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2. Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients

Author

Mantovani, S., Daga, S., Fallerini, C., Baldassarri, M., Benetti, E., Picchiotti, N., Fava, F., Galli, A., Zibellini, S., Bruttini, M., Palmieri, M., Croci, S., Amitrano, S., Alaverdian, D., Capitani, K., Furini, S., Mari, F., Meloni, I., Montagnani, F., Tumbarello, M., Rancan, I., Fabbiani, M., Rossetti, B., Bergantini, L., D'Alessandro, M., Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Raffaelli, C. S., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Romani, D., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Pisani, M., Ognibene, A., Pancrazzi, A., Lorubbio, M., Vaghi, M., D'Arminio Monforte, A., Miraglia, F. G., Bruno, R., Vecchia, M., Girardis, M., Venturelli, S., Busani, S., Cossarizza, A., Antinori, A., Vergori, A., Emiliozzi, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Tommasi, A., Scotton, P. G., Andretta, F., Panese, S., Baratti, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, E., Degli Antoni, M., Antoni, M. D., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Aucella, F., Raggi, P., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Guarnaccia, A., Valente, S., De Vivo, O., Doddato, G., Lista, M., Beligni, G., Valentino, F., Zguro, K., Tita, R., Giliberti, A., Mencarelli, M. A., Rizzo, C. L., Pinto, A. M., Ariani, F., Di Sarno, L., Bargagli, E., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Lacerenza, G., Mussini, C., Martinelli, E., Tavecchia, L., Belli, M. A., Crotti, L., Parati, G., Sanarico, M., Raimondi, F., Biscarini, F., Stella, A., Bachetti, T., La Rovere, M. T., Ludovisi, S., Bussotti, M., Dei, S., Ravaglia, S., Artuso, R., Andreucci, E., Gori, G., Pagliazzi, A., Fiorentini, E., Perrella, A., Bianchi, F., Bergomi, P., Catena, E., Colombo, R., Luchi, S., Morelli, G., Petrocelli, P., Iacopini, S., Modica, S., Baroni, S., Segala, F. V., Falcone, M., Tiseo, G., Barbieri, C., Matucci, T., Grassi, D., Ferri, C., Marinangeli, F., Brancati, F., Vincenti, A., Borgo, V., Lombardi, S., Lenzi, M., Di Pietro, M. A., Vichi, F., Romanin, B., Attala, L., Costa, C., Gabbuti, A., Mene, R., Colaneri, M., Casprini, P., Merla, G., Squeo, G. M., Maffezzoni, M., Frullanti, E., Mondelli, M. U., Renieri, A., Mantovani, S., Daga, S., Fallerini, C., Baldassarri, M., Benetti, E., Picchiotti, N., Fava, F., Galli, A., Zibellini, S., Bruttini, M., Palmieri, M., Croci, S., Amitrano, S., Alaverdian, D., Capitani, K., Furini, S., Mari, F., Meloni, I., Montagnani, F., Tumbarello, M., Rancan, I., Fabbiani, M., Rossetti, B., Bergantini, L., D'Alessandro, M., Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Raffaelli, C. S., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Romani, D., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Pisani, M., Ognibene, A., Pancrazzi, A., Lorubbio, M., Vaghi, M., D'Arminio Monforte, A., Miraglia, F. G., Bruno, R., Vecchia, M., Girardis, M., Venturelli, S., Busani, S., Cossarizza, A., Antinori, A., Vergori, A., Emiliozzi, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Tommasi, A., Scotton, P. G., Andretta, F., Panese, S., Baratti, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, E., Antoni, M. D., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Aucella, F., Raggi, P., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Guarnaccia, A., Valente, S., De Vivo, O., Doddato, G., Lista, M., Beligni, G., Valentino, F., Zguro, K., Tita, R., Giliberti, A., Mencarelli, M. A., Rizzo, C. L., Pinto, A. M., Ariani, F., Di Sarno, L., Bargagli, E., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Lacerenza, G., Mussini, C., Martinelli, E., Tavecchia, L., Belli, M. A., Crotti, L., Parati, G., Sanarico, M., Raimondi, F., Biscarini, F., Stella, A., Bachetti, T., La Rovere, M. T., Ludovisi, S., Bussotti, M., Dei, S., Ravaglia, S., Artuso, R., Andreucci, E., Gori, G., Pagliazzi, A., Fiorentini, E., Perrella, A., Bianchi, F., Bergomi, P., Catena, E., Colombo, R., Luchi, S., Morelli, G., Petrocelli, P., Iacopini, S., Modica, S., Baroni, S., Segala, F. V., Falcone, M., Tiseo, G., Barbieri, C., Matucci, T., Grassi, D., Ferri, C., Marinangeli, F., Brancati, F., Vincenti, A., Borgo, V., Lombardi, S., Lenzi, M., Di Pietro, M. A., Vichi, F., Romanin, B., Attala, L., Costa, C., Gabbuti, A., Mene, R., Colaneri, M., Casprini, P., Merla, G., Squeo, G. M., Maffezzoni, M., Frullanti, E., Mondelli, M. U., Renieri, A., Mantovani, S, Daga, S, Fallerini, C, Baldassarri, M, Benetti, E, Picchiotti, N, Fava, F, Galli, A, Zibellini, S, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Alaverdian, D, Capitani, K, Furini, S, Mari, F, Meloni, I, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D'Arminio Monforte, A, Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Parisi, S, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Mencarelli, M, Rizzo, C, Pinto, A, Ariani, F, Di Sarno, L, Bargagli, E, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Mussini, C, Martinelli, E, Tavecchia, L, Belli, M, Crotti, L, Parati, G, Sanarico, M, Raimondi, F, Biscarini, F, Stella, A, Bachetti, T, La Rovere, M, Ludovisi, S, Bussotti, M, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Segala, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Mene, R, Colaneri, M, Casprini, P, Merla, G, Squeo, G, Maffezzoni, M, Frullanti, E, Mondelli, M, and Renieri, A

Subjects
Male, COVID-19, Cytokines, Down-Regulation, Humans, Leukocytes, Mononuclear, SARS-CoV-2, Toll-Like Receptor 7, Toll-Like Receptor 8. [MeSH], toll-like receptor 7, Immunology, Mononuclear, virus diseases, rare variants, Brief Communication, Toll-Like Receptor 8, Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, covid-19, Genetics, Leukocytes, Genetics (clinical)
Abstract

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

Published
2021
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3. An explainable model of host genetic interactions linked to COVID-19 severity

Author

Onoja, A., Picchiotti, N., Fallerini, C., Baldassarri, M., Fava, F., Mari, F., Daga, S., Benetti, E., Bruttini, M., Palmieri, Marco, Croci, S., Amitrano, S., Meloni, I., Frullanti, E., Doddato, G., Lista, Maddalena, Beligni, G., Valentino, Francesca, Zguro, K., Tita, R., Giliberti, A., Mencarelli, Marta, Rizzo, C. L., Pinto, A. M., Ariani, F., Di Sarno, Lorenzo, Montagnani, F., Tumbarello, Mario, Rancan, I., Fabbiani, M., Rossetti, Barbara, Bergantini, L., D'Alessandro, Michele, Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, Francesca, Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Raffaelli, C. S., Feri, M., Donati, Andrea, Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Romani, D., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Pisani, M., Ognibene, A., Pancrazzi, A., Lorubbio, M., Vaghi, M., D'Arminio Monforte, A., Miraglia, F. G., Bruno, R., Vecchia, M., Girardis, M., Venturelli, S., Busani, S., Cossarizza, A., Antinori, Armando, Vergori, A., Emiliozzi, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Tommasi, A., Zuccon, U., Vietri, L., Scotton, P. G., Andretta, F., Panese, S., Baratti, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, E., Antoni, M. D., Zanella, I., Della Monica, M., Piscopo, C., Capasso, Monica, Russo, R., Andolfo, I., Iolascon, A., Fiorentino, Giuseppe, Carella, M., Castori, M., Aucella, F., Raggi, P., Perna, Raffaella, Bassetti, M., Di Biagio, Anna, Sanguinetti, Maurizio, Masucci, Luca, Guarnaccia, A., Valente, S., De Vivo, O., Bargagli, E., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, Francesco, Lacerenza, G., Coviello, D. A., Mussini, C., Martinelli, E., Tavecchia, L., Belli, M. A., Crotti, L., Parati, G., Sanarico, M., Biscarini, F., Stella, A., Rizzi, M., Maggiolo, F., Ripamonti, D., Suardi, C., Bachetti, T., La Rovere, M. T., Sarzi-Braga, S., Bussotti, M., Capitani, K., Dei, S., Ravaglia, S., Artuso, R., Andreucci, E., Gori, Giovanni Cristiano, Pagliazzi, A., Fiorentini, E., Perrella, A., Bianchi, F., Bergomi, P., Catena, E., Colombo, R., Luchi, S., Morelli, G., Petrocelli, Paolo, Iacopini, S., Modica, S., Baroni, Silvia, Segala, F. V., Menichetti, F., Falcone, M., Tiseo, G., Barbieri, Cristiano, Matucci, T., Grassi, D., Ferri, C., Marinangeli, F., Brancati, F., Vincenti, A., Borgo, V., Lombardi, S., Lenzi, M., Di Pietro, Maria Luisa, Vichi, F., Romanin, B., Attala, L., Costa, C., Gabbuti, A., Mene, R., Colaneri, M., Casprini, P., Merla, G., Squeo, G. M., Maffezzoni, M., Mantovani, Susanna, Mondelli, M. U., Ludovisi, S., Colombo, F., Chiaromonte, F., Renieri, A., Furini, S., Raimondi, F., Palmieri M. (ORCID:0000-0001-8263-336X), Lista M., Valentino F., Mencarelli M. A., Di Sarno L., Tumbarello M. (ORCID:0000-0002-9519-8552), Rossetti B., D'Alessandro M., Franchi F., Donati A., Antinori A. (ORCID:0000-0002-6019-2417), Capasso M., Fiorentino G., Perna R., Di Biagio A., Sanguinetti M. (ORCID:0000-0002-9780-7059), Masucci L. (ORCID:0000-0002-8358-6726), Lena F. (ORCID:0000-0001-5528-319X), Gori G. (ORCID:0000-0002-3308-5309), Petrocelli P., Barbieri C., Di Pietro M. A. (ORCID:0000-0002-3893-8788), Mantovani S., Onoja, A., Picchiotti, N., Fallerini, C., Baldassarri, M., Fava, F., Mari, F., Daga, S., Benetti, E., Bruttini, M., Palmieri, Marco, Croci, S., Amitrano, S., Meloni, I., Frullanti, E., Doddato, G., Lista, Maddalena, Beligni, G., Valentino, Francesca, Zguro, K., Tita, R., Giliberti, A., Mencarelli, Marta, Rizzo, C. L., Pinto, A. M., Ariani, F., Di Sarno, Lorenzo, Montagnani, F., Tumbarello, Mario, Rancan, I., Fabbiani, M., Rossetti, Barbara, Bergantini, L., D'Alessandro, Michele, Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, Francesca, Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Raffaelli, C. S., Feri, M., Donati, Andrea, Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Romani, D., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Pisani, M., Ognibene, A., Pancrazzi, A., Lorubbio, M., Vaghi, M., D'Arminio Monforte, A., Miraglia, F. G., Bruno, R., Vecchia, M., Girardis, M., Venturelli, S., Busani, S., Cossarizza, A., Antinori, Armando, Vergori, A., Emiliozzi, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Tommasi, A., Zuccon, U., Vietri, L., Scotton, P. G., Andretta, F., Panese, S., Baratti, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, E., Antoni, M. D., Zanella, I., Della Monica, M., Piscopo, C., Capasso, Monica, Russo, R., Andolfo, I., Iolascon, A., Fiorentino, Giuseppe, Carella, M., Castori, M., Aucella, F., Raggi, P., Perna, Raffaella, Bassetti, M., Di Biagio, Anna, Sanguinetti, Maurizio, Masucci, Luca, Guarnaccia, A., Valente, S., De Vivo, O., Bargagli, E., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, Francesco, Lacerenza, G., Coviello, D. A., Mussini, C., Martinelli, E., Tavecchia, L., Belli, M. A., Crotti, L., Parati, G., Sanarico, M., Biscarini, F., Stella, A., Rizzi, M., Maggiolo, F., Ripamonti, D., Suardi, C., Bachetti, T., La Rovere, M. T., Sarzi-Braga, S., Bussotti, M., Capitani, K., Dei, S., Ravaglia, S., Artuso, R., Andreucci, E., Gori, Giovanni Cristiano, Pagliazzi, A., Fiorentini, E., Perrella, A., Bianchi, F., Bergomi, P., Catena, E., Colombo, R., Luchi, S., Morelli, G., Petrocelli, Paolo, Iacopini, S., Modica, S., Baroni, Silvia, Segala, F. V., Menichetti, F., Falcone, M., Tiseo, G., Barbieri, Cristiano, Matucci, T., Grassi, D., Ferri, C., Marinangeli, F., Brancati, F., Vincenti, A., Borgo, V., Lombardi, S., Lenzi, M., Di Pietro, Maria Luisa, Vichi, F., Romanin, B., Attala, L., Costa, C., Gabbuti, A., Mene, R., Colaneri, M., Casprini, P., Merla, G., Squeo, G. M., Maffezzoni, M., Mantovani, Susanna, Mondelli, M. U., Ludovisi, S., Colombo, F., Chiaromonte, F., Renieri, A., Furini, S., Raimondi, F., Palmieri M. (ORCID:0000-0001-8263-336X), Lista M., Valentino F., Mencarelli M. A., Di Sarno L., Tumbarello M. (ORCID:0000-0002-9519-8552), Rossetti B., D'Alessandro M., Franchi F., Donati A., Antinori A. (ORCID:0000-0002-6019-2417), Capasso M., Fiorentino G., Perna R., Di Biagio A., Sanguinetti M. (ORCID:0000-0002-9780-7059), Masucci L. (ORCID:0000-0002-8358-6726), Lena F. (ORCID:0000-0001-5528-319X), Gori G. (ORCID:0000-0002-3308-5309), Petrocelli P., Barbieri C., Di Pietro M. A. (ORCID:0000-0002-3893-8788), and Mantovani S.

Abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

Published
2022

4. An explainable model of host genetic interactions linked to COVID-19 severity

Author

Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, Serena Ludovisi, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, and Serena Ludovisi

Abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

Published
2022

7. An explainable model of host genetic interactions linked to COVID-19 severity

Author

Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco GEN-COVID Multicenter Study: Francesca Mari, Sergio, Daga, Elisa, Benetti, Mirella, Bruttini, Maria, Palmieri, Susanna, Croci, Sara, Amitrano, Ilaria, Meloni, Elisa, Frullanti, Gabriella, Doddato, Mirjam, Lista, Giada, Beligni, Floriana, Valentino, Kristina, Zguro, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca, Ariani, Laura Di Sarno, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, Barbara, Rossetti, Laura, Bergantini, Miriana, D'Alessandro, Paolo, Cameli, David, Bennett, Federico, Anedda, Simona, Marcantonio, Sabino, Scolletta, Federico, Franchi, Maria Antonietta Mazzei, Susanna, Guerrini, Edoardo, Conticini, Luca, Cantarini, Bruno, Frediani, Danilo, Tacconi, Chiara Spertilli Raffaelli, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Agostino, Ognibene, Alessandro, Pancrazzi, Maria, Lorubbio, Massimo, Vaghi, Antonella D'Arminio Monforte, Federica Gaia Miraglia, Raffaele, Bruno, Marco, Vecchia, Massimo, Girardis, Sophie, Venturelli, Stefano, Busani, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Francesco, Paciosi, Andrea, Tommasi, Umberto, Zuccon, Lucia, Vietri, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Oreste De Vivo, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Filippo, Biscarini, Alessandra, Stella, Marco, Rizzi, Franco, Maggiolo, Diego, Ripamonti, Claudia, Suardi, Tiziana, Bachetti, Maria Teresa La Rovere, Simona, Sarzi-Braga, Maurizio, Bussotti, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Giulia, Gori, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Sauro, Luchi, Giovanna, Morelli, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Francesco Vladimiro Segala, Francesco, Menichetti, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti, Valentina, Borgo, Lombardi, Stefania, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Roberto, Menè, Marta, Colaneri, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Stefania, Mantovani, Mario, U Mondelli, Serena, Ludovisi, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, nbsp, Multicenter Study, GEN-COVID, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, and Ludovisi, S

Subjects
Genetics, Coronavirus disease 2019 (COVID-19), Host (biology), COVID-19, Medicine (miscellaneous), Settore BIO/11 - Biologia Molecolare, Biology, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, Whole Exome Sequencing, General Biochemistry, Genetics and Molecular Biology, machine learning, Phenotype, Exome Sequencing, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, General Agricultural and Biological Sciences, COVID, Human
Abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with training of multiple supervised classifiers, to predict severity on the basis of screened features. Feature importance analysis from tree-based models allowed to identify a handful of 16 variants with highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with good accuracy (ACC=81.88%; ROC_AUC=96%; MCC=61.55%). Principal Component Analysis (PCA) and clustering of patients on important variants orthogonally identified two groups of individuals with a higher fraction of severe cases. Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response, such as JAK-STAT, Cytokine, Interleukin, and C-type lectin receptor signaling. It also identified additional processes cross-talking with immune pathways, such as GPCR signalling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, confirming their link with COVID-19 severity outcome. Taken together, our analysis suggests that curated genetic information can be effectively integrated along with other patient clinical covariates to forecast COVID-19 disease severity and dissect the underlying host genetic mechanisms for personalized medicine treatments.

Published
2022
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8. Detection of possible factors favouring the evolution of migraine without aura into chronic migraine

Author

Cecilia Camarda, Paola Torelli, G. C. Manzoni, S. Lana, M. Maffezzoni, L. L. Lombardi, Manzoni, G, Lombardi, L, Lana, S, Maffezzoni, M, Camarda, C, and Torelli, P

Subjects
Adult, Male, medicine.medical_specialty, Neurology, Time Factors, Aura, Migraine Disorders, Dermatology, Young Adult, Chronic Migraine, Migraine, Migraine without aura, Chronic migraine , Chronic daily headache , Chronic headache, Internal medicine, medicine, Humans, Young adult, Depression (differential diagnoses), business.industry, Depression, General Medicine, Middle Aged, medicine.disease, Comorbidity, Natural history, Psychiatry and Mental health, Migraine, Chronic Disease, Hypertension, Physical therapy, Disease Progression, Female, Settore MED/26 - Neurologia, Neurology (clinical), business
Abstract

In a minority of cases, the natural history of migraine without aura (MO) is characterised over time by its evolution into a form of chronic migraine (CM). In order to detect the possible factors predicting this negative evolution of MO, we searched in our Headache Centre files for all clinical records that met the following criteria: (a) first visit between 1976 and 1998; (b) diagnosis of MO or of common migraine at the first observation, with or without association with other primary headache types; (c)

Published
2012

9. Con: Mechanical Ventilation During Cardiopulmonary Bypass.

Author

Maffezzoni M and Bellini V

Subjects
Humans, Cardiopulmonary Bypass, Lung, Continuous Positive Airway Pressure, Respiration, Artificial methods, Cardiac Surgical Procedures
Abstract

The ventilatory strategy to adopt during cardiopulmonary bypass is still being debated. The rationale for using continuous positive airway pressure or mechanical ventilation would be to counteract alveolar collapse and improve ischemia phenomena and passive alveolar diffusion of oxygen. Although there are several studies supporting the hypothesis of a positive effect on oxygenation and systemic inflammatory response, the real clinical impact of ventilation during cardiopulmonary bypass is controversial. Furthermore, the biases present in the literature make the studies' results nonunique in their interpretation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2024
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10. Metaverse and Anesthesia.

Author

Bellini V, Maffezzoni M, and Bignami E

Subjects
Anesthesia adverse effects, Anesthesiology
Abstract

Competing Interests: The authors declare no conflicts of interest.

Published
2024
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11. Reduction of BSI associated mortality after a sepsis project implementation in the ER of a tertiary referral hospital.

Author

Seminari E, Colaneri M, Corbella M, De Silvestri A, Muzzi A, Perlini S, Martino IF, Marvulli LN, Arcuri A, Maffezzoni M, Minucci R, Bono E, Cambieri P, Marone P, and Bruno R

Subjects
Humans, Tertiary Care Centers, Retrospective Studies, Hospital Mortality, Emergency Service, Hospital, Hospitalization, Sepsis
Abstract

The emergency room (ER) is the first gateway for patients with sepsis to inpatient units, and identifying best practices and benchmarks to be applied in this setting might crucially result in better patient's outcomes. In this study, we want to evaluate the results in terms of decreased the in-hospital mortality of patients with sepsis of a Sepsis Project developed in the ER. All patients admitted to the ER of our Hospital from the 1st January, 2016 to the 31stJuly 2019 with suspect of sepsis (MEWS score ≥ of 3) and positive blood culture upon ER admission were included in this retrospective observational study. The study comprises of two periods: Period A: From the 1st Jan 2016 to the 31st Dec 2017, before the implementation of the Sepsis project. Period B: From the 1st Jan 2018 to the 31stJul 2019, after the implementation of the Sepsis project. To analyze the difference in mortality between the two periods, a univariate and multivariate logistic regression was used. The risk of in-hospital mortality was expressed as an odds ratio (OR) and a 95% confidence interval (95% CI). Overall, 722 patients admitted in ER had positive BC on admissions, 408 in period A and 314 in period B. In-hospital mortality was 18.9% in period A and 12.7% in period B (p = 0.03). At multivariable analysis, mortality was still reduced in period B compared to period A (OR 0.64, 95% CI 0.41-0.98; p = 0.045). Having an infection due to GP bacteria or polymicrobial was associated with an increased risk of death, as it was having a neoplasm or diabetes. A marked reduction in in-hospital mortality of patients with documented BSI associated with signs or symptoms of sepsis after the implementation of a sepsis project based on the application of sepsis bundles in the ER., (© 2023. The Author(s).)

Published
2023
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12. Evolution of Hybrid Intelligence and Its Application in Evidence-Based Medicine: A Review.

Author

Bellini V, Badino M, Maffezzoni M, Bezzi F, and Bignami E

Subjects
Humans, Evidence-Based Medicine, Health Facilities, Artificial Intelligence, Intelligence
Abstract

Modern medicine, both in clinical practice and research, has become more and more based on data, which is changing equally in type and quality with the advent and development of healthcare digitalization. The first part of the present paper aims to present the steps through which data, and subsequently clinical and research practice, have evolved from paper-based to digital, proposing a possible future of this digitalization in terms of potential applications and integration of digital tools in medical practice. Noting that digitalization is no more a possible future, but a concrete reality, there is a strong need for a new definition of evidence-based medicine, which must take into account the progressive integration of artificial intelligence (AI) in all decision-making processes. So, leaving behind the traditional research concept of human intelligence versus AI, poorly adaptable to real-world clinical practice, a Human and AI hybrid model, seen as a deep integration of AI and human thinking, is proposed as a new healthcare governance system. The second part of our review is focused on some of the major challenges the digitalization process has to face, particularly privacy issues, system complexity and opacity, and ethical concerns related to legal aspects and healthcare disparities. Analyzing these open issues, we aim to present some of the future directions that in our opinion should be pursued to implement AI in clinical practice.

Published
2023
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13. The infection risk after transjugular intrahepatic portosystemic shunt: A multiple competing risk analysis from a tertiary care center.

Author

Colaneri M, Lombardi A, Maffezzoni M, Sambo M, Fabbiani M, Quaretti P, Asperges E, Moramarco L, Sacchi P, and Bruno R

Subjects
Humans, Retrospective Studies, Tertiary Care Centers, Proportional Hazards Models, Risk Assessment, Treatment Outcome, Portasystemic Shunt, Transjugular Intrahepatic adverse effects, Portasystemic Shunt, Transjugular Intrahepatic methods
Abstract

Background: Infections following transjugular intrahepatic portosystemic shunt (TIPS) placement have been poorly described. We aim to investigate the rate and the potential predictors of infections occurring after TIPS placement., Methods: Single center, retrospective, observational study. All patients who had undergone TIPS placement in the last 10 years with a minimum 1-year FU, were considered. Multiple competing risk analyses were performed to identify infection risk factors and a multivariable Cox proportional-hazard regression model to evaluate the predictors of death., Results: Forty-nine patients were considered. Among these, 23 (46%) developed at least 1 infection during the FU, at a median time of 237.7 days (IQR 151.5) from the TIPS placement. We did not find any predictor of infection, while MELD score and cancer were associated with death (p = .04; HR 1.14; CI 1.00- 1.30)., Conclusion: We found a high rate of all-type infections during the FU times. However, most of these infections occurred as late-onset infections and were caused by Gram-positive microorganisms. Thus, TIPS procedure itself does not seem to be burdened with high infectious perioperative risk., Competing Interests: Declaration of Competing Interest None related to the content of this manuscript., (Copyright © 2022. Published by Elsevier Ltd.)

Published
2022
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14. Current Applications of Artificial Intelligence in Bariatric Surgery.

Author

Bellini V, Valente M, Turetti M, Del Rio P, Saturno F, Maffezzoni M, and Bignami E

Subjects
Algorithms, Artificial Intelligence, Humans, Machine Learning, Bariatric Surgery, Obesity, Morbid surgery
Abstract

The application of artificial intelligence technologies is growing in several fields of healthcare settings. The aim of this article is to review the current applications of artificial intelligence in bariatric surgery. We performed a review of the literature on Scopus, PubMed and Cochrane databases, screening all relevant studies published until September 2021, and finally including 36 articles. The use of machine learning algorithms in bariatric surgery is explored in all steps of the clinical pathway, from presurgical risk-assessment and intraoperative management to complications and outcomes prediction. The models showed remarkable results helping physicians in the decision-making process, thus improving the quality of care, and contributing to precision medicine. Several legal and ethical hurdles should be overcome before these methods can be used in common practice., (© 2022. The Author(s).)

Published
2022
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16. [Dialectical-behavioral outpatient therapy for adolescents with impulsive and self-harming behavior].

Author

Maffezzoni M and Steinhausen HC

Subjects
Adolescent, Affective Symptoms diagnosis, Affective Symptoms psychology, Affective Symptoms therapy, Combined Modality Therapy, Disruptive, Impulse Control, and Conduct Disorders diagnosis, Disruptive, Impulse Control, and Conduct Disorders psychology, Female, Humans, Interpersonal Relations, Male, Psychopathology, Self-Injurious Behavior diagnosis, Self-Injurious Behavior psychology, Switzerland, Ambulatory Care, Cognitive Behavioral Therapy methods, Disruptive, Impulse Control, and Conduct Disorders therapy, Self-Injurious Behavior therapy
Abstract

A slightly modified version of the Dialectical-Behavioral Therapy for Adolescents (DBT-A) for impulsive and self-injurious adolescents has been implemented in the Child and Adolescent Psychiatric Service in Zurich, Switzerland, since 2005. This DBT-A comprises individual therapy, skills training, and a single parent meeting over a 6-month period. This article reports on the translation of this approach into clinical practice and presents an evaluation based on the clinical quality of control assessments. Participants of the treatment program were 43 female adolescents aged 14 to 19 living in the Zurich area and showing impulsive and self-injurious behavior and problems regulating their emotions and relationships. Each skill group contained 4-6 adolescents. Our mostly positive experiences with this approach were supplemented by evaluation data from a quality control group based on self- and parent-report of a total of 19 participants. There is convincing evidence that DBT-A leads to reductions in both general and specific psychopathology.

Published
2017
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17. A framework for ethical decision making in neonatal intensive care.

Author

Baumann-Hölzle R, Maffezzoni M, and Bucher HU

Subjects
Adult, Critical Care, Female, Humans, Infant, Newborn, Male, Palliative Care, Patient Care Team, Algorithms, Decision Making, Ethics, Clinical, Intensive Care Units, Neonatal organization & administration
Abstract

Unlabelled: Intensive care for neonates with high risks of severe impairment and the possibility of a prolonged dying process represents a frequent ethical issue in neonatal units. The aim of this paper is to present a framework for structured decision making that has been developed in a neonatal intensive care unit and to demonstrate its impact on the healthcare team and on survival of critically ill neonates. This framework attempts to integrate the best interests of the infants and their parents, the possibilities of high-tech neonatal intensive care interventions, and the perspective of the nurses and doctors. An external evaluation of 84 sessions over 3 y revealed a beneficial effect on the quality of the decision-making process itself and on the quality of the teamwork in the unit. Survival time was shorter (median 2 d, interquartile range 1-7 d) in 26 infants that died after structured decision making compared with 26 controls matched for gestational age, malformation and intracranial haemorrhage (median 7 d, interquartile range 4-15 d)., Conclusion: The introduction of this framework for structured decision making involving doctors and nurses improved the quality of the teamwork. It shortened futile intensive care, and thereby suffering for both infants and parents.

Published
2005
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