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1. Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

Author

Chai, Ming G., Tu, Quyen, Cotta, Menino O., Bauer, Michelle J., Balch, Ross, Okafor, Charles, Comans, Tracy, Kruger, Peter, Meyer, Jason, Shekar, Kiran, Brady, Kara, Fourie, Cheryl, Sharp, Natalie, Vlad, Luminita, Whiley, David, Ungerer, Jacobus P. J., Mcwhinney, Brett C., Farkas, Andras, Paterson, David L., Clark, Julia E., Hajkowicz, Krispin, Raman, Sainath, Bialasiewicz, Seweryn, Lipman, Jeffrey, Forde, Brian M., Harris, Patrick N. A., Schlapbach, Luregn J., Coin, Lachlan, Roberts, Jason A., and Irwin, Adam D.

Published
2024
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2. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

Author

Jackson, Heather R, Miglietta, Luca, Habgood-Coote, Dominic, D'Souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp KA, Beudeker, Coco R, Brengel-Pesce, Karen, Carrol, Enitan D, Carter, Michael J, De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J, Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J, Tremoulet, Adriana H, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey, Burns, Jane C, Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A, Rodriguez-Manzano, Jesus, Kaforou, Myrsini, and Levin, Michael

Subjects
Paediatrics, Medical Microbiology, Biomedical and Clinical Sciences, Pediatric, Genetics, Infectious Diseases, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Child, Humans, COVID-19, Systemic Inflammatory Response Syndrome, Hospitals, Mucocutaneous Lymph Node Syndrome, COVID-19 Testing, MIS-C, diagnostic signature, host diagnostics, host response, pediatric infectious diseases, rapid diagnostics, transcriptomics, Medical microbiology
Abstract

BackgroundTo identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections.MethodsChildren presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39).ResultsIn the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV.ConclusionsMIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Published
2023

3. Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study

Author

Levin, Michael, Coin, Lachlan, Gormley, Stuart, Hamilton, Shea, Hoggart, Clive, Kaforou, Myrsini, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stephanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Shailes, Hannah, Thakker, Clare, Bokhandi, S., Power, Sue, Barham, Heather, Pathan, N., Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S., Patel, S., McCorkell, Jenni, Davies, P., Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R., Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Pollard, Andrew, Willis, Louise, Young, Zoe, Royad, C., White, Sonia, Fortune, Peter-Marc, Hudnott, Phil, Martinón-Torres, Federico, Salas, Antonio, Álvez González, Fernando, Barral-Arca, Ruth, Cebey-López, Miriam, Curras-Tuala, María José, García, Natalia, García Vicente, Luisa, Gómez-Carballa, Alberto, Gómez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leboráns Iglesias, Pilar, Martínez Santos, Alba Elena, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Morillo Gutiérrez, Beatriz, Mosquera Pérez, Belén, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, Rivero-Calle, Irene, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriaga, Antonio, Fernández, Sonia Serén, del Sol Porto Silva, María, Vega, Ana, Vilanova Trillo, Lucía, Reyes, Susana Beatriz, Cruz León León, María, Navarro Mingorance, Álvaro, Gabaldó Barrio, Xavier, Oñate Vergara, Eider, Concha Torre, Andrés, Vivanco, Ana, Fernández, Reyes, Giménez Sánchez, Francisco, Sánchez Forte, Miguel, Rojo, Pablo, Contreras, J. Ruiz, Palacios, Alba, Epalza Ibarrondo, Cristina, Fernández Cooke, Elizabeth, Navarro, Marisa, Álvarez Álvarez, Cristina, José Lozano, María, Carreras, Eduardo, Brió Sanagustín, Sonia, Neth, Olaf, Martínez Padilla, Mª del Carmen, Prieto Tato, Luis Manuel, Guillén, Sara, Fernández Silveira, Laura, Moreno, David, de Groot, R., Tutu van Furth, A.M., van der Flier, M., Boeddha, N.P., Driessen, G.J.A., Emonts, M., Hazelzet, J.A., Kuijpers, T.W., Pajkrt, D., Sanders, E.A.M., van de Beek, D., van der Ende, A., Philipsen, H.L.A., Adeel, A.O.A., Breukels, M.A., Brinkman, D.M.C., de Korte, C.C.M.M., de Vries, E., de Waal, W.J., Dekkers, R., Dings-Lammertink, A., Doedens, R.A., Donker, A.E., Dousma, M., Faber, T.E., Gerrits, G.P.J.M., Gerver, J.A.M., Heidema, J., Homan-van der Veen, J., Jacobs, M.A.M., Jansen, N.J.G., Kawczynski, P., Klucovska, K., Kneyber, M.C.J., Koopman-Keemink, Y., Langenhorst, V.J., Leusink, J., Loza, B.F., Merth, I.T., Miedema, C.J., Neeleman, C., Noordzij, J.G., Obihara, C.C., van Overbeek- van Gils, A.L.T., Poortman, G.H., Potgieter, S.T., Potjewijd, J., Rosias, P.P.R., Sprong, T., ten Tussher, G.W., Thio, B.J., Tramper-Stranders, G.A., van Deuren, M., van der Meer, H., van Kuppevelt, A.J.M., van Wermeskerken, A.M., Verwijs, W.A., Wolfs, T.F.W., Schlapbach, Luregn J., Agyeman, Philipp, Aebi, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Berger, Christoph, Carrol, Enitan D., Paulus, Stéphane, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Fink, Colin G, Pinnock, Elli, Emonts, Marieke, Agbeko, Rachel, Anderson, Suzanne, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Saidykhan, Momodou, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Zenz, Werner, Kohlfürst, Daniela S., Binder, Alexander, Schweintzger, Nina A., Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Jürgen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Köster, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Rödl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wüller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, Žukovskaja, Veslava, Hibberd, Martin L., Davila, Sonia, Delany, Isabel, Schlapbach, Luregn J, Raman, Sainath, Sharp, Nathalie, Phillips, Natalie, Irwin, Adam, Balch, Ross, Harley, Amanda, Johnson, Kerry, Sever, Zoe, George, Shane, Grimwood, Keith, Snelling, Peter J, Chavan, Arjun, Kitcatt, Eleanor, Lawton, Luke, Hempenstall, Allison, Pilot, Pelista, Gibbons, Kristen S, Le Marsney, Renate, Blumenthal, Antje, Ganesamoorthy, Devika, Pardo, Carolyn, Kling, Jessica, McPherson, Stephen, MacDonald, Anna D, Bialasiewicz, Seweryn, Pham, Trang, Wilson, Clare, Sharp, Natalie, Kling, Jessica C, McPherson, Stephen J, Herberg, Jethro A, and Coin, Lachlan J M

Published
2024
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4. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Author

Jackson, Heather Ruth, Zandstra, Judith, Menikou, Stephanie, Hamilton, Shea, McArdle, Andrew J, De, Tisham, Agyeman, Philipp K A, Von Both, Ulrich, Carrol, Enitan D, Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, De Groot, Ronald, Moll, Henriette A, Pokorn, Marko, Pollard, Andrew, Schlapbach, Luregn J, Tsolia, Maria, Usuf, Effua, Wright, Victoria, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey J, Martinon-Torres, Federico, Herberg, Jethro, De Jonge, Marien I, Levin, Michael, Kuijpers, Taco, Kaforou, Myrsini, Abdulla, Amina, Aebi, Christoph, Agbeko, Rachel, Ali, Ladan, Alkema, Wynand, Allen, Karen, Anderson, Suzanne, Ansari, Imran, Arif, Tasnim, Avramoska, Tanja, Baas, Bryan, Bahovec, Natalija, Balode, Anda, Bãrdzdina, Arta, Barendregt, A M, Barral-Arca, Ruth, Bath, David, Bauchinger, Sebastian, Baumard, Lucas, Baumgart, Hinrich, Baxter, Frances, Bell, Kathryn, Bell, Ashley, Bello, Xabier, Bellos, Evangelos, Benesch, Martin, Bennet, Joshua, Berger, Christoph, Bernhard-Stirnemann, Sara, Bibi, Sagida, Bidlingmaier, Christoph, Binder, Alexander, Binder, Vera, Blackmore, Jennifer, Bojang, Kalifa, Borensztajn, Dorine M, Brengel-Pesce, Karen, Broderick, Claire, Buschbeck, Judith, Calvo-Bado, Leonides, Carnota, Sandra, Carter, Michael J, Castro, María Barreiro, Cebey-López, Miriam, Ceesay, Samba, Ceolotto, Astrid, Chan, Adora, Cocklin, Elizabeth, Collings, Kalvin, Crulley, Stephen, Curras-Tuala, María José, D'alessandro, Umberto, D'Souza, Giselle, Danhauser, Katharina, Darboe, Saffiatou, Darnell, Sarah, De Haan, L, De Vries, Gabriella, Deksne, Dãrta, Devine, Kirsty, Dewez, Juan Emmanuel, Dik, W, Dudley, Julia, Eber, Ernst, Fabian, Daniel, Farto, Cristina Balo, Fernández, Sonia Serén, Fidler, Katy, Fitchett, Elizabeth, Galassini, Rachel, Gallisti, Siegfried, García, Mirian Ben, Gardovska, Dace, Geissler, J, Gerrits, G P J M, Giannoni, Eric, Gloerich, Jolein, Gómez-Carballa, Alberto, González, Fernando Álves, Gores, Gunther, Grãvele, Dagne, Griese, Matthias, Grope, Ilze, Gurung, Meeru, Haas, Nikolaus, Habgood-Coote, Dominic, Hagedoorn, Nienke N, Haidl, Harald, Harrison, Rebekah, Hauer, Almuthe, Heidema, J, Heininger, Ulrich, Henriet, Stefanie, Hibberd, Martin, Hoggart, Cllive, Hösele, Susanne, Hourmat, Sara, Hude, Christa, Huijnen, Martijn, Iglesias, Pilar Leboráns, Iglesias, Marisol Vilas, Jennings, Rebecca, Johnson, Joanne, Jongerius, Ilse, Jorgensen, Rikke, Kahlert, Christian, Kandasamy, Rama, Kappler, Matthias, Keldorfer, Markus, Kelly, Dominic F, Khanijau, Aakash, Kim, Nayoung, Kim, Eunjung, King, Sharon, Kolberg, Laura, Kolnik, Mojca, Kloosterhuis, Lieke, Kohlfürst, Daniela S, Kohlmaier, Benno, Krenn, Larissa, Leigh, Simon, Leitner, Manuel, Leurent, Baptiste, Lim, Emma, Lin, Naomi, Liu, Ching-Chuan, Löffler, Sabine, Lurz, Eberhard, Mackerness, Christine, Maconochie, Ian, Mallet, Francois, Marmarinos, Antonis, Martin, Alex, Martin, Mike, Martinón Sánchez, José María, Martinón-Torres, Nazareth, McAlinden, Paul, McDonald, Sam, McDonell, Anne, Meiere, Anija, Meierford, Anne, Miedema, C J, Miners, Alec, Mistry, Ravi, Mommert, Marine, Morris, Sophie, Muench, Georg, Murdoch, David R, Mustafa, Sobia, Natalucci, Giancarlo, Neeleman, C, Newall, Karen, Nichols, Samuel, Niederer-Loher, Anita, Niedrist, Tobias, Nijman, Ruud, Nokalna, Ieve, Nordberg, Gudrun, O'Connor, Daniel, Obihara, C C, Oliver, Zoe, Oosthoek, Wilma, Ora, Miguel Sadiki, Osterman, Veronika, Pachot, Alexandre, Pajkrt, D, Pardo-Seco, Jacobo, Pavãre, Jana, Paz, Ivonne Pena, Paulus, Stéphane, Pérez, Belén Mosquera, Persand, Salina, Pfleger, Andreas, Pfurtscheller, Klaus, Philipsen, Ria, Pickering, Alisa, Pierce, Benjamin, Pilch, Heidemarie, Pischedda, Sara, Pölz, Lena, Posfay-Barbe, Klara M, Powell, Oliver, Prunk, Petra, Pučuka, Zanda, Rajic, Glorija, Rashid, Aqeela, Redondo-Collazo, Lorenzo, Reiter, Karl, Relly, Christa, Rhodes, Mathew, Rial, Jose Gómez, Richmond, Vivien, Riedel, Thomas, Rivero Calle, Irene, Roca, Anna, Rödl, Siegfried, Rodríguez, Lidia Piñeiro, Rodríguez-Tenreiro, Carmen, Romaine, Sam, Rowlands, Emily, Rudzate, Aleksandra, Sagmeister, Manfred, Saidykhan, Momodou, Sallas, Antonio, Sarr, Isatou, Schoen, Carola, Schonenberg, D, Schweintzger, Nina, Secka, Fatou, Selecka, Katrīna, Shah, Priyen, Shen, Ching-Fen, Shrestha, Shrijana, Skrabl-Baumgartner, Andrea, Soon, Joshua, Sperl, Matthias, Sprenkeler, Evelien, Spyridis, Nikos, Srovin, Tina Plankar, Stampfer, Laura, Stevens, Molly, Stocker, Martin, Strenger, Volker, Suárez, Carlos Durán, Svile, Dace, Syggelou, Kelly, Tal, Chantal, Tambouratzi, Maria, Tavliavini, Emma, Thakker, Clare, Thomson, Evelyn, Throson, Stephen, Till, Holger, Tramper-Stranders, G A, Trasorras, Cristina Serén, Trobisch, Andreas, Urbãne, Urzula Nora, Usman, Mariama, Valentine, Lucille, Van Aerde, Koen, Van den Berg, J M, Van den Broek, Bryan, Van der Giessen, Ilona, Van der Kuip, M, Van der Velden, Fabian, Van Furth, A M, Van Gool, Alain J, Van Leur, M, van Mierlo, G, Vázquez, Sara Ray, Vermont, Clementien, Vicente, Luisa García, Vincek, Katarina, Vito, Ortensia, Voice, Marie, Wallia, Diane, Walsh, Ben, Wang, Shih-Min, Wedderburn, Catherine, Willems, Esther, Wilson, Clare, Wood, Amanda, Woodsford, Phil, Wyss, Verena, Xagorari, Marietta, Zachariasse, Joany, Zaman, Syed M A, Zurl, Christoph, Zwerenz, Manuela, Jackson, Heather R, Hamilton, Melissa Shea, Fischer, Roman, Thorne, Adam M, Huang, Honglei, Tanck, Michael W, Jansen, Machiel H, Pollard, Andrew J, Tsolia, Maria N, Wright, Victoria J, Coin, Lachlan J M, Casals-Pascual, Climent, Herberg, Jethro A, de Jonge, Marien I, and Kuijpers, Taco W

Published
2023
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5. Uncovering strain- and age-dependent innate immune responses to SARS-CoV-2 infection in air-liquid-interface cultured nasal epithelia

Author

Chang, Jessie J.-Y., Grimley, Samantha L., Tran, Bang M., Deliyannis, Georgia, Tumpach, Carolin, Nguyen, An N.T., Steinig, Eike, Zhang, JianShu, Schröder, Jan, Caly, Leon, McAuley, Julie, Wong, Sharon L., Waters, Shafagh A., Stinear, Timothy P., Pitt, Miranda E., Purcell, Damian, Vincan, Elizabeth, and Coin, Lachlan J.M.

Published
2024
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7. Detection of Streptococcus pyogenes M1UK in Australia and characterization of the mutation driving enhanced expression of superantigen SpeA

Author

Davies, Mark R., Keller, Nadia, Brouwer, Stephan, Jespersen, Magnus G., Cork, Amanda J., Hayes, Andrew J., Pitt, Miranda E., De Oliveira, David M. P., Harbison-Price, Nichaela, Bertolla, Olivia M., Mediati, Daniel G., Curren, Bodie F., Taiaroa, George, Lacey, Jake A., Smith, Helen V., Fang, Ning-Xia, Coin, Lachlan J. M., Stevens, Kerrie, Tong, Steven Y. C., Sanderson-Smith, Martina, Tree, Jai J., Irwin, Adam D., Grimwood, Keith, Howden, Benjamin P., Jennison, Amy V., and Walker, Mark J.

Published
2023
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9. Correction: Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

Author

Chai, Ming G., Tu, Quyen, Cotta, Menino O., Bauer, Michelle J., Balch, Ross, Okafor, Charles, Comans, Tracy, Kruger, Peter, Meyer, Jason, Shekar, Kiran, Brady, Kara, Fourie, Cheryl, Sharp, Natalie, Vlad, Luminita, Whiley, David, Ungerer, Jacobus P. J., Mcwhinney, Brett C., Farkas, Andras, Paterson, David L., Clark, Julia E., Hajkowicz, Krispin, Raman, Sainath, Bialasiewicz, Seweryn, Lipman, Jeffrey, Forde, Brian M., Harris, Patrick N. A., Schlapbach, Luregn J., Coin, Lachlan, Roberts, Jason A., and Irwin, Adam D.

Published
2024
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10. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases

Author

Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching-Fen, Tsolia, Maria, Usuf, Effua, van der Flier, Michiel, Vermont, Clementien, von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, and Hamilton, Shea

Published
2024
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13. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature

Author

Habgood-Coote, Dominic, Wilson, Clare, Shimizu, Chisato, Barendregt, Anouk M., Philipsen, Ria, Galassini, Rachel, Calle, Irene Rivero, Workman, Lesley, Agyeman, Philipp K.A., Ferwerda, Gerben, Anderson, Suzanne T., van den Berg, J. Merlijn, Emonts, Marieke, Carrol, Enitan D., Fink, Colin G., de Groot, Ronald, Hibberd, Martin L., Kanegaye, John, Nicol, Mark P., Paulus, Stéphane, Pollard, Andrew J., Salas, Antonio, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Walther, Michael, Zenz, Werner, Van der Flier, Michiel, Zar, Heather J., Kuijpers, Taco, Burns, Jane C., Martinón-Torres, Federico, Wright, Victoria J., Coin, Lachlan J.M., Cunnington, Aubrey J., Herberg, Jethro A., Levin, Michael, and Kaforou, Myrsini

Published
2023
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14. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

Author

Shah, Priyen, Voice, Marie, Calvo-Bado, Leonides, Calle, Irene Rivero, Morris, Sophie, Nijman, Ruud, Broderick, Claire, De, Tisham, Eleftheriou, Irini, Galassini, Rachel, Khanijau, Aakash, Kolberg, Laura, Kolnik, Mojca, Rudzate, Aleksandra, Sagmeister, Manfred, Schweintzger, Nina, Secka, Fatou, Thakker, Clare, Van der Velden, Fabian, Vermont, Clementien, Vincek, Katarina, Agyeman, Philipp K.A., Cunnington, Aubrey J., De Groot, Ronald, Emonts, Marieke, Fidler, Katy, Kuijpers, Taco, Mommert-Tripon, Marine, Brengel-Pesce, Karen, Mallet, Francois, Moll, Henriette, Paulus, Stéphane, Pokorn, Marko, Pollard, Andrew, Schlapbach, Luregn J., Shen, Ching-Fen, Tsolia, Maria, Usuf, Effua, Van der Flier, Michiel, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Wright, Victoria, Carrol, Enitan D., Kaforou, Myrsini, Martinon-Torres, Federico, Fink, Colin, Levin, Michael, Herberg, Jethro, Baumard, Lucas, Bellos, Evangelos, Coin, Lachlan, D'Souza, Giselle, Habgood-Coote, Dominic, Hamilton, Shea, Hoggart, Cllive, Hourmat, Sara, Jackson, Heather, Lin, Naomi, Menikou, Stephanie, Nichols, Samuel, Paz, Ivonne Pena, Powell, Oliver, Vito, Ortensia, Wilson, Clare, Abdulla, Amina, Ali, Ladan, Darnell, Sarah, Jorgensen, Rikke, Maconochie, Ian, Mustafa, Sobia, Persand, Salina, Walsh, Ben, Stevens, Molly, Kim, Nayoung, Kim, Eunjung, Pierce, Benjamin, Dudley, Julia, Richmond, Vivien, Tavliavini, Emma, Liu, Ching-Chuan, Wang, Shih-Min, González, Fernando Álves, Farto, Cristina Balo, Barral-Arca, Ruth, Castro, María Barreiro, Bello, Xabier, Ben García, Mirian, Carnota, Sandra, Cebey-López, Miriam, Curras-Tuala, María José, Suárez, Carlos Durán, Vicente, Luisa García, Gómez-Carballa, Alberto, Rial, Jose Gómez, Iglesias, Pilar Leboráns, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Pérez, Belén Mosquera, Pardo-Seco, Jacobo, Rodríguez, Lidia Piñeiro, Pischedda, Sara, Vázquez, Sara Ray, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Ora, Miguel Sadiki, Sallas, Antonio, Fernández, Sonia Serén, Trasorras, Cristina Serén, Iglesias, Marisol Vilas, Balode, Anda, Bãrdzdina, Arta, Deksne, Dãrta, Gardovska, Dace, Grãvele, Dagne, Grope, Ilze, Meiere, Anija, Nokalna, Ieve, Pavãre, Jana, Pučuka, Zanda, Selecka, Katrīna, Svile, Dace, Urbãne, Urzula Nora, Bojang, Kalifa, Zaman, Syed M.A., Anderson, Suzanne, Roca, Anna, Sarr, Isatou, Saidykhan, Momodou, Darboe, Saffiatou, Ceesay, Samba, D'alessandro, Umberto, Borensztajn, Dorine M., Hagedoorn, Nienke N., Tal, Chantal, Zachariasse, Joany, Dik, W., Aebi, Christoph, Berger, Christoph, Wyss, Verena, Usman, Mariama, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Natalucci, Giancarlo, Relly, Christa, Riedel, Thomas, Cocklin, Elizabeth, Jennings, Rebecca, Johnson, Joanne, Leigh, Simon, Newall, Karen, Romaine, Sam, Tambouratzi, Maria, Marmarinos, Antonis, Xagorari, Marietta, Syggelou, Kelly, Spyridis, Nikos, Blackmore, Jennifer, Harrison, Rebekah, Kohlmaier, Benno, Kohlfürst, Daniela S., Zurl, Christoph, Binder, Alexander, Hösele, Susanne, Leitner, Manuel, Pölz, Lena, Rajic, Glorija, Bauchinger, Sebastian, Baumgart, Hinrich, Benesch, Martin, Ceolotto, Astrid, Eber, Ernst, Gallisti, Siegfried, Gores, Gunther, Haidl, Harald, Hauer, Almuthe, Hude, Christa, Keldorfer, Markus, Krenn, Larissa, Pilch, Heidemarie, Pfleger, Andreas, Pfurtscheller, Klaus, Nordberg, Gudrun, Niedrist, Tobias, Rödl, Siegfried, Skrabl-Baumgartner, Andrea, Sperl, Matthias, Stampfer, Laura, Strenger, Volker, Till, Holger, Trobisch, Andreas, Löffler, Sabine, Dewez, Juan Emmanuel, Hibberd, Martin, Bath, David, Miners, Alec, Fitchett, Elizabeth, Wedderburn, Catherine, Meierford, Anne, Leurent, Baptiste, De Jonge, Marien I., van Aerde, Koen, Alkema, Wynand, van den Broek, Bryan, Gloerich, Jolein, Van Gool, Alain J., Henriet, Stefanie, Huijnen, Martijn, Philipsen, Ria, Willems, Esther, Gerrits, G.P.J.M., Van Leur, M., Heidema, J., De Haan, L., Miedema, C.J., Neeleman, C., Obihara, C.C., Tramper-Stranders, G.A., Kandasamy, Rama, Carter, Michael J., O'Connor, Daniel, Bibi, Sagida, Kelly, Dominic F., Gurung, Meeru, Throson, Stephen, Ansari, Imran, Murdoch, David R., Shrestha, Shrijana, Oliver, Zoe, Lim, Emma, Valentine, Lucille, Allen, Karen, Bell, Kathryn, Chan, Adora, Crulley, Stephen, Devine, Kirsty, Fabian, Daniel, King, Sharon, McAlinden, Paul, McDonald, Sam, McDonell, Anne, Pickering, Alisa, Thomson, Evelyn, Wood, Amanda, Wallia, Diane, Woodsford, Phil, Baxter, Frances, Bell, Ashley, Rhodes, Mathew, Agbeko, Rachel, Mackerness, Christine, Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, Arif, Tasnim, Bennet, Joshua, Collings, Kalvin, Van der Giessen, Ilona, Martin, Alex, Rashid, Aqeela, Rowlands, Emily, Soon, Joshua, De Vries, Gabriella, van der Velden, Fabian, Martin, Mike, Mistry, Ravi, Zwerenz, Manuela, Buschbeck, Judith, Bidlingmaier, Christoph, Binder, Vera, Danhauser, Katharina, Haas, Nikolaus, Griese, Matthias, Kappler, Matthias, Lurz, Eberhard, Muench, Georg, Reiter, Karl, Schoen, Carola, Pachot, Alexandre, Mommert, Marine, Srovin, Tina Plankar, Bahovec, Natalija, Prunk, Petra, Osterman, Veronika, Avramoska, Tanja, Jongerius, Ilse, van den Berg, J.M., Schonenberg, D., Barendregt, A.M., Pajkrt, D., van der Kuip, M., van Furth, A.M., Sprenkeler, Evelien, Zandstra, Judith, van Mierlo, G., Geissler, J., Rivero-Calle, Irene, Sagmeister, Manfred G., Schweintzger, Nina A., Kuijpers, Taco W., van der Flier, Michiel, and von Both, Ulrich

Published
2023
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17. HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease

Author

Shimizu, Chisato, Kim, Jihoon, Eleftherohorinou, Hariklia, Wright, Victoria J, Hoang, Long T, Tremoulet, Adriana H, Franco, Alessandra, Hibberd, Martin L, Takahashi, Atsushi, Kubo, Michiaki, Ito, Kaoru, Tanaka, Toshihiro, Onouchi, Yoshihiro, Coin, Lachlan JM, Levin, Michael, Burns, Jane C, Shike, Hiroko, and Consortium, on behalf of International Kawasaki Disease Genetic

Subjects
Biomedical and Clinical Sciences, Immunology, Autoimmune Disease, Pediatric, Genetics, Prevention, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Alleles, Amino Acid Sequence, Amino Acid Substitution, Antigen Presentation, Binding Sites, Cohort Studies, Gene Frequency, Genetic Predisposition to Disease, Genotype, HLA-C Antigens, Histocompatibility Testing, Humans, Japan, Mucocutaneous Lymph Node Syndrome, Peptides, Polymorphism, Single Nucleotide, Protein Binding, Protein Domains, T-Lymphocytes, Cytotoxic, Kawasaki disease, HLA-C, Antigen presentation, Amino acid substitution, Cytotoxic T cells, International Kawasaki Disease Genetic Consortium
Abstract

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

Published
2019

23. Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.

Author

Wright, Victoria J, Herberg, Jethro A, Kaforou, Myrsini, Shimizu, Chisato, Eleftherohorinou, Hariklia, Shailes, Hannah, Barendregt, Anouk M, Menikou, Stephanie, Gormley, Stuart, Berk, Maurice, Hoang, Long Truong, Tremoulet, Adriana H, Kanegaye, John T, Coin, Lachlan JM, Glodé, Mary P, Hibberd, Martin, Kuijpers, Taco W, Hoggart, Clive J, Burns, Jane C, Levin, Michael, and Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG)

Subjects
Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group, Humans, Mucocutaneous Lymph Node Syndrome, RNA, Genetic Markers, Diagnosis, Differential, Severity of Illness Index, Retrospective Studies, Reproducibility of Results, Gene Expression Profiling, Transcription, Genetic, Child, Preschool, Infant, Female, Male, Clinical Research, Pediatric, Genetics, Infectious Diseases, Prevention, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Infection, Good Health and Well Being, Paediatrics and Reproductive Medicine, Pediatrics
Abstract

ImportanceTo date, there is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms.ObjectiveTo identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design, setting, and participantsThe case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness. The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States. The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls. The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls. The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017.Main outcomes and measuresWhole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search). The ability of transcript signatures (implemented as disease risk scores) to discriminate KD cases from controls was assessed by area under the curve (AUC), sensitivity, and specificity at the optimal cut point according to the Youden index.ResultsAmong 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male). Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male). A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set, with AUC of 96.2% (95% CI, 92.5%-99.9%), sensitivity of 81.7% (95% CI, 60.0%-94.8%), and specificity of 92.1% (95% CI, 84.0%-97.0%). In the validation set, the signature distinguished KD from febrile controls, with AUC of 94.6% (95% CI, 91.3%-98.0%), sensitivity of 85.9% (95% CI, 76.8%-92.6%), and specificity of 89.1% (95% CI, 83.0%-93.7%). The signature was applied to clinically defined categories of definite, highly probable, and possible KD, resulting in AUCs of 98.1% (95% CI, 94.5%-100%), 96.3% (95% CI, 93.3%-99.4%), and 70.0% (95% CI, 53.4%-86.6%), respectively, mirroring certainty of clinical diagnosis.Conclusions and relevanceIn this study, a 13-transcript blood gene expression signature distinguished KD from other febrile conditions. Diagnostic accuracy increased with certainty of clinical diagnosis. A test incorporating the 13-transcript disease risk score may enable earlier diagnosis and treatment of KD and reduce inappropriate treatment in those with other diagnoses.

Published
2018

28. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children from Other Pediatric Infectious and Inflammatory Diseases

Author

Infectieziekten patientenzorg, Child Health, Infection & Immunity, Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching Fen, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Vermont, Clementien, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, Hamilton, Shea, Infectieziekten patientenzorg, Child Health, Infection & Immunity, Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching Fen, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Vermont, Clementien, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, and Hamilton, Shea

Published
2024

29. Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

Author

Chai, Ming G, Tu, Quyen, Cotta, Menino O, Bauer, Michelle J, Balch, Ross, Okafor, Charles, Comans, Tracy, Kruger, Peter, Meyer, Jason, Shekar, Kiran, Brady, Kara, Fourie, Cheryl, Sharp, Natalie, Vlad, Luminita, Whiley, David, Ungerer, Jacobus P J, Mcwhinney, Brett C, Farkas, Andras, Paterson, David L, Clark, Julia E, Hajkowicz, Krispin, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Lipman, Jeffrey, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, Irwin, Adam D; https://orcid.org/0000-0001-8974-6789, Chai, Ming G, Tu, Quyen, Cotta, Menino O, Bauer, Michelle J, Balch, Ross, Okafor, Charles, Comans, Tracy, Kruger, Peter, Meyer, Jason, Shekar, Kiran, Brady, Kara, Fourie, Cheryl, Sharp, Natalie, Vlad, Luminita, Whiley, David, Ungerer, Jacobus P J, Mcwhinney, Brett C, Farkas, Andras, Paterson, David L, Clark, Julia E, Hajkowicz, Krispin, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Lipman, Jeffrey, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, and Irwin, Adam D; https://orcid.org/0000-0001-8974-6789

Abstract

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

Published
2024

30. Rapid nanopore sequencing and predictive susceptibility testing of positive blood cultures from intensive care patients with sepsis

Author

Papp-Wallace, Krisztina M, Papp-Wallace, K M ( Krisztina M ), Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Bauer, Michelle J, Lüftinger, Lukas, Beisken, Stephan, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Balch, Ross, Cotta, Menino; https://orcid.org/0000-0002-2058-2314, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Shekar, Kiran, Krüger, Peter; https://orcid.org/0000-0002-1247-9886, Lipman, Jeff, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, Paterson, David L, Irwin, Adam D, Papp-Wallace, Krisztina M, Papp-Wallace, K M ( Krisztina M ), Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Bauer, Michelle J, Lüftinger, Lukas, Beisken, Stephan, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Balch, Ross, Cotta, Menino; https://orcid.org/0000-0002-2058-2314, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Shekar, Kiran, Krüger, Peter; https://orcid.org/0000-0002-1247-9886, Lipman, Jeff, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, Paterson, David L, and Irwin, Adam D

Abstract

We aimed to evaluate the performance of Oxford Nanopore Technologies (ONT) sequencing from positive blood culture (BC) broths for bacterial identification and antimicrobial susceptibility prediction. Patients with suspected sepsis in four intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using ONT (MinION). Species abundance was estimated using Kraken2, and a cloud-based system (AREScloud) provided in silico predictive antimicrobial susceptibility testing (AST) from assembled contigs. Results were compared to conventional identification and phenotypic AST. Species-level agreement between conventional methods and AST predicted from sequencing was 94.2% (49/52), increasing to 100% in monomicrobial infections. In 262 high-quality AREScloud AST predictions across 24 samples, categorical agreement (CA) was 89.3%, with major error (ME) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g.,Staphylococcus aureus) but was suboptimal for Pseudomonas aeruginosa. In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME, and VME rates were 87.7%, 8.3%, and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species/antibiotic combinations with few representative resistant isolates. Time to reporting from sequencing could be achieved within 8–16 h from BC positivity. Direct sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species. ONT-based approaches may be faster but significant improvements in accuracy are required before it can be considered for clinical use. IMPORTANCE Sepsis and bloodstream infections carry a high risk of morbidity and mortality. Rapid identification and susceptibility prediction of causative pathogens, using Nanopore sequencing direct from blood cultures, may offer clinical benefit. We ass

Published
2024

31. Wastewater Microbiome Analysis for Population Alcohol Abuse.

Author

Wu, Jiangping, Chen, Yan, Zhao, Jiawei, Prosun, Tanjila Alam, O'Brien, Jake William, Coin, Lachlan, Hai, Faisal I., Sanderson-Smith, Martina, and Jiang, Guangming

Subjects
FISHER discriminant analysis, ALCOHOLISM, GUT microbiome, HUMAN microbiota, CELL communication
Abstract

This study aims to unveil correlations between wastewater microbiota and the catchment-specific population health risk, specifically alcohol abuse, with smoking and obesity as confounding factors. Our study highlights the importance of extracting human-associated microbial communities from wastewater metagenomes by excluding environmental microorganisms, due to their irrelevance to human health. After excluding environmental microbes, we observed strong associations of all three health risk factors, including alcohol abuse, smoking and obesity, with the human gut microbiome in wastewater. The linear discriminant analysis effect size (LEfSe) analysis showed Lactococcus_A, Leuconostoc, Aeromicrobium, Akkermansia, Weissella, Limosilactobacillus, Klebsiella_A, Desulfovibrio and Cloacibacillus as potential microbial biomarkers for alcoholism, after accounting for the confounding effects of smoking and obesity. Functional annotations of microorganisms linked with lower alcoholism rates are primarily related to energy metabolism and intercellular communication. Microorganisms associated with higher alcoholism rates are predominantly involved in immune regulation and cellular DNA architecture. This study highlights the need for a comprehensive exploration of different health risk factors together to identify potential associations between the wastewater microbiome and population lifestyle. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Rapid nanopore sequencing and predictive susceptibility testing of positive blood cultures from intensive care patients with sepsis

Author

Harris, Patrick N. A., primary, Bauer, Michelle J., additional, Lüftinger, Lukas, additional, Beisken, Stephan, additional, Forde, Brian M., additional, Balch, Ross, additional, Cotta, Menino, additional, Schlapbach, Luregn, additional, Raman, Sainath, additional, Shekar, Kiran, additional, Kruger, Peter, additional, Lipman, Jeff, additional, Bialasiewicz, Seweryn, additional, Coin, Lachlan, additional, Roberts, Jason A., additional, Paterson, David L., additional, and Irwin, Adam D., additional

Published
2024
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34. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children

Author

Herberg, Jethro A, Kaforou, Myrsini, Wright, Victoria J, Shailes, Hannah, Eleftherohorinou, Hariklia, Hoggart, Clive J, Cebey-López, Miriam, Carter, Michael J, Janes, Victoria A, Gormley, Stuart, Shimizu, Chisato, Tremoulet, Adriana H, Barendregt, Anouk M, Salas, Antonio, Kanegaye, John, Pollard, Andrew J, Faust, Saul N, Patel, Sanjay, Kuijpers, Taco, Martinón-Torres, Federico, Burns, Jane C, Coin, Lachlan JM, and Levin, Michael

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Infectious Diseases, Vaccine Related, Genetics, Clinical Research, Emerging Infectious Diseases, Detection, screening and diagnosis, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, 2.2 Factors relating to the physical environment, 4.2 Evaluation of markers and technologies, Infection, Good Health and Well Being, Anti-Bacterial Agents, Antigens, Area Under Curve, Bacterial Infections, Biomarkers, Child, Preschool, Coinfection, Cytoskeletal Proteins, Diagnosis, Differential, Female, Fever, Gene Expression Profiling, Genetic Markers, Humans, Infant, Logistic Models, Male, Prospective Studies, RNA, Risk, Sensitivity and Specificity, Severity of Illness Index, Virus Diseases, IRIS Consortium, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceBecause clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others.ObjectiveTo identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.Design, setting, and participantsFebrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.ExposuresA 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.Main outcomes and measuresDefinite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group.ResultsThe discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 100%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment.Conclusions and relevanceThis study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.

Published
2016

36. Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

Author

Chai, Gene M, primary, Tu, Quyen, additional, Cotta, Menino O, additional, Bauer, Michelle J, additional, Balch, Ross, additional, Okafor, Charles, additional, Comans, Tracy, additional, Kruger, Peter, additional, Meyer, Jason, additional, Shekar, Kiran, additional, Brady, Kara, additional, Fourie, Cheryl, additional, Sharp, Natalie, additional, Vlad, Luminita, additional, Whiley, David, additional, Ungerer, Jacobus PJ, additional, Mcwhinney, Brett C, additional, Farkas, Andras, additional, Paterson, David L, additional, Clark, Julia E, additional, Hajkowicz, Krispin, additional, Raman, Sainath, additional, Bialasiewicz, Seweryn, additional, Lipman, Jeffrey, additional, Forde, Brian M, additional, Harris, Patrick NA, additional, Schlapbach, Luregn J, additional, Coin, Lachlan, additional, Roberts, Jason A, additional, and Irwin, Adam D, additional

Published
2023
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37. Influenza infected macrophages release viral ribonucleoproteins that shape the local host response

Author

Fritzlar, Svenja, primary, Lakdawala, Seema, additional, Roberts, Jason A, additional, Coin, Lachlan J M, additional, Deng, Yi-Mo, additional, Moselen, Jean, additional, Le Sage, Valerie, additional, Mackenzie, Jason, additional, Labzin, Larisa, additional, Brooks, Andrew G, additional, Reading, Patrick, additional, and Londrigan, Sarah, additional

Published
2023
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38. Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study

Author

Schlapbach, Luregn J, Ganesamoorthy, Devika, Wilson, Clare, Raman, Sainath, George, Shane, Snelling, Peter J, Phillips, Natalie, Irwin, Adam, Sharp, Natalie, Le Marsney, Renate, Chavan, Arjun, Hempenstall, Allison, Bialasiewicz, Seweryn, MacDonald, Anna D, Grimwood, Keith, Kling, Jessica C, McPherson, Stephen J, Blumenthal, Antje, Kaforou, Myrsini, Levin, Michael, Herberg, Jethro A, Gibbons, Kristen S, Coin, Lachlan J M, Levin, Michael, Coin, Lachlan, Gormley, Stuart, Hamilton, Shea, Hoggart, Clive, Kaforou, Myrsini, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stephanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Shailes, Hannah, Thakker, Clare, Bokhandi, S., Power, Sue, Barham, Heather, Pathan, N., Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S., Patel, S., McCorkell, Jenni, Davies, P., Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R., Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Pollard, Andrew, Willis, Louise, Young, Zoe, Royad, C., White, Sonia, Fortune, Peter-Marc, Hudnott, Phil, Martinón-Torres, Federico, Salas, Antonio, Álvez González, Fernando, Barral-Arca, Ruth, Cebey-López, Miriam, Curras-Tuala, María José, García, Natalia, García Vicente, Luisa, Gómez-Carballa, Alberto, Gómez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leboráns Iglesias, Pilar, Martínez Santos, Alba Elena, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Morillo Gutiérrez, Beatriz, Mosquera Pérez, Belén, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, Rivero-Calle, Irene, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriaga, Antonio, Fernández, Sonia Serén, del Sol Porto Silva, María, Vega, Ana, Vilanova Trillo, Lucía, Reyes, Susana Beatriz, Cruz León León, María, Navarro Mingorance, Álvaro, Gabaldó Barrio, Xavier, Oñate Vergara, Eider, Concha Torre, Andrés, Vivanco, Ana, Fernández, Reyes, Giménez Sánchez, Francisco, Sánchez Forte, Miguel, Rojo, Pablo, Contreras, J. Ruiz, Palacios, Alba, Epalza Ibarrondo, Cristina, Fernández Cooke, Elizabeth, Navarro, Marisa, Álvarez Álvarez, Cristina, José Lozano, María, Carreras, Eduardo, Brió Sanagustín, Sonia, Neth, Olaf, Martínez Padilla, Mª del Carmen, Prieto Tato, Luis Manuel, Guillén, Sara, Fernández Silveira, Laura, Moreno, David, de Groot, R., Tutu van Furth, A.M., van der Flier, M., Boeddha, N.P., Driessen, G.J.A., Emonts, M., Hazelzet, J.A., Kuijpers, T.W., Pajkrt, D., Sanders, E.A.M., van de Beek, D., van der Ende, A., Philipsen, H.L.A., Adeel, A.O.A., Breukels, M.A., Brinkman, D.M.C., de Korte, C.C.M.M., de Vries, E., de Waal, W.J., Dekkers, R., Dings-Lammertink, A., Doedens, R.A., Donker, A.E., Dousma, M., Faber, T.E., Gerrits, G.P.J.M., Gerver, J.A.M., Heidema, J., Homan-van der Veen, J., Jacobs, M.A.M., Jansen, N.J.G., Kawczynski, P., Klucovska, K., Kneyber, M.C.J., Koopman-Keemink, Y., Langenhorst, V.J., Leusink, J., Loza, B.F., Merth, I.T., Miedema, C.J., Neeleman, C., Noordzij, J.G., Obihara, C.C., van Overbeek- van Gils, A.L.T., Poortman, G.H., Potgieter, S.T., Potjewijd, J., Rosias, P.P.R., Sprong, T., ten Tussher, G.W., Thio, B.J., Tramper-Stranders, G.A., van Deuren, M., van der Meer, H., van Kuppevelt, A.J.M., van Wermeskerken, A.M., Verwijs, W.A., Wolfs, T.F.W., Schlapbach, Luregn J., Agyeman, Philipp, Aebi, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Berger, Christoph, Carrol, Enitan D., Paulus, Stéphane, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Fink, Colin G, Pinnock, Elli, Emonts, Marieke, Agbeko, Rachel, Anderson, Suzanne, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Saidykhan, Momodou, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Zenz, Werner, Kohlfürst, Daniela S., Binder, Alexander, Schweintzger, Nina A., Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Jürgen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Köster, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Rödl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wüller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, Žukovskaja, Veslava, Hibberd, Martin L., Davila, Sonia, Delany, Isabel, Schlapbach, Luregn J, Raman, Sainath, Sharp, Nathalie, Phillips, Natalie, Irwin, Adam, Balch, Ross, Harley, Amanda, Johnson, Kerry, Sever, Zoe, George, Shane, Grimwood, Keith, Snelling, Peter J, Chavan, Arjun, Kitcatt, Eleanor, Lawton, Luke, Hempenstall, Allison, Pilot, Pelista, Gibbons, Kristen S, Le Marsney, Renate, Blumenthal, Antje, Ganesamoorthy, Devika, Pardo, Carolyn, Kling, Jessica, McPherson, Stephen, MacDonald, Anna D, Bialasiewicz, Seweryn, Pham, Trang, and Coin, Lachlan

Abstract

Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection.

Published
2024
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40. Quantitative trait loci and differential gene expression analyses reveal the genetic basis for negatively associated β-carotene and starch content in hexaploid sweetpotato [Ipomoea batatas (L.) Lam.]

Author

Gemenet, Dorcus C., da Silva Pereira, Guilherme, De Boeck, Bert, Wood, Joshua C., Mollinari, Marcelo, Olukolu, Bode A., Diaz, Federico, Mosquera, Veronica, Ssali, Reuben T., David, Maria, Kitavi, Mercy N., Burgos, Gabriela, Felde, Thomas Zum, Ghislain, Marc, Carey, Edward, Swanckaert, Jolien, Coin, Lachlan J. M., Fei, Zhangjun, Hamilton, John P., Yada, Benard, Yencho, G. Craig, Zeng, Zhao-Bang, Mwanga, Robert O. M., Khan, Awais, Gruneberg, Wolfgang J., and Buell, C. Robin

Published
2020
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41. YHap: software for probabilistic assignment of Y haplogroups from population re-sequencing data

Author

Zhang, Fan, Chen, Ruoyan, Liu, Dongbing, Yao, Xiaotian, Li, Guoqing, Jin, Yabin, Yu, Chang, Li, Yingrui, and Coin, Lachlan

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Genomics
Abstract

Y haplogroup analyses are an important component of genealogical reconstruction, population genetic analyses, medical genetics and forensics. These fields are increasingly moving towards use of low-coverage, high throughput sequencing. However, there is as yet no software available for using sequence data to assign Y haplogroup groups probabilistically, such that the posterior probability of assignment fully reflects the information present in the data, and borrows information across all samples sequenced from a population. YHap addresses this problem., Comment: 2 pages 3 tables

Published
2013

43. Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations

Author

Ganesh, Santhi K, Chasman, Daniel I, Larson, Martin G, Guo, Xiuqing, Verwoert, Germain, Bis, Joshua C, Gu, Xiangjun, Smith, Albert V, Yang, Min-Lee, Zhang, Yan, Ehret, Georg, Rose, Lynda M, Hwang, Shih-Jen, Papanicolau, George J, Sijbrands, Eric J, Rice, Kenneth, Eiriksdottir, Gudny, Pihur, Vasyl, Ridker, Paul M, Vasan, Ramachandran S, Newton-Cheh, Christopher, Consortium, Global Blood Pressure Genetics, Johnson, Toby, Gateva, Vesela, Tobin, Martin D, Bochud, Murielle, Coin, Lachlan, Najjar, Samer S, Zhao, Jing Hua, Heath, Simon C, Eyheramendy, Susana, Papadakis, Konstantinos, Voight, Benjamin F, Scott, Laura J, Zhang, Feng, Farrall, Martin, Tanaka, Toshiko, Wallace, Chris, Chambers, John C, Khaw, Kay-Tee, Nilsson, Peter, van der Harst, Pim, Polidoro, Silvia, Grobbee, Diederick E, Onland-Moret, N Charlotte, Bots, Michiel L, Wain, Louise V, Elliott, Katherine S, Teumer, Alexander, Luan, Jian’an, Lucas, Gavin, Kuusisto, Johanna, Burton, Paul R, Hadley, David, McArdle, Wendy L, Brown, Morris, Dominiczak, Anna, Newhouse, Stephen J, Samani, Nilesh J, Webster, John, Zeggini, Eleftheria, Beckmann, Jacques S, Bergmann, Sven, Lim, Noha, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Waterworth, Dawn M, Yuan, Xin, Groop, Leif, Orho-Melander, Marju, Allione, Alessandra, Di Gregorio, Alessandra, Guarrera, Simonetta, Panico, Salvatore, Ricceri, Fulvio, Romanazzi, Valeria, Sacerdote, Carlotta, Vineis, Paolo, Barroso, Inês, Sandhu, Manjinder S, Luben, Robert N, Crawford, Gabriel J, Jousilahti, Pekka, Perola, Markus, Boehnke, Michael, Bonnycastle, Lori L, Collins, Francis S, Jackson, Anne U, Mohlke, Karen L, Stringham, Heather M, Valle, Timo T, Willer, Cristen J, Bergman, Richard N, Morken, Mario A, Döring, Angela, Gieger, Christian, Illig, Thomas, and Meitinger, Thomas

Subjects
Genetics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Blood Pressure, Genome-Wide Association Study, Humans, Longitudinal Studies, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Global Blood Pressure Genetics Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

Published
2014

46. Cross-Border Movement of Highly Drug-Resistant Mycobacterium tuberculosis from Papua New Guinea to Australia through Torres Strait Protected Zone, 2010-2015

Author

Bainomugisa, Arnold, Pandey, Sushil, Donnan, Ellen, Simpson, Graham, Foster, J'Belle, Lavu, Evelyn, Hiasihri, Stenard, McBryde, Emma S., Moke, Rendi, Vincent, Steven, Sintchenko, Vitali, Marais, Ben J., Coin, Lachlan J.M., and Coulter, Christopher

Subjects
Genomes, Tuberculosis -- Drug therapy, Antitubercular agents, DNA sequencing, Genomics, Microbial drug resistance -- Drug therapy, Drug resistance, Ethionamide, Health, World Health Organization
Abstract

Tuberculosis (TB) is the leading infectious cause of death globally (1). To reduce the burden of TB, many countries committed to achieving a 90% reduction in TB incidence by 2035 [...]

Published
2019
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48. Haplotype and isoform specific expression estimation using multi-mapping RNA-seq reads

Author

Turro, Ernest, Su, Shu-Yi, Gonçalves, Ângela, Coin, Lachlan JM, Richardson, Sylvia, and Lewin, Alex

Abstract

Abstract We present a novel pipeline and methodology for simultaneously estimating isoform expression and allelic imbalance in diploid organisms using RNA-seq data. We achieve this by modeling the expression of haplotype-specific isoforms. If unknown, the two parental isoform sequences can be individually reconstructed. A new statistical method, MMSEQ, deconvolves the mapping of reads to multiple transcripts (isoforms or haplotype-specific isoforms). Our software can take into account non-uniform read generation and works with paired-end reads.

Published
2011

49. Hundreds of variants clustered in genomic loci and biological pathways affect human height

Author

Lango Allen, Hana, Estrada, Karol, Lettre, Guillaume, Berndt, Sonja I, Weedon, Michael N, Rivadeneira, Fernando, Willer, Cristen J, Jackson, Anne U, Vedantam, Sailaja, Raychaudhuri, Soumya, Ferreira, Teresa, Wood, Andrew R, Weyant, Robert J, Segrè, Ayellet V, Speliotes, Elizabeth K, Wheeler, Eleanor, Soranzo, Nicole, Park, Ju-Hyun, Yang, Jian, Gudbjartsson, Daniel, Heard-Costa, Nancy L, Randall, Joshua C, Qi, Lu, Vernon Smith, Albert, Mägi, Reedik, Pastinen, Tomi, Liang, Liming, Heid, Iris M, Luan, Jian’an, Thorleifsson, Gudmar, Winkler, Thomas W, Goddard, Michael E, Sin Lo, Ken, Palmer, Cameron, Workalemahu, Tsegaselassie, Aulchenko, Yurii S, Johansson, Åsa, Carola Zillikens, M, Feitosa, Mary F, Esko, Tõnu, Johnson, Toby, Ketkar, Shamika, Kraft, Peter, Mangino, Massimo, Prokopenko, Inga, Absher, Devin, Albrecht, Eva, Ernst, Florian, Glazer, Nicole L, Hayward, Caroline, Hottenga, Jouke-Jan, Jacobs, Kevin B, Knowles, Joshua W, Kutalik, Zoltán, Monda, Keri L, Polasek, Ozren, Preuss, Michael, Rayner, Nigel W, Robertson, Neil R, Steinthorsdottir, Valgerdur, Tyrer, Jonathan P, Voight, Benjamin F, Wiklund, Fredrik, Xu, Jianfeng, Hua Zhao, Jing, Nyholt, Dale R, Pellikka, Niina, Perola, Markus, Perry, John RB, Surakka, Ida, Tammesoo, Mari-Liis, Altmaier, Elizabeth L, Amin, Najaf, Aspelund, Thor, Bhangale, Tushar, Boucher, Gabrielle, Chasman, Daniel I, Chen, Constance, Coin, Lachlan, Cooper, Matthew N, Dixon, Anna L, Gibson, Quince, Grundberg, Elin, Hao, Ke, Juhani Junttila, M, Kaplan, Lee M, Kettunen, Johannes, König, Inke R, Kwan, Tony, Lawrence, Robert W, Levinson, Douglas F, Lorentzon, Mattias, McKnight, Barbara, Morris, Andrew P, Müller, Martina, Suh Ngwa, Julius, Purcell, Shaun, Rafelt, Suzanne, Salem, Rany M, and Salvi, Erika

Subjects
Biological Sciences, Genetics, Health Sciences, Mathematical Sciences, Statistics, Human Genome, Clinical Research, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P

Published
2010

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