Deep learning analysis of electrocardiogram for risk prediction of drug-induced arrhythmias and diagnosis of long QT syndrome.

AIMS: Congenital long-QT syndromes (cLQTS) or drug-induced long-QT syndromes (diLQTS) can cause torsade de pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for the identification of drugs at the high risk of TdP relies on measuring the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG). However, QTc has a low positive predictive value. METHODS AND RESULTS: We used convolutional neural network (CNN) models to quantify ECG alterations induced by sotalol, an IKr blocker associated with TdP, aiming to provide new tools (CNN models) to enhance the prediction of drug-induced TdP (diTdP) and diagnosis of cLQTS. Tested CNN models used single or multiple 10-s recordings/patient using 8 leads or single leads in various cohorts: 1029 healthy subjects before and after sotalol intake (n = 14 135 ECGs); 487 cLQTS patients (n = 1083 ECGs: 560 type 1, 456 type 2, 67 type 3); and 48 patients with diTdP (n = 1105 ECGs, with 147 obtained within 48 h of a diTdP episode). CNN models outperformed models using QTc to identify exposure to sotalol [area under the receiver operating characteristic curve (ROC-AUC) = 0.98 vs. 0.72, P ≤ 0.001]. CNN models had higher ROC-AUC using multiple vs. single 10-s ECG (P ≤ 0.001). Performances were comparable for 8-lead vs. single-lead models. CNN models predicting sotalol exposure also accurately detected the presence and type of cLQTS vs. healthy controls, particularly for cLQT2 (AUC-ROC = 0.9) and were greatest shortly after a diTdP event and declining over time (P ≤ 0.001), after controlling for QTc and intake of culprit drugs. ECG segment analysis identified the J-Tpeak interval as the best discriminator of sotalol intake. CONCLUSION: CNN models applied to ECGs outperform QTc measurements to identify exposure to drugs altering the QT interval, congenital LQTS, and are greatest shortly after a diTdP episode.

Impact of Real-World Data on Market Authorization, Reimbursement Decision & Price Negotiation.

Real-world data (RWD) and real-world evidence (RWE) appear now as complementary to traditional randomized controlled trials (RCT), that remain the gold standard of the evidence. This review aims to illustrate how health authorities in France, United States (USA) and United Kingdom (UK) can integrate RWD and RWE in market authorization discussions and in new pathways of price and reimbursement negotiations. We conducted a review from the literature, online investigations and interviews. RWD and RWE can be valuable in the context of market access, reimbursement decisions, price negotiation, pharmacovigilance and positive patient outcomes. While RWD could open new areas of innovative approaches and improve the efficiency of health systems, they have methodological limitations requiring further analysis to reach a sufficient level of proof. Moreover, misleading use of "RWD" and "RWE" terms is very frequent and even the definitions used by stakeholders (when they have one) are heterogenous. Because of the intrinsic characteristics of each product, the value given to these RWD may differ a lot, making them a useful tool more than an indispensable one. In sum, RWD and, more precisely, RWE have the potential to bring value to the health system at every step of the drug development process, from the discovery to the pharmacovigilance phase.

A brain-computer interface for the continuous, real-time monitoring of working memory load in real-world environments.

We developed a brain-computer interface (BCI) able to continuously monitor working memory (WM) load in real-time (considering the last 2.5 s of brain activity). The BCI is based on biomarkers derived from spectral properties of non-invasive electroencephalography (EEG), subsequently classified by a linear discriminant analysis classifier. The BCI was trained on a visual WM task, tested in a real-time visual WM task, and further validated in a real-time cross task (mental arithmetic). Throughout each trial of the cross task, subjects were given real or sham feedback about their WM load. At the end of the trial, subjects were asked whether the feedback provided was real or sham. The high rate of correct answers provided by the subjects validated not only the global behaviour of the WM-load feedback, but also its real-time dynamics. On average, subjects were able to provide a correct answer 82% of the time, with one subject having 100% accuracy. Possible cognitive and motor confounding factors were disentangled to support the claim that our EEG-based markers correspond indeed to WM.

Classification Accuracy of Neuroimaging Biomarkers in Attention-Deficit/Hyperactivity Disorder: Effects of Sample Size and Circular Analysis.

BACKGROUND: Motivated by an inconsistency between reports of high diagnosis-classification accuracies and known heterogeneity in attention-deficit/hyperactivity disorder (ADHD), this study assessed classification accuracy in studies of ADHD as a function of methodological factors that can bias results. We hypothesized that high classification results in ADHD diagnosis are inflated by methodological factors. METHODS: We reviewed 69 studies (of 95 studies identified) that used neuroimaging features to predict ADHD diagnosis. Based on reported methods, we assessed the prevalence of circular analysis, which inflates classification accuracy, and evaluated the relationship between sample size and accuracy to test if small-sample models tend to report higher classification accuracy, also an indicator of bias. RESULTS: Circular analysis was detected in 15.9% of ADHD classification studies, lack of independent test set was noted in 13%, and insufficient methodological detail to establish its presence was noted in another 11.6%. Accuracy of classification ranged from 60% to 80% in the 59.4% of reviewed studies that met criteria for independence of feature selection, model construction, and test datasets. Moreover, there was a negative relationship between accuracy and sample size, implying additional bias contributing to reported accuracies at lower sample sizes. CONCLUSIONS: High classification accuracies in neuroimaging studies of ADHD appear to be inflated by circular analysis and small sample size. Accuracies on independent datasets were consistent with known heterogeneity of the disorder. Steps to resolve these issues, and a shift toward accounting for sample heterogeneity and prediction of future outcomes, will be crucial in future classification studies in ADHD.