Jiang, Zhihao
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Publication Computer Aided Clinical Trials for Implantable Cardiac Devices(2018-07-12) Jang, Kuk Jin; Weimer, James; Abbas, Houssam; Jiang, Zhihao; Liang, Jackson; Dixit, Sanjay; Mangharam, RahulIn this paper we aim to answer the question, ``How can modeling and simulation of physiological systems be used to evaluate life-critical implantable medical devices?'' Clinical trials for medical devices are becoming increasingly inefficient as they take several years to conduct, at very high cost and suffer from high rates of failure. For example, the Rhythm ID Goes Head-to-head Trial (RIGHT) sought to evaluate the performance of two arrhythmia discriminator algorithms for implantable cardioverter defibrillators, Vitality 2 vs. Medtronic, in terms of time-to-first inappropriate therapy, but concluded with results contrary to the initial hypothesis - after 5 years, 2,000+ patients and at considerable ethical and monetary cost. In this paper, we describe the design and performance of a computer-aided clinical trial (CACT) for Implantable Cardiac Devices where previous trial information, real patient data and closed-loop device models are effectively used to evaluate the trial with high confidence. We formulate the CACT in the context of RIGHT using a Bayesian statistical framework. We define a hierarchical model of the virtual cohort generated from a physiological model which captures the uncertainty in the parameters and allows for the systematic incorporation of information available at the design of the trial. With this formulation, the CACT estimates the inappropriate therapy rate of Vitality 2 compared to Medtronic as 33.22% vs 15.62% (pPublication Heart-on-a-Chip: A Closed-loop Testing Platform for Implantable Pacemakers(2014-07-02) Jiang, Zhihao; Radhakrishnan, Sriram; Sampath, Varun; Sarode, Shilpa; Mangharam, RahulImplantable cardiac pacemakers restore normal heart rhythm by delivering external electrical pacing to the heart. The pacemaker software is life-critical as the timing of the pulses determine its ability to control the heart rate. Recalls due to software issues have been on the rise with the increasing complexity of pacing algorithms. Open-loop testing remains the primary approach to evaluate the safety of pacemaker software. While this tests how the pacemaker responds to stimulus, it cannot reveal pacemaker malfunctions which drive the heart into an unsafe state over multiple cycles. To evaluate the safety and efficacy of pacemaker software we have developed a heart model to generate different heart conditions and interact with real pacemakers. In this paper, we introduce the closed-loop testing platform which consists of a programmable hardware implementation of the heart that can interact with a commercial pacemaker in closed-loop. The heart-on-a-chip implementation is automatically generated from the Virtual Heart Model in Simulink which models different heart conditions. We describe a case study of Endless Loop Tachycardia to demonstrate potential closed-loop pacemaker malfunctions which inappropriately increase the heart rate. The test platform is part of our model-based design framework for verification and testing of medical devices with the patient--in-the-loop.Publication Model-Based Conformance Testing for Implantable Pacemakers(2013-07-31) Chen, George; Jiang, Zhihao; Mangharam, RahulPublication Cyber-Physical Modeling of Implantable Cardiac Medical Devices(2011-12-29) Jiang, Zhihao; Pajic, Miroslav; Mangharam, RahulThe design of bug-free and safe medical device software is challenging, especially in complex implantable devices that control and actuate organs in unanticipated contexts. Safety recalls of pacemakers and implantable cardioverter defibrillators between 1990 and 2000 affected over 600,000 devices. Of these, 200,000 or 41%, were due to firmware issues and their effect continues to increase in frequency. There is currently no formal methodology or open experimental platform to test and verify the correct operation of medical device software within the closed-loop context of the patient. To this effect, a real-time Virtual Heart Model (VHM) has been developed to model the electrophysiological operation of the functioning and malfunctioning (i.e., during arrhythmia) heart. By extracting the timing properties of the heart and pacemaker device, we present a methodology to construct a timed-automata model for functional and formal testing and verification of the closed-loop system. The VHM's capability of generating clinically-relevant response has been validated for a variety of common arrhythmias. Based on a set of requirements, we describe a closed-loop testing environment that allows for interactive and physiologically relevant model-based test generation for basic pacemaker device operations such as maintaining the heart rate, atrial-ventricle synchrony and complex conditions such as pacemaker-mediated tachycardia. This system is a step toward a testing and verification approach for medical cyber-physical systems with the patient-in-the-loop.Publication Real-time Heart Model for Implantable Cardiac Device Validation and Verification(2010-01-20) Jiang, Zhihao; Pajic, Miroslav; Connolly, Allison T; Dixit, Sanjay; Mangharam, RahulDesigning bug-free medical device software is dif- ficult, especially in complex implantable devices that may be used in unanticipated contexts. Safety recalls of pacemakers and implantable cardioverter defibrillators due to firmware problems between 1990 and 2000 affected over 200,000 devices, comprising 41% of the devices recalled and are increasing in frequency. There is currently no formal methodology or open experimental platform to validate and verify the correct operation of medical device software. To this effect, a real-time Virtual Heart Model (VHM) has been developed to model the electrophysiological operation of the functioning (i.e. during normal sinus rhythm) and malfunctioning (i.e. during arrhythmia) heart. We present a methodology to extract timing properties of the heart to construct a timed-automata model. The platform exposes functional and formal interfaces for validation and verification of implantable cardiac devices. We demonstrate the VHM is capable of generating clinically-relevant response to intrinsic (i.e. premature stimuli) and external (i.e. artificial pacemaker) signals for a variety of common arrhythmias. By connecting the VHM with a pacemaker model, we are able to pace and synchronize the heart during the onset of irregular heart rhythms. The VHM has also been implemented on a hardware platform for closed-loop experimentation with existing and virtual medical devices. The VHM allows for exploratory electrophysiology studies for physicians to evaluate their diagnosis and determine the appropriate device therapy. This integrated functional and formal device design approach will potentially help expedite medical device certification for safer operation.Publication Modeling and Verification of a Dual Chamber Implantable Pacemaker(2012-04-16) Jiang, Zhihao; Pajic, Miroslav; Moarref, Salar; Alur, Rajeev; Mangharam, RahulThe design and implementation of software for medical devices is challenging due to their rapidly increasing functionality and the tight coupling of computation, control, and communication. The safety-critical nature and the lack of existing industry standards for verification, make this an ideal domain for exploring applications of formal modeling and analysis. In this paper, we use a dual chamber implantable pacemaker as a case study for modeling and verification of control algorithms for medical devices in UPPAAL. We present detailed models of different components of the pacemaker based on the algorithm descriptions from Boston Scientific. We formalize basic safety requirements based on specifications from Boston Scientific as well as additional physiological knowledge. The most critical potential safety violation for a pacemaker is that it may lead the closed-loop system into an undesirable pattern (for example, Tachycardia). Modern pacemakers are implemented with termination algorithms to prevent such conditions. We show how to identify these conditions and check correctness of corresponding termination algorithms by augmenting the basic models with monitors for detecting undesirable patterns. Along with emerging tools for code generation from UPPAAL models, this effort enables model driven design and certification of software for medical devices.Publication From Verified Models to Verified Code for Safe Medical Devices(2016-01-01) Jiang, ZhihaoMedical devices play an essential role in the care of patients around the world, and can have a life-saving effect. An emerging category of autonomous medical devices like implantable pacemakers and implantable cardioverter defibrillators (ICD) diagnose conditions of the patient and autonomously deliver therapies. Without trained professionals in the loop, the software component of autonomous medical devices is responsible for making critical therapeutic decisions, which pose a new set of challenges to guarantee patient safety. As regulation effort to guarantee patient safety, device manufacturers are required to submit evidence for the safety and efficacy of the medical devices before they can be released to the market. Due to the closed-loop interaction between the device and the patient, the safety and efficacy of autonomous medical devices must ultimately be evaluated within their physiological context. Currently the primary closed-loop validation of medical devices is in form of clinical trials, in which the devices are evaluated on real patients. Clinical trials are expensive and expose the patients to risks associated with untested devices. Clinical trials are also conducted after device development, therefore issues found during clinical trials are expensive to fix. There is urgent need for closed-loop validation of autonomous medical devices before the devices are used in clinical trials. In this thesis, I used implantable cardiac devices to demonstrate the applications of model-based approaches during and after device development to provide confidence towards the safety and efficacy of the devices. A heart model structure is developed to mimic the electrical behaviors of the heart in various heart conditions. The heart models created with the model structure are capable of interacting with implantable cardiac devices in closed-loop and can provide physiological interpretations for a large variety of heart conditions. With the heart models, I demonstrated that closed-loop model checking is capable of identifying known and unknown safety violations within the pacemaker design. More importantly, I developed a framework to choose the most appropriate heart models to cover physiological conditions that the pacemaker may encounter, and provide physiological context to counter-examples returned by the model checker. A model translation tool UPP2SF is then developed to translate the pacemaker design in UPPAAL to Stateflow, and automatically generated to C code. The automated and rigorous translation ensures that the properties verified during model checking still hold in the implementation, which justifies the model checking effort. Finally, the devices are evaluated with a virtual patient cohort consists of a large number of heart models before evaluated in clinical trials. These in-silico pre-clinical trials provide useful insights which can be used to increase the success rate of a clinical trial. The work in this dissertation demonstrated the importance and challenges to represent physiological behaviors during closed-loop validation of autonomous medical devices, and demonstrated the capability of model-based approaches to provide safety and efficacy evidence during and after device development.Publication Demo Abstract: A Platform for Implantable Medical Device Validation(2010-10-01) Pajic, Miroslav; Jiang, Zhihao; Mangharam, Rahul; Connolly, Allison; Dixit, SanjayPublication From Verification to Implementation: A Model Translation Tool and a Pacemaker Case Study(2012-01-01) Pajic, Miroslav; Jiang, Zhihao; Lee, Insup; Sokolsky, Oleg; Mangharam, RahulModel-Driven Design (MDD) of cyber-physical systems advocates for design procedures that start with formal modeling of the real-time system, followed by the model’s verification at an early stage. The verified model must then be translated to a more detailed model for simulation-based testing and finally translated into executable code in a physical implementation. As later stages build on the same core model, it is essential that models used earlier in the pipeline are valid approximations of the more detailed models developed downstream. The focus of this effort is on the design and development of a model translation tool, UPP2SF, and how it integrates system modeling, verification, model-based WCET analysis, simulation, code generation and testing into an MDD based framework. UPP2SF facilitates automatic conversion of verified timed automata-based models (in UPPAAL) to models that may be simulated and tested (in Simulink/Stateflow). We describe the design rules to ensure the conversion is correct, efficient and applicable to a large class of models. We show how the tool enables MDD of an implantable cardiac pacemaker. We demonstrate that UPP2SF preserves behaviors of the pacemaker model from UPPAAL to Stateflow. The resultant Stateflow chart is automatically converted into C and tested on a hardware platform for a set of requirements.Publication Real-time Heart Model for Implantable Cardiac Device Validation and Verification(2010-07-06) Jiang, Zhihao; Pajic, Miroslav; Connolly, Allison; Dixit, Sanjay; Mangharam, RahulDesigning bug-free medical device software is challenging, especially in complex implantable devices that may be used in unanticipated contexts. Safety recalls of pacemakers and implantable cardioverter defibrillators due to firmware problems between 1990 and 2000 affected over 200, 000 devices. This encompasses 41% of the devices recalled and continues to increase in frequency. There is currently no formal methodology or open experimental platform to validate and verify the correct operation of medical device software. To this effect, a real-time Virtual Heart Model (VHM) has been developed to model the electrophysiological operation of the functioning (i.e. during normal sinus rhythm) and malfunctioning (i.e. during arrhythmia) heart. We present a methodology to construct a timed-automata model by extracting timing properties of the heart. The platform employs functional and formal interfaces for validation and verification of implantable cardiac devices. We demonstrate the VHM is capable of generating clinically-relevant response to intrinsic (i.e. premature stimuli) and external (i.e. artificial pacemaker) signals for a variety of common arrhythmias. By connecting the VHM with a pacemaker model, we are able to pace and synchronize the heart during the onset of irregular heart rhythms. The VHM has also been implemented on a hardware platform for closed-loop experimentation with existing and virtual medical devices. This integrated functional and formal device design approach has potential to help expedite medical device certification for safe operation.