Early prediction of gestational diabetes mellitus using maternal demographic and clinical risk factors.

OBJECTIVE: To build and validate an early risk prediction model for gestational diabetes mellitus (GDM) based on first-trimester electronic medical records including maternal demographic and clinical risk factors. METHODS: To develop and validate a GDM prediction model, two datasets were used in this retrospective study. One included data of 14,015 pregnant women from Máxima Medical Center (MMC) in the Netherlands. The other was from an open-source database nuMoM2b including data of 10,038 nulliparous pregnant women, collected in the USA. Widely used maternal demographic and clinical risk factors were considered for modeling. A GDM prediction model based on elastic net logistic regression was trained from a subset of the MMC data. Internal validation was performed on the remaining MMC data to evaluate the model performance. For external validation, the prediction model was tested on an external test set from the nuMoM2b dataset. RESULTS: An area under the receiver-operating-characteristic curve (AUC) of 0.81 was achieved for early prediction of GDM on the MMC test data, comparable to the performance reported in previous studies. While the performance markedly decreased to an AUC of 0.69 when testing the MMC-based model on the external nuMoM2b test data, close to the performance trained and tested on the nuMoM2b dataset only (AUC = 0.70).

Wearable monitoring of sleep-disordered breathing: estimation of the apnea-hypopnea index using wrist-worn reflective photoplethysmography.

A large part of the worldwide population suffers from obstructive sleep apnea (OSA), a disorder impairing the restorative function of sleep and constituting a risk factor for several cardiovascular pathologies. The standard diagnostic metric to define OSA is the apnea-hypopnea index (AHI), typically obtained by manually annotating polysomnographic recordings. However, this clinical procedure cannot be employed for screening and for long-term monitoring of OSA due to its obtrusiveness and cost. Here, we propose an automatic unobtrusive AHI estimation method fully based on wrist-worn reflective photoplethysmography (rPPG), employing a deep learning model exploiting cardiorespiratory and sleep information extracted from the rPPG signal trained with 250 recordings. We tested our method with an independent set of 188 heterogeneously disordered clinical recordings and we found it estimates the AHI with a good agreement to the gold standard polysomnography reference (correlation = 0.61, estimation error = 3±10 events/h). The estimated AHI was shown to reliably assess OSA severity (weighted Cohen's kappa = 0.51) and screen for OSA (ROC-AUC = 0.84/0.86/0.85 for mild/moderate/severe OSA). These findings suggest that wrist-worn rPPG measurements that can be implemented in wearables such as smartwatches, have the potential to complement standard OSA diagnostic techniques by allowing unobtrusive sleep and respiratory monitoring.

Respiratory activity extracted from wrist-worn reflective photoplethysmography in a sleep-disordered population.

OBJECTIVE: Respiratory activity is an essential parameter to monitor healthy and disordered sleep, and unobtrusive measurement methods have important clinical applications in diagnostics of sleep-related breathing disorders. We propose a respiratory activity surrogate extracted from wrist-worn reflective photoplethysmography validated on a heterogeneous dataset of 389 sleep recordings. APPROACH: The surrogate was extracted by interpolating the amplitude of the PPG pulses after evaluation of pulse morphological quality. Subsequent multistep post-processing was applied to remove parts of the surrogate with low quality and high motion levels. In addition to standard respiration rate performance, we evaluated the similarity between surrogate respiratory activity and reference inductance plethysmography of the thorax, using Spearman's correlations and spectral coherence, and assessed the influence of PPG signal quality, motion levels, sleep stages and obstructive sleep apnea. MAIN RESULTS: Prior to post-processing, the surrogate already had a strong similarity with the reference (correlation = 0.54, coherence = 0.81), and reached respiration rate estimation performance in line with the literature (estimation error = 0.76± 2.11 breaths/min). Detrimental effects of low PPG quality, high motion levels and sleep-dependent physiological phenomena were significantly mitigated by the proposed post-processing steps (correlation = 0.62, coherence = 0.88, estimation error = 0.53± 1.85 breaths/min). SIGNIFICANCE: Wrist-worn PPG can be used to extract respiratory activity, thus allowing respiration monitoring in real-world sleep medicine applications using (consumer) wearable devices.

Doppler Ultrasound Technology for Fetal Heart Rate Monitoring: A Review.

Fetal well-being is commonly assessed by monitoring the fetal heart rate (fHR). In clinical practice, the de facto standard technology for fHR monitoring is based on the Doppler ultrasound (US). Continuous monitoring of the fHR before and during labor is performed using a US transducer fixed on the maternal abdomen. The continuous fHR monitoring, together with simultaneous monitoring of the uterine activity, is referred to as cardiotocography (CTG). In contrast, for intermittent measurements of the fHR, a handheld Doppler US transducer is typically used. In this article, the technology of Doppler US for continuous fHR monitoring and intermittent fHR measurements is described, with emphasis on fHR monitoring for CTG. Special attention is dedicated to the measurement environment, which includes the clinical setting in which fHR monitoring is commonly performed. In addition, to understand the signal content of acquired Doppler US signals, the anatomy and physiology of the fetal heart and the surrounding maternal abdomen are described. The challenges encountered in these measurements have led to different technological strategies, which are presented and critically discussed, with a focus on the US transducer geometry, Doppler signal processing, and fHR extraction methods.

Protocol of the SOMNIA project: an observational study to create a neurophysiological database for advanced clinical sleep monitoring.

INTRODUCTION: Polysomnography (PSG) is the primary tool for sleep monitoring and the diagnosis of sleep disorders. Recent advances in signal analysis make it possible to reveal more information from this rich data source. Furthermore, many innovative sleep monitoring techniques are being developed that are less obtrusive, easier to use over long time periods and in the home situation. Here, we describe the methods of the Sleep and Obstructive Sleep Apnoea Monitoring with Non-Invasive Applications (SOMNIA) project, yielding a database combining clinical PSG with advanced unobtrusive sleep monitoring modalities in a large cohort of patients with various sleep disorders. The SOMNIA database will facilitate the validation and assessment of the diagnostic value of the new techniques, as well as the development of additional indices and biomarkers derived from new and/or traditional sleep monitoring methods. METHODS AND ANALYSIS: We aim to include at least 2100 subjects (both adults and children) with a variety of sleep disorders who undergo a PSG as part of standard clinical care in a dedicated sleep centre. Full-video PSG will be performed according to the standards of the American Academy of Sleep Medicine. Each recording will be supplemented with one or more new monitoring systems, including wrist-worn photoplethysmography and actigraphy, pressure sensing mattresses, multimicrophone recording of respiratory sounds including snoring, suprasternal pressure monitoring and multielectrode electromyography of the diaphragm. ETHICS AND DISSEMINATION: The study was reviewed by the medical ethical committee of the Maxima Medical Center (Eindhoven, the Netherlands, File no: N16.074). All subjects provide informed consent before participation.The SOMNIA database is built to facilitate future research in sleep medicine. Data from the completed SOMNIA database will be made available for collaboration with researchers outside the institute.

Estimation of the apnea-hypopnea index in a heterogeneous sleep-disordered population using optimised cardiovascular features.

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder, which results in daytime symptoms, a reduced quality of life as well as long-term negative health consequences. OSA diagnosis and severity rating is typically based on the apnea-hypopnea index (AHI) retrieved from overnight poly(somno)graphy. However, polysomnography is costly, obtrusive and not suitable for long-term recordings. Here, we present a method for unobtrusive estimation of the AHI using ECG-based features to detect OSA-related events. Moreover, adding ECG-based sleep/wake scoring yields a fully automatic method for AHI-estimation. Importantly, our algorithm was developed and validated on a combination of clinical datasets, including datasets selectively including OSA-pathology but also a heterogeneous, "real-world" clinical sleep disordered population (262 participants in the validation set). The algorithm provides a good representation of the current gold standard AHI (0.72 correlation, estimation error of 0.56 ± 14.74 events/h), and can also be employed as a screening tool for a large range of OSA severities (ROC AUC ≥ 0.86, Cohen's kappa ≥ 0.53 and precision ≥70%). The method compares favourably to other OSA monitoring strategies, showing the feasibility of cardiovascular-based surrogates for sleep monitoring to evolve into clinically usable tools.

Fetal Heart Rate Monitoring Implemented by Dynamic Adaptation of Transmission Power of a Flexible Ultrasound Transducer Array.

Fetal heart rate (fHR) monitoring using Doppler Ultrasound (US) is a standard method to assess fetal health before and during labor. Typically, an US transducer is positioned on the maternal abdomen and directed towards the fetal heart. Due to fetal movement or displacement of the transducer, the relative fetal heart location (fHL) with respect to the US transducer can change, leading to frequent periods of signal loss. Consequently, frequent repositioning of the US transducer is required, which is a cumbersome task affecting clinical workflow. In this research, a new flexible US transducer array is proposed which allows for measuring the fHR independently of the fHL. In addition, a method for dynamic adaptation of the transmission power of this array is introduced with the aim of reducing the total acoustic dose transmitted to the fetus and the associated power consumption, which is an important requirement for application in an ambulatory setting. The method is evaluated using an in-vitro setup of a beating chicken heart. We demonstrate that the signal quality of the Doppler signal acquired with the proposed method is comparable to that of a standard, clinical US transducer. At the same time, our transducer array is able to measure the fHR for varying fHL while only using 50% of the total transmission power of standard, clinical US transducers.

On the generalizability of ECG-based obstructive sleep apnea monitoring: merits and limitations of the Apnea-ECG database.

Obstructive sleep apnea syndrome (OSAS) is a sleep disorder that affects a large part of the population and the development of algorithms using cardiovascular features for OSAS monitoring has been an extensively researched topic in the last two decades. Several studies regarding automatic apneic event classification using ECG derived features are based on the public Apnea-ECG database available on PhysioNet. Although this database is an excellent starting point for apnea topic investigations, in our study we show that algorithms for apneic-epochs classification that are successfully trained on this database (sensitivity < 85%, false detection rate <20%) perform poorly (sensitivity\textit<55%, false detection rate < 40%) in other databases which include patients with a broader spectrum of apneic events and sleep disorders. The reduced performance can be related to the complexity of breathing events, the increased number of non-breathing related sleep events, and the presence of non-OSAS sleep pathologies.

Sinus or not: a new beat detection algorithm based on a pulse morphology quality index to extract normal sinus rhythm beats from wrist-worn photoplethysmography recordings.

OBJECTIVE: Wrist-worn photoplethysmography (PPG) can enable free-living physiological monitoring of people during diverse activities, ranging from sleep to physical exercise. In many applications, it is important to remove the pulses not related to sinus rhythm beats from the PPG signal before using it as a cardiovascular descriptor. In this manuscript, we propose an algorithm to assess the morphology of the PPG signal in order to reject non-sinus rhythm pulses, such as artefacts or pulses related to arrhythmic beats. APPROACH: The algorithm segments the PPG signal into individual pulses and dynamically evaluates their morphological likelihood of being normal sinus rhythm pulses via a template-matching approach that accounts for the physiological variability of the signal. The normal sinus rhythm likelihood of each pulse is expressed as a quality index that can be employed to reject artefacts and pulses related to arrhythmic beats. MAIN RESULTS: Thresholding the pulse quality index enables near-perfect detection of normal sinus rhythm beats by rejecting most of the non-sinus rhythm pulses (positive predictive value 98%-99%), both in healthy subjects and arrhythmic patients. The rejection of arrhythmic beats is almost complete (sensitivity to arrhythmic beats 7%-3%), while the sensitivity to sinus rhythm beats is not compromised (96%-91%). SIGNIFICANCE: The developed algorithm consistently detects normal sinus rhythm beats in a PPG signal by rejecting artefacts and, as a first of its kind, arrhythmic beats. This increases the reliability in the extraction of features which are adversely influenced by the presence of non-sinus pulses, whether related to inter-beat intervals or to pulse morphology, from wrist-worn PPG signals recorded in free-living conditions.

Neu3CA-RT: A framework for real-time fMRI analysis.

Real-time functional magnetic resonance imaging (rtfMRI) allows visualisation of ongoing brain activity of the subject in the scanner. Denoising algorithms aim to rid acquired data of confounding effects, enhancing the blood oxygenation level-dependent (BOLD) signal. Further image processing and analysis methods, like general linear models (GLM) or multivariate analysis, then present application-specific information to the researcher. These processes are typically applied to regions of interest but, increasingly, rtfMRI techniques extract and classify whole brain functional networks and dynamics as correlates for brain states or behaviour, particularly in neuropsychiatric and neurocognitive disorders. We present Neu3CA-RT: a Matlab-based rtfMRI analysis framework aiming to advance scientific knowledge on real-time cognitive brain activity and to promote its translation into clinical practice. Design considerations are listed based on reviewing existing rtfMRI approaches. The toolbox integrates established SPM preprocessing routines, real-time GLM mapping of fMRI data to a basis set of spatial brain networks, correlation of activity with 50 behavioural profiles from the BrainMap database, and an intuitive user interface. The toolbox is demonstrated in a task-based experiment where a subject executes visual, auditory and motor tasks inside a scanner. In three out of four experiments, resulting behavioural profiles agreed with the expected brain state.

Functional network abnormalities consistent with behavioral profile in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which the severity of symptoms varies over subjects. The iCAPs model (innovation-driven co-activation patterns) is a recently developed spatio-temporal model to describe fMRI data. In this study, the iCAPs model was employed to find functional imaging biomarkers for ASD in resting-state fMRI data. MRI data from 125 ASD patients and 243 healthy controls was selected from the online ABIDE data repository. Following standard fMRI preprocessing steps, the iCAP patterns were fitted to the data to obtain network time series. Furthermore, specific combinations of iCAPs were mapped to behavioral domain time series. To quantify to which extent the time series contribute to the fMRI dynamics, their (temporal) standard deviation was calculated and compared between patients and controls. Abnormalities were found in networks involving subcortical and limbic areas and default mode network regions. When mapping the network dynamics to behavioral domain time series, abnormalities were found in emotional and visual behavioral subdomains, and within the ASD spectrum were more pronounced in subjects with autism compared to Asperger's syndrome. Also a trend towards impairment in networks facilitating social cognition was found. The functional imaging abnormalities are consistent with the behavioral impairments typical for ASD.

Photoplethysmography beat detection and pulse morphology quality assessment for signal reliability estimation.

Photoplethysmography (PPG) is one of the key technologies for unobtrusive physiological monitoring, with ongoing attempts to use it in several medical fields, ranging from night to night sleep analysis to continuous cardiac arrhythmia monitoring. However, the PPG signals are susceptible to be corrupted by noise and artifacts, caused, e.g., by limb or sensor movement. These artifacts affect the morphology of PPG waves and prevent the accurate detection and localization of beats and subsequent cardiovascular feature extraction. In this paper a new algorithm for beat detection and pulse quality assessment is described. The algorithm segments the PPG signal in pulses, localizes each beat and grades each segment with a quality index. The obtained index results from a comparison between each pulse and a template derived from the surrounding pulses, by mean of dynamic time warping barycenter averaging. The quality index is used to discard corrupted pulse beats. The algorithm is evaluated by comparing the detected beats with annotated PPG signals and the results are published over the same data. The described method achieves an improved sensitivity and a higher predictive value.

Improved ultrasound transducer positioning by fetal heart location estimation during Doppler based heart rate measurements.

OBJECTIVE: Doppler ultrasound (US) is the most commonly applied method to measure the fetal heart rate (fHR). When the fetal heart is not properly located within the ultrasonic beam, fHR measurements often fail. As a consequence, clinical staff need to reposition the US transducer on the maternal abdomen, which can be a time consuming and tedious task. APPROACH: In this article, a method is presented to aid clinicians with the positioning of the US transducer to produce robust fHR measurements. A maximum likelihood estimation (MLE) algorithm is developed, which provides information on fetal heart location using the power of the Doppler signals received in the individual elements of a standard US transducer for fHR recordings. The performance of the algorithm is evaluated with simulations and in vitro experiments performed on a beating-heart setup. MAIN RESULTS: Both the experiments and the simulations show that the heart location can be accurately determined with an error of less than 7 mm within the measurement volume of the employed US transducer. SIGNIFICANCE: The results show that the developed algorithm can be used to provide accurate feedback on fetal heart location for improved positioning of the US transducer, which may lead to improved measurements of the fHR.

Ultrasound transducer positioning aid for fetal heart rate monitoring.

Fetal heart rate (fHR) monitoring is usually performed by Doppler ultrasound (US) techniques. For reliable fHR measurements it is required that the fetal heart is located within the US beam. In clinical practice, clinicians palpate the maternal abdomen to identify the fetal presentation and then the US transducer is fixated on the maternal abdomen where the best fHR signal can be obtained. Finding the optimal transducer position is done by listening to the strength of the Doppler audio output and relying on a signal quality indicator of the cardiotocographic (CTG) measurement system. Due to displacement of the US transducer or displacement of the fetal heart out of the US beam, the fHR signal may be lost. Therefore, it is often necessary that the obstetrician repeats the tedious procedure of US transducer positioning to avoid long periods of fHR signal loss. An intuitive US transducer positioning aid would be highly desirable to increase the work flow for the clinical staff. In this paper, the possibility to determine the fetal heart location with respect to the transducer by exploiting the received signal power in the transducer elements is shown. A commercially available US transducer used for fHR monitoring is connected to an US open platform, which allows individual driving of the elements and raw US data acquisition. Based on the power of the received Doppler signals in the transducer elements, the fetal heart location can be estimated. A beating fetal heart setup was designed and realized for validation. The experimental results show the feasibility of estimating the fetal heart location with the proposed method. This can be used to support clinicians in finding the optimal transducer position for fHR monitoring more easily.

Using an injection signal to reduce motion artifacts in capacitive ECG measurements.

Capacitive electrodes are a promising alternative to the conventional adhesive ECG electrodes. They provide more comfort to the patient when integrated in everyday objects (e.g. beds or seats) for long-term monitoring. However, the application of such electrodes is limited by their high sensitivity to motion artifacts. Artifacts caused by variation of the coupling capacitance are studied here. An injection signal is proposed to track these variations in real-time. An adaptive filter then estimates the motion artifact and cancels it from the recorded ECG. The amplitude of the motion artifact is reduced in average by 29 dB in simulation and by 20 dB in a lab environment. Our method has the advantages that it is able to reduce motion artifacts occurring in the frequency band of the ECG and that it does not require knowledge about the measurement system.

Novel Bayesian vectorcardiographic loop alignment for improved monitoring of ECG and fetal movement.

The continuous analysis of electrocardiographic (ECG) signals is complicated by morphological variability in the ECG due to movement of the heart. By aligning vectorcardiographic loops, movement-induced ECG variations can be partly corrected for. Existing methods for loop alignment can account for loop rotation, scaling, and time delays, but they lack the possibility to include a priori information on any of these transformations, and they are unreliable in case of low-quality signals, such as fetal ECG signals. The inclusion of a priori information might aid in the robustness of loop alignment and is, hence, proposed in this paper. We provide a generic Bayesian framework to derive our loop alignment method. In this framework, existing methods can be readily derived as well, as a simplification of our method. The loop alignment is evaluated by comparing its performance in loop alignment to two existing methods, for both adult and fetal ECG recordings. For the adult ECG recordings, a quantitative performance assessment shows that the developed method outperforms the existing method in terms of robustness. For the fetal ECG recordings, it is demonstrated that the developed method can be used to correct ECG signals for movement-induced morphology changes (enabling diagnostics) and that the method is capable of classifying recorded ECG signals to periods of fetal movement or rest ( 0.01). This information on fetal movement can also serve as a valuable diagnostic tool.

An adaptive Kalman filter for ECG signal enhancement.

The ongoing trend of ECG monitoring techniques to become more ambulatory and less obtrusive generally comes at the expense of decreased signal quality. To enhance this quality, consecutive ECG complexes can be averaged triggered on the heartbeat, exploiting the quasi-periodicity of the ECG. However, this averaging constitutes a tradeoff between improvement of the SNR and loss of clinically relevant physiological signal dynamics. Using a bayesian framework, in this paper, a sequential averaging filter is developed that, in essence, adaptively varies the number of complexes included in the averaging based on the characteristics of the ECG signal. The filter has the form of an adaptive Kalman filter. The adaptive estimation of the process and measurement noise covariances is performed by maximizing the bayesian evidence function of the sequential ECG estimation and by exploiting the spatial correlation between several simultaneously recorded ECG signals, respectively. The noise covariance estimates thus obtained render the filter capable of ascribing more weight to newly arriving data when these data contain morphological variability, and of reducing this weight in cases of no morphological variability. The filter is evaluated by applying it to a variety of ECG signals. To gauge the relevance of the adaptive noise-covariance estimation, the performance of the filter is compared to that of a Kalman filter with fixed, (a posteriori) optimized noise covariance. This comparison demonstrates that, without using a priori knowledge on signal characteristics, the filter with adaptive noise estimation performs similar to the filter with optimized fixed noise covariance, favoring the adaptive filter in cases where no a priori information is available or where signal characteristics are expected to fluctuate.

Noninvasive estimation of the electrohysterographic action-potential conduction velocity.

Electrophysiological monitoring of the fetal-heart and the uterine-muscle activity, referred to as an electrohysterogram, is essential to permit timely treatment during pregnancy. While remarkable progress is reported for fetal-cardiac-activity monitoring, the electrohysterographic (EHG) measurement and interpretation remain challenging. In particular, little attention has been paid to the analysis of the EHG propagation, whose characteristics might be predictive of the preterm delivery. Therefore, this paper focuses, for the first time, on the noninvasive estimation of the conduction velocity of the EHG-action potentials. To this end, multichannel EHG recording and surface high-density electrodes are used. A maximum-likelihood method is employed for analyzing the EHG-action-potential propagation in two dimensions. The use of different weighting strategies of the derived cost function is introduced to deal with the poor signal similarity between different channels. The presented methods were evaluated by specific simulations proving the best weighting strategy to lead to an accuracy improvement of 56.7%. EHG measurements on ten women with uterine contractions confirmed the feasibility of the method by leading to conduction velocity values within the expected physiological range.

Bayesian approach to patient-tailored vectorcardiography.

For assessment of specific cardiac pathologies, vectorcardiography is generally considered superior with respect to electrocardiography. Existing vectorcardiography methods operate by calculating the vectorcardiogram (VCG) as a fixed linear combination of ECG signals. These methods, with the inverse Dower matrix method the current standard, are therefore not flexible with respect to different body compositions and geometries. Hence, they cannot be applied with accuracy on patients that do not conform to the fixed standard. Typical examples of such patients are obese patients or fetuses. For the latter category, when recording the fetal ECG from the maternal abdomen the distance of the fetal heart with respect to the electrodes is unknown. Consequently, also the signal attenuation/transformation per electrode is not known. In this paper, a Bayesian method is developed that estimates the VCG and, to some extent, also the signal attenuation in multichannel ECG recordings from either the adult 12-lead ECG or the maternal abdomen. This is done by determining for which VCG and signal attenuation the joint probability over both these variables is maximal given the observed ECG signals. The underlying joint probability distribution is determined by assuming the ECG signals to originate from scaled VCG projections and additive noise. With this method, a VCG, tailored to each specific patient, is determined. The method is compared to the inverse Dower matrix method by applying both methods on standard 12-lead ECG recordings and evaluating the performance in predicting ECG signals from the determined VCG. In addition, to model nonstandard patients, the 12-lead ECG signals are randomly scaled and, once more, the performance in predicting ECG signals from the VCG is compared between both methods. Finally, both methods are also compared on fetal ECG signals that are obtained from the maternal abdomen. For patients conforming to the standard, both methods perform similarly, with the developed method performing marginally better. For scaled ECG signals and fetal ECG signals, the developed method significantly outperforms the inverse Dower matrix method.

Modeling and identification of the electrohysterographic volume conductor by high-density electrodes.

The surface electrohysterographic (EHG) signal represents the bioelectrical activity that triggers the mechanical contraction of the uterine muscle. Previous work demonstrated the relevance of the EHG signal analysis for fetal and maternal monitoring as well as for prognosis of preterm labor. However, for the introduction in the clinical practice of diagnostic and prognostic EHG techniques, further insights are needed on the properties of the uterine electrical activation and its propagation through biological tissues. An important contribution for studying these phenomena in humans can be provided by mathematical modeling. A five-parameter analytical model of the EHG volume conductor and the cellular action potential (AP) is proposed here and tested on EHG signals recorded by a grid of 64 high-density electrodes. The model parameters are identified by a least-squares optimization method that uses a subset of electrodes. The parameters representing fat and abdominal muscle thickness are also measured by echography. The mean correlation coefficient and standard deviation of the difference between the echographic and EHG estimates were 0.94 and 1.9 mm, respectively. No bias was present. These results suggest that the model provides an accurate description of the EHG AP and the volume conductor, with promising perspectives for future applications.