Comparability of Heart Rate Turbulence Methodology: 15 Intervals Suffice to Calculate Turbulence Slope - A Methodological Analysis Using PhysioNet Data of 1074 Patients.

Heart rate turbulence (HRT) is a characteristic heart rate pattern triggered by a ventricular premature contraction (VPC). It can be used to assess autonomic function and health risk for various conditions, e.g., coronary artery disease or cardiomyopathy. While comparability is essential for scientific analysis, especially for research focusing on clinical application, the methodology of HRT still varies widely in the literature. Particularly, the ECG measurement and parameter calculation of HRT differs, including the calculation of turbulence slope (TS). In this article, we focus on common variations in the number of intervals after the VPC that are used to calculate TS (#TSRR) posing two questions: 1) Does a change in #TSRR introduce noticeable changes in HRT parameter values and classification? and 2) Do larger values of turbulence timing (TT) enabled by a larger #TSRR still represent distinct HRT? We compiled a free-access data set of 1,080 annotated long-term ECGs provided by Physionet. HRT parameter values and risk classes were determined both with #TSRR 15 and 20. A standard local tachogram was created by averaging the tachograms of only the files with the best heart rate variability values. The shape of this standard VPC sequence was compared to all VPC sequences grouped by their TT value using dynamic time warping (DTW) in order to identify HRT shapes. When calculated with different #TSRR, our results show only a little difference between the number of files with enough valid VPC sequences to calculate HRT (<1%) and files with different risk classes (5 and 6% for HRT0-2 and HRTA-C, respectively). In the DTW analysis, the difference between averaged sequences with a specific TT and the standard sequence increased with increasing TT. Our analysis suggests that HRT occurs in the early intervals after the VPC and TS calculated from late intervals reflects common heart rate variability rather than a distinct response to the VPC. Even though the differences in classification are marginal, this can lead to problems in clinical application and scientific research. Therefore, we recommend uniformly using #TSRR 15 in HRT analysis.

Countering reproducibility issues in mathematical models with software engineering techniques: A case study using a one-dimensional mathematical model of the atrioventricular node.

One should assume that in silico experiments in systems biology are less susceptible to reproducibility issues than their wet-lab counterparts, because they are free from natural biological variations and their environment can be fully controlled. However, recent studies show that only half of the published mathematical models of biological systems can be reproduced without substantial effort. In this article we examine the potential causes for failed or cumbersome reproductions in a case study of a one-dimensional mathematical model of the atrioventricular node, which took us four months to reproduce. The model demonstrates that even otherwise rigorous studies can be hard to reproduce due to missing information, errors in equations and parameters, a lack in available data files, non-executable code, missing or incomplete experiment protocols, and missing rationales behind equations. Many of these issues seem similar to problems that have been solved in software engineering using techniques such as unit testing, regression tests, continuous integration, version control, archival services, and a thorough modular design with extensive documentation. Applying these techniques, we reimplement the examined model using the modeling language Modelica. The resulting workflow is independent of the model and can be translated to SBML, CellML, and other languages. It guarantees methods reproducibility by executing automated tests in a virtual machine on a server that is physically separated from the development environment. Additionally, it facilitates results reproducibility, because the model is more understandable and because the complete model code, experiment protocols, and simulation data are published and can be accessed in the exact version that was used in this article. We found the additional design and documentation effort well justified, even just considering the immediate benefits during development such as easier and faster debugging, increased understandability of equations, and a reduced requirement for looking up details from the literature.

Characteristics of mathematical modeling languages that facilitate model reuse in systems biology: a software engineering perspective.

Reuse of mathematical models becomes increasingly important in systems biology as research moves toward large, multi-scale models composed of heterogeneous subcomponents. Currently, many models are not easily reusable due to inflexible or confusing code, inappropriate languages, or insufficient documentation. Best practice suggestions rarely cover such low-level design aspects. This gap could be filled by software engineering, which addresses those same issues for software reuse. We show that languages can facilitate reusability by being modular, human-readable, hybrid (i.e., supporting multiple formalisms), open, declarative, and by supporting the graphical representation of models. Modelers should not only use such a language, but be aware of the features that make it desirable and know how to apply them effectively. For this reason, we compare existing suitable languages in detail and demonstrate their benefits for a modular model of the human cardiac conduction system written in Modelica.

An Understandable, Extensible, and Reusable Implementation of the Hodgkin-Huxley Equations Using Modelica.

The Hodgkin-Huxley model of the squid giant axon has been used for decades as the basis of many action potential models. These models are usually communicated using just a list of equations or a circuit diagram, which makes them unnecessarily complicated both for novices and for experts. We present a modular version of the Hodgkin-Huxley model that is more understandable than the usual monolithic implementations and that can be easily reused and extended. Our model is written in Modelica using software engineering concepts, such as object orientation and inheritance. It retains the electrical analogy, but names and explains individual components in biological terms. We use cognitive load theory to measure understandability as the amount of items that have to be kept in working memory simultaneously. The model is broken down into small self-contained components in human-readable code with extensive documentation. Additionally, it features a hybrid diagram that uses biological symbols in an electrical circuit and that is directly tied to the model code. The new model design avoids many redundancies and reduces the cognitive load associated with understanding the model by a factor of 6. Extensions can be easily applied due to an unifying interface and inheritance from shared base classes. The model can be used in an educational context as a more approachable introduction to mathematical modeling in electrophysiology. Additionally the modeling approach and the base components can be used to make complex Hodgkin-Huxley-type models more understandable and reusable.

HRT assessment reviewed: a systematic review of heart rate turbulence methodology.

Heart rate turbulence (HRT) is a biphasic reaction to a ventricular premature contraction (VPC) mainly mediated by the baroreflex. It can be used for risk stratification in different disease patterns. Despite existing standards there is a lot of variation in terms of measuring and calculating HRT, which complicates research and application. OBJECTIVE: This systematic review outlines and evaluates the methodological spectrum of HRT research, especially filtering criteria, parameter calculation and thresholds. APPROACH: The analysis includes all research papers written in English that have been published before 12.10.2018, are listed on PubMed and involve calculation of HRT parameter values. MAIN RESULTS: HRT assessment is still being performed in various ways and important specifications of the methodology are not given in many articles. Nevertheless, some suggestions regarding HRT methodology can be made: a normalised turbulence slope should be used to uncouple the parameter from heart rate and frequency of extrasystoles. Filtering criteria as formerly reviewed in the guidelines should be met and mentioned. The minimal number of VPC snippets (VPCSs) as well as new cut-off values for different risks need to be further evaluated. Most importantly, the exact and complete methodology must be described to ensure reproducibility and comparability. SIGNIFICANCE: Methodical variation hinders comparability of research and medical application. Our continuing questions help to further standardise the measurement and calculation of HRT and increase its value for medical risk stratification.