Mathematical modeling of the molecular switch of TNFR1-mediated signaling pathways applying Petri net formalism and in silico knockout analysis.

The paper describes a mathematical model of the molecular switches of cell survival, apoptosis, and necroptosis in cellular signaling pathways initiated by tumor necrosis factor 1. Based on experimental findings in the literature, we constructed a Petri net model based on detailed molecular reactions of the molecular players, protein complexes, post-translational modifications, and cross talk. The model comprises 118 biochemical entities, 130 reactions, and 299 edges. We verified the model by evaluating invariant properties of the system at steady state and by in silico knockout analysis. Applying Petri net analysis techniques, we found 279 pathways, which describe signal flows from receptor activation to cellular response, representing the combinatorial diversity of functional pathways.120 pathways steered the cell to survival, whereas 58 and 35 pathways led to apoptosis and necroptosis, respectively. For 65 pathways, the triggered response was not deterministic and led to multiple possible outcomes. We investigated the in silico knockout behavior and identified important checkpoints of the TNFR1 signaling pathway in terms of ubiquitination within complex I and the gene expression dependent on NF-κB, which controls the caspase activity in complex II and apoptosis induction. Despite not knowing enough kinetic data of sufficient quality, we estimated system's dynamics using a discrete, semi-quantitative Petri net model.

Detecting myocardial scar using electrocardiogram data and deep neural networks.

Ischaemic heart disease is among the most frequent causes of death. Early detection of myocardial pathologies can increase the benefit of therapy and reduce the number of lethal cases. Presence of myocardial scar is an indicator for developing ischaemic heart disease and can be detected with high diagnostic precision by magnetic resonance imaging. However, magnetic resonance imaging scanners are expensive and of limited availability. It is known that presence of myocardial scar has an impact on the well-established, reasonably low cost, and almost ubiquitously available electrocardiogram. However, this impact is non-specific and often hard to detect by a physician. We present an artificial intelligence based approach - namely a deep learning model - for the prediction of myocardial scar based on an electrocardiogram and additional clinical parameters. The model was trained and evaluated by applying 6-fold cross-validation to a dataset of 12-lead electrocardiogram time series together with clinical parameters. The proposed model for predicting the presence of scar tissue achieved an area under the curve score, sensitivity, specificity, and accuracy of 0.89, 70.0, 84.3, and 78.0%, respectively. This promisingly high diagnostic precision of our electrocardiogram-based deep learning models for myocardial scar detection may support a novel, comprehensible screening method.

Bioinformatics analysis of whole slide images reveals significant neighborhood preferences of tumor cells in Hodgkin lymphoma.

In pathology, tissue images are evaluated using a light microscope, relying on the expertise and experience of pathologists. There is a great need for computational methods to quantify and standardize histological observations. Computational quantification methods become more and more essential to evaluate tissue images. In particular, the distribution of tumor cells and their microenvironment are of special interest. Here, we systematically investigated tumor cell properties and their spatial neighborhood relations by a new application of statistical analysis to whole slide images of Hodgkin lymphoma, a tumor arising in lymph nodes, and inflammation of lymph nodes called lymphadenitis. We considered properties of more than 400, 000 immunohistochemically stained, CD30-positive cells in 35 whole slide images of tissue sections from subtypes of the classical Hodgkin lymphoma, nodular sclerosis and mixed cellularity, as well as from lymphadenitis. We found that cells of specific morphology exhibited significantly favored and unfavored spatial neighborhood relations of cells in dependence of their morphology. This information is important to evaluate differences between Hodgkin lymph nodes infiltrated by tumor cells (Hodgkin lymphoma) and inflamed lymph nodes, concerning the neighborhood relations of cells and the sizes of cells. The quantification of neighborhood relations revealed new insights of relations of CD30-positive cells in different diagnosis cases. The approach is general and can easily be applied to whole slide image analysis of other tumor types.

isiKnock: in silico knockouts in signaling pathways.

SUMMARY: isiKnock is a new software that automatically conducts in silico knockouts for mathematical models of signaling pathways. The software allows for the prediction of the behavior of biological systems after single or multiple knockout. The implemented algorithm applies transition invariants and the novel concept of Manatee invariants. A knockout matrix visualizes the results. The tool enables the analysis of dependencies, for example, in signal flows from the receptor activation to the cell response at steady state. AVAILABILITY AND IMPLEMENTATION: isiKnock is an open-source tool, freely available at http://www.bioinformatik.uni-frankfurt.de/tools/isiKnock/. It requires at least Java 8 and runs under Microsoft Windows, Linux, and Mac OS.

The Disruption of Trust in the Digital Transformation Leading to Health 4.0.

The specification and application of policies and guidelines for public health, medical education and training, and screening programmes for preventative medicine are all predicated on trust relationships between medical authorities, health practitioners and patients. These relationships are in turn predicated on a verbal contract that is over two thousand years old. The impact of information and communication technology (ICT), underpinning Health 4.0, has the potential to disrupt this analog relationship in several dimensions; but it also presents an opportunity to strengthen it, and so to increase the take-up and effectiveness of new policies. This paper develops an analytic framework for the trust relationships in Health 4.0, and through three use cases, assesses a medical policy, the introduction of a new technology, and the implications of that technology for the trust relationships. We integrate this assessment in a set of actionable recommendations, in particular that the trust framework should be part of the design methodology for developing and deploying medical applications. In a concluding discussion, we advocate that, in a post-pandemic world, IT to support policies and programmes to address widespread socio-medical problems with mental health, long Covid, physical inactivity and vaccine misinformation will be essential, and for that, strong trust relationships between all the stakeholders are absolutely critical.

Identifying Heart Failure in ECG Data With Artificial Intelligence-A Meta-Analysis.

Introduction: Electrocardiography (ECG) is a quick and easily accessible method for diagnosis and screening of cardiovascular diseases including heart failure (HF). Artificial intelligence (AI) can be used for semi-automated ECG analysis. The aim of this evaluation was to provide an overview of AI use in HF detection from ECG signals and to perform a meta-analysis of available studies. Methods and Results: An independent comprehensive search of the PubMed and Google Scholar database was conducted for articles dealing with the ability of AI to predict HF based on ECG signals. Only original articles published in peer-reviewed journals were considered. A total of five reports including 57,027 patients and 579,134 ECG datasets were identified including two sets of patient-level data and three with ECG-based datasets. The AI-processed ECG data yielded areas under the receiver operator characteristics curves between 0.92 and 0.99 to identify HF with higher values in ECG-based datasets. Applying a random-effects model, an sROC of 0.987 was calculated. Using the contingency tables led to diagnostic odds ratios ranging from 3.44 [95% confidence interval (CI) = 3.12-3.76] to 13.61 (95% CI = 13.14-14.08) also with lower values in patient-level datasets. The meta-analysis diagnostic odds ratio was 7.59 (95% CI = 5.85-9.34). Conclusions: The present meta-analysis confirms the ability of AI to predict HF from standard 12-lead ECG signals underlining the potential of such an approach. The observed overestimation of the diagnostic ability in artificial ECG databases compared to patient-level data stipulate the need for robust prospective studies.