Network Medicine-Based Approach Reveals Cyclosporine and Selinexor Drug Combination as an Effective Therapy against SARS-COV-2 (preprint)

The proliferation of SARS-COV-2 through enhanced viral replication and its subsequent triggering of cytokine storm, are some of the hallmark phenotypes in severe COVID-19 patient cases. Cyclosporine, an immunosuppressant drug and Selinexor, an inhibitor of nuclear transporter protein, both have been successfully demonstrated to be effective against SARS-COV-2 infection by targeting those functions individually. However, the highly multifactorial pathology of SARS-COV-2 infection hinders any mono-therapeutic strategy to become an optimal option. In this study, we assess the potential efficacy of the Cyclosporine-Selinexor combination on an integrated interactome by adopting a network-medicine-based repositioning technique, where disease proximity, functional proximity and their topological separation are evaluated, followed by a robust statistical significance test. Results have shown that both drug target modules are highly proximal to the SARS-COV-2 disease modules in terms of network topology and functional associations, in a statistically significant manner, individually. Functional enrichment of both drug modules and SARS-COV-2 infected modules has shown that two drugs target the functions related to viral replication and cytokine storm during infection. Moreover, a high degree of network separation been those two drug target modules has been observed, revealing ``complementary exposure`` patterns, rendering this drug combination as an effective one against SARS-COV-2 infection. We hope that our results will encourage researchers to further investigate the potency of Cyclosporine and Selinexor combination in vivo or in vitro, and ultimately lead that up to clinical trials to treat SARS-COV-2 patients.

Adverse effects of COVID-19 vaccination: machine learning and statistical approach to identify and classify incidences of morbidity and post-vaccination reactogenicity (preprint)

Good vaccine safety and reliability are essential to prevent infectious disease spread. A small but significant number of apparent adverse reactions to the new COVID-19 vaccines have been reported. Here, we aim to identify possible common causes for such adverse reactions with a view to enabling strategies that reduce patient risk by using patient data to classify and characterise patients those at risk of such reactions. We examined patient medical histories and data documenting post-vaccination effects and outcomes. The data analyses were conducted by different statistical approaches followed by a set of machine learning classification algorithms. In most cases, similar features were significantly associated with poor patient reactions. These included patient prior illnesses, admission to hospitals and SARS-CoV-2 reinfection. The analyses indicated that patient age, gender, allergic history, taking other medications, type-2 diabetes, hypertension and heart disease are the most significant pre-existing factors associated with risk of poor outcome and long duration of hospital treatments, pyrexia, headache, dyspnoea, chills, fatigue, various kind of pain and dizziness are the most significant clinical predictors. The machine learning classifiers using medical history were also able to predict patients most likely to have complication-free vaccination with an accuracy score above 85%. Our study identifies profiles of individuals that may need extra monitoring and care (e.g., vaccination at a location with access to comprehensive clinical support) to reduce negative outcomes through classification approaches. Important classifiers achieving these reactions notably included allergic susceptibility and incidence of heart disease or type-2 diabetes.

An Integrative Resource for Network-Based Investigation of COVID-19 Combinatorial Drug Repositioning and Mechanism of Action (preprint)

Repurposing of the existing medications has become the mainstream focus of anti-COVID-19 drug discovery as it offers rapid and cost-effective solutions for therapeutic development. However, there is still a great deal to enhance efficacy of repurposing therapeutic options through combination therapy, in which promising drugs with varying mechanisms of action are administered together. Nonetheless, our ability to identify and validate effective combinations is limited due to the huge number of possible drug pairs. Yet, there is no available resource which can systematically guide to identify or choose the effective individual drugs or best possible synergistic drug combinations for the treatment of SARS-CoV-2 infection. To address this resource gap, we developed a web-based platform that displays the network-based mechanism of action of drug combinations, thus simultaneously giving a visual of the cellular interactome involved in the mode of action of the chosen drugs. The platform allows the freedom to choose two or more drug combinations and provides the options to investigate network-based efficacy of drug combinations and understand the similarity score, primary indications, and contraindications of using these drugs combinations. In a nutshell, the platform (accessible via: http://vafaeelab.com/COVID19_repositioning.html) is of the first of its type which provides a systematic approach for pre-clinical investigation of combination therapy for treating COVID-19 on the fingertips of the clinicians or researchers.

Predicting Patient COVID-19 Disease Severity by means of Statistical and Machine Learning Analysis of Blood Cell Transcriptome Data (preprint)

Introduction: For COVID-19 patients accurate prediction of disease severity and mortality risk would greatly improve care delivery and resource allocation. There are many patient-related factors, such as pre-existing comorbidities that affect disease severity. Since rapid automated profiling of peripheral blood samples is widely available, we investigated how such data from the peripheral blood of COVID-19 patients might be used to predict clinical outcomes. Methods: We thus investigated such clinical datasets from COVID-19 patients with known outcomes by combining statistical comparison and correlation methods with machine learning algorithms; the latter included decision tree, random forest, variants of gradient boosting machine, support vector machine, K-nearest neighbour and deep learning methods. Results: Our work revealed several clinical parameters measurable in blood samples, which discriminated between healthy people and COVID-19 positive patients and showed predictive value for later severity of COVID-19 symptoms. We thus developed a number of analytic methods that showed accuracy and precision for disease severity and mortality outcome predictions that were above 90%. Conclusions: In sum, we developed methodologies to analyse patient routine clinical data which enables more accurate prediction of COVID-19 patient outcomes. This type of approaches could, by employing standard hospital laboratory analyses of patient blood, be utilised to identify, COVID-19 patients at high risk of mortality and so enable their treatment to be optimised.

Real-time time-series modelling for prediction of COVID-19 spread and intervention assessment (preprint)

Substantial amount of data about the COVID-19 pandemic is generated every day. Yet, data streaming, while considerably visualized, is not accompanied with advanced modelling techniques to provide real-time insights. This study introduces a unified platform which integrates visualization capabilities with advanced statistical methods for predicting the virus spread in the short run, using real-time data. The platform is backed up by advanced time series models to capture any possible non-linearity in the data which is enhanced by the capability of measuring the expected impact of preventive interventions such as social distancing and lockdowns. The platform enables lay users, and experts, to examine the data and develop several customized models with different restriction such as models developed for specific time window of the data. Our policy assessment of the case of Australia, shows that social distancing and travel ban restriction significantly affect the reduction of number of cases, as an effective policy.