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- Use of biochemical tests and machine learning in the search for potential diagnostic biomarkers of COVID-19, HIV/AIDS, and pulmonary tuberculosisPublication . Cobre, Alexandre; Morais, Amiel; Selege, Fosfato; Stremel, Dile; Wiens, Astrid; Ferreira, Luana; Tonin, Fernanda; Pontarolo, RobertoThis study aims to develop, validate, and evaluate machine learning algorithms for predicting the diagnosis of coronavirus disease (COVID-19), human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), pulmonary tuberculosis (TB), and HIV/TB co-infection. We also investigated potential biomarkers associated with the diagnosis. Data from biochemical and hematological tests of infected and controls were collected in a single general hospital, totalizing 6,418 patients. The discriminant analysis by partial least squares (PLS-DA) model had the highest performance in predicting the diagnosis of COVID-19, HIV/AIDS, TB, and HIV/TB co-infection with an accuracy of 94, 97, 95, and 96%, respectively. The biomarkers calcium, lactate dehydrogenase, red blood cells (RBC), white blood cells, neutrophils, basophils, eosinophils, hemoglobin, and hematocrit were associated with COVID-19. HIV infection was associated with mean corpuscular volume, platelets, neutrophils, and mean platelet volume. Red blood cell distribution width and urea were associated with infection by Mycobacterium tuberculosis. The following biomarkers were associated with HIV/TB co-infection: lymphocytes, RBC, hematocrit, hemoglobin, aspartate transaminase, alanine transaminase, and glycemia. The PLS-DA model can optimize COVID-19, HIV/AIDS, TB, and HIV/TB co-infection diagnostics. Some biomarkers were potential diagnostic indicators and could be evaluated during the screening of these diseases.
- Novel COVID-19 biomarkers identified through multi-omics data analysis: N-acetyl-4-O-acetylneuraminic acid, N-acetyl-L-alanine, N-acetyltriptophan, palmitoylcarnitine, and glycerol 1-myristatePublication . Cobre, Alexandre de Fátima; Alves, Alexessander Couto; Gotine, Ana Raquel; Domingues, Karime Zeraik; Lazo, Raul Edison; Ferreira, Luana Mota; Tonin, Fernanda; Pontarolo, RobertoThis study aims to apply machine learning models to identify new biomarkers associated with the early diagnosis and prognosis of SARS-CoV-2 infection. Plasma and serum samples from COVID-19 patients (mild, moderate, and severe), patients with other pneumonia (but with negative COVID-19 RT-PCR), and healthy volunteers (control) from hospitals in four different countries (China, Spain, France, and Italy) were analyzed by GC-MS, LC-MS, and NMR. Machine learning models (PCA and PLS-DA) were developed to predict the diagnosis and prognosis of COVID-19 and identify biomarkers associated with these outcomes. A total of 1410 patient samples were analyzed. The PLS-DA model presented a diagnostic and prognostic accuracy of around 95% of all analyzed data. A total of 23 biomarkers (e.g., spermidine, taurine, L-aspartic, L-glutamic, L-phenylalanine and xanthine, ornithine, and ribothimidine) have been identified as being associated with the diagnosis and prognosis of COVID-19. Additionally, we also identified for the first time five new biomarkers (N-Acetyl-4-O-acetylneuraminic acid, N-Acetyl-L-Alanine, N-Acetyltriptophan, palmitoylcarnitine, and glycerol 1-myristate) that are also associated with the severity and diagnosis of COVID-19. These five new biomarkers were elevated in severe COVID-19 patients compared to patients with mild disease or healthy volunteers. The PLS-DA model was able to predict the diagnosis and prognosis of COVID-19 around 95%. Additionally, our investigation pinpointed five novel potential biomarkers linked to the diagnosis and prognosis of COVID-19: N-Acetyl-4-O-acetylneuraminic acid, N-Acetyl-L-Alanine, N-Acetyltriptophan, palmitoylcarnitine, and glycerol 1-myristate. These biomarkers exhibited heightened levels in severe COVID-19 patients compared to those with mild COVID-19 or healthy volunteers.
- Diagnosis and prognosis of COVID-19 employing analysis of patients' plasma and serum via LC-MS and machine learningPublication . Cobre, Alexandre de Fátima; Surek, Monica; Stremel, Dile Pontarolo; Fachi, Mariana Millan; Borba, Helena Hiemisch; Tonin, Fernanda; Pontarolo, RobertoObjective: To implement and evaluate machine learning (ML) algorithms for the prediction of COVID-19 diagnosis, severity, and fatality and to assess biomarkers potentially associated with these outcomes. Material and methods: Serum (n = 96) and plasma (n = 96) samples from patients with COVID-19 (acute, severe, and fatal illness) from two independent hospitals in China were analyzed by LC-MS. Samples from healthy volunteers and from patients with pneumonia caused by other viruses (i.e. negative RT-PCR for COVID-19) were used as controls. Seven different ML-based models were built: PLS-DA, ANNDA, XGBoostDA, SIMCA, SVM, LREG, and KNN. Results: The PLS-DA model presented the best performance for both datasets, with accuracy rates to predict the diagnosis, severity, and fatality of COVID-19 of 93%, 94%, and 97%, respectively. Low levels of the metabolites ribothymidine, 4-hydroxyphenylacetoylcarnitine and uridine were associated with COVID-19 positivity, whereas high levels of N-acetyl-glucosamine-1-phosphate, cysteinylglycine, methyl isobutyrate, l-ornithine, and 5,6-dihydro-5-methyluracil were significantly related to greater severity and fatality from COVID-19. Conclusion: The PLS-DA model can help to predict SARS-CoV-2 diagnosis, severity, and fatality in daily practice. Some biomarkers typically increased in COVID-19 patients’ serum or plasma (i.e. ribothymidine, N-acetyl-glucosamine-1-phosphate, l-ornithine, 5,6-dihydro-5-methyluracil) should be further evaluated as prognostic indicators of the disease.
- Accuracy of COVID-19 diagnostic tests via infrared spectroscopy: a systematic review and meta-analysisPublication . Cobre, Alexandre de Fátima; Fachi, Mariana Millan; Domingues, Karime Zeraik Abdalla; Lazo, Raul Edison Luna; Ferreira, Luana Mota; Tonin, Fernanda; Pontarolo, RobertoThis study aims to synthesize the evidence on the accuracy parameters of COVID-19 diagnosis methods using infrared spectroscopy (FTIR). A systematic review with searches in PubMed and Embase was performed (September 2023). Studies reporting data on test specificity, sensitivity, true positive, true negative, false positive, and false negative using different human samples were included. Meta-analysis of accuracy estimates with 95 % confidence intervals and area under the ROC Curve (AUC) were conducted (Meta-Disc 1.4.7). Seventeen studies were included - all of them highlighted regions 650-1800 cm-1 and 2300-3900 cm-1 as most important for diagnosing COVID-19. The FTIR technique presented high sensitivity [0.912 (95 %CI, 0.878-0.939), especially in vaccinated [0.959 (CI95 %, 0.908-0.987)] compared to unvaccinated [0.625 (CI95 %, 0.584-0.664)] individuals for COVID-19. Overall specificity was also high [0.886 (95 %CI, 0.855-0.912), with increased rates in vaccinated [0.884 (CI95 %, 0.819-0.932)] than in unvaccinated [0.667 (CI95 %, 0.629-0.704)] patients. These findings reveal that FTIR is an accurate technique for detecting SARS-CoV-2 infection in different biological matrices with advantages including low cost, rapid and environmentally friendly with minimal preparation analyses. This could lead to an easy implementation of this technique in practice as a screening tool for patients with suspected COVID-19, especially in low-income countries.
- Machine learning-based virtual screening, molecular docking, drug-likeness, pharmacokinetics and toxicity analyses to identify new natural inhibitors of the glycoprotein spike (S1) od SARS-CoV-2Publication . Cobre, Alexandre; Böger, Beatriz; Fachi, Mariana; Ehrenfried, Carlos; Stremel, Dile; De Melo, Eduardo; Tonin, Fernanda; Pontarolo, RobertoTo identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) by means of in silico assays. NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening and molecular docking to identify those with higher affinity to the spike protein. Eight machine learning models were used to validate the results: Principal Component Analysis (PCA), Artificial Neural Network (ANN), Support Vector Machine (SVM), k-Nearest Neighbors (KNN), Partial Least Squares-Discriminant Analysis (PLS-DA), Gradient Boosted Tree Discriminant Analysis (XGBoostDA), Soft Independent Modelling of Class Analogies (SIMCA) and Logistic Regression Discriminate Analysis (LREG). Selected NBCs were submitted to drug-likeness prediction using Lipinski’s and Veber’s rule of five. A prediction of pharmacokinetic parameters and toxicity was also performed (ADMET). Antivirals currently used for COVID-19 (remdesivir and molnupiravir) were used as a comparator. A total of 170,906 compounds were analyzed. Of these, 34 showed a greater affinity with the S1 (affinity energy < -7 kcal mol-1). Most of these compounds belonged to the class of coumarins (benzopyrones), presenting a benzene ring fused to a lactone (group of heterosides). The PLS-DA model was able to reproduce the results of the virtual screening and molecular docking (accuracy of 97.0%). Of the 34 compounds, only NBC5 (feselol), NBC14, NBC15, and NBC27 had better results in ADMET predictions. These had a similar binding affinity to S1 when compared to remdesivir and molnupirvir. Feselol and three other NBCs were the most promising candidates for treating COVID-19. In vitro and in vivo studies are needed to confirm these findings.