ECGMiner: A flexible software for accurately digitizing ECG.

BACKGROUND AND OBJECTIVE: The electrocardiogram (ECG) is the most important non-invasive method for elucidating information about heart and cardiovascular disease diagnosis. Typically, the ECG system manufacturing companies provide ECG images, but store the numerical data in a proprietary format that is not interpretable and is not therefore useful for automatic diagnosis. There have been many efforts to digitize paper-based ECGs. The main limitations of previous works in ECG digitization are that they require manual selection of the regions of interest, only partly provide signal digitization, and offer limited accuracy. METHODS: We have developed the ECGMiner, an open-source software to digitize ECG images. It is precise, fast, and simple to use. This software digitizes ECGs in four steps: 1) recognizing the image composition; 2) removing the gridline; 3) extracting the signals; 4) post-processing and storing the data. RESULTS: We have evaluated the ECGMiner digitization capabilities using the Pearson Correlation Coefficient (PCC) and the Root Mean Square Error (RMSE) measures, and we consider ECG from two large, public, and widely used databases, LUDB and PTB-XL. The actual and digitized values of signals in both databases have been compared. The software's ability to correctly identify the location of characteristic waves has also been validated. Specifically, the PCC values are between 0.971 and 0.995, and the RMSE values are between 0.011 and 0.031 mV. CONCLUSIONS: The ECGMiner software presented in this paper is open access, easy to install, easy to use, and capable of precisely recovering the paper-based/digital ECG signal data, regardless of the input format and signal complexity. ECGMiner outperforms existing digitization algorithms in terms of PCC and RMSE values.

CIRCUST: A novel methodology for temporal order reconstruction of molecular rhythms; validation and application towards a daily rhythm gene expression atlas in humans.

The circadian system drives near-24-h oscillations in behaviors and biological processes. The underlying core molecular clock regulates the expression of other genes, and it has been shown that the expression of more than 50 percent of genes in mammals displays 24-h rhythmic patterns, with the specific genes that cycle varying from one tissue to another. Determining rhythmic gene expression patterns in human tissues sampled as single timepoints has several challenges, including the reconstruction of temporal order of highly noisy data. Previous methodologies have attempted to address these challenges in one or a small number of tissues for which rhythmic gene evolutionary conservation is assumed to be preserved. Here we introduce CIRCUST, a novel CIRCular-robUST methodology for analyzing molecular rhythms, that relies on circular statistics, is robust against noise, and requires fewer assumptions than existing methodologies. Next, we validated the method against four controlled experiments in which sampling times were known, and finally, CIRCUST was applied to 34 tissues from the Genotype-Tissue Expression (GTEx) dataset with the aim towards building a comprehensive daily rhythm gene expression atlas in humans. The validation and application shown here indicate that CIRCUST provides a flexible framework to formulate and solve the issues related to the analysis of molecular rhythms in human tissues. CIRCUST methodology is publicly available at https://github.com/yolandalago/CIRCUST/.

A unique cardiac electrocardiographic 3D model. Toward interpretable AI diagnosis.

Mathematical models of cardiac electrical activity are one of the most important tools for elucidating information about heart diagnostics. In this paper, we present an efficient mathematical formulation for this modeling simple enough to be easily parameterized and rich enough to provide realistic signals. It relies on a five dipole representation of the cardiac electric source, each one associated with the well-known waves of the electrocardiogram signal. Beyond the physical basis of the model, the parameters are physiologically interpretable as they characterize the wave shape, similar to what a physician would look for in signals, thus making them very useful in diagnosis. The model accurately reproduces the electrocardiogram signals of any diseased or healthy heart. This new discovery represents a significant advance in electrocardiography research. It is especially useful for diagnosis, patient follow-up or decision-making on new therapies; is also a promising tool for well-performing, transparent and interpretable AI approaches.

Compelling new electrocardiographic markers for automatic diagnosis.

BACKGROUND AND OBJECTIVE: The automatic diagnosis of heart diseases from the electrocardiogram (ECG) signal is crucial in clinical decision-making. However, the use of computer-based decision rules in clinical practice is still deficient, mainly due to their complexity and a lack of medical interpretation. The objetive of this research is to address these issues by providing valuable diagnostic rules that can be easily implemented in clinical practice. In this research, efficient diagnostic rules friendly in clinical practice are provided. METHODS: In this paper, interesting parameters obtained from the ECG signals analysis are presented and two simple rules for automatic diagnosis of Bundle Branch Blocks are defined using new markers derived from the so-called FMMecg delineator. The main advantages of these markers are the good statistical properties and their clear interpretation in clinically meaningful terms. RESULTS: High sensitivity and specificity values have been obtained using the proposed rules with data from more than 35,000 patients from well known benchmarking databases. In particular, to identify Complete Left Bundle Branch Blocks and differentiate this condition from subjects without heart diseases, sensitivity and specificity values ranging from 93% to 99% and from 96% to 99%, respectively. The new markers and the automatic diagnosis are easily available at https://fmmmodel.shinyapps.io/fmmEcg/, an app specifically developed for any given ECG signal. CONCLUSIONS: The proposal is different from others in the literature and it is compelling for three main reasons. On the one hand, the markers have a concise electrocardiographic interpretation. On the other hand, the diagnosis rules have a very high accuracy. Finally, the markers can be provided by any device that registers the ECG signal and the automatic diagnosis is made straightforwardly, in contrast to the black-box and deep learning algorithms.

Real-time imaging of asthmatic epithelial cells identifies migratory deficiencies under type-2 conditions.

BACKGROUND: The epithelium is increasingly recognized as a pathologic contributor to asthma and its phenotypes. Although delayed wound closure by asthmatic epithelial cells is consistently observed, underlying mechanisms remain poorly understood, partly due to difficulties in studying dynamic physiologic processes involving polarized multilayered cell systems. Although type-2 immunity has been suggested to play a role, the mechanisms by which repair is diminished are unclear. OBJECTIVES: This study sought to develop and utilize primary multilayered polarized epithelial cell systems, derived from patients with asthma, to evaluate cell migration in response to wounding under type-2 and untreated conditions. METHODS: A novel wounding device for multilayered polarized cells, along with time-lapse live cell/real-time confocal imaging were evaluated under IL-13 and untreated conditions. The influence of inhibition of 15 lipoxygenase (15LO1), a type-2 enzyme, on the process was also addressed. Cell migration patterns were analyzed by high-dimensional frequency modulated Möbius for statistical comparisons. RESULTS: IL-13 stimulation negatively impacts wound healing by altering the total speed, directionality, and acceleration of individual cells. Inhibition 15LO1 partially improved the wound repair through improving total speed. CONCLUSIONS: Migration abnormalities contributed to markedly slower wound closure of IL-13 treated cells, which was modestly reversed by 15LO1 inhibition, suggesting its potential as an asthma therapeutic target. These novel methodologies offer new ways to dynamically study cell movements and identify contributing pathologic processes.

The hidden waves in the ECG uncovered revealing a sound automated interpretation method.

A novel approach for analysing cardiac rhythm data is presented in this paper. Heartbeats are decomposed into the five fundamental P, Q, R, S and T waves plus an error term to account for artifacts in the data which provides a meaningful, physical interpretation of the heart's electric system. The morphology of each wave is concisely described using four parameters that allow all the different patterns in heartbeats to be characterized and thus differentiated This multi-purpose approach solves such questions as the extraction of interpretable features, the detection of the fiducial marks of the fundamental waves, or the generation of synthetic data and the denoising of signals. Yet the greatest benefit from this new discovery will be the automatic diagnosis of heart anomalies as well as other clinical uses with great advantages compared to the rigid, vulnerable and black box machine learning procedures, widely used in medical devices. The paper shows the enormous potential of the method in practice; specifically, the capability to discriminate subjects, characterize morphologies and detect the fiducial marks (reference points) are validated numerically using simulated and real data, thus proving that it outperforms its competitors.

Order restricted inference in chronobiology.

This paper is motivated by applications in oscillatory systems where researchers are typically interested in discovering components of those systems that display rhythmic temporal patterns. The contributions of this paper are twofold. First, a methodology is developed based on a circular signal plus error model that is defined using order restrictions. This mathematical formulation of rhythmicity is simple, easily interpretable and very flexible, with the latter property derived from the nonparametric formulation of the signal. Second, we address various commonly encountered problems in the analysis of oscillatory systems data. Specifically, we propose a methodology for (a) detecting rhythmic signals in an oscillatory system and (b) estimating the unknown sampling time that occurs when tissues are obtained from subjects whose time of death is unknown. The proposed methodology is computationally efficient, outperforms the existing methods, and is broadly applicable to address a wide range of questions related to oscillatory systems.

Frequency Modulated Möbius Model Accurately Predicts Rhythmic Signals in Biological and Physical Sciences.

Motivated by applications in physical and biological sciences, we developed a Frequency Modulated Möbius (FMM) model to describe rhythmic patterns in oscillatory systems. Unlike standard symmetric sinusoidal models, FMM is a flexible parametric model that allows deformations to sinusoidal shape to accommodate commonly seen asymmetries in applications. FMM model parameters are easy to estimate and the model is easy to interpret complex rhythmic data. We illustrate FMM model in three disparate applications, namely, circadian clock gene expression, corticoptropin levels in depressed patients and the temporal light intensity patterns of distant stars. In each case, FMM model is demonstrated to be flexible, scientifically plausible and easy to interpret. Analysis of synthetic data derived from patterns of real data, suggest that FMM model fits the data very well both visually as well as in terms of the goodness of fit measure total mean squared error. An R language based software for implementing FMM model is available.

Microarray Data Normalization and Robust Detection of Rhythmic Features.

Data derived from microarray technologies are generally subject to various sources of noise and accordingly the raw data are pre-processed before formally analysed. Data normalization is a key pre-processing step when dealing with microarray experiments, such as circadian gene-expressions, since it removes systematic variations across arrays. A wide variety of normalization methods are available in the literature. However, from our experience in the study of rhythmic expression patterns in oscillatory systems (e.g. cell-cycle, circadian clock), the choice of the normalization method may substantially impair the identification of rhythmic genes. Hence, the identification of a gene as rhythmic could be just as an artefact of how the data were normalized. Yet, gene rhythmicity detection is crucial in modern toxicological and pharmacological studies, thus a procedure to truly identify rhythmic genes that are robust to the choice of a normalization method is required.To perform the task of detecting rhythmic features, we propose a rhythmicity measure based on bootstrap methodology to robustly identify rhythmic genes in oscillatory systems. Although our methodology can be extended to any high-throughput experiment, in this chapter, we illustrate how to apply it to a publicly available circadian clock microarray gene-expression data and give full details (both statistical and computational) so that the methodology can be used in an easy way. We will show that the choice of normalization method has very little effect on the proposed methodology since the results derived from the bootstrap-based rhythmicity measure are highly rank correlated for any pair of normalization methods considered. This suggests, on the one hand, that the rhythmicity measure proposed is robust to the choice of the normalization method, and on the other hand, that gene rhythmicity detected using this measure is potentially not a mere artefact of the normalization method used. In this way the researcher using this methodology will be protected against the possible effect of different normalizations, as the conclusions obtained will not depend so strongly on them. Additionally, the described bootstrap methodology can also be employed as a tool to simulate gene-expression participating in an oscillatory system from a reference data set.

A Bootstrap Based Measure Robust to the Choice of Normalization Methods for Detecting Rhythmic Features in High Dimensional Data.

Motivation: Gene-expression data obtained from high throughput technologies are subject to various sources of noise and accordingly the raw data are pre-processed before formally analyzed. Normalization of the data is a key pre-processing step, since it removes systematic variations across arrays. There are numerous normalization methods available in the literature. Based on our experience, in the context of oscillatory systems, such as cell-cycle, circadian clock, etc., the choice of the normalization method may substantially impact the determination of a gene to be rhythmic. Thus rhythmicity of a gene can purely be an artifact of how the data were normalized. Since the determination of rhythmic genes is an important component of modern toxicological and pharmacological studies, it is important to determine truly rhythmic genes that are robust to the choice of a normalization method. Results: In this paper we introduce a rhythmicity measure and a bootstrap methodology to detect rhythmic genes in an oscillatory system. Although the proposed methodology can be used for any high-throughput gene expression data, in this paper we illustrate the proposed methodology using several publicly available circadian clock microarray gene-expression datasets. We demonstrate that the choice of normalization method has very little effect on the proposed methodology. Specifically, for any pair of normalization methods considered in this paper, the resulting values of the rhythmicity measure are highly correlated. Thus it suggests that the proposed measure is robust to the choice of a normalization method. Consequently, the rhythmicity of a gene is potentially not a mere artifact of the normalization method used. Lastly, as demonstrated in the paper, the proposed bootstrap methodology can also be used for simulating data for genes participating in an oscillatory system using a reference dataset. Availability: A user friendly code implemented in R language can be downloaded from http://www.eio.uva.es/~miguel/robustdetectionprocedure.html.

Order restricted inference for oscillatory systems for detecting rhythmic signals.

MOTIVATION: Many biological processes, such as cell cycle, circadian clock, menstrual cycles, are governed by oscillatory systems consisting of numerous components that exhibit rhythmic patterns over time. It is not always easy to identify such rhythmic components. For example, it is a challenging problem to identify circadian genes in a given tissue using time-course gene expression data. There is a great potential for misclassifying non-rhythmic as rhythmic genes and vice versa. This has been a problem of considerable interest in recent years. In this article we develop a constrained inference based methodology called Order Restricted Inference for Oscillatory Systems (ORIOS) to detect rhythmic signals. Instead of using mathematical functions (e.g. sinusoidal) to describe shape of rhythmic signals, ORIOS uses mathematical inequalities. Consequently, it is robust and not limited by the biologist's choice of the mathematical model. We studied the performance of ORIOS using simulated as well as real data obtained from mouse liver, pituitary gland and data from NIH3T3, U2OS cell lines. Our results suggest that, for a broad collection of patterns of gene expression, ORIOS has substantially higher power to detect true rhythmic genes in comparison to some popular methods, while also declaring substantially fewer non-rhythmic genes as rhythmic. AVAILABILITY AND IMPLEMENTATION: A user friendly code implemented in R language can be downloaded from http://www.niehs.nih.gov/research/atniehs/labs/bb/staff/peddada/index.cfm CONTACT: peddada@niehs.nih.gov.