiac electrophysiology for advanced characterisation of the cardiac tissue, dueto their potential to identify impaired sites. These are often characterised by abnormal electrical conduction, which may cause locally disorganised propagation wavefronts.To quantify it, a novel heterogeneity parameter based on vector field analysis is proposed, utilising finite differences to measure direction changes between adjacent cliques. The proposed Vector Field Heterogeneity metric has been evaluated on a set of simulations with controlled levels of organisation in vector maps, and a variety of grid sizes. Furthermore, it has been tested on animal experimental models of isolated Langendorff-perfused rabbit hearts. The proposed parameter exhibited superior capturing ability of heterogeneous propagation wavefronts compared to the classical Spatial Inhomogeneity Index, and simulations proved that the metric effectively captures gradual increments in disorganisation in propagation patterns. Notably, it yielded robust and consistent outcomes for 4 × 4 grid sizes, underscoring its suitability for the latest generation of orientation-independent cardiac catheters. Index Terms—Animal experimental models, cardiac signal processing, electrophysiology, high-density electrode catheters, vector field heterogeneity. Impact Statement—The authors introduce the Vector Field Heterogeneity (VFH) metric, which provides a precise evaluation of disorganisation in electrical propagation maps within cardiac tissue, potentially improving the diagnosis and characterisation of electrophysiological conditions.

L Pancorbo^*, S Ruipérez-Campillo^*, A Tormos, A Guill, R Cervigón, A Alberola, FJ Chorro, J Millet, F Castells
^* denotes shared first authorship

IEEE Open Journal of Engineering in Medicine and Biology

23.02.2024

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Pulmonary hypertension (PH) in newborns and infants is a complex condition associated with several pulmonary, cardiac, and systemic diseases contributing to morbidity and mortality. Thus, accurate and early detection of PH and the classification of its severity is crucial for appropriate and successful management. Using echocardiography, the primary diagnostic tool in pediatrics, human assessment is both time-consuming and expertise-demanding, raising the need for an automated approach. Little effort has been directed towards automatic assessment of PH using echocardiography, and the few proposed methods only focus on binary PH classification on the adult population. In this work, we present an explainable multi-view video-based deep learning approach to predict and classify the severity of PH for a cohort of 270 newborns using echocardiograms. We use spatio-temporal convolutional architectures for the prediction of PH from each view, and aggregate the predictions of the different views using majority voting. Our results show a mean F1-score of 0.84 for severity prediction and 0.92 for binary detection using 10-fold cross-validation and 0.63 for severity prediction and 0.78 for binary detection on the held-out test set. We complement our predictions with saliency maps and show that the learned model focuses on clinically relevant cardiac structures, motivating its usage in clinical practice. To the best of our knowledge, this is the first work for an automated assessment of PH in newborns using echocardiograms.

Hanna Ragnarsdottir^*, Ece Özkan Elsen^*, Holger Michel^*, Kieran Chin-Cheong, Laura Manduchi, Sven Wellmann^†, Julia E. Vogt^†
* denotes shared first authorship, ^† denotes shared last authorship

International Journal of Computer Vision

06.02.2024

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Background and Objectives: The extensive collection of electrocardiogram (ECG) recordings stored in paper format has provided opportunities for numerous digitization studies. However, the traditional 10 s 12-lead ECG printout typically splits the ECG signals into four asynchronous sections of 3 leads and 2.5 s each. Since each lead corresponds to different time instants, developing a synchronization method becomes necessary for applications such as vectorcardiogram (VCG) reconstruction. Methods: A beat-level synchronization method has been developed and validated using a dataset of 21,674 signals. This method effectively addresses synchronization distortions caused by RR interval variations and preserves the time lags between R peaks across different leads for each beat. Results: The results demonstrate that the proposed method successfully synchronizes the ECG, allowing a VCG reconstruction with an average Pearson Correlation Coefficient of 0.9815±0.0426. The Normalized Root Mean Squared Error (NRMSE) and Mean Absolute Error (MAE) values for the reconstructed VCG are 0.0248±0.0214 mV and 0.0133±0.0123 mV, respectively. These metrics indicate the reliability of the VCG reconstruction achieved by means of the proposed synchronization method. Conclusions: The synchronization method has demonstrated its robustness and high performance compared to existing techniques in the field. Its effectiveness has been observed across a wide variety of signals, showcasing its applicability in real clinical environments. Moreover, its ability to handle a large number of signals makes it suitable for various applications, including retrospective studies and the development of machine learning methods.

E Ramírez, S Ruipérez-Campillo, F Castells, R Casado-Arroyo, J Millet

Biomedical Signal Processing and Control

05.01.2024

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Background Risk stratification for ventricular arrhythmias currently relies on static measurements that fail to adequately capture dynamic interactions between arrhythmic substrate and triggers over time. We trained and internally validated a dynamic machine learning (ML) model and neural network that extracted features from longitudinally collected electrocardiograms (ECG), and used these to predict the risk of malignant ventricular arrhythmias. Methods A multicentre study in patients implanted with an implantable cardioverter-defibrillator (ICD) between 2007 and 2021 in two academic hospitals was performed. Variational autoencoders (VAEs), which combine neural networks with variational inference principles, and can learn patterns and structure in data without explicit labelling, were trained to encode the mean ECG waveforms from the limb leads into 16 variables. Supervised dynamic ML models using these latent ECG representations and clinical baseline information were trained to predict malignant ventricular arrhythmias treated by the ICD. Model performance was evaluated on a hold-out set, using time-dependent receiver operating characteristic (ROC) and calibration curves. Findings 2942 patients (61.7 ± 13.9 years, 25.5% female) were included, with a total of 32,129 ECG recordings during a mean follow-up of 43.9 ± 35.9 months. The mean time-varying area under the ROC curve for the dynamic model was 0.738 ± 0.07, compared to 0.639 ± 0.03 for a static (i.e. baseline-only model). Feature analyses indicated dynamic changes in latent ECG representations, particularly those affecting the T-wave morphology, were of highest importance for model predictions. Interpretation Dynamic ML models and neural networks effectively leverage routinely collected longitudinal ECG recordings for personalised and updated predictions of malignant ventricular arrhythmias, outperforming static models.

MZH Kolk, S Ruipérez-Campillo, L Alvarez-Florez, B Deb, EJ Bekkers, CP Allaart, ALCJ van der Lingen, P Clopton, I Isgum, AAM Wilde, RE Knops, SM Narayan, FVY Tjong

Lancet eBiomedicine

01.01.2024

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Background: The overarching goal of blood glucose forecasting is to assist individuals with type 1 diabetes (T1D) in avoiding hyper- or hypoglycemic conditions. While deep learning approaches have shown promising results for blood glucose forecasting in adults with T1D, it is not known if these results generalize to children. Possible reasons are physical activity (PA), which is often unplanned in children, as well as age and development of a child, which both have an effect on the blood glucose level. Materials and Methods: In this study, we collected time series measurements of glucose levels, carbohydrate intake, insulin-dosing and physical activity from children with T1D for one week in an ethics approved prospective observational study, which included daily physical activities. We investigate the performance of state-of-the-art deep learning methods for adult data—(dilated) recurrent neural networks and a transformer—on our dataset for short-term (30  min) and long-term (2  h) prediction. We propose to integrate static patient characteristics, such as age, gender, BMI, and percentage of basal insulin, to account for the heterogeneity of our study group. Results: Integrating static patient characteristics (SPC) proves beneficial, especially for short-term prediction. LSTMs and GRUs with SPC perform best for a prediction horizon of 30  min (RMSE of 1.66  mmol/l), a vanilla RNN with SPC performs best across different prediction horizons, while the performance significantly decays for long-term prediction. For prediction during the night, the best method improves to an RMSE of 1.50  mmol/l. Overall, the results for our baselines and RNN models indicate that blood glucose forecasting for children conducting regular physical activity is more challenging than for previously studied adult data. Conclusion: We find that integrating static data improves the performance of deep-learning architectures for blood glucose forecasting of children with T1D and achieves promising results for short-term prediction. Despite these improvements, additional clinical studies are warranted to extend forecasting to longer-term prediction horizons.

Alexander Marx, Francesco Di Stefano, Heike Leutheuser, Kieran Chin-Cheong, Marc Pfister, Marie-Anne Burckhardt, Sara Bachmann^†, Julia E. Vogt^†
† denotes shared last authorship

Frontiers in Pediatrics

14.12.2023

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Background: Hyperbilirubinemia of the newborn infant is a common disease worldwide. However, recognized early and treated appropriately, it typically remains innocuous. We recently developed an early phototherapy prediction tool (EPPT) by means of machine learning (ML) utilizing just one bilirubin measurement and few clinical variables. The aim of this study is to test applicability and performance of the EPPT on a new patient cohort from a different population. Materials and methods: This work is a retrospective study of prospectively recorded neonatal data from infants born in 2018 in an academic hospital, Regensburg, Germany, meeting the following inclusion criteria: born with 34 completed weeks of gestation or more, at least two total serum bilirubin (TSB) measurement prior to phototherapy. First, the original EPPT—an ensemble of a logistic regression and a random forest—was used in its freely accessible version and evaluated in terms of the area under the receiver operating characteristic curve (AUROC). Second, a new version of the EPPT model was re-trained on the data from the new cohort. Third, the predictive performance, variable importance, sensitivity and specificity were analyzed and compared across the original and re-trained models. Results: In total, 1,109 neonates were included with a median (IQR) gestational age of 38.4 (36.6–39.9) and a total of 3,940 bilirubin measurements prior to any phototherapy treatment, which was required in 154 neonates (13.9%). For the phototherapy treatment prediction, the original EPPT achieved a predictive performance of 84.6% AUROC on the new cohort. After re-training the model on a subset of the new dataset, 88.8% AUROC was achieved as evaluated by cross validation. The same five variables as for the original model were found to be most important for the prediction on the new cohort, namely gestational age at birth, birth weight, bilirubin to weight ratio, hours since birth, bilirubin value. Discussion: The individual risk for treatment requirement in neonatal hyperbilirubinemia is robustly predictable in different patient cohorts with a previously developed ML tool (EPPT) demanding just one TSB value and only four clinical parameters. Further prospective validation studies are needed to develop an effective and safe clinical decision support system.

Imant Daunhawer, Kai Schumacher, Anna Badura, Julia E. Vogt, Holger Michel, Sven Wellmann

Frontiers in Pediatrics, 2023

09.10.2023

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A precise method to measure spasticity is fundamental in improving the quality of life of spastic patients. The measurement methods that exist for spasticity have long been considered scarce and inadequate, which can partly be explained by a lack of consensus in the definition of spasticity. Spasticity quantification methods can be roughly classified according to whether they are based on neurophysiological or biomechanical mechanisms, clinical scales, or imaging techniques. This article reviews methods from all classes and further discusses instrumentation, dimensionality, and EMG onset detection methods. The objective of this article is to provide a review on spasticity measurement methods used to this day in an effort to contribute to the advancement of both the quantification and treatment of spasticity.

KO Kristinsdottir, S Ruipérez-Campillo, T Helgason

Chapter of the Book "Stroke-Management Pearls"

04.10.2023

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Background Segmentation of computed tomography (CT) is important for many clinical procedures including personalized cardiac ablation for the management of cardiac arrhythmias. While segmentation can be automated by machine learning (ML), it is limited by the need for large, labeled training data that may be difficult to obtain. We set out to combine ML of cardiac CT with domain knowledge, which reduces the need for large training datasets by encoding cardiac geometry, which we then tested in independent datasets and in a prospective study of atrial fibrillation (AF) ablation. Methods We mathematically represented atrial anatomy with simple geometric shapes and derived a model to parse cardiac structures in a small set of N = 6 digital hearts. The model, termed “virtual dissection,” was used to train ML to segment cardiac CT in N = 20 patients, then tested in independent datasets and in a prospective study. Results In independent test cohorts (N = 160) from 2 Institutions with different CT scanners, atrial structures were accurately segmented with Dice scores of 96.7% in internal (IQR: 95.3%–97.7%) and 93.5% in external (IQR: 91.9%–94.7%) test data, with good agreement with experts (r = 0.99; p < 0.0001). In a prospective study of 42 patients at ablation, this approach reduced segmentation time by 85% (2.3 ± 0.8 vs. 15.0 ± 6.9 min, p < 0.0001), yet provided similar Dice scores to experts (93.9% (IQR: 93.0%–94.6%) vs. 94.4% (IQR: 92.8%–95.7%), p = NS). Conclusions Encoding cardiac geometry using mathematical models greatly accelerated training of ML to segment CT, reducing the need for large training sets while retaining accuracy in independent test data. Combining ML with domain knowledge may have broad applications.

Ruibin Feng, Brototo Deb, Prasanth Ganesan, Fleur VY Tjong, Albert J Rogers, Samuel Ruipérez-Campillo, Sulaiman Somani, Paul Clopton, Tina Baykaner, Miguel Rodrigo, James Zou, Fracois Haddad, Matei Zahari, Sanjiv M. Narayan

Frontiers in cardiovascular medicine

02.10.2023

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Aims Left ventricular ejection fraction (LVEF) is suboptimal as a sole marker for predicting sudden cardiac death (SCD). Machine learning (ML) provides new opportunities for personalized predictions using complex, multimodal data. This study aimed to determine if risk stratification for implantable cardioverter-defibrillator (ICD) implantation can be improved by ML models that combine clinical variables with 12-lead electrocardiograms (ECG) time-series features. Methods and results A multicentre study of 1010 patients (64.9 ± 10.8 years, 26.8% female) with ischaemic, dilated, or non-ischaemic cardiomyopathy, and LVEF ≤ 35% implanted with an ICD between 2007 and 2021 for primary prevention of SCD in two academic hospitals was performed. For each patient, a raw 12-lead, 10-s ECG was obtained within 90 days before ICD implantation, and clinical details were collected. Supervised ML models were trained and validated on a development cohort (n = 550) from Hospital A to predict ICD non-arrhythmic mortality at three-year follow-up (i.e. mortality without prior appropriate ICD-therapy). Model performance was evaluated on an external patient cohort from Hospital B (n = 460). At three-year follow-up, 16.0% of patients had died, with 72.8% meeting criteria for non-arrhythmic mortality. Extreme gradient boosting models identified patients with non-arrhythmic mortality with an area under the receiver operating characteristic curve (AUROC) of 0.90 [95% confidence intervals (CI) 0.80-1.00] during internal validation. In the external cohort, the AUROC was 0.79 (95% CI 0.75-0.84). Conclusions ML models combining ECG time-series features and clinical variables were able to predict non-arrhythmic mortality within three years after device implantation in a primary prevention population, with robust performance in an independent cohort.

MZH Kolk, S Ruipérez-Campillo, B Deb, E Bekkers, CP Allaart, AJ Rogers, ACJ Van Der Lingen, I Isgum, B De Vos, P Clopton, others

Europace

15.09.2023

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High-density catheters combined with Orientation Independent Sensing (OIS) methods have emerged as a groundbreaking technology for cardiac substrate characterisation. In this study, we aim to assess the arrangements and constraints to reliably estimate the so-called omnipolar electrogram (oEGM). Performance was evaluated using an experimental animal model. Thirty-eight recordings from nine retrospective experiments on isolated perfused rabbit hearts with an epicardial HD multielectrode were used. We estimated oEGMs according to the classic triangular clique (4 possible orientations) and a novel cross-orientation clique arrangement. Furthermore, we tested the effects of interelectrode spacing from 1 to 4 mm. Performance was evaluated by means of several parameters that measured amplitude rejection ratios, electric field loop area, activation pulse width and morphology distortion. Most reliable oEGM estimations were obtained with cross-configurations and interelectrode spacings <=2 mm. Estimations from triangular cliques resulted in wider electric field loops and unreliable detection of the direction of the propagation wavefront. Moreover, increasing interelectrode distance resulted in increased pulse width and morphology distortion. The results prove that current oEGM estimation techniques are insufficiently accurate. This study opens a new standpoint for the design of new-generation HD catheters and mapping software.

S Ruipérez-Campillo, M Crespo, A Tormos, A Guill, A Cebrián, A Alberola, J Heimer, FJ Chorro, J Millet, F Castells

Physical and Engineering Sciences in Medicine

26.06.2023

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces B and T cell responses, contributing to virus neutralization. In a cohort of 2,911 young adults, we identified 65 individuals who had an asymptomatic or mildly symptomatic SARS-CoV-2 infection and characterized their humoral and T cell responses to the Spike (S), Nucleocapsid (N) and Membrane (M) proteins. We found that previous infection induced CD4 T cells that vigorously responded to pools of peptides derived from the S and N proteins. By using statistical and machine learning models, we observed that the T cell response highly correlated with a compound titer of antibodies against the Receptor Binding Domain (RBD), S and N. However, while serum antibodies decayed over time, the cellular phenotype of these individuals remained stable over four months. Our computational analysis demonstrates that in young adults, asymptomatic and paucisymptomatic SARS-CoV-2 infections can induce robust and long-lasting CD4 T cell responses that exhibit slower decays than antibody titers. These observations imply that next-generation COVID-19 vaccines should be designed to induce stronger cellular responses to sustain the generation of potent neutralizing antibodies.

Ricards Marcinkevics^*, Pamuditha N. Silva^*, Anna-Katharina Hankele^*, Charlyn Dörnte, Sarah Kadelka, Katharina Csik, Svenja Godbersen, Algera Goga, Lynn Hasenöhrl, Pascale Hirschi, Hasan Kabakci, Mary P. LaPierre, Johanna Mayrhofer, Alexandra C. Title, Xuan Shu, Nouell Baiioud, Sandra Bernal, Laura Dassisti, Mara D. Saenz-de-Juano, Meret Schmidhauser, Giulia Silvestrelli, Simon Z. Ulbrich, Thea J. Ulbrich, Tamara Wyss, Daniel J. Stekhoven, Faisal S. Al-Quaddoomi, Shuqing Yu, Mascha Binder, Christoph Schultheiβ, Claudia Zindel, Christoph Kolling, Jörg Goldhahn, Bahram Kasmapour Seighalani, Polina Zjablovskaja, Frank Hardung, Marc Schuster, Anne Richter, Yi-Ju Huang, Gereon Lauer, Herrad Baurmann, Jun Siong Low, Daniela Vaqueirinho, Sandra Jovic, Luca Piccoli, Sandra Ciesek, Julia E. Vogt, Federica Sallusto, Markus Stoffel^†, Susanne E. Ulbrich^†
* denotes shared first authorship, ^† denotes shared last authorship

Frontiers in Immunology

29.05.2023

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Aims There is a clinical spectrum for atrial tachyarrhythmias wherein most patients with atrial tachycardia (AT) and some with atrial fibrillation (AF) respond to ablation, while others do not. It is undefined if this clinical spectrum has pathophysiological signatures. This study aims to test the hypothesis that the size of spatial regions showing repetitive synchronized electrogram (EGM) shapes over time reveals a spectrum from AT, to AF patients who respond acutely to ablation, to AF patients without acute response. Methods and results We studied n = 160 patients (35% women, 65.0 ± 10.4 years) of whom (i) n = 75 had AF terminated by ablation propensity matched to (ii) n = 75 without AF termination and (iii) n = 10 with AT. All patients had mapping by 64-pole baskets to identify areas of repetitive activity (REACT) to correlate unipolar EGMs in shape over time. Synchronized regions (REACT) were largest in AT, smaller in AF termination, and smallest in non-termination cohorts (0.63 ± 0.15, 0.37 ± 0.22, and 0.22 ± 0.18, P < 0.001). Area under the curve for predicting AF termination in hold-out cohorts was 0.72 ± 0.03. Simulations showed that lower REACT represented greater variability in clinical EGM timing and shape. Unsupervised machine learning of REACT and extensive (50) clinical variables yielded four clusters of increasing risk for AF termination (P < 0.01, χ2), which were more predictive than clinical profiles alone (P < 0.001). Conclusion The area of synchronized EGMs within the atrium reveals a spectrum of clinical response in atrial tachyarrhythmias. These fundamental EGM properties, which do not reflect any predetermined mechanism or mapping technology, predict outcome and offer a platform to compare mapping tools and mechanisms between AF patient groups.

P Ganesan, B Deb, F Feng, M Rodrigo, S Ruipérez-Campillo, AJ Rogers, P Clopton, JJ Wang, S Zeemering, U Schotten, WJ Rappel, SM Narayan

Europace

18.03.2023

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Objective: The aim of this study is to propose a method to reduce the sensitivity of the estimated omnipolar electrogram (oEGM) with respect to the angle of the propagation wavefront. Methods: A novel configuration of cliques taking into account all four electrodes of a squared cell is proposed. To test this approach, simulations of HD grids of cardiac activations at different propagation angles, conduction velocities, interelectrode distance and electrogram waveforms are considered. Results: The proposed approach successfully provided narrower loops (essentially a straight line) of the electrical field described by the bipole pair with respect to the conventional approach. Estimation of the direction of propagation was improved. Additionally, estimated oEGMs presented larger amplitude, and estimations of the local activation times were more accurate. Conclusions: A novel method to improve the estimation of oEGMs in HD grid of electrodes is proposed. This approach is superior to the existing methods and avoids pitfalls not yet resolved. Relevance: Robust tools for quantifying the cardiac substrate are crucial to determine with accuracy target ablation sites during an electrophysiological procedure.

F Castells^*, S Ruipérez-Campillo^*, I Segarra, R Cervigón, R Casado-Arroyo, JL Merino, J Millet
^* denotes shared first authorship

Computers in Biology and Medicine

01.03.2023

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Background Ventricular arrhythmia (VA) precipitating sudden cardiac arrest (SCD) is among the most frequent causes of death and pose a high burden on public health systems worldwide. The increasing availability of electrophysiological signals collected through conventional methods (e.g. electrocardiography (ECG)) and digital health technologies (e.g. wearable devices) in combination with novel predictive analytics using machine learning (ML) and deep learning (DL) hold potential for personalised predictions of arrhythmic events. Methods This systematic review and exploratory meta-analysis assesses the state-of-the-art of ML/DL models of electrophysiological signals for personalised prediction of malignant VA or SCD, and studies potential causes of bias (PROSPERO, reference: CRD42021283464). Five electronic databases were searched to identify eligible studies. Pooled estimates of the diagnostic odds ratio (DOR) and summary area under the curve (AUROC) were calculated. Meta-analyses were performed separately for studies using publicly available, ad-hoc datasets, versus targeted clinical data acquisition. Studies were scored on risk of bias by the PROBAST tool. Findings 2194 studies were identified of which 46 were included in the systematic review and 32 in the meta-analysis. Pooling of individual models demonstrated a summary AUROC of 0.856 (95% CI 0.755–0.909) for short-term (time-to-event up to 72 h) prediction and AUROC of 0.876 (95% CI 0.642–0.980) for long-term prediction (time-to-event up to years). While models developed on ad-hoc sets had higher pooled performance (AUROC 0.919, 95% CI 0.867–0.952), they had a high risk of bias related to the re-use and overlap of small ad-hoc datasets, choices of ML tool and a lack of external model validation. Interpretation ML and DL models appear to accurately predict malignant VA and SCD. However, wide heterogeneity between studies, in part due to small ad-hoc datasets and choice of ML model, may reduce the ability to generalise and should be addressed in future studies.

MZH Kolk, B Deb, S Ruipérez-Campillo, NK Bhatia, P Clopton, AAM Wilde, SM Narayan, RE Knops, FVY Tjong

The Lancet eBiomedicine

01.03.2023

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Three-dimensional imaging of live processes at a cellular level is a challenging task. It requires high-speed acquisition capabilities, low phototoxicity, and low mechanical disturbances. Three-dimensional imaging in microfluidic devices poses additional challenges as a deep penetration of the light source is required, along with a stationary setting, so the flows are not perturbed. Different types of fluorescence microscopy techniques have been used to address these limitations; particularly, confocal microscopy and light sheet fluorescence microscopy (LSFM). This manuscript proposes a novel architecture of a type of LSFM, single-plane illumination microscopy (SPIM). This custom-made microscope includes two mirror galvanometers to scan the sample vertically and reduce shadowing artifacts while avoiding unnecessary movement. In addition, two electro-tunable lenses fine-tune the focus position and reduce the scattering caused by the microfluidic devices. The microscope has been fully set up and characterized, achieving a resolution of 1.50 μ m in the x-y plane and 7.93 μ m in the z-direction. The proposed architecture has risen to the challenges posed when imaging microfluidic devices and live processes, as it can successfully acquire 3D volumetric images together with time-lapse recordings, and it is thus a suitable microscopic technique for live tracking miniaturized tissue and disease models.

Clara Gomez-Cruz, Sonia Laguna, Ariadna Bachiller-Pulido, Cristina Quilez, Marina Ca\~nadas-Ortega, Ignacio Albert-Smet, Jorge Ripoll, Arrate Mu\~noz-Barrutia

Biosensors

01.12.2022

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Synthetic super-resolved images generated by a machine learning algorithm from portable low-field-strength (0.064-T) brain MRI had good agreement with real images at high field strength (1.5–3 T).

Juan Eugenio Iglesias, Riana Schleicher, Sonia Laguna, Benjamin Billot, Pamela Schaefer, Brenna McKaig, Joshua N Goldstein, Kevin N Sheth, Matthew S Rosen, W Taylor Kimberly

Radiology

08.11.2022

LinkDOI

Background: Arm use metrics derived from wrist-mounted movement sensors are widely used to quantify the upper limb performance in real-life conditions of individuals with stroke throughout motor recovery. The calculation of real-world use metrics, such as arm use duration and laterality preferences, relies on accurately identifying functional movements. Hence, classifying upper limb activity into functional and non-functional classes is paramount. Acceleration thresholds are conventionally used to distinguish these classes. However, these methods are challenged by the high inter and intra-individual variability of movement patterns. In this study, we developed and validated a machine learning classifier for this task and compared it to methods using conventional and optimal thresholds.Methods: Individuals after stroke were video-recorded in their home environment performing semi-naturalistic daily tasks while wearing wrist-mounted inertial measurement units. Data were labeled frame-by-frame following the Taxonomy of Functional Upper Limb Motion definitions, excluding whole-body movements, and sequenced into 1-s epochs. Actigraph counts were computed, and an optimal threshold for functional movement was determined by receiver operating characteristic curve analyses on group and individual levels. A logistic regression classifier was trained on the same labels using time and frequency domain features. Performance measures were compared between all classification methods.Results: Video data (6.5 h) of 14 individuals with mild-to-severe upper limb impairment were labeled. Optimal activity count thresholds were ≥20.1 for the affected side and ≥38.6 for the unaffected side and showed high predictive power with an area under the curve (95% CI) of 0.88 (0.87,0.89) and 0.86 (0.85, 0.87), respectively. A classification accuracy of around 80% was equivalent to the optimal threshold and machine learning methods and outperformed the conventional threshold by ∼10%. Optimal thresholds and machine learning methods showed superior specificity (75–82%) to conventional thresholds (58–66%) across unilateral and bilateral activities.Conclusion: This work compares the validity of methods classifying stroke survivors’ real-life arm activities measured by wrist-worn sensors excluding whole-body movements. The determined optimal thresholds and machine learning classifiers achieved an equivalent accuracy and higher specificity than conventional thresholds. Our open-sourced classifier or optimal thresholds should be used to specify the intensity and duration of arm use.

Johannes Pohl, Alain Ryser, Janne Marieke Veerbeek, Geert Verheyden, Julia Elisabeth Vogt, Andreas Rüdiger Luft, Chris Awai Easthope

Frontiers in Physiology

28.09.2022

LinkDOI

Background: Stroke leads to motor impairment which reduces physical activity, negatively affects social participation, and increases the risk of secondary cardiovascular events. Continuous monitoring of physical activity with motion sensors is promising to allow the prescription of tailored treatments in a timely manner. Accurate classification of gait activities and body posture is necessary to extract actionable information for outcome measures from unstructured motion data. We here develop and validate a solution for various sensor configurations specifically for a stroke population.Methods: Video and movement sensor data (locations: wrists, ankles, and chest) were collected from fourteen stroke survivors with motor impairment who performed real-life activities in their home environment. Video data were labeled for five classes of gait and body postures and three classes of transitions that served as ground truth. We trained support vector machine (SVM), logistic regression (LR), and k-nearest neighbor (kNN) models to identify gait bouts only or gait and posture. Model performance was assessed by the nested leave-one-subject-out protocol and compared across five different sensor placement configurations.Results: Our method achieved very good performance when predicting real-life gait versus non-gait (Gait classification) with an accuracy between 85% and 93% across sensor configurations, using SVM and LR modeling. On the much more challenging task of discriminating between the body postures lying, sitting, and standing as well as walking, and stair ascent/descent (Gait and postures classification), our method achieves accuracies between 80% and 86% with at least one ankle and wrist sensor attached unilaterally. The Gait and postures classification performance between SVM and LR was equivalent but superior to kNN.Conclusion: This work presents a comparison of performance when classifying Gait and body postures in post-stroke individuals with different sensor configurations, which provide options for subsequent outcome evaluation. We achieved accurate classification of gait and postures performed in a real-life setting by individuals with a wide range of motor impairments due to stroke. This validated classifier will hopefully prove a useful resource to researchers and clinicians in the increasingly important field of digital health in the form of remote movement monitoring using motion sensors.

Johannes Pohl, Alain Ryser, Janne Marieke Veerbeek, Geert Verheyden, Julia Elisabeth Vogt, Andreas Rüdiger Luft, Chris Awai Easthope

Frontiers in Physiology

26.09.2022

LinkDOI

Motivation: Global acronyms are used in written text without their formal definitions. This makes it difficult to automatically interpret their sense as acronyms tend to be ambiguous. Supervised machine learning approaches to sense disambiguation require large training datasets. In clinical applications, large datasets are difficult to obtain due to patient privacy. Manual data annotation creates an additional bottleneck. Results: We proposed an approach to automatically modifying scientific abstracts to (i) simulate global acronym usage and (ii) annotate their senses without the need for external sources or manual intervention. We implemented it as a web-based application, which can create large datasets that in turn can be used to train supervised approaches to word sense disambiguation of biomedical acronyms. Availability and implementation: The datasets will be generated on demand based on a user query and will be downloadable from https://datainnovation.cardiff.ac.uk/acronyms/.

Maxim Filimonov, Daphné Chopard, Irena Spasić

Bioinformatics

26.05.2022

LinkPubmedDOI

Using artificial intelligence to improve patient care is a cutting-edge methodology, but its implementation in clinical routine has been limited due to significant concerns about understanding its behavior. One major barrier is the explainability dilemma and how much explanation is required to use artificial intelligence safely in healthcare. A key issue is the lack of consensus on the definition of explainability by experts, regulators, and healthcare professionals, resulting in a wide variety of terminology and expectations. This paper aims to fill the gap by defining minimal explainability standards to serve the views and needs of essential stakeholders in healthcare. In that sense, we propose to define minimal explainability criteria that can support doctors’ understanding, meet patients’ needs, and fulfill legal requirements. Therefore, explainability need not to be exhaustive but sufficient for doctors and patients to comprehend the artificial intelligence models’ clinical implications and be integrated safely into clinical practice. Thus, minimally acceptable standards for explainability are context-dependent and should respond to the specific need and potential risks of each clinical scenario for a responsible and ethical implementation of artificial intelligence.

Laura Arbelaez Ossa, Georg Starke, Giorgia Lorenzini, Julia E Vogt, David M Shaw, Bernice Simone Elger

DIGITAL HEALTH

11.02.2022

LinkDOI

The recent introduction of portable, low-field MRI (LF-MRI) into the clinical setting has the potential to transform neuroimaging. However, LF-MRI is limited by lower resolution and signal-to-noise ratio, leading to incomplete characterization of brain regions. To address this challenge, recent advances in machine learning facilitate the synthesis of higher resolution images derived from one or multiple lower resolution scans. Here, we report the extension of a machine learning super-resolution (SR) algorithm to synthesize 1 mm isotropic MPRAGElike scans from LF-MRI T1-weighted and T2-weighted sequences. Our initial results on a paired dataset of LF and high-field (HF, 1.5T-3T) clinical scans show that: (i) application of available automated segmentation tools directly to LF-MRI images falters; but (ii) segmentation tools succeed when applied to SR images with high correlation to gold standard measurements from HF-MRI (e.g., r = 0.85 for hippocampal volume, r = 0.84 for the thalamus, r = 0.92 for the whole cerebrum). This work demonstrates proof-of-principle postprocessing image enhancement from lower resolution LF-MRI sequences. These results lay the foundation for future work to enhance the detection of normal and abnormal image findings at LF and ultimately improve the diagnostic performance of LF-MRI. Our tools are publicly available on FreeSurfer (surfer.nmr.mgh.harvard.edu/)

Juan Eugenio Iglesias, Riana Schleicher, Sonia Laguna, Benjamin Billot, Pamela Schaefer, Brenna McKaig, Joshua N Goldstein, Kevin N Sheth, Matthew S Rosen, W Taylor Kimberly

arXiv preprint arXiv:2202.03564

07.02.2022

Objective: To report the outcomes of active surveillance (AS) for low-risk prostate cancer (PCa) in a single-center cohort. Patients and Methods: This is a prospective, single-center, observational study. The cohort included all patients who underwent AS for PCa between December 1999 and December 2020 at our institution. Follow-up appointments (FU) ended in February 2021. Results: A total of 413 men were enrolled in the study, and 391 had at least one FU. Of those who followed up, 267 had PCa diagnosed by transrectal ultrasound (TRUS)-guided biopsy (T1c: 68.3%), while 124 were diagnosed after transurethral resection of the prostate (TURP) (T1a/b: 31.7%). Median FU was 46 months (IQR 25&ndash;90). Cancer specific survival was 99.7% and overall survival was 92.3%. Median reclassification time was 11.2 years. After 20 years, 25% of patients were reclassified within 4.58 years, 6.6% opted to switch to watchful waiting, 4.1% died, 17.4% were lost to FU, and 46.8% remained on AS. Those diagnosed by TRUS had a significantly higher reclassification rate than those diagnosed by TURP (p &lt; 0.0001). Men diagnosed by targeted MRI/TRUS fusion biopsy tended to have a higher reclassification probability than those diagnosed by conventional template biopsies (p = 0.083). Conclusions: Our single-center cohort spanning over two decades revealed that AS remains a safe option for low-risk PCa even in the long term. Approximately half of AS enrollees will eventually require definitive treatment due to disease progression. Men with incidental prostate cancer were significantly less likely to have disease progression.

Sarah Hagmann, Venkat Ramakrishnan, Alexander Tamalunas, Marc Hofmann, Moritz Vandenhirtz, Silvan Vollmer, Jsmea Hug, Philipp Niggli, Antonio Nocito, Rahel A. Kubik-Huch, Kurt Lehmann, Lukas John Hefermehl

Cancers

12.01.2022

LinkDOI

Background: Pharmacovigilance and safety reporting, which involve processes for monitoring the use of medicines in clinical trials, play a critical role in the identification of previously unrecognized adverse events or changes in the patterns of adverse events. Objective: This study aims to demonstrate the feasibility of automating the coding of adverse events described in the narrative section of the serious adverse event report forms to enable statistical analysis of the aforementioned patterns. Methods: We used the Unified Medical Language System (UMLS) as the coding scheme, which integrates 217 source vocabularies, thus enabling coding against other relevant terminologies such as the International Classification of Diseases–10th Revision, Medical Dictionary for Regulatory Activities, and Systematized Nomenclature of Medicine). We used MetaMap, a highly configurable dictionary lookup software, to identify the mentions of the UMLS concepts. We trained a binary classifier using Bidirectional Encoder Representations from Transformers (BERT), a transformer-based language model that captures contextual relationships, to differentiate between mentions of the UMLS concepts that represented adverse events and those that did not. Results: The model achieved a high F1 score of 0.8080, despite the class imbalance. This is 10.15 percent points lower than human-like performance but also 17.45 percent points higher than that of the baseline approach. Conclusions: These results confirmed that automated coding of adverse events described in the narrative section of serious adverse event reports is feasible. Once coded, adverse events can be statistically analyzed so that any correlations with the trialed medicines can be estimated in a timely fashion.

Daphné Chopard, Matthias S Treder, Padraig Corcoran, Nagheen Ahmed, Claire Johnson, Monica Busse, Irena Spasić, others

JMIR Medical Informatics

24.12.2021

LinkPubmedDOI

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (+/-8.8%) and an area-under-the-precision-recall-curve of 28.42% (+/-11.5%). The predictive performance of the model with RFs alone was comparable with random. Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

Martin Stocker, Imant Daunhawer, Wendy van Herk, Salhab el Helou, Sourabh Dutta, Frank A. B. A.Schuerman, Rita K. van den Tooren-de Groot, ; Jantien W. Wieringa, Jan Janota, Laura H. van der Meer-Kappelle, Rob Moonen, Sintha D. Sie, Esther de Vries, Albertine E. Donker, Urs Zimmerman, Luregn J. Schlapbach, Amerik C. de Mol, Angelique Hoffmann-Haringsma, Madan Roy, Maren Tomaske, René F. Kornelisse, Juliette van Gijsel, Frans B. Plötz, Sven Wellmann, Niek B Achten, Dirk Lehnick, Annemarie M. C. van Rossum, Julia E. Vogt

The Pediatric Infectious Disease Journal, 2022

09.09.2021

LinkDOI

Understanding how epigenetic variation in non-coding regions is involved in distal gene-expression regulation is an important problem. Regulatory regions can be associated to genes using large-scale datasets of epigenetic and expression data. However, for regions of complex epigenomic signals and enhancers that regulate many genes, it is difficult to understand these associations. We present StitchIt, an approach to dissect epigenetic variation in a gene-specific manner for the detection of regulatory elements (REMs) without relying on peak calls in individual samples. StitchIt segments epigenetic signal tracks over many samples to generate the location and the target genes of a REM simultaneously. We show that this approach leads to a more accurate and refined REM detection compared to standard methods even on heterogeneous datasets, which are challenging to model. Also, StitchIt REMs are highly enriched in experimentally determined chromatin interactions and expression quantitative trait loci. We validated several newly predicted REMs using CRISPR-Cas9 experiments, thereby demonstrating the reliability of StitchIt. StitchIt is able to dissect regulation in superenhancers and predicts thousands of putative REMs that go unnoticed using peak-based approaches suggesting that a large part of the regulome might be uncharted water.

Florian Schmidt, Alexander Marx, Nina Baumgarten, Marie Hebel, Martin Wegner, Manuel Kaulich, Matthias S Leisegang, Ralf P Brandes, Jonathan Göke, Jilles Vreeken, Marcel H Schulz

Nucleic Acids Research

01.09.2021

DOICode

Objective: To evaluate the association of self-reported physical function with subjective and objective measures as well as temporospatial gait features in lumbar spinal stenosis (LSS). Design: Cross-sectional pilot study. Setting: Outpatient multispecialty clinic. Participants: Participants with LSS and matched controls without LSS (n=10 per group; N=20). Interventions: Not applicable. Main outcome measures: Self-reported physical function (36-Item Short Form Health Survey [SF-36] physical functioning domain), Oswestry Disability Index, Swiss Spinal Stenosis Questionnaire, the Neurogenic Claudication Outcome Score, and inertia measurement unit (IMU)-derived temporospatial gait features. Results: Higher self-reported physical function scores (SF-36 physical functioning) correlated with lower disability ratings, neurogenic claudication, and symptom severity ratings in patients with LSS (P<.05). Compared with controls without LSS, patients with LSS have lower scores on physical capacity measures (median total distance traveled on 6-minute walk test: controls 505 m vs LSS 316 m; median total distance traveled on self-paced walking test: controls 718 m vs LSS 174 m). Observed differences in IMU-derived gait features, physical capacity measures, disability ratings, and neurogenic claudication scores between populations with and without LSS were statistically significant. Conclusions: Further evaluation of the association of IMU-derived temporospatial gait with self-reported physical function, pain related-disability, neurogenic claudication, and spinal stenosis symptom severity score in LSS would help clarify their role in tracking LSS outcomes.

Charles A Odonkor, Salam Taraben, Christy Tomkins-Lane, Wei Zhang, Amir Muaremi, H. Leutheuser, Ruopeng Sun, Matthew Smuck

Archives of Rehabilitation Research and Clinical Translation

01.09.2021

DOI

Background Preterm neonates frequently experience hypernatremia (plasma sodium concentrations >145 mmol/l), which is associated with clinical complications, such as intraventricular hemorrhage. Study design In this single center retrospective observational study, the following 7 risk factors for hypernatremia were analyzed in very low gestational age (VLGA, below 32 weeks) neonates: gestational age (GA), delivery mode (DM; vaginal or caesarian section), sex, birth weight, small for GA, multiple birth, and antenatal corticosteroids. Machine learning (ML) approaches were applied to obtain probabilities for hypernatremia. Results 824 VLGA neonates were included (median GA 29.4 weeks, median birth weight 1170g, caesarean section 83%). 38% of neonates experienced hypernatremia. Maximal sodium concentration of 144 mmol/l (interquartile range 142–147) was observed 52 hours (41–65) after birth. ML identified vaginal delivery and GA as key risk factors for hypernatremia. The risk of hypernatremia increased with lower GA from 22% for GA >= 31–32 weeks to 46% for GA < 31 weeks and 60% for GA < 27 weeks. A linear relationship between maximal sodium concentrations and GA was found, showing decreases of 0.29 mmol/l per increasing week GA in neonates with vaginal delivery and 0.49 mmol/l/week after cesarean section. Sex, multiple birth and antenatal corticosteroids were not associated hypernatremia. Conclusion VLGA neonates with vaginal delivery and low GA have the highest risk for hypernatremia. Early identification of neonates at risk and early intervention may prevent extreme sodium excursions and associated clinical complications.

Nadia S. Eugster, Florence Corminboeuf, Gilbert Koch, Julia E. Vogt, Thomas Sutter, Tamara van Donge, Marc Pfister, Roland Gerull

Klinische Pädiatrie

07.06.2021

LinkDOI

Background: Given the absence of consolidated and standardized international guidelines for managing pediatric appendicitis and the few strictly data-driven studies in this specific, we investigated the use of machine learning (ML) classifiers for predicting the diagnosis, management and severity of appendicitis in children. Materials and Methods: Predictive models were developed and validated on a dataset acquired from 430 children and adolescents aged 0-18 years, based on a range of information encompassing history, clinical examination, laboratory parameters, and abdominal ultrasonography. Logistic regression, random forests, and gradient boosting machines were used for predicting the three target variables. Results: A random forest classifier achieved areas under the precision-recall curve of 0.94, 0.92, and 0.70, respectively, for the diagnosis, management, and severity of appendicitis. We identified smaller subsets of 6, 17, and 18 predictors for each of targets that sufficed to achieve the same performance as the model based on the full set of 38 variables. We used these findings to develop the user-friendly online Appendicitis Prediction Tool for children with suspected appendicitis. Discussion: This pilot study considered the most extensive set of predictor and target variables to date and is the first to simultaneously predict all three targets in children: diagnosis, management, and severity. Moreover, this study presents the first ML model for appendicitis that was deployed as an open access easy-to-use online tool. Conclusion: ML algorithms help to overcome the diagnostic and management challenges posed by appendicitis in children and pave the way toward a more personalized approach to medical decision-making. Further validation studies are needed to develop a finished clinical decision support system.

Ricards Marcinkevics^*, Patricia Reis Wolfertstetter^*, Sven Wellmann, Christian Knorr^†, Julia E Vogt^†
* denotes shared first authorship, ^† denotes shared last authorship

Frontiers in Pediatrics

29.04.2021

LinkDOICode

Background and objectives Macroreentrant atrial tachyarrhythmias (MRATs) can be caused by different reentrant circuits. The treatment for each MRAT type may require ablation at different sites, either at the right or left atria. Unfortunately, the reentrant circuit that drives the arrhythmia cannot be ascertained previous to the electrophysiological intervention. Methods A noninvasive approach based on the comparison of atrial vectorcardiogram (VCG) loops is proposed. An archetype for each group was created, which served as a reference to measure the similarity between loops. Methods were tested in a variety of simulations and real data obtained from the most common right (peritricuspid) and left (perimitral) macroreentrant circuits, each divided into clockwise and counterclockwise subgroups. Adenosine was administered to patients to induce transient AV block, allowing the recording of the atrial signal without the interference of ventricular signals. From the vectorcardiogram, we measured intrapatient loop consistence, similarity of the pathway to archetypes, characterisation of slow velocity regions and pathway complexity. Results Results show a considerably higher similarity with the loop of its corresponding archetype, in both simulations and real data. We found the capacity of the vectorcardiogram to reflect a slow velocity region, consistent with the mechanisms of MRAT, and the role that it plays in the characterisation of the reentrant circuit. The intra-patient loop consistence was over 0.85 for all clinical cases while the similarity of the pathway to archetypes was found to be 0.85 ± 0.03, 0.95 ± 0.03, 0.87 ± 0.04 and 0.91 ± 0.02 for the different MRAT types (and p<0.02 for 3 of the 4 groups), and pathway complexity also allowed to discriminate among cases (with p<0.05). Conclusions We conclude that the presented methodology allows us to differentiate between the most common forms of right and left MRATs and predict the existence and location of a slow conduction zone. This approach may be useful in planning ablation procedures in advance.

S Ruipérez-Campillo, S Castrejón, M Martínez, R Cervigón, OMeste, JL Merino, J Millet, FCastells

Computer methods and programs in biomedicine

01.02.2021

LinkDOI

Rationale Tuberculosis diagnosis in children remains challenging. Microbiological confirmation of tuberculosis disease is often lacking, and standard immunodiagnostic including the tuberculin skin test and interferon-gamma release assay for tuberculosis infection has limited sensitivity. Recent research suggests that inclusion of novel Mycobacterium tuberculosis antigens has the potential to improve standard immunodiagnostic tests for tuberculosis. Objective To identify optimal antigen–cytokine combinations using novel Mycobacterium tuberculosis antigens and cytokine read-outs by machine learning algorithms to improve immunodiagnostic assays for tuberculosis. Methods A total of 80 children undergoing investigation of tuberculosis were included (15 confirmed tuberculosis disease, five unconfirmed tuberculosis disease, 28 tuberculosis infection and 32 unlikely tuberculosis). Whole blood was stimulated with 10 novel Mycobacterium tuberculosis antigens and a fusion protein of early secretory antigenic target (ESAT)-6 and culture filtrate protein (CFP) 10. Cytokines were measured using xMAP multiplex assays. Machine learning algorithms defined a discriminative classifier with performance measured using area under the receiver operating characteristics. Measurements and main results We found the following four antigen–cytokine pairs had a higher weight in the discriminative classifier compared to the standard ESAT-6/CFP-10-induced interferon-gamma: Rv2346/47c- and Rv3614/15c-induced interferon-gamma inducible protein-10; Rv2031c-induced granulocyte-macrophage colony-stimulating factor and ESAT-6/CFP-10-induced tumor necrosis factor-alpha. A combination of the 10 best antigen–cytokine pairs resulted in area under the curve of 0.92 +/- 0.04. Conclusion We exploited the use of machine learning algorithms as a key tool to evaluate large immunological datasets. This identified several antigen–cytokine pairs with the potential to improve immunodiagnostic tests for tuberculosis in children.

Noemi Rebecca Meier, Thomas M. Sutter, Marc Jacobsen, Tom H. M. Ottenhoff, Julia E. Vogt, Nicole Ritz

Frontiers in Cellular and Infection Microbiology

08.01.2021

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Unplanned hospital readmissions are a burden to patients and increase healthcare costs. A wide variety of machine learning (ML) models have been suggested to predict unplanned hospital readmissions. These ML models were often specifically trained on patient populations with certain diseases. However, it is unclear whether these specialized ML models—trained on patient subpopulations with certain diseases or defined by other clinical characteristics—are more accurate than a general ML model trained on an unrestricted hospital cohort. In this study based on an electronic health record cohort of consecutive inpatient cases of a single tertiary care center, we demonstrate that accurate prediction of hospital readmissions may be obtained by general, disease-independent, ML models. This general approach may substantially decrease the cost of development and deployment of respective ML models in daily clinical routine, as all predictions are obtained by the use of a single model.

Thomas Sutter, Jan A Roth, Kieran Chin-Cheong, Balthasar L Hug, Julia E Vogt

Journal of the American Medical Informatics Association

18.12.2020

LinkDOI

Background Functional ambulation limitations are features of lumbar spinal stenosis (LSS) and knee osteoarthritis (OA). With numerous validated walking assessment protocols and a vast number of spatiotemporal gait parameters available from sensor-based assessment, there is a critical need for selection of appropriate test protocols and variables for research and clinical applications. Research question In patients with knee OA and LSS, what are the best sensor-derived gait parameters and the most suitable clinical walking test to discriminate between these patient populations and controls? Methods We collected foot-mounted inertial measurement unit (IMU) data during three walking tests (fast-paced walk test-FPWT, 6-min walk test– 6MWT, self-paced walk test – SPWT) for subjects with LSS, knee OA and matched controls (N = 10 for each group). Spatiotemporal gait characteristics were extracted and pairwise compared (Omega partial squared – w_p^2) between patients and controls. Results We found that normal paced walking tests (6MWT, SPWT) are better suited for distinguishing gait characteristics between patients and controls. Among the sensor-based gait parameters, stance and double support phase timing were identified as the best gait characteristics for the OA population discrimination, whereas foot flat ratio, gait speed, stride length and cadence were identified as the best gait characteristics for the LSS population discrimination. Significance These findings provide guidance on the selection of sensor-derived gait parameters and clinical walking tests to detect alterations in mobility for people with LSS and knee OA.

C. Odonkor, A. Kuwabara, C. Tomkins-Lane, W. Zhang, A. Muaremi, H. Leutheuser, R. Sun, M. Smuck

Gait&Posture

01.07.2020

DOI

Background The mortality risk remains significant in paediatric and adult patients on chronic haemodialysis (HD) treatment. We aimed to identify factors associated with mortality in patients who started HD as children and continued HD as adults. Methods The data originated from a cohort of patients < 30 years of age who started HD in childhood (<= 19 years) on thrice-weekly HD in outpatient DaVita dialysis centres between 2004 and 2016. Patients with at least 5 years of follow-up since the initiation of HD or death within 5 years were included; 105 variables relating to demographics, HD treatment and laboratory measurements were evaluated as predictors of 5-year mortality utilizing a machine learning approach (random forest). Results A total of 363 patients were included in the analysis, with 84 patients having started HD at < 12 years of age. Low albumin and elevated lactate dehydrogenase (LDH) were the two most important predictors of 5-year mortality. Other predictors included elevated red blood cell distribution width or blood pressure and decreased red blood cell count, haemoglobin, albumin:globulin ratio, ultrafiltration rate, z-score weight for age or single-pool K_t/V (below target). Mortality was predicted with an accuracy of 81%. Conclusions Mortality in paediatric and young adult patients on chronic HD is associated with multifactorial markers of nutrition, inflammation, anaemia and dialysis dose. This highlights the importance of multimodal intervention strategies besides adequate HD treatment as determined by K_t/V alone. The association with elevated LDH was not previously reported and may indicate the relevance of blood–membrane interactions, organ malperfusion or haematologic and metabolic changes during maintenance HD in this population.

Verena Gotta, Georgi Tancev, Olivera Marsenic, Julia E. Vogt, Marc Pfister

Nephrology Dialysis Transplantation

08.06.2020

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Clinical pharmacology is a multi-disciplinary data sciences field that utilizes mathematical and statistical methods to generate maximal knowledge from data. Pharmacometrics (PMX) is a well-recognized tool to characterize disease progression, pharmacokinetics and risk factors. Since the amount of data produced keeps growing with increasing pace, the computational effort necessary for PMX models is also increasing. Additionally, computationally efficient methods such as machine learning (ML) are becoming increasingly important in medicine. However, ML is currently not an integrated part of PMX, for various reasons. The goals of this article are to (i) provide an introduction to ML classification methods, (ii) provide examples for a ML classification analysis to identify covariates based on specific research questions, (iii) examine a clinically relevant example to investigate possible relationships of ML and PMX, and (iv) present a summary of ML and PMX tasks to develop clinical decision support tools.

Gilbert Koch, Marc Pfister, Imant Daunhawer, Melanie Wilbaux, Sven Wellmann, Julia E. Vogt

Clinical Pharmacology & Therapeutics, 2020

11.01.2020

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Despite the application of advanced statistical and pharmacometric approaches to pediatric trial data, a large pediatric evidence gap still remains. Here, we discuss how to collect more data from children by using real-world data from electronic health records, mobile applications, wearables, and social media. The large datasets collected with these approaches enable, and may demand, the use of artificial intelligence and machine learning to allow the data to be analyzed for decision-making. Applications of this approach are presented, which include the prediction of future clinical complications, medical image analysis, identification of new pediatric endpoints and biomarkers, the prediction of treatment non-responders and the prediction of placebo-responders for trial enrichment. Finally, we discuss how to bring machine learning from science to pediatric clinical practice. We conclude that advantage should be taken of the current opportunities offered by innovations in data science and machine learning to close the pediatric evidence gap.

Sebastiaan C. Goulooze, Laura B. Zwep, Julia E. Vogt, Elke H.J. Krekels, Thomas Hankemeier, John N. van den Anker, Catherijne A.J. Knibbe

Clinical Pharmacology & Therapeutics

19.12.2019

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We consider the problem of inferring the causal direction between two univariate numeric random variables X and Y from observational data. This case is especially challenging as the graph X causes Y is Markov equivalent to the graph Y causes X, and hence it is impossible to determine the correct direction using conditional independence tests. To tackle this problem, we follow an information theoretic approach based on the algorithmic Markov condition. This postulate states that in terms of Kolmogorov complexity the factorization given by the true causal model is the most succinct description of the joint distribution. This means that we can infer that X is a likely cause of Y when we need fewer bits to first transmit the data over X, and then the data of Y as a function of X, than for the inverse direction. That is, in this paper we perform causal inference by compression. To put this notion to practice, we employ the Minimum Description Length principle, and propose a score to determine how many bits we need to transmit the data using a class of regression functions that can model both local and global functional relations. To determine whether an inference, i.e. the difference in compressed sizes, is significant, we propose two analytical significance tests based on the no-hypercompression inequality. Last, but not least, we introduce the linear-time Slope and Sloper algorithms that through thorough empirical evaluation we show outperform the state of the art by a wide margin.

Alexander Marx, Jilles Vreeken

Knowledge and Information Systems

01.09.2019

DOICode

Background Machine learning models may enhance the early detection of clinically relevant hyperbilirubinemia based on patient information available in every hospital. Methods We conducted a longitudinal study on preterm and term born neonates with serial measurements of total serum bilirubin in the first two weeks of life. An ensemble, that combines a logistic regression with a random forest classifier, was trained to discriminate between the two classes phototherapy treatment vs. no treatment. Results Of 362 neonates included in this study, 98 had a phototherapy treatment, which our model was able to predict up to 48 h in advance with an area under the ROC-curve of 95.20%. From a set of 44 variables, including potential laboratory and clinical confounders, a subset of just four (bilirubin, weight, gestational age, hours since birth) suffices for a strong predictive performance. The resulting early phototherapy prediction tool (EPPT) is provided as an open web application. Conclusion Early detection of clinically relevant hyperbilirubinemia can be enhanced by the application of machine learning. Existing guidelines can be further improved to optimize timing of bilirubin measurements to avoid toxic hyperbilirubinemia in high-risk patients while minimizing unneeded measurements in neonates who are at low risk.

Imant Daunhawer, Severin Kasser, Gilbert Koch, Lea Sieber, Hatice Cakal, Janina Tütsch, Marc Pfister, Sven Wellman, Julia E. Vogt

Pediatric Research, 2019

30.03.2019

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To exploit the full potential of big routine data in healthcare and to efficiently communicate and collaborate with information technology specialists and data analysts, healthcare epidemiologists should have some knowledge of large-scale analysis techniques, particularly about machine learning. This review focuses on the broad area of machine learning and its first applications in the emerging field of digital healthcare epidemiology.

Jan A. Roth, Manuel Battegay, Fabrice Juchler, Julia E. Vogt, Andreas F. Widmer

Infection Control & Hospital Epidemiology, 2018

04.11.2018

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Wearable health sensors are about to change our health system. While several technological improvements have been presented to enhance performance and energy-efficiency, battery runtime is still a critical concern for practical use of wearable biomedical sensor systems. The runtime limitation is directly related to the battery size, which is another concern regarding practicality and customer acceptance. We introduced ULPSEK-Ultra-Low-Power Sensor Evaluation Kit-for evaluation of biomedical sensors and monitoring applications (http://ulpsek.com). ULPSEK includes a multiparameter sensor measuring and processing electrocardiogram, respiration, motion, body temperature, and photoplethysmography. Instead of a battery, ULPSEK is powered using an efficient body heat harvester. The harvester produced 171 W on average, which was sufficient to power the sensor below 25 C ambient temperature. We present design issues regarding the power supply and the power distribution network of the ULPSEK sensor platform. Due to the security aspect of self-powered health sensors, we suggest a hybrid solution consisting of a battery charged by a harvester.

A. Tobola, H. Leutheuser, M. Pollak, P. Spies, C. Hofmann, C. Weigand, B.M. Eskofier, G. Fischer

IEEE J Biomed Health Inform.

01.01.2018

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The second most common cause of diving fatalities is cardiovascular diseases. Monitoring the cardiovascular system in actual underwater conditions is necessary to gain insights into cardiac activity during immersion and to trigger preventive measures. We developed a wearable, current-based electrocardiogram (ECG) device in the eco-system of the FitnessSHIRT platform. It can be used for normal/dry ECG measuring purposes but is specifically designed to allow underwater signal acquisition without having to use insulated electrodes. Our design is based on a transimpedance amplifier circuit including active current feedback. We integrated additional cascaded filter components to counter noise characteristics specific to the immersed condition of such a system. The results of the evaluation show that our design is able to deliver high-quality ECG signals underwater with no interferences or loss of signal quality. To further evaluate the applicability of the system, we performed an applied study with it using 12 healthy subjects to examine whether differences in the heart rate variability exist between sitting and supine positions of the human body immersed in water and outside of it. We saw significant differences, for example, in the RMSSD and SDSD between sitting outside the water (36 ms) and sitting immersed in water (76 ms) and the pNN50 outside the water (6.4%) and immersed in water (18.2%). The power spectral density for the sitting positions in the TP and HF increased significantly during water immersion while the LF/HF decreased significantly. No significant changes were found for the supine position.

S. Gradl, T. Cibis, J. Lauber, R. Richer, R. Rybalko, N. Pfeiffer, H. Leutheuser, M. Wirth, V. Tscharner, B. M. Eskofier

Appl Sci.

08.12.2017

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Objective: Respiratory inductance plethysmography (RIP) provides an unobtrusive method for measuring breathing characteristics. Accurately adjusted RIP provides reliable measurements of ventilation during rest and exercise if data are acquired via two elastic measuring bands surrounding the rib cage (RC) and abdomen (AB). Disadvantageously, the most accurate reported adjusted model for RIP in literature-least squares regression-requires simultaneous RIP and flowmeter (FM) data acquisition. An adjustment method without simultaneous measurement (reference-free) of RIP and FM would foster usability enormously. Methods: In this paper, we develop generalizable, functional, and reference-free algorithms for RIP adjustment incorporating anthropometric data. Further, performance of only one-degree of freedom (RC or AB) instead of two (RC and AB) is investigated. We evaluate the algorithms with data from 193 healthy subjects who performed an incremental running test using three different datasets: training, reliability, and validation dataset. The regression equation is improved with machine learning techniques such as sequential forward feature selection and 10-fold cross validation. Results: Using the validation dataset, the best reference-free adjustment model is the combination of both bands with 84.69% breaths within 20% limits of equivalence compared to 43.63% breaths using the best comparable algorithm from literature. Using only one band, we obtain better results using the RC band alone. Conclusion: Reference-free adjustment for RIP reveals tidal volume differences of up to 0.25 l when comparing to the best possible adjustment currently present which needs the simultaneous measurement of RIP and FM. Significance: This demonstrates that RIP has the potential for usage in wide applications in ambulatory settings.

H. Leutheuser, C. Heyde, K. Roecker, A. Gollhofer, B. M Eskofier

IEEE Trans Biomed Eng.

01.12.2017

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Respiratory motion analysis based on range imaging (RI) has emerged as a popular means of generating respiration surrogates to guide motion management strategies in computer-assisted interventions. However, existing approaches employ heuristics, require substantial manual interaction, or yield highly redundant information. In this paper, we propose a framework that uses preprocedurally obtained 4-D shape priors from patient-specific breathing patterns to drive intraprocedural RI-based real-time respiratory motion analysis. As the first contribution, we present a shape motion model enabling an unsupervised decomposition of respiration induced high-dimensional body surface displacement fields into a low-dimensional representation encoding thoracic and abdominal breathing. Second, we propose a method designed for GPU architectures to quickly and robustly align our models to high-coverage multiview RI body surface data. With our fully automatic method, we obtain respiration surrogates yielding a Pearson correlation coefficient (PCC) of 0.98 with conventional surrogates based on manually selected regions on RI body surface data. Compared to impedance pneumography as a respiration signal that measures the change of lung volume, we obtain a PCC of 0.96. Using off-the-shelf hardware, our framework enables high temporal resolution respiration analysis at 50 Hz.

J. Wasza, P. Fischer, H. Leutheuser, T. Oefner, C. Bert, A. Maier, J. Hornegger

IEEE Trans Biomed Eng.

01.03.2016

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Molecular classification of hepatocellular carcinomas (HCC) could guide patient stratification for personalizedtherapies targeting subclass-specific cancer 'driver pathways'. Currently, there are several transcriptome-basedmolecular classifications of HCC with different subclass numbers, ranging from two to six. They were estab-lished using resected tumours that introduce a selection bias towards patients without liver cirrhosis and withearly stage HCCs. We generated and analyzed gene expression data from paired HCC and non-cancerous livertissue biopsies from 60 patients as well as five normal liver samples. Unbiased consensus clustering of HCCbiopsy profiles identified 3 robust classes. Class membership correlated with survival, tumour size and withEdmondson and Barcelona Clinical Liver Cancer (BCLC) stage. When focusing only on the gene expression ofthe HCC biopsies, we could validate previously reported classifications of HCC based on expression patterns ofsignature genes. However, the subclass-specific gene expression patterns were no longer preserved when thefold-change relative to the normal tissue was used. The majority of genes believed to be subclass-specificturned out to be cancer-related genes differentially regulated in all HCC patients, with quantitative ratherthan qualitative differences between the molecular subclasses. With the exception of a subset of samples with a definitive \beta-catenin gene signature, biological pathway analysis could not identify class-specific pathwaysreflecting the activation of distinct oncogenic programs. In conclusion, we have found that gene expressionprofiling of HCC biopsies has limited potential to direct therapies that target specific driver pathways, but canidentify subgroups of patients with different prognosis.

Zuzanna Makowska, Tujana Boldanova, David Adametz, Luca Quagliata, Julia E. Vogt, Michael T. Dill, Mathias S. Matter, Volker Roth, Luigi Terracciano, Markus H. Heim

Journal of Pathology: Clinical Research, 2016

05.01.2016

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In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon–Mann–Whitney (WMW) test is among the most popular hypothesis tests in medicine and life science to analyze if two groups of samples are equally distributed. This nonparametric statistical homogeneity test is commonly applied in molecular diagnosis. Generally, the solution of the WMW test takes a high combinatorial effort for large sample cohorts containing a significant number of ties. Hence, P value is frequently approximated by a normal distribution. We developed EDISON-WMW, a new approach to calculate the exact permutation of the two-tailed unpaired WMW test without any corrections required and allowing for ties. The method relies on dynamic programing to solve the combinatorial problem of the WMW test efficiently. Beyond a straightforward implementation of the algorithm, we presented different optimization strategies and developed a parallel solution. Using our program, the exact P value for large cohorts containing more than 1000 samples with ties can be calculated within minutes. We demonstrate the performance of this novel approach on randomly-generated data, benchmark it against 13 other commonly-applied approaches and moreover evaluate molecular biomarkers for lung carcinoma and chronic obstructive pulmonary disease (COPD). We found that approximated P values were generally higher than the exact solution provided by EDISON-WMW. Importantly, the algorithm can also be applied to high-throughput omics datasets, where hundreds or thousands of features are included. To provide easy access to the multi-threaded version of EDISON-WMW, a web-based solution of our algorithm is freely available at http://www.ccb.uni-saarland.de/software/wtest/.

Alexander Marx, Christina Backes, Eckart Meese, Hans-Peter Lenhof, Andreas Keller

Genomics, Proteomics & Bioinformatics

01.01.2016

DOICode

Purpose Exercise and physical activity is a driving force for mental health. Major challenges in the treatment of psychological diseases are accurate activity profiles and the adherence to exercise intervention programs. We present the development and validation of CHRONACT, a wearable realtime activity tracker based on inertial sensor data to support mental health. Methods CHRONACT comprised a Human Activity Recognition (HAR) algorithm that determined activity levels based on their Metabolic Equivalent of Task (MET) with sensors on ankle and wrist. Special emphasis was put on wearability, real-time data analysis and runtime to be able to use the system as augmented feedback device. For the development, data of 47 healthy subjects performing clinical intervention program activities were collected to train different classification models. The most suitable model according to the accuracy and processing power tradeoff was selected for an embedded implementation on CHRONACT. Results A validation trial (six subjects, 6 h of data) showed the accuracy of the system with a classification rate of 85.6%. The main source of error was identified in acyclic activities that contained activity bouts of neighboring classes. The runtime of the system was more than 7 days and continuous result logging was available for 39 h. Conclusions In future applications, the CHRONACT system can be used to create accurate and unobtrusive patient activity profiles. Furthermore, the system is ready to assess the effects of individual augmented feedback for exercise adherence.

U. Jensen, H. Leutheuser, S. Hofmann, B. Schuepferling, G. Suttner, K. Seiler, J. Kornhuber, B. M Eskofier

Biomed Eng Lett.

18.07.2015

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We present a novel probabilistic clustering model for objects that are represented via pairwise distances and observed at different time points. The proposed method utilizes the information given by adjacent time points to find the underlying cluster structure and obtain a smooth cluster evolution. This approach allows the number of objects and clusters to differ at every time point, and no identification on the identities of the objects is needed. Further, the model does not require the number of clusters being specified in advance—they are instead determined automatically using a Dirichlet process prior. We validate our model on synthetic data showing that the proposed method is more accurate than state-of-the-art clustering methods. Finally, we use our dynamic clustering model to analyze and illustrate the evolution of brain cancer patients over time.

Julia E. Vogt, Marius Kloft, Stefan Stark, Sandhya Prabhakaran, Sudhir Raman, Volker Roth and Gunnar Rätsch

Machine Learning Journal, 2015

16.07.2015

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A major challenge in computational biology is to find simple representations of high-dimensional data that best reveal the underlying structure. In this work, we present an intuitive and easy-to-implement method based on ranked neighborhood comparisons that detects structure in unsupervised data. The method is based on ordering objects in terms of similarity and on the mutual overlap of nearest neighbors. This basic framework was originally introduced in the field of social network analysis to detect actor communities. We demonstrate that the same ideas can successfully be applied to biomedical data sets in order to reveal complex underlying structure. The algorithm is very efficient and works on distance data directly without requiring a vectorial embedding of data. Comprehensive experiments demonstrate the validity of this approach. Comparisons with state-of-the-art clustering methods show that the presented method outperforms hierarchical methods as well as density based clustering methods and model-based clustering. A further advantage of the method is that it simultaneously provides a visualization of the data. Especially in biomedical applications, the visualization of data can be used as a first pre-processing step when analyzing real world data sets to get an intuition of the underlying data structure. We apply this model to synthetic data as well as to various biomedical data sets which demonstrate the high quality and usefulness of the inferred structure.

Julia E. Vogt

IEEE/ACM Transactions on Computational Biology and Bioinformatics (Volume: 12 , Issue: 4 , July-Aug. 1 2015)

26.01.2015

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Introduction: The aim of this study was to provide a rationale for future validations of a priori calibrated respiratory inductance plethysmography (RIP) when used under exercise conditions. Therefore, the validity of a posteriori-adjusted gain factors and accuracy in resultant breath-by-breath RIP data recorded under resting and running conditions were examined. Methods: Healthy subjects, 98 men and 88 women (mean ± SD: height = 175.6 ± 8.9 cm, weight = 68.9 ± 11.1 kg, age = 27.1 ± 8.3 yr), underwent a standardized test protocol, including a period of standing still, an incremental running test on treadmill, and multiple periods of recovery. Least square regression was used to calculate gain factors, respectively, for complete individual data sets as well as several data subsets. In comparison with flowmeter data, the validity of RIP in breathing rate (fR) and inspiratory tidal volume (VTIN) were examined using coefficients of determination (R). Accuracy was estimated from equivalence statistics. Results: Calculated gains between different data subsets showed no equivalence. After gain adjustment for the complete individual data set, fR and VTIN between methods were highly correlated (R = 0.96 ± 0.04 and 0.91 ± 0.05, respectively) in all subjects. Under conditions of standing still, treadmill running, and recovery, 86%, 98%, and 94% (fR) and 78%, 97%, and 88% (VTIN), respectively, of all breaths were accurately measured within ± 20% limits of equivalence. Conclusion: In case of the best possible gain adjustment, RIP confidentially estimates tidal volume accurately within ± 20% under exercise conditions. Our results can be used as a rationale for future validations of a priori calibration procedures.

C. Heyde, H. Leutheuser, B. M. Eskofier, K. Roecker, A. Gollhofer

Med Sci Sports Exerc.

01.03.2014

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The use of pegylated interferon-\alpha (pegIFN-\alpha) has replaced unmodified recombinant IFN-\alpha for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-\alpha is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-\alpha in the liver have not been studied. Here, we analyzed pegIFN-\alpha–induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-\alpha injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-\alpha in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-\alpha administration. Evaluation of liver biopsies revealed that pegIFN-\alpha induces hundreds of genes that can be classified into four clusters based on different temporal expression profiles. In all clusters, gene transcription was mainly driven by IFN-stimulated gene factor 3 (ISGF3). Compared with conventional IFN-\alpha therapy, pegIFN-\alpha induced a broader spectrum of gene expression, including many genes involved in cellular immunity. IFN-induced secondary transcription factors did not result in additional waves of gene expression. Our data indicate that the superior antiviral efficacy of pegIFN-\alpha is not the result of prolonged Jak/STAT pathway activation in hepatocytes, but rather is due to induction of additional genes that are involved in cellular immune responses.

Michael T. Dill, Zuzanna Makowska, Gaia Trincucci, Andreas J. Gruber, Julia E. Vogt, Magdalena Filipowicz, Diego Calabrese, Ilona Krol, Daryl T. Lau, Luigi Terracciano, Erik van Nimwegen, Volker Roth and Markus H. Heim

The Journal of Clinical Investigation

23.02.2014

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Insufficient physical activity is the 4th leading risk factor for mortality. Methods for assessing the individual daily life activity (DLA) are of major interest in order to monitor the current health status and to provide feedback about the individual quality of life. The conventional assessment of DLAs with self-reports induces problems like reliability, validity, and sensitivity. The assessment of DLAs with small and light-weight wearable sensors (e.g. inertial measurement units) provides a reliable and objective method. State-of-the-art human physical activity classification systems differ in e.g. the number and kind of sensors, the performed activities, and the sampling rate. Hence, it is difficult to compare newly proposed classification algorithms to existing approaches in literature and no commonly used dataset exists. We generated a publicly available benchmark dataset for the classification of DLAs. Inertial data were recorded with four sensor nodes, each consisting of a triaxial accelerometer and a triaxial gyroscope, placed on wrist, hip, chest, and ankle. Further, we developed a novel, hierarchical, multi-sensor based classification system for the distinction of a large set of DLAs. Our hierarchical classification system reached an overall mean classification rate of 89.6% and was diligently compared to existing state-of-the-art algorithms using our benchmark dataset. For future research, the dataset can be used in the evaluation process of new classification algorithms and could speed up the process of getting the best performing and most appropriate DLA classification system.

H. Leutheuser, D. Schuldhaus, B. M. Eskofier

PLOS ONE

09.10.2013

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We present a Bayesian approach for estimating the relative frequencies of multi-single nucleotide polymorphism (SNP) haplotypes in populations of the malaria parasite Plasmodium falciparum by using microarray SNP data from human blood samples. Each sample comes from a malaria patient and contains one or several parasite clones that may genetically differ. Samples containing multiple parasite clones with different genetic markers pose a special challenge. The situation is comparable with a polyploid organism. The data from each blood sample indicates whether the parasites in the blood carry a mutant or a wildtype allele at various selected genomic positions. If both mutant and wildtype alleles are detected at a given position in a multiply infected sample, the data indicates the presence of both alleles, but the ratio is unknown. Thus, the data only partially reveals which specific combinations of genetic markers (i.e. haplotypes across the examined SNPs) occur in distinct parasite clones. In addition, SNP data may contain errors at non-negligible rates. We use a multinomial mixture model with partially missing observations to represent this data and a Markov chain Monte Carlo method to estimate the haplotype frequencies in a population. Our approach addresses both challenges, multiple infections and data errors.

Leonore Wigger, Julia E. Vogt, Volker Roth

Statistics in Medicine: 04/2013

19.09.2013

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The normal oscillation of the heart rate is called Heart Rate Variability (HRV). HRV parameters change under different conditions like rest, physical exercise, mental stress, and body posture changes. However, results how HRV parameters adapt to physical exercise have been inconsistent. This study investigated how different HRV parameters changed during one hour of running. We used datasets of 295 athletes where each dataset had a total length of about 65 minutes. Data was divided in segments of five minutes and three HRV parameters and one kinematic parameter were calculated for each segment. We applied two different analysis of variance (ANOVA) models to analyze the differences in the means of each segment for every parameter. The two ANOVA models were univariate ANOVA with repeated measures and multivariate ANOVA with repeated measures. The obligatory post-hoc procedure consisted of multiple dependent t tests with Bonferroni correction. We investigated the last three segments of the parameters in more detail and detected a delay of one minute between varying running speed and measured heart rate. Hence, the circulatory system of our population needed one minute to adapt to a change in running speed. The method we provided can be used to further investigate more HRV parameters.

H. Leutheuser, B. M. Eskofier

Int J Comp Sci Sport

01.01.2013

Partitioning methods for observations represented by pairwise dissimilarities are studied. Particular emphasis is put on their properties when applied to dissimilarity matrices that do not admit a loss-free embedding into a vector space. Specifically, the Pairwise Clustering cost function is shown to exhibit a shift invariance property which basically means that any symmetric dissimilarity matrix can be modified to allow a vector-space representation without distorting the optimal group structure. In an approximate sense, the same holds true for a probabilistic generalization of Pairwise Clustering, the so-called Wishart–Dirichlet Cluster Process. This shift-invariance property essentially means that these clustering methods are “blind” against Euclidean or metric violations. From the application side, such blindness against metric violations might be seen as a highly desired feature, since it broadens the applicability of certain algorithms. From the viewpoint of theory building, however, the same property might be viewed as a “negative” result, since studying these algorithms will not lead to any new insights on the role of metricity in clustering problems.

Volker Roth, Thomas J. Fuchs, Julia E. Vogt, Sandhya Prabhakaran, Joachim M. Buhmann

Similarity-Based Pattern Analysis and Recognition, 157-177

31.12.2012

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Introduction IFN-\alpha signals through the Jak-STAT pathway to induce expression of IFN-stimulated genes (ISGs) with antiviral functions. USP18 is an IFN-inducible negative regulator of the Jak-STAT pathway. Upregulation of USP18 results in a long-lasting desensitization of IFN-\alpha signalling. As a result of this IFN-induced refractoriness, ISG levels decrease back to baseline despite continuous presence of the cytokine. Pegylated forms of IFN-\alpha (pegIFN-\alpha) are currently in clinical use for treatment of chronic hepatitis C virus infection. PegIFN-\alphas show increased anti-hepatitis C virus efficacy compared to nonpegylated IFN-\alpha. This has been attributed to the significantly longer plasma half-life of the pegylated form. However, the underlying assumption that persistently high plasma levels obtained with pegIFN-\alpha therapy result in ongoing stimulation of ISGs in the liver has never been tested. In the present study we therefore investigated the kinetics of Jak-STAT pathway activation and ISG induction in the human liver at several time points during the first week of pegIFN-\alpha therapy. Methods 18 patients with chronic hepatitis C underwent a liver biopsy 4 h (n = 6), 16 h, 48 h, 96 h or 144 h (all n = 3) after the first injection of pegIFN-\alpha-2b. Additional 3 patients received pegIFN-\alpha-2a and were biopsied at 144 h. The activation of Jak-STAT signalling and USP18 upregulation were assessed by immunohistochemistry and Western blot. Gene expression analysis was performed using Human Genome U133 Plus 2.0 arrays and Bioconductor packages of R statistical environment. Results A single dose of pegIFN-\alpha-2b resulted in elevated IFN-\alpha plasma levels throughout the one-week dosing interval. Despite the continuous IFN-\alpha exposure, strong activation of the Jak-STAT pathway was only observed at early time points after administration. Almost 500 genes were significantly upregulated in the liver samples following pegIFN-\alpha stimulation. The breadth of transcriptional response to pegIFN-\alpha was maximal 16 h post-injection and decreased gradually, with only few genes significantly upregulated after 144 h of treatment. Bayesian clustering of the gene expression data revealed 4 distinct groups of the ISGs based on the temporal patterns of regulation. Of 494 upregulated ISGs, the expression of 474 peaked 4 h or 16 h after pegIFN-\alpha administration, followed by a steady decline of mRNA levels through the remaining 128 h of treatment. This transient activation of the Jak-STAT pathway coincided with elevated expression of USP18 on the protein level, which was first detectable 16 post-injection. Conclusion PegIFN-\alpha induces a transient activation of Jak-STAT signalling and ISG upregulation in human liver, in spite of persistent high serum concentrations. The short-lived STAT1 phosphorylation and gene induction can be explained by upregulation of USP18 and establishment of refractory state. The superior efficacy of pegIFN-\alpha compared to conventional IFN-\alpha for chronic hepatitis C therapy cannot be explained by persistent signalling and ISG induction during the one-week dosing interval.

Z. Makowska, M. T. Dill, Julia E. Vogt, Magdalena Filipowicz Sinnreich, L. Terraciano, Volker Roth, M. H. Heim

Cytokine 59(3):563–564, 2012

11.08.2012

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BACKGROUND & AIMS: The host immune response during the chronic phase of hepatitis C virus infection varies among individuals; some patients have a no interferon (IFN) response in the liver, whereas others have full activation of IFN-stimulated genes (ISGs). Preactivation of this endogenous IFN system is associated with nonresponse to pegylated IFN-\alpha (pegIFN-\alpha) and ribavirin. Genome-wide association studies have associated allelic variants near the IL28B (IFN\lambda3) gene with treatment response. We investigated whether IL28B genotype determines the constitutive expression of ISGs in the liver and compared the abilities of ISG levels and IL28B genotype to predict treatment outcome. METHODS: We genotyped 109 patients with chronic hepatitis C for IL28B allelic variants and quantified the hepatic expression of ISGs and of IL28B. Decision tree ensembles, in the form of a random forest classifier, were used to calculate the relative predictive power of these different variables in a multivariate analysis. RESULTS: The minor IL28B allele was significantly associated with increased expression of ISG. However, stratification of the patients according to treatment response revealed increased ISG expression in nonresponders, irrespective of IL28B genotype. Multivariate analysis of ISG expression, IL28B genotype, and several other factors associated with response to therapy identified ISG expression as the best predictor of treatment response. CONCLUSIONS: IL28B genotype and hepatic expression of ISGs are independent predictors of response to treatment with pegIFN-\alpha and ribavirin in patients with chronic hepatitis C. The most accurate prediction of response was obtained with a 4-gene classifier comprising IFI27, ISG15, RSAD2, and HTATIP2.

Michael T. Dill, Francois H.T. Duong, Julia E. Vogt, Stephanie Bibert, Pierre-Yves Bochud, Luigi Terracciano, Andreas Papassotiropoulos, Volker Roth and Markus H. Heim

Gastroenterology, 2011 Mar;140(3):1021-1031.e10

28.02.2011

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