A Lumped-Parameter Model of the Cardiovascular System Response for Evaluating Automated Fluid Resuscitation Systems.

Physiological closed-loop controlled (PCLC) medical devices, such as those designed for blood pressure regulation, can be tested for safety and efficacy in real-world clinical settings. However, relying solely on limited animal and clinical studies may not capture the diverse range of physiological conditions. Credible mathematical models can complement these studies by allowing the testing of the device against simulated patient scenarios. This research involves the development and validation of a low-order lumped-parameter mathematical model of the cardiovascular system's response to fluid perturbation. The model takes rates of hemorrhage and fluid infusion as inputs and provides hematocrit and blood volume, heart rate, stroke volume, cardiac output and mean arterial blood pressure as outputs. The model was calibrated using data from 27 sheep subjects, and its predictive capability was evaluated through a leave-one-out cross-validation procedure, followed by independent validation using 12 swine subjects. Our findings showed small model calibration error against the training dataset, with the normalized root-mean-square error (NRMSE) less than 10% across all variables. The mathematical model and virtual patient cohort generation tool demonstrated a high level of predictive capability and successfully generated a sufficient number of subjects that closely resembled the test dataset. The average NRMSE for the best virtual subject, across two distinct samples of virtual subjects, was below 12.7% and 11.9% for the leave-one-out cross-validation and independent validation dataset. These findings suggest that the model and virtual cohort generator are suitable for simulating patient populations under fluid perturbation, indicating their potential value in PCLC medical device evaluation.

Clinical Evaluation of the ECG Noise Extraction Tool as a Component of ECG Analysis Algorithms Evaluation.

OBJECTIVE: The aim of this work is to demonstrate the performance of the ECG noise extraction tool (ECGNExT) which provides estimates of ECG noise that are not significantly different from the inherent noise in an ECG generated by motion artifacts and other sources. In addition, this paper elaborates on use of ECGNExT in an algorithm evaluation context comparing two QRS detection algorithms. METHODS: 140 simultaneous pairs of clean ECGs and ECGs corrupted with motion-induced noise from 29 participants under five different and separate motion conditions were collected and analyzed. Estimates of the noise component of the ECGs recorded with noise were obtained using ECGNExT and were then added to the clean ECGs yielding estimated ECGs with noise. Root mean squared error (RMSE) between the recorded and estimated ECGs with noise was calculated for temporal comparison, and band powers of the signals were calculated for spectral comparison. RESULTS: A t-test revealed that the mean RMSE < 150-microvolts with p-value < 0.001 and, and equivalence tests showed that the band powers of the two ECGs were statistically equivalent with . CONCLUSION: ECGNExT can reliably estimate the underlying ECG noise while preserving temporal and spectral features. SIGNIFICANCE: We previously proposed ECGNExT as a component of ECG analysis algorithm testing during noise conditions and reported its performance based on simulated ECG data. This work provides additional support of the performance and functionality of the ECGNExT algorithm from a study with pairs of simultaneously recorded ECGs with and without noise from human subjects.

Tissue mimicking materials and finger phantom design for pulse oximetry.

Pulse oximetry represents a ubiquitous clinical application of optics in modern medicine. Recent studies have raised concerns regarding the potential impact of confounders, such as variable skin pigmentation and perfusion, on blood oxygen saturation measurement accuracy in pulse oximeters. Tissue-mimicking phantom testing offers a low-cost, well-controlled solution for characterizing device performance and studying potential error sources, which may thus reduce the need for costly in vivo trials. The purpose of this study was to develop realistic phantom-based test methods for pulse oximetry. Material optical and mechanical properties were reviewed, selected, and tuned for optimal biological relevance, e.g., oxygenated tissue absorption and scattering, strength, elasticity, hardness, and other parameters representing the human finger's geometry and composition, such as blood vessel size and distribution, and perfusion. Relevant anatomical and physiological properties are summarized and implemented toward the creation of a preliminary finger phantom. To create a preliminary finger phantom, we synthesized a high-compliance silicone matrix with scatterers for embedding flexible tubing and investigated the addition of these scatterers to novel 3D printing resins for optical property control without altering mechanical stability, streamlining the production of phantoms with biologically relevant characteristics. Phantom utility was demonstrated by applying dynamic, pressure waveforms to produce tube volume change and resultant photoplethysmography (PPG) signals. 3D printed phantoms achieved more biologically relevant conditions compared to molded phantoms. These preliminary results indicate that the phantoms show strong potential to be developed into tools for evaluating pulse oximetry performance. Gaps, recommendations, and strategies are presented for continued phantom development.

AFE-GAN: Synthesizing Electrocardiograms with Atrial Fibrillation Characteristics Using Generative Adversarial Networks.

Labeled ECG data in diseased state are, however, relatively scarce due to various concerns including patient privacy and low prevalence. We propose the first study in its kind that synthesizes atrial fibrillation (AF)-like ECG signals from normal ECG signals using the AFE-GAN, a generative adversarial network. Our AFE-GAN adjusts both beat morphology and rhythm variability when generating the atrial fibrillation-like ECG signals. Two publicly available arrhythmia detectors classified 72.4% and 77.2% of our generated signals as AF in a four-class (normal, AF, other abnormal, noisy) classification. This work shows the feasibility to synthesize abnormal ECG signals from normal ECG signals.Clinical significance - The AF ECG signal generated with our AFE-GAN has the potential to be used as training materials for health practitioners or be used as class-balance supplements for training automatic AF detectors.

Mock circulatory loop generated database for dynamic characterization of pressure-based cardiac output monitoring systems.

Pulse contour cardiac output monitoring systems allow real-time and continuous estimation of hemodynamic variables such as cardiac output (CO) and stroke volume variation (SVV) by analysis of arterial blood pressure waveforms. However, evaluating the performance of CO monitoring systems to measure the small variations in these variables sometimes used to guide fluid therapy is a challenge due to limitations in clinical reference methods. We developed a non-clinical database as a tool for assessing the dynamic attributes of pressure-based CO monitoring systems, including CO response time and CO and SVV resolutions. We developed a mock circulation loop (MCL) that can simulate rapid changes in different parameters, such as CO and SVV. The MCL was configured to simulate three different states (normovolemic, cardiogenic shock, and hyperdynamic) representing a range of flow and pressure conditions. For each state, we simulated stepwise changes in the MCL flow and collected datasets for characterizing pressure-based CO systems. Nine datasets were generated that contain hours of peripheral pressure, central flow and pressure waveforms. The MCL-generated database is provided open access as a tool for evaluating dynamic characteristics of pressure-based CO algorithms and systems in detecting variations in CO and SVV indices. In an example application of the database, a CO response time of 10 s, CO and SVV resolutions with lower and upper limits of (-9.1%, 8.4%) and (-5.0%, 3.8%), respectively, were determined for a pressure-based CO benchtop system. This tool will support a more comprehensive assessment of pressure-based CO monitoring systems and algorithms.

A Mathematical Model for Simulation of Vasoplegic Shock and Vasopressor Therapy.

OBJECTIVE: To develop a high-fidelity mathematical model intended to replicate the cardiovascular (CV) responses of a critically ill patient to vasoplegic shock-induced hypotension and vasopressor therapy. METHODS: The mathematical model consists of a lumped-parameter CV physiology model with baroreflex modulation feedback and a phenomenological dynamic dose-response model of a vasopressor. The adequacy of the proposed mathematical model was investigated using an experimental dataset acquired from 10 pigs receiving phenylephrine (PHP) therapy after vasoplegic shock induced via sodium nitroprusside (SNP). RESULTS: Upon calibration, the mathematical model could (i) faithfully replicate the effects of PHP on dynamic changes in blood pressure (BP), cardiac output (CO), and systemic vascular resistance (SVR) (root-mean-squared errors between measured and calibrated mathematical responses: mean arterial BP 2.5+/-1.0 mmHg, CO 0.2+/-0.1 lpm, SVR 2.4+/-1.5 mmHg/lpm; r value: mean arterial BP 0.96+/-0.01, CO 0.65+/-0.45, TPR 0.92+/-0.10) and (ii) predict physiologically plausible behaviors of unmeasured internal CV variables as well as secondary baroreflex modulation effects. CONCLUSION: This mathematical model is perhaps the first of its kind that can comprehensively replicate both primary (i.e., direct) and secondary (i.e., baroreflex modulation) effects of a vasopressor drug on an array of CV variables, rendering it ideally suited to pre-clinical virtual evaluation of the safety and efficacy of closed-loop control algorithms for autonomous vasopressor administration once it is extensively validated. SIGNIFICANCE: This mathematical model architecture incorporating both direct and baroreflex modulation effects may generalize to serve as part of an effective platform for high-fidelity in silico simulation of CV responses to vasopressors during vasoplegic shock.

Development and validation of a mathematical model of heart rate response to fluid perturbation.

Physiological closed-loop controlled (PCLC) medical devices monitor and automatically adjust the patient's condition by using physiological variables as feedback, ideally with minimal human intervention to achieve the target levels set by a clinician. PCLC devices present a challenge when it comes to evaluating their performance, where conducting large clinical trials can be expensive. Virtual physiological patients simulated by validated mathematical models can be utilized to obtain pre-clinical evidence of safety and assess the performance of the PCLC medical device during normal and worst-case conditions that are unlikely to happen in a limited clinical trial. A physiological variable that plays a major role during fluid resuscitation is heart rate (HR). For in silico assessment of PCLC medical devices regarding fluid perturbation, there is currently no mathematical model of HR validated in terms of its predictive capability performance. This paper develops and validates a mathematical model of HR response using data collected from sheep subjects undergoing hemorrhage and fluid infusion. The model proved to be accurate in estimating the HR response to fluid perturbation, where averaged between 21 calibration datasets, the fitting performance showed a normalized root mean square error (NRMSE) of [Formula: see text]. The model was also evaluated in terms of model predictive capability performance via a leave-one-out procedure (21 subjects) and an independent validation dataset (6 subjects). Two different virtual cohort generation tools were used in each validation analysis. The generated envelope of virtual subjects robustly met the defined acceptance criteria, in which [Formula: see text] of the testing datasets presented simulated HR patterns that were within a deviation of 50% from the observed data. In addition, out of 16000 and 18522 simulated subjects for the leave-one-out and independent datasets, the model was able to generate at least one virtual subject that was close to the real subject within an error margin of [Formula: see text] and [Formula: see text] NRMSE, respectively. In conclusion, the model can generate valid virtual HR physiological responses to fluid perturbation and be incorporated into future non-clinical simulated testing setups for assessing PCLC devices intended for fluid resuscitation.

A Computational Modeling and Simulation Workflow to Investigate the Impact of Patient-Specific and Device Factors on Hemodynamic Measurements from Non-Invasive Photoplethysmography.

Cardiovascular disease is the leading cause of death globally. To provide continuous monitoring of blood pressure (BP), a parameter which has shown to improve health outcomes when monitored closely, many groups are trying to measure blood pressure via noninvasive photoplethysmography (PPG). However, the PPG waveform is subject to variation as a function of patient-specific and device factors and thus a platform to enable the evaluation of these factors on the PPG waveform and subsequent hemodynamic parameter prediction would enable device development. Here, we present a computational workflow that combines Monte Carlo modeling (MC), gaussian combination, and additive noise to create synthetic dataset of volar fingertip PPG waveforms representative of a diverse cohort. First, MC is used to determine PPG amplitude across age, skin tone, and device wavelength. Then, gaussian combination generates accurate PPG waveforms, and signal processing enables data filtration and feature extraction. We improve the limitations of current synthetic PPG frameworks by enabling inclusion of physiological and anatomical effects from body site, skin tone, and age. We then show how the datasets can be used to examine effects of device characteristics such as wavelength, analog to digital converter specifications, filtering method, and feature extraction. Lastly, we demonstrate the use of this framework to show the insensitivity of a support vector machine predictive algorithm compared to a neural network and bagged trees algorithm.

Simulating Radial Pressure Waveforms with a Mock Circulatory Flow Loop to Characterize Hemodynamic Monitoring Systems.

PURPOSE: Mock circulatory loops (MCLs) can reproducibly generate physiologically relevant pressures and flows for cardiovascular device testing. These systems have been extensively used to characterize the performance of therapeutic cardiac devices, but historically MCLs have had limited use for assessing patient monitoring systems. Here, we adapted an MCL to include peripheral components and evaluated its utility for qualitative and quantitative benchtop testing of hemodynamic monitoring devices. METHODS: An MCL was designed to simulate three physiological hemodynamic states: normovolemia, cardiogenic shock, and hyperdynamic circulation. The system was assessed for stability in pressure and flow values over time, repeatability, waveform morphology, and systemic-peripheral pressure relationships. RESULTS: For each condition, cardiac output was controlled to the nearest 0.2 L/min, and flow rate and mean arterial pressure remained stable and repeatable over a 60-s period (n = 5, standard deviation of ± 0.1 L/min and ± 0.84 mmHg, respectively). Transfer function analyses showed that the systemic-peripheral relationships could be adequately manipulated. The results from this MCL were comparable to those from other published MCLs and computational simulations. However, resolving current limitations of the system would further improve its utility. Three pulse contour analysis algorithms were applied to the pressure and flow data from the MCL to demonstrate the potential role of MCLs in characterizing hemodynamic monitoring systems. CONCLUSION: Overall, the development of robust analysis methods in conjunction with modified MCLs can expand device testing applications to hemodynamic monitoring systems. Properly validated MCLs can create a stable and reproducible environment for testing patient monitoring systems over their entire operating ranges prior to clinical use.

Monitoring Respiratory Motion With Wi-Fi CSI: Characterizing Performance and the BreatheSmart Algorithm.

Respiratory motion (i.e., motion pattern and rate) can provide valuable information for many medical situations. This information may help in the diagnosis of different health disorders and diseases. Wi-Fi-based respiratory monitoring schemes utilizing commercial off-the-shelf (COTS) devices can provide contactless, low-cost, simple, and scalable respiratory monitoring without requiring specialized hardware. Despite intense research efforts, an in-depth investigation on how to evaluate this type of technology is missing. We demonstrated and assessed the feasibility of monitoring and extracting human respiratory motion from Wi-Fi channel state information (CSI) data. This demonstration involves implementing an end-to-end system for a COTS-based hardware platform, control software, data acquisition, and a proposed processing algorithm. The processing algorithm is a novel deep-learning-based approach that exploits small changes in both CSI amplitude and phase information to learn high-level abstractions of breathing-induced chest movements and to reveal the unique characteristics of their difference. We also conducted extensive laboratory experiments demonstrating an assessment technique that can be replicated when quantifying the performance of similar systems. The results indicate that the proposed scheme can classify respiratory patterns and rates with an accuracy of 99.54% and 98.69%, respectively, in moderately degraded RF channels. Comprehensive data acquisition revealed the capability of the proposed system in detecting and classifying respiratory motions. Understanding the feasible limits and potential failure factors of Wi-Fi CSI-based respiratory monitoring scheme - and how to evaluate them - is an essential step toward the practical deployment of this technology. This study discusses ideas for further expansion of this technology.

Model-based approach to investigate equipment-induced error in pressure-waveform derived hemodynamic measurements.

Objective.Advanced hemodynamic monitoring systems have provided less invasive methods for estimating pressure-derived measurements such as pressure-derived cardiac output (CO) measurements. These devices apply algorithms to arterial pressure waveforms recorded via pressure recording components that transmit the pressure signal to a pressure monitor. While standards have been developed for pressure monitoring equipment, it is unclear how the equipment-induced error can affect secondary measurements from pressure waveforms. We propose an approach for modelling different components of a pressure monitoring system and use this model-based approach to investigate the effect of different pressure recording configurations on pressure-derived hemodynamic measurements.Approach.The proposed model-based approach is a three step process. (1) Modelling the response of pressure recording components using bench tests; (2) verifying the identified models through nonparametric equivalence tests; and (3) assessing the effects of pressure recording components on pressure-derived measurements. To delineate the application of this approach, we performed a series of model-based analyses to quantify the combined effect of a wide range of tubing configurations with various damping ratios and natural frequencies and monitors with different bandwidths on pressure waveforms and CO measurements by six pulse contour algorithms.Results.Model-based results show the error in pressure-derived CO measurements because of tubing configurations with different natural frequencies and damping ratios. Tubing configurations with low natural frequencies (<23 Hz) altered characteristics of pressure waveforms in a way that affected the CO measurement, some by as much as 20%.Significance.Our method can serve as a tool to quantify the performance of pressure recording systems with different dynamic properties. This approach can be applied to investigate the effects of physiologic signal recording configurations on various pressure-derived hemodynamic measurements.

Credibility Assessment of a Subject-Specific Mathematical Model of Blood Volume Kinetics for Prediction of Physiological Response to Hemorrhagic Shock and Fluid Resuscitation.

Subject-specific mathematical models for prediction of physiological parameters such as blood volume, cardiac output, and blood pressure in response to hemorrhage have been developed. In silico studies using these models may provide an effective tool to generate pre-clinical safety evidence for medical devices and help reduce the size and scope of animal studies that are performed prior to initiation of human trials. To achieve such a goal, the credibility of the mathematical model must be established for the purpose of pre-clinical in silico testing. In this work, the credibility of a subject-specific mathematical model of blood volume kinetics intended to predict blood volume response to hemorrhage and fluid resuscitation during fluid therapy was evaluated. A workflow was used in which: (i) the foundational properties of the mathematical model such as structural identifiability were evaluated; (ii) practical identifiability was evaluated both pre- and post-calibration, with the pre-calibration results used to determine an optimal splitting of experimental data into calibration and validation datasets; (iii) uncertainty in model parameters and the experimental uncertainty were quantified for each subject; and (iv) the uncertainty was propagated through the blood volume kinetics model and its predictive capability was evaluated via validation tests. The mathematical model was found to be structurally identifiable. Pre-calibration identifiability analysis led to splitting the 180 min of time series data per subject into 50 and 130 min calibration and validation windows, respectively. The average root mean squared error of the mathematical model was 12.6% using the calibration window of (0 min, 50 min). Practical identifiability was established post-calibration after fixing one of the parameters to a nominal value. In the validation tests, 82 and 75% of the subject-specific mathematical models were able to correctly predict blood volume response when predictive capability was evaluated at 180 min and at the time when amount of infused fluid equals fluid loss.

Simulating Study Design Choice Effects on Observed Performance of Predictive Patient Monitoring Alarm Algorithms.

There are multiple study design choices to be selected in order to perform evaluations of predictive patient monitoring algorithms related to the event and true positive alarm definitions (e.g., how far ahead of the event is a true positive alarm). Often, passively collected patient monitoring datasets from clinical environments are available to perform these types of studies, so that the effects of different study design choices can be simulated to evaluate the robustness of an algorithm to those choices. Here, we simulate the effects of varying alarm and event definition criteria on the reported performance of the early warning score to predict hypotensive events. A total of 432 combinations of study design choices were simulated. Area under the receiver-operating characteristic curve varied from greater than 0.8 to less than 0.5 by adjusting alarm and event definition criteria. Traditional metrics for evaluating diagnostic systems were modulated across a wide range by adjusting study design choices for a predictive algorithm using a patient monitoring dataset. This highlights the importance of examining study design choices for new predictive patient monitoring algorithms and presents an approach to simulate different study designs with retrospective patient monitoring data as part of a robustness evaluation.

Accuracy assessment methods for physiological model selection toward evaluation of closed-loop controlled medical devices.

Physiological closed-loop controlled (PCLC) medical devices are complex systems integrating one or more medical devices with a patient's physiology through closed-loop control algorithms; introducing many failure modes and parameters that impact performance. These control algorithms should be tested through safety and efficacy trials to compare their performance to the standard of care and determine whether there is sufficient evidence of safety for their use in real care setting. With this aim, credible mathematical models have been constructed and used throughout the development and evaluation phases of a PCLC medical device to support the engineering design and improve safety aspects. Uncertainties about the fidelity of these models and ambiguities about the choice of measures for modeling performance need to be addressed before a reliable PCLC evaluation can be achieved. This research develops tools for evaluating the accuracy of physiological models and establishes fundamental measures for predictive capability assessment across different physiological models. As a case study, we built a refined physiological model of blood volume (BV) response by expanding an original model we developed in our prior work. Using experimental data collected from 16 sheep undergoing hemorrhage and fluid resuscitation, first, we compared the calibration performance of the two candidate physiological models, i.e., original and refined, using root-mean-squared error (RMSE), Akiake information criterion (AIC), and a new multi-dimensional approach utilizing normalized features extracted from the fitting error. Compared to the original model, the refined model demonstrated a significant improvement in calibration performance in terms of RMSE (9%, P = 0.03) and multi-dimensional measure (48%, P = 0.02), while a comparable AIC between the two models verified that the enhanced calibration performance in the refined model is not due to data over-fitting. Second, we compared the physiological predictive capability of the two models under three different scenarios: prediction of subject-specific steady-state BV response, subject-specific transient BV response to hemorrhage perturbation, and leave-one-out inter-subject BV response. Results indicated enhanced accuracy and predictive capability for the refined physiological model with significantly larger proportion of measurements that were within the prediction envelope in the transient and leave-one-out prediction scenarios (P < 0.02). All together, this study helps to identify and merge new methods for credibility assessment and physiological model selection, leading to a more efficient process for PCLC medical device evaluation.

Technical considerations for evaluating clinical prediction indices: a case study for predicting code blue events with MEWS.

Objective.There have been many efforts to develop tools predictive of health deterioration in hospitalized patients, but comprehensive evaluation of their predictive ability is often lacking to guide implementation in clinical practice. In this work, we propose new techniques and metrics for evaluating the performance of predictive alert algorithms and illustrate the advantage of capturing the timeliness and the clinical burden of alerts through the example of the modified early warning score (MEWS) applied to the prediction of in-hospital code blue events.Approach. Different implementations of MEWS were calculated from available physiological parameter measurements collected from the electronic health records of ICU adult patients. The performance of MEWS was evaluated using conventional and a set of non-conventional metrics and approaches that take into account the timeliness and practicality of alarms as well as the false alarm burden.Main results. MEWS calculated using the worst-case measurement (i.e. values scoring 3 points in the MEWS definition) over 2 h intervals significantly reduced the false alarm rate by over 50% (from 0.19/h to 0.08/h) while maintaining similar sensitivity levels as MEWS calculated from raw measurements (∼80%). By considering a prediction horizon of 12 h preceding a code blue event, a significant improvement in the specificity (∼60%), the precision (∼155%), and the work-up to detection ratio (∼50%) could be achieved, at the cost of a relatively marginal decrease in sensitivity (∼10%).Significance. Performance aspects pertaining to the timeliness and burden of alarms can aid in understanding the potential utility of a predictive alarm algorithm in clinical settings.

Practical Use of Regularization in Individualizing a Mathematical Model of Cardiovascular Hemodynamics Using Scarce Data.

Individualizing physiological models to a patient can enable patient-specific monitoring and treatment in critical care environments. However, this task often presents a unique "practical identifiability" challenge due to the conflict between model complexity and data scarcity. Regularization provides an established framework to cope with this conflict by compensating for data scarcity with prior knowledge. However, regularization has not been widely pursued in individualizing physiological models to facilitate patient-specific critical care. Thus, the goal of this work is to garner potentially generalizable insight into the practical use of regularization in individualizing a complex physiological model using scarce data by investigating its effect in a clinically significant critical care case study of blood volume kinetics and cardiovascular hemodynamics in hemorrhage and circulatory resuscitation. We construct a population-average model as prior knowledge and individualize the physiological model via regularization to illustrate that regularization can be effective in individualizing a physiological model to learn salient individual-specific characteristics (resulting in the goodness of fit to individual-specific data) while restricting unnecessary deviations from the population-average model (achieving practical identifiability). We also illustrate that regularization yields parsimonious individualization of only sensitive parameters as well as adequate physiological plausibility and relevance in predicting internal physiological states.

Evaluation of Fluid Resuscitation Control Algorithms via a Hardware-in-the-Loop Test Bed.

OBJECTIVE: This paper presents a hardware-in-the-loop (HIL) testing platform for evaluating the performance of fluid resuscitation control algorithms. The proposed platform is a cyber-physical system that integrates physical devices with computational models and computer-based algorithms. METHODS: The HIL test bed is evaluated against in silico and in vivo data to ensure the hemodynamic variables are appropriately predicted in the proposed platform. The test bed is then used to investigate the performance of two fluid resuscitation control algorithms: a decision table (rule-based) and a proportional-integral-derivative (PID) controller. RESULTS: The statistical evaluation of test bed indicates that similar results are observed in the HIL test bed, in silico implementation, and the in vivo data, verifying that the HIL test bed can adequately predict the hemodynamic responses. Comparison of the two fluid resuscitation controllers reveals that both controllers stabilized hemodynamic variables over time and had similar speed to efficiently achieve the target level of the hemodynamic endpoint. However, the accuracy of the PID controller was higher than the rule-based for the scenarios tested in the HIL platform. CONCLUSION: The results demonstrate the potential of the HIL test bed for realistic testing of physiologic controllers by incorporating physical devices with computational models of physiology and disturbances. SIGNIFICANCE: This type of testing enables relatively fast evaluation of physiologic closed-loop control systems to aid in iterative design processes and offers complementary means to existing techniques (e.g., in silico, in vivo, and clinical studies) for testing of such systems against a wide range of disturbances and scenarios.

A framework to characterize the performance of early warning index alarm systems for patient monitoring.

In [Scully, C.G., and Daluwatte, C., Evaluating performance of early warning indices to predict physiological instabilities. J Biomed Inform. 75 (2017) 14-21], a framework was presented to characterize the performance of warning indices to provide information on the 1) probability a critical health event will occur when a warning is given (analogous to positive predictive value) and 2) proportion of warned events to all events (analogous to sensitivity). This framework also provides information about the timeliness of the warnings with respect to event occurrence and the warning burden of the system. •In the current work, we provide information on how this framework can be used when cases without events are present in a dataset to examine the proportion of warned non-events to all non-events (analogous to false positive rate).•Information on steps to apply the method, software, data and results for the case study are also provided to enable implementation of the framework.•Application and extension of the framework is demonstrated and discussed by adding non-event records to our previous case study comparing two warning strategies to predict physiologic instabilities.

Credibility Evidence for Computational Patient Models Used in the Development of Physiological Closed-Loop Controlled Devices for Critical Care Medicine.

Physiological closed-loop controlled medical devices automatically adjust therapy delivered to a patient to adjust a measured physiological variable. In critical care scenarios, these types of devices could automate, for example, fluid resuscitation, drug delivery, mechanical ventilation, and/or anesthesia and sedation. Evidence from simulations using computational models of physiological systems can play a crucial role in the development of physiological closed-loop controlled devices; but the utility of this evidence will depend on the credibility of the computational model used. Computational models of physiological systems can be complex with numerous non-linearities, time-varying properties, and unknown parameters, which leads to challenges in model assessment. Given the wide range of potential uses of computational patient models in the design and evaluation of physiological closed-loop controlled systems, and the varying risks associated with the diverse uses, the specific model as well as the necessary evidence to make a model credible for a use case may vary. In this review, we examine the various uses of computational patient models in the design and evaluation of critical care physiological closed-loop controlled systems (e.g., hemodynamic stability, mechanical ventilation, anesthetic delivery) as well as the types of evidence (e.g., verification, validation, and uncertainty quantification activities) presented to support the model for that use. We then examine and discuss how a credibility assessment framework (American Society of Mechanical Engineers Verification and Validation Subcommittee, V&V 40 Verification and Validation in Computational Modeling of Medical Devices) for medical devices can be applied to computational patient models used to test physiological closed-loop controlled systems.

A method to extract realistic artifacts from electrocardiogram recordings for robust algorithm testing.

OBJECTIVE: Recordings of signal noise and artifacts can be added to clean electrocardiogram (ECG) records to assess the performance of ECG and arrhythmia analysis algorithms in the presence of noise. We present a method to estimate device-specific signal noise and artifacts from ECG records. This method can be applied to obtain noise estimates from healthy subjects on any ECG lead, allowing a simple device-specific recording. The proposed approach is assessed using the MIT-BIH Noise Stress Test Database recordings combined with simulated ECGs. METHODS: The proposed noise-estimation method is based on the subtraction of a time-aligned median beat from a noisy ECG recording. To test our method, electrode motion and muscle artifact noise from MIT-BIH Noise Stress Test database were added to simulated ECG signals at signal-noise ratios (SNR) from -6 to 20 dB. A comparison between noise and estimated noise signal statistical characteristics was made including root-mean squared error and assessment of the power content in three frequency bands (cardiac [0.5-5 Hz], mid [5-25 Hz], and high [25-40 Hz]). RESULTS: Visual assessment and frequency analysis demonstrate the good quality of noise estimation. Root-mean squared error between noise and estimated noise signals was <0.5 Normalized Units across all SNR levels. Band power error was stable across SNR levels with median percentage error between noise and estimate noise signals of <10% for cardiac and mid frequency bands. CONCLUSION: Estimating noise from ECG records is a viable approach to generate noise and artifacts-only signals. These signals are device-specific and easy to collect from healthy subjects without requiring special electrode set-ups. Therefore, they may be suitable for use with annotated ECG databases to assess the robustness of ECG analysis algorithms in the presence of noise.