TREAP: A New Topological Approach to Drug Target Inference.

Over 50% of drugs fail in stage 3 clinical trials, many because of a poor understanding of the drug's mechanisms of action (MoA). A better comprehension of drug MoA will significantly improve research and development (R&D). Current proposed algorithms, such as ProTINA and DeMAND, can be overly complex. Additionally, they are unable to predict whether the drug-induced gene expression or the topology of the networks used to model gene regulation primarily impacts accurate drug target inference. In this work, we evaluate how network and gene expression data affect ProTINA's accuracy. We find that network topology predominantly determines the accuracy of ProTINA's predictions. We further show that the size of an interaction network and/or selecting cell-specific networks has a limited effect on accuracy. We then demonstrate that a specific network topology measure, betweenness, can be used to improve drug target prediction. Based on these results, we create a new algorithm, TREAP, that combines betweenness values and adjusted p-values for target inference. TREAP offers an alternative approach to drug target inference and is advantageous because it is not computationally demanding, provides easy-to-interpret results, and is often more accurate at predicting drug targets than current state-of-the-art approaches.

Blood Inflammatory Biomarkers Differentiate Inpatient and Outpatient Coronavirus Disease 2019 From Influenza.

Background: The ongoing circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a diagnostic challenge because symptoms of coronavirus disease 2019 (COVID-19) are difficult to distinguish from other respiratory diseases. Our goal was to use statistical analyses and machine learning to identify biomarkers that distinguish patients with COVID-19 from patients with influenza. Methods: Cytokine levels were analyzed in plasma and serum samples from patients with influenza and COVID-19, which were collected as part of the Centers for Disease Control and Prevention's Hospitalized Adult Influenza Vaccine Effectiveness Network (inpatient network) and the US Flu Vaccine Effectiveness (outpatient network). Results: We determined that interleukin (IL)-10 family cytokines are significantly different between COVID-19 and influenza patients. The results suggest that the IL-10 family cytokines are a potential diagnostic biomarker to distinguish COVID-19 and influenza infection, especially for inpatients. We also demonstrate that cytokine combinations, consisting of up to 3 cytokines, can distinguish SARS-CoV-2 and influenza infection with high accuracy in both inpatient (area under the receiver operating characteristics curve [AUC] = 0.84) and outpatient (AUC = 0.81) groups, revealing another potential screening tool for SARS-CoV-2 infection. Conclusions: This study not only reveals prospective screening tools for COVID-19 infections that are independent of polymerase chain reaction testing or clinical condition, but it also emphasizes potential pathways involved in disease pathogenesis that act as potential targets for future mechanistic studies.