Lars Johannesen

Center for Drug Evaluation and Research

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Co-Authors

José Vicente

Center for Drug Evaluation and Research

David G. Strauss

United States Food and Drug Administration

Norman Stockbridge

United States Food and Drug Administration

Christine Garnett

Center for Drug Evaluation and Research

Loriano Galeotti

United States Food and Drug Administration

Marek Malík

Imperial College London

Katerina Hnatkova

Lung Institute

Jay W. Mason

Spaulding Clinical Research (United States)

Ksenia Blinova

United States Food and Drug Administration

Meisam Hosseini

United States Food and Drug Administration

Cooperative Institutions

Inserm

232

University College London

145

Istituti di Ricovero e Cura a Carattere Scientifico

136

Centre National de la Recherche Scientifique

135

Sorbonne Université

123

Assistance Publique – Hôpitaux de Paris

112

University of Milan

105

National Hospital for Neurology and Neurosurgery

Université Paris Cité

Heidelberg University

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Robust algorithm to locate heart beats from multiple physiological waveforms by individual signal detector voting

Physiological Measurement (2015)

Loriano Galeotti Christopher G. Scully José Vicente Lars Johannesen David G. Strauss

Alarm fatigue is a top medical device hazard in patient monitoring that could be reduced by merging physiological information from multiple sensors, minimizing the impact of a single sensor failing. We developed a heart beat detection algorithm that utilizes multi-modal physiological signals (e.g. electrocardiogram, blood pressure, stroke volume, photoplethysmogram and electro-encephalogram) by merging the heart beats obtained from signal-specific detectors. We used the PhysioNet/Computing in Cardiology Challenge 2014 training set to develop the algorithm, and we refined it with a mix of signals from the multiparameter intelligent monitoring in intensive care (MIMIC II) database and artificially disrupted waveforms. The algorithm had an average sensitivity of 95.67% and positive predictive value (PPV) of 92.28% when applied to the PhysioNet/Computing in Cardiology Challenge 2014 200 record training set. On a refined dataset obtained by removing 5 records with arrhythmias and inconsistent reference annotations we obtained an average sensitivity of 97.43% and PPV of 94.17%. Algorithm performance was assessed with the Physionet Challenge 2014 test set that consisted of 200 records (each up to 10 min length) containing multiple physiological signals and reference annotations verified by the PhysioNet/Computing in Cardiology Challenge 2014 organizers. Our algorithm had a sensitivity of 92.74% and PPV of 87.37% computed over all annotated beats, and a record average sensitivity of 91.08%, PPV of 86.96% and an overall score (average of all 4 measures) of 89.53%. Our algorithm is an example of a data fusion approach that can improve patient monitoring and reduce false alarms by reducing the effect of individual signal failures.

Photoplethysmogram

Data set

SIGNAL (programming language)

10.1088/0967-3334/36/8/1705

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Citations (17)

Robust algorithm to locate heart beats from multiple physiological waveforms

Computing in Cardiology (2014)

Lars Johannesen José Vicente Christopher G. Scully Loriano Galeotti David G. Strauss

Alarm fatigue is a major issue in patient monitoring that could be reduced by merging physiological information from multiple sensors, minimizing the impact of a single sensor failing. We developed a heart beat detection algorithm that utilizes multi-modal physiological waveforms (e.g. ECG, blood pressure, stroke volume, photoplethysmogram and electroencephalogram). The 100 record training set from the Physionet challenge 2014 was used for development. The algorithm was evaluated at three testing phases during the 2014 challenge consisting of 100 (phase I), 200 (phase II) and 300 (phase III) hidden records, respectively. A true positive was declared if a beat was detected within 150 ms of a reference annotation. The algorithm had a sensitivity of >99.9%, Positive Predictive Value of 99.7%, and an overall score (average of sensitivity and Positive Predictive Value) of 99.8% when applied to the training set. The best overall performance on the test sets were: 88.9%, 76.3% and 84.4% for phases I, II and III, respectively. We developed a robust heart beat detector that fuses annotations from multiple individual detectors. The algorithm improves the training results compared to ECG detections alone, and performs well on the test sets. Data fusion approaches like this one can improve patient monitoring and reduce false alarms.

Photoplethysmogram

Heart beat

Beat (acoustics)

False alarm

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Citations (8)

Electrocardiographic biomarkers to confirm drug's electrophysiological effects used for proarrhythmic risk prediction under CiPA

Journal of Electrocardiology (2017)

José Vicente Meisam Hosseini Lars Johannesen David G. Strauss

hERG

Proarrhythmia

Drug Development

10.1016/j.jelectrocard.2017.08.003

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Citations (18)

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias

Toxicological Sciences (2016)

Ksenia Blinova Jayna Stohlman José Vicente Dulciana Chan Lars Johannesen

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

Proarrhythmia

Safety pharmacology

hERG

Prolongation

Anti-Arrhythmia Agents

Cardiac action potential

Afterdepolarization

10.1093/toxsci/kfw200

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Citations (242)

The IQ‐CSRC Prospective Clinical Phase 1 Study: “Can Early QT Assessment Using Exposure Response Analysis Replace the Thorough QT Study?”

Annals of Noninvasive Electrocardiology (2013)

Börje Darpö Nenad Sarapa Christine Garnett Charles T. Benson Corina Dota

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure–response (ER) analysis of data generated from First‐in‐Man single ascending dose (SAD) studies. Six marketed drugs with well‐characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo‐controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed‐effects ER models. Criteria for QT‐positive drugs will be the demonstration of an upper bound (UB) of the 2‑sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT‐negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.

10.1111/anec.12128

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Citations (97)

Electrocardiographic Data Quality in Thorough QT/QTc Studies

Drug Safety (2014)

Lars Johannesen Christine Garnett Marek Malik

Crossover study

10.1007/s40264-014-0140-4

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Citations (15)

A Modeling and Experimental Investigation on an Innovative Substrate for DPF Applications

SAE technical papers on CD-ROM/SAE technical paper series (2010)

Shahrokh Hajireza Lars Johannesen Thomas Wolff G. C. Koltsakis Zissis Samaras

10.4271/2010-01-0891

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Citations (6)

Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the Ci PA Phase I ECG Biomarker Validation Study

Clinical Pharmacology & Therapeutics (2018)

José Vicente Robbert Zusterzeel Lars Johannesen Roberto Carlos Ochoa-Jimenez Jay W. Mason

Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐T peak (J‐T peak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐T peak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔ QT c and ΔΔJ‐T peak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced Δ QT c prolongation, but shortened ΔJ‐T peak c and prolonged ΔT peak ‐T end . Absence of J‐T peak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.

10.1002/cpt.1303

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Citations (81)

ECGlab: User friendly ECG/VCG analysis tool for research environments

Computing in Cardiology Conference (2013)

José Vicente Lars Johannesen Loriano Galeotti David G. Strauss

We present ECGlab, a cross-platform, user friendly, graphical user interface for assessing results from automated analysis of ECGs in research environments. ECGlab allows visual inspection and adjudication of ECGs. It is part of our recently developed framework to automatically analyze ECGs from clinical studies, including those in the US Food and Drug Administration (FDA) ECG Warehouse. ECGlab is written in C++ using open-source libraries. Supported ECG formats include Physionet, ISHNE and FDA XML HL7. ECG processing and automated analysis is done with ECGlib (ECG analysis library). ECGs can be loaded individually or grouped using ECGlib index format and information such as demographics or signal quality metrics can be loaded from metafiles to navigate through the ECGs and guide their review. The user can graphically adjudicate the ECGs in a semi-automatic or manual fashion. Vectorcardiograms can be assessed as well. A prototype for automatic extraction, based on heart rate stability and signal quality, of 10 seconds ECGs from continuous Holter recordings is also available. ECGlab, which has been successfully tested in Linux and Microsoft Windows, is currently being used to assess ECGs from clinical studies. We are working on making ECGlab open-source in order to facilitate ECG research.

Graphical user interface

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Citations (19)

Abstract 245: Assessing Proarrhythmic Potential of Drugs Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes and Optical Recordings With Voltage-sensitive Dyes

Circulation Research (2015)

Ksenia Blinova Jayna Stohlman Dulciana Chan Maria Hortigon Victor Z Rodriquez

Background: Drug-induced arrhythmias have been a leading reason for withdrawing drugs from the market and abandoning the development of new drugs. For the past decade FDA has required new drugs to be tested for block of the hERG potassium channel and QT interval prolongation. While these requirements have prevented arrhythmia-related drug recalls, some new drugs affecting multiple ion channels are being dropped from development inappropriately. Human induced pluripotent stem cell derived cardiomyocytes (iPS-CMs) are a new technology for preclinical risk assessment; however they have not been fully characterized or validated. Methods: We studied 26 drugs and 3 drug combinations that block multiple cardiac ion channels with two commercially available iPS-CM lines from Axiogenesis and Cellular Dynamics using optical recordings of action potentials with voltage-sensitive dyes. Drug-induced action potential duration (APD) prolongation was compared to clinical QT prolongation from two FDA-sponsored clinical trials. The effects of the drugs on multiple individual cardiac ion channels were assessed using manual patch clamp of overexpressed cell lines. Cardiac ion channel gene expression in the iPS-CMs was quantified and compared to primary human heart cell controls. Results: Of 19 drugs with an FDA label of clinical QT prolongation, 15 exhibited iPS-CM APD prolongation after acute drug exposure. None of the 6 drugs without clinical QT prolongation caused iPS-CM APD prolongation. Of 14 drugs with arrhythmia risk on the FDA label, nine caused arrhythmias in iPS-CMs. iPS-CM response had good correlation with clinical QT data for drugs that block hERG and calcium channels, while drugs blocking the late sodium current had variable response. This was in line with gene expression data, which showed most robust expression of hERG and calcium channels. Conclusion: Optical recordings from iPS-CMs with voltage sensitive dyes is a promising technology for high-throughput toxicity assessment for drug-induced arrhythmias. This study provides a comprehensive characterization of the cardiac ion channel properties of multiple commercially available iPS-CMs to support a potential new paradigm for assessing the arrhythmia risk of all new drugs.

hERG

Safety pharmacology

Cardiac action potential

Prolongation

Cardiac Electrophysiology

10.1161/res.117.suppl_1.245

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