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2. Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Author

Anstee, Quentin M, Daly, Ann K, Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J, Day, Christopher P, Wonders, Kristy, Missier, Paolo, McTeer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M, Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G, Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M, Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K, Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioannis, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J, Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, McGlinchey, Aiden, Mato, Jose M, Millet, Óscar, Dufour, Jean-François, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Rasmussen, Daniel Guldager Kring, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattias, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M P, Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andreas, Trautwein, Christian, Reißing, Johanna, Aithal, Guruprasad P, Francis, Susan, Palaniyappan, Naaventhan, Bradley, Christopher, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W, Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, McLeod, Euan James, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Coxson, Harvey, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Kjær, Mette Skalshøi, Harder, Lea Mørch, Davidsen, Peter, Ellegaard, Jens, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Douglas, Shankar, Sudha, Torstenson, Richard, Lindén, Daniel, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D, Billin, Andrew, Doward, Lynda, Twiss, James, Thakker, Paresh, Derdak, Zoltan, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, Mózes, Ferenc E, Lee, Jenny A, Alzoubi, Osama, Staufer, Katharina, Trauner, Michael, Paternostro, Rafael, Stauber, Rudolf E, van Dijk, Anne-Marieke, Mak, Anne Linde, de Saint Loup, Marc, Shima, Toshihide, Gaia, Silvia, Shalimar, Lupșor-Platon, Monica, Wong, Vincent Wai-Sun, Li, Guanlin, Wong, Grace Lai-Hung, Karlas, Thomas, Wiegand, Johannes, Sebastiani, Giada, Tsochatzis, Emmanuel, Liguori, Antonio, Yoneda, Masato, Nakajima, Atsushi, Hagström, Hannes, Akbari, Camilla, Hirooka, Masashi, Chan, Wah-Kheong, Mahadeva, Sanjiv, Rajaram, Ruveena, Zheng, Ming-Hua, George, Jacob, Eslam, Mohammed, Viganò, Mauro, Ridolfo, Sofia, Aithal, Guruprasad Padur, Lee, Dae Ho, Nasr, Patrik, Cassinotto, Christophe, de Lédinghen, Victor, Mendoza, Yuly P, Noureddin, Mazen, Truong, Emily, and Harrison, Stephen A

Published
2023
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6. PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

Author

Madsen, Maria Stahl, Broekema, Marjoleine F., Madsen, Martin Rønn, Koppen, Arjen, Borgman, Anouska, Gräwe, Cathrin, Thomsen, Elisabeth G. K., Westland, Denise, Kranendonk, Mariette E. G., Koerkamp, Marian Groot, Hamers, Nicole, Bonvin, Alexandre M. J. J., Pittol, José M. Ramos, Natarajan, Kedar Nath, Kersten, Sander, Holstege, Frank C. P., Monajemi, Houshang, van Mil, Saskia W. C., Vermeulen, Michiel, Kragelund, Birthe B., Cassiman, David, Mandrup, Susanne, and Kalkhoven, Eric

Published
2022
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7. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, Yunis, Carla, Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Johnson, Katherine, Leary, Peter J., Govaere, Olivier, Barter, Matthew J., Charlton, Sarah H., Cockell, Simon J., Tiniakos, Dina, Zatorska, Michalina, Bedossa, Pierre, Brosnan, M. Julia, Cobbold, Jeremy F., Ekstedt, Mattias, Aithal, Guruprasad P., Clément, Karine, Schattenberg, Jörn M., Boursier, Jerome, Ratziu, Vlad, Bugianesi, Elisabetta, Anstee, Quentin M., and Daly, Ann K.

Published
2022
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11. Dietary cystine restriction increases the proliferative capacity of the small intestine of mice

Author

CMM, CMM Groep Van Mil, Cancer, CMM Groep Burgering, MMB Research line 2, Infection & Immunity, CMM Groep Vercoulen, Child Health, de Jong, Judith C.W., van Rooijen, Kristel S., Stigter, Edwin C.A., Gülersönmez, M. Can, de Zoete, Marcel R., Top, Janetta, Baars, Matthijs J.D., Vercoulen, Yvonne, Kuipers, Folkert, Van Mil, Saskia W.C., Ijssennagger, Noortje, CMM, CMM Groep Van Mil, Cancer, CMM Groep Burgering, MMB Research line 2, Infection & Immunity, CMM Groep Vercoulen, Child Health, de Jong, Judith C.W., van Rooijen, Kristel S., Stigter, Edwin C.A., Gülersönmez, M. Can, de Zoete, Marcel R., Top, Janetta, Baars, Matthijs J.D., Vercoulen, Yvonne, Kuipers, Folkert, Van Mil, Saskia W.C., and Ijssennagger, Noortje

Published
2024

13. Dietary cystine restriction increases the proliferative capacity of the small intestine of mice

Author

de Jong, Judith C. W., primary, van Rooijen, Kristel S., additional, Stigter, Edwin C. A., additional, Gülersönmez, M. Can, additional, de Zoete, Marcel R., additional, Top, Janetta, additional, Baars, Matthijs J. D., additional, Vercoulen, Yvonne, additional, Kuipers, Folkert, additional, van Mil, Saskia W. C., additional, and Ijssennagger, Noortje, additional

Published
2024
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14. Dietary cystine restriction increases the proliferative capacity of the small intestine of mice

Author

de Jong, Judith C.W., primary, van Rooijen, Kristel S., additional, Stigter, Edwin C.A., additional, Can Gülersönmez, M., additional, de Zoete, Marcel R., additional, Top, Janetta, additional, Baars, Matthijs J.D., additional, Vercoulen, Yvonne, additional, Kuipers, Folkert, additional, van Mil, Saskia W.C., additional, and Ijssennagger, Noortje, additional

Published
2023
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15. Data from Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer

Author

Stoepker, Chantal, primary, Ameziane, Najim, primary, van der Lelij, Petra, primary, Kooi, Irsan E., primary, Oostra, Anneke B., primary, Rooimans, Martin A., primary, van Mil, Saskia E., primary, Brink, Arjen, primary, Dietrich, Ralf, primary, Balk, Jesper A., primary, Ylstra, Bauke, primary, Joenje, Hans, primary, Feller, Stephan M., primary, and Brakenhoff, Ruud H., primary

Published
2023
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16. Supplemetal Material and Methods, Figure 1-7 and Table 1 from Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer

Author

Stoepker, Chantal, primary, Ameziane, Najim, primary, van der Lelij, Petra, primary, Kooi, Irsan E., primary, Oostra, Anneke B., primary, Rooimans, Martin A., primary, van Mil, Saskia E., primary, Brink, Arjen, primary, Dietrich, Ralf, primary, Balk, Jesper A., primary, Ylstra, Bauke, primary, Joenje, Hans, primary, Feller, Stephan M., primary, and Brakenhoff, Ruud H., primary

Published
2023
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18. Issue Cover

Author

de Wit, Koos, primary, Beuers, Ulrich, additional, Mukha, Anna, additional, Stigter, Edwin C. A., additional, Gulersonmez, M. Can, additional, Ramos Pittol, Jose M., additional, Middendorp, Sabine, additional, Takkenberg, R. Bart, additional, and van Mil, Saskia W. C., additional

Published
2023
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19. Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study

Author

Jenny, Lee, Max, Westphal, Yasaman, Vali, Jerome, Boursier, Salvatorre, Petta, Rachel, Ostroff, Leigh, Alexander, Yu, Chen, Celine, Fournier, Andreas, Geier, Sven, Francque, Kristy, Wonder, Dina, Tiniako, Pierre, Bedossa, Mike, Allison, Georgios, Papatheodoridi, Helena, Cortez-Pinto, Raluca, Pai, Jean-Francois, Dufour, Diana Julie, Leeming, Stephen, Harrison, Jeremy, Cobbold, Adriaan G, Holleboom, Hannele, Yki-Järvinen, Javier, Crespo, Mattias, Ekstedt, Guruprasad P, Aithal, Elisabetta, Bugianesi, Manuel, Romero-Gomez, Richard, Torstenson, Morten, Karsdal, Carla, Yuni, Jörn M, Schattenberg, Detlef, Schuppan, Vlad, Ratziu, Clifford, Bra, Kevin, Duffin, Koos, Zwinderman, Michael, Pavlide, Quentin M, Anstee, Patrick M, Bossuyt, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J., Day, Christopher P., Wonders, Kristy, Missier, Paolo, Mcteer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G., Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M., Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K., Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioanni, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J., Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, Mcglinchey, Aiden, Mato, Jose M., Millet, Óscar, Dufour, Jean-Françoi, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Guldager Kring Rasmussen, Daniel, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattia, Kechagias, Stergio, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M. P., Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andrea, Trautwein, Christian, Aithal, Guruprasad P., Francis, Susan, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W., Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, Mcleod, Euan Jame, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Skalshøi Kjær, Mette, Mørch Harder, Lea, Davidsen, Peter, Mikkelsen, Lars Frii, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Dougla, Shankar, Sudha, Torstenson, Richard, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D., Billin, Andrew, Doward, Lynda, Twiss, Jame, Thakker, Paresh, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, Luca, Miele (ORCID:0000-0003-3464-0068), Jenny, Lee, Max, Westphal, Yasaman, Vali, Jerome, Boursier, Salvatorre, Petta, Rachel, Ostroff, Leigh, Alexander, Yu, Chen, Celine, Fournier, Andreas, Geier, Sven, Francque, Kristy, Wonder, Dina, Tiniako, Pierre, Bedossa, Mike, Allison, Georgios, Papatheodoridi, Helena, Cortez-Pinto, Raluca, Pai, Jean-Francois, Dufour, Diana Julie, Leeming, Stephen, Harrison, Jeremy, Cobbold, Adriaan G, Holleboom, Hannele, Yki-Järvinen, Javier, Crespo, Mattias, Ekstedt, Guruprasad P, Aithal, Elisabetta, Bugianesi, Manuel, Romero-Gomez, Richard, Torstenson, Morten, Karsdal, Carla, Yuni, Jörn M, Schattenberg, Detlef, Schuppan, Vlad, Ratziu, Clifford, Bra, Kevin, Duffin, Koos, Zwinderman, Michael, Pavlide, Quentin M, Anstee, Patrick M, Bossuyt, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J., Day, Christopher P., Wonders, Kristy, Missier, Paolo, Mcteer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G., Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M., Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K., Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioanni, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J., Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, Mcglinchey, Aiden, Mato, Jose M., Millet, Óscar, Dufour, Jean-Françoi, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Guldager Kring Rasmussen, Daniel, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattia, Kechagias, Stergio, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M. P., Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andrea, Trautwein, Christian, Aithal, Guruprasad P., Francis, Susan, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W., Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, Mcleod, Euan Jame, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Skalshøi Kjær, Mette, Mørch Harder, Lea, Davidsen, Peter, Mikkelsen, Lars Frii, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Dougla, Shankar, Sudha, Torstenson, Richard, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D., Billin, Andrew, Doward, Lynda, Twiss, Jame, Thakker, Paresh, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, and Luca, Miele (ORCID:0000-0003-3464-0068)

Abstract

Background and aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. Approach and results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.

Published
2023

20. Multi-country metabolic signature discovery for chicken health classification

Author

CMM, CMM Groep Van Mil, Cancer, CMM Groep Burgering, Genetica Sectie Metabole Diagnostiek, Brain, Child Health, CMM Groep De Ridder, Wolthuis, Joanna C., Magnúsdóttir, Stefanía, Stigter, Edwin, Tang, Yuen Fung, Jans, Judith, Gilbert, Myrthe, van der Hee, Bart, Langhout, Pim, Gerrits, Walter, Kies, Arie, de Ridder, Jeroen, van Mil, Saskia, CMM, CMM Groep Van Mil, Cancer, CMM Groep Burgering, Genetica Sectie Metabole Diagnostiek, Brain, Child Health, CMM Groep De Ridder, Wolthuis, Joanna C., Magnúsdóttir, Stefanía, Stigter, Edwin, Tang, Yuen Fung, Jans, Judith, Gilbert, Myrthe, van der Hee, Bart, Langhout, Pim, Gerrits, Walter, Kies, Arie, de Ridder, Jeroen, and van Mil, Saskia

Published
2023

21. Rifaximin stimulates nitrogen detoxification by PXR-independent mechanisms in human small intestinal organoids

Author

CMM Groep Van Mil, Cancer, CMM Groep Burgering, Child Health, Regenerative Medicine and Stem Cells, CMM, de Wit, Koos, Beuers, Ulrich, Mukha, Anna, Stigter, Edwin, Gulersonmez, M Can, Ramos Pittol, Jose M, Middendorp, Sabine, Takkenberg, R Bart, van Mil, Saskia W C, CMM Groep Van Mil, Cancer, CMM Groep Burgering, Child Health, Regenerative Medicine and Stem Cells, CMM, de Wit, Koos, Beuers, Ulrich, Mukha, Anna, Stigter, Edwin, Gulersonmez, M Can, Ramos Pittol, Jose M, Middendorp, Sabine, Takkenberg, R Bart, and van Mil, Saskia W C

Published
2023

23. Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Author

Mózes, Ferenc E, Lee, Jenny A, Vali, Yasaman, Alzoubi, Osama, Staufer, Katharina, Trauner, Michael, Paternostro, Rafael, Stauber, Rudolf E, Holleboom, Adriaan G, van Dijk, Anne-Marieke, Mak, Anne Linde, Boursier, Jérôme, de Saint Loup, Marc, Shima, Toshihide, Bugianesi, Elisabetta, Gaia, Silvia, Armandi, Angelo, Shalimar, Lupșor-Platon, Monica, Wong, Vincent Wai-Sun, Li, Guanlin, Wong, Grace Lai-Hung, Cobbold, Jeremy, Karlas, Thomas, Wiegand, Johannes, Sebastiani, Giada, Tsochatzis, Emmanuel, Liguori, Antonio, Yoneda, Masato, Nakajima, Atsushi, Hagström, Hannes, Akbari, Camilla, Hirooka, Masashi, Chan, Wah-Kheong, Mahadeva, Sanjiv, Rajaram, Ruveena, Zheng, Ming-Hua, George, Jacob, Eslam, Mohammed, Petta, Salvatore, Pennisi, Grazia, Viganò, Mauro, Ridolfo, Sofia, Aithal, Guruprasad Padur, Palaniyappan, Naaventhan, Lee, Dae Ho, Ekstedt, Mattias, Nasr, Patrik, Cassinotto, Christophe, de Lédinghen, Victor, Berzigotti, Annalisa, Mendoza, Yuly P, Noureddin, Mazen, Truong, Emily, Fournier-Poizat, Céline, Geier, Andreas, Martic, Miljen, Tuthill, Theresa, Anstee, Quentin M, Harrison, Stephen A, Bossuyt, Patrick M, Pavlides, Michael, Anstee, Quentin M, Daly, Ann K, Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J, Day, Christopher P, Wonders, Kristy, Missier, Paolo, McTeer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M, Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G, Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M, Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K, Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioannis, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J, Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, McGlinchey, Aiden, Mato, Jose M, Millet, Óscar, Dufour, Jean-François, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Rasmussen, Daniel Guldager Kring, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattias, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M P, Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andreas, Trautwein, Christian, Reißing, Johanna, Aithal, Guruprasad P, Francis, Susan, Palaniyappan, Naaventhan, Bradley, Christopher, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W, Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, McLeod, Euan James, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Coxson, Harvey, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Kjær, Mette Skalshøi, Harder, Lea Mørch, Davidsen, Peter, Ellegaard, Jens, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Douglas, Shankar, Sudha, Torstenson, Richard, Lindén, Daniel, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D, Billin, Andrew, Doward, Lynda, Twiss, James, Thakker, Paresh, Derdak, Zoltan, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, and Hytiroglou, Prodromos

Abstract

Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.

Published
2023
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24. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Johnson, Katherine, Leary, Peter J., Govaere, Olivier, Barter, Matthew J., Charlton, Sarah H., Cockell, Simon J., Tiniakos, Dina, Zatorska, Michalina, Bedossa, Pierre, Brosnan, M. Julia, Cobbold, Jeremy F., Ekstedt, Mattias, Aithal, Guruprasad P., Boursier, Jerome, Ratziu, Vlad, Bugianesi, Elisabetta, Anstee, Quentin M., Daly, Ann K., Clark, James, Cockell, Simon, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, McGlinchey, Aidan, Sen, Partho, Mato, Jose, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, Yunis, Carla, Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, and Twiss, James

Subjects
Hepatology, Gastroenterology, Internal Medicine, Immunology and Allergy, digestive system diseases
Abstract

Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.

Published
2022

25. Rifaximin stimulates nitrogen detoxification by PXR‐independent mechanisms in human small intestinal organoids.

Author

de Wit, Koos, Beuers, Ulrich, Mukha, Anna, Stigter, Edwin C. A., Gulersonmez, M. Can, Ramos Pittol, Jose M., Middendorp, Sabine, Takkenberg, R. Bart, and van Mil, Saskia W. C.

Subjects
RIFAXIMIN, PREGNANE X receptor, AMINO acid metabolism, HEPATIC encephalopathy, ORGANOIDS
Abstract

Background and Aims: Recurrent hepatic encephalopathy (HE) is characterized by hyperammonaemia in combination with neuropsychiatric abnormalities and is treated with lactulose and rifaximin. Rifaximin is a pregnane X receptor (PXR) agonist with low systemic and high intestinal bioavailability. The mechanisms by which it alleviates HE are unclear. We used human small intestinal (hSI) organoids to study whether rifaximin, via PXR activation, affects the epithelial biotransformation machinery, and to gain understanding of its low systemic availability. Methods: We generated PXR knockdown hSI organoids via lentiviral delivery of short hairpin RNAs. Organoids were cultured for 24 h with rifaximin or rifampicin. RNA‐sequencing and metabolomics were performed to analyse gene expression and amino acid metabolism. Luminal rifaximin was quantified by photospectrometry. Results: Treatment of wild‐type hSI organoids with rifaximin resulted in >twofold differential expression of 131 genes compared to DMSO. These effects were largely PXR independent and related to amino acid metabolism. Rifaximin decreased expression of glutaminase‐2 and increased expression of asparagine synthetase and solute carrier 7A11, thereby increasing intracellular glutamine and asparagine concentrations, indicating active ammonia detoxification. Rifaximin was apically excreted into the lumen in an ATP binding cassette B1 (ABCB1)‐dependent manner. Conclusions: Rifaximin—after uptake into enterocytes—stimulates intracellular nitrogen detoxification by PXR‐independent mechanisms. Active apical excretion of rifaximin by ABCB1 into the intestinal lumen explains its low systemic bioavailability. Our study implies that rifaximin, next to modulation of the microbiome, has direct effects on ammonia scavenging in the human small intestinal epithelium. [ABSTRACT FROM AUTHOR]

Published
2023
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26. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis

Author

Selvaraj, Emmanuel Anandraj, primary, Mózes, Ferenc Emil, additional, Jayaswal, Arjun Narayan Ajmer, additional, Zafarmand, Mohammad Hadi, additional, Vali, Yasaman, additional, Lee, Jenny A., additional, Levick, Christina Kim, additional, Young, Liam Arnold Joseph, additional, Palaniyappan, Naaventhan, additional, Liu, Chang-Hai, additional, Aithal, Guruprasad Padur, additional, Romero-Gómez, Manuel, additional, Brosnan, M. Julia, additional, Tuthill, Theresa A., additional, Anstee, Quentin M., additional, Neubauer, Stefan, additional, Harrison, Stephen A., additional, Bossuyt, Patrick M., additional, Pavlides, Michael, additional, Anstee, Quentin, additional, Daly, Ann, additional, Johnson, Katherine, additional, Govaere, Olivier, additional, Cockell, Simon, additional, Tiniakos, Dina, additional, Bedossa, Pierre, additional, Oakley, Fiona, additional, Cordell, Heather, additional, Day, Chris, additional, Wonders, Kristy, additional, Bossuyt, Patrick, additional, Zafarmand, Hadi, additional, Lee, Jenny, additional, Ratziu, Vlad, additional, Clement, Karine, additional, Pais, Raluca, additional, Schuppan, Detlef, additional, Schattenberg, Jörn, additional, Vidal-Puig, Toni, additional, Vacca, Michele, additional, Rodrigues-Cuenca, Sergio, additional, Allison, Mike, additional, Kamzolas, Ioannis, additional, Petsalaki, Evangelia, additional, Oresic, Matej, additional, Hyötyläinen, Tuulia, additional, McGlinchey, Aiden, additional, Mato, Jose M., additional, Millet, Oscar, additional, Dufour, Jean-François, additional, Berzigotti, Annalisa, additional, Harrison, Stephen, additional, Cobbold, Jeremy, additional, Mozes, Ferenc, additional, Akhtar, Salma, additional, Banerjee, Rajarshi, additional, Kelly, Matt, additional, Shumbayawonda, Elizabeth, additional, Dennis, Andrea, additional, Erpicum, Charlotte, additional, Gómez-González, Emilio, additional, Ampuero, Javier, additional, Castell, Javier, additional, Gallego-Durán, Rocío, additional, Fernández, Isabel, additional, Montero-Vallejo, Rocío, additional, Karsdal, Morten, additional, Erhardtsen, Elisabeth, additional, Rasmussen, Daniel, additional, Leeming, Diana Julie, additional, Fisker, Mette Juul, additional, Sinisi, Antonia, additional, Musa, Kishwar, additional, Betsou, Fay, additional, Sandt, Estelle, additional, Tonini, Manuela, additional, Bugianesi, Elisabetta, additional, Rosso, Chiara, additional, Armandi, Angelo, additional, Marra, Fabio, additional, Gastaldelli, Amalia, additional, Svegliati, Gianluca, additional, Boursier, Jérôme, additional, Francque, Sven, additional, Vonghia, Luisa, additional, Ekstedt, Mattias, additional, Kechagias, Stergios, additional, Yki-Jarvinen, Hannele, additional, Luukkonen, Panu, additional, van Mil, Saskia, additional, Papatheodoridis, George, additional, Cortez-Pinto, Helena, additional, Valenti, Luca, additional, Petta, Salvatore, additional, Miele, Luca, additional, Geier, Andreas, additional, Trautwein, Christian, additional, Aithal, Guru, additional, Hockings, Paul, additional, Newsome, Philip, additional, Wenn, David, additional, Pereira Rodrigues, Cecília Maria, additional, Chaumat, Pierre, additional, Hanf, Rémy, additional, Trylesinski, Aldo, additional, Ortiz, Pablo, additional, Duffin, Kevin, additional, Brosnan, Julia, additional, Tuthill, Theresa, additional, McLeod, Euan, additional, Ertle, Judith, additional, Younes, Ramy, additional, Ostroff, Rachel, additional, Alexander, Leigh, additional, Kjær, Mette Skalshøi, additional, Mikkelsen, Lars Friis, additional, Balp, Maria-Magdalena, additional, Brass, Clifford, additional, Jennings, Lori, additional, Martic, Miljen, additional, Loeffler, Juergen, additional, Hanauer, Guido, additional, Shankar, Sudha, additional, Fournier, Céline, additional, Pepin, Kay, additional, Ehman, Richard, additional, Myers, Joel, additional, Ho, Gideon, additional, Torstenson, Richard, additional, Myers, Rob, additional, and Doward, Lynda, additional

Published
2021
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27. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Raluca Pais, Rachel Ostroff, Stephen Harrison, Lars Friis Mikkelsen, Elisabeth Erhardtsen, Sudha Shankar, Kimmo Porthan, Jérôme Boursier, Antonia Sinisi, Michael Kalutkiewicz, Sven Francque, Miljen Martic, Vanessa Pellegrinelli, Phil N. Newsome, Guido Hanauer, Hannele Yki-Järvinen, Rebecca Darlay, Joel Myers, Carla Yunis, Salvatore Petta, Mette Skalshøi Kjær, Pablo Ortiz, Ann K. Daly, James H. Clark, Dina Tiniakos, Yasaman Vali, Hadi Zafarmand, Matej Orešič, Maurizio Parola, Estelle Sandt, Lori L. Jennings, Matt Kelly, Tuulia Hyötyläinen, Detlef Schuppan, Céline Fournier, Chiara Rosso, Diane E. Shevell, Maria Manuela Tonini, Paul Hockings, Aidan McGlinchey, Salma Akhtar, Mette Juul Fisker, Morten A. Karsdal, Diane Whalley, Melissa R. Miller, Aldo Trylesinski, Mattias Ekstedt, Stefan Neubauer, Jeremy M. Palmer, Partho Sen, Michael Pavlides, Per Qvist, Isabel Fernández, Luca Miele, Fabio Marra, Stergios Kechagias, Richard Torstenson, Katherine Johnson, Jean-François Dufour, Elisabetta Bugianesi, M. Julia Brosnan, George V. Papatheodoridis, Kay M. Pepin, Daniel Guldager Kring Rasmussen, Henrik Landgren, Rachel Queen, Simon Cockell, Michael Allison, Patrick M.M. Bossuyt, Rocío Gallego-Durán, Christian Rosenquist, Leigh Alexander, Elizabeth Shumbayawonda, Michele Vacca, Antonio Vidal-Puig, David Wenn, Rémy Hanf, Oscar Millet, Michalina Zatorska, R. Myers, José M. Mato, Jenny Lee, Theresa Tuthill, James Twiss, Ramy Younes, Peter Leary, Lynda Doward, Kristy Wonders, Guruprasad P. Aithal, Sarah Charlton, Vlad Ratziu, Cecília M. P. Rodrigues, Christian Trautwein, Helena Cortez-Pinto, Gideon Ho, Matt J. Barter, Judith Ertle, Jörn M. Schattenberg, Maria-Magdalena Balp, Yang-Lin Liu, Clifford A. Brass, Olivier Govaere, Amalia Gastaldelli, Sergio Rodriguez Cuenca, Pierre Chaumat, Fiona Oakley, Luca Valenti, Simon J. Cockell, Saskia W.C. van Mil, Ferenc E. Mózes, Andreas Geier, Timothy Hardy, Pierre Bedossa, Andrea Dennis, Richard L. Ehman, Charlotte Erpicum, Karine Clément, Jeremy F. L. Cobbold, Christopher P. Day, Rajarshi Banerjee, Manuel Romero-Gómez, Quentin M. Anstee, Adriaan G. Holleboom, Heather J. Cordell, Kevin L. Duffin, Diana Julie Leeming, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Investigators, LITMUS Consortium, Johnson K., Leary P.J., Govaere O., Barter M.J., Charlton S.H., Cockell S.J., Tiniakos D., Zatorska M., Bedossa P., Brosnan M.J., Cobbold J.F., Ekstedt M., Aithal G.P., Clement K., Schattenberg J.M., Boursier J., Ratziu V., Bugianesi E., Anstee Q.M., Daly A.K., Clark J., Cordell H.J., Darlay R., Day C.P., Hardy T., Liu Y.-L., Oakley F., Palmer J., Queen R., Wonders K., Bossuyt P.M., Holleboom A.G., Zafarmand H., Vali Y., Lee J., Pais R., Schuppan D., Allison M., Cuenca S.R., Pellegrinelli V., Vacca M., Vidal-Puig A., Hyotylainen T., McGlinchey A., Oresic M., Sen P., Mato J., Millet O., Dufour J.-F., Harrison S., Neubauer S., Pavlides M., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Romero-Gomez M., Gallego-Duran R., Fernandez I., Karsdal M., Leeming D., Fisker M.J., Erhardtsen E., Rasmussen D., Qvist P., Sinisi A., Sandt E., Tonini M.M., Parola M., Rosso C., Marra F., Gastaldelli A., Francque S., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Petta S., Miele L., Geier A., Trautwein C., Hockings P., Newsome P., Wenn D., Pereira Rodrigues C.M., Hanf R., Chaumat P., Rosenquist C., Trylesinski A., Ortiz P., Duffin K., Yunis C., Miller M., Tuthill T., Ertle J., Younes R., Alexander L., Ostroff R., Kjaer M.S., Mikkelsen L.F., Brass C., Jennings L., Balp M.-M., Martic M., Hanauer G., Shankar S., Torstenson R., Fournier C., Ehman R., Kalutkiewicz M., Pepin K., Myers J., Shevell D., Ho G., Landgren H., Myers R., Doward L., Whalley D., Twiss J., Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, and Yunis, Carla

Subjects
SCORING SYSTEM, CPM, counts per million, AUROC, area under the receiver operating characteristic, RC799-869, AST, aspartate aminotransferase, MicroRNA, Non-alcoholic fatty liver disease, Biomarker, Sequencing, TGF-β, transforming growth factor-beta, Gastroenterology, STEATOHEPATITIS, Liver disease, 0302 clinical medicine, Fibrosis, miRNA, microRNA, logFC, log2 fold change, FIBROSIS, Immunology and Allergy, 0303 health sciences, education.field_of_study, NAS, NAFLD activity score, medicine.diagnostic_test, Fatty liver, GTEx, Genotype-Tissue Expression, Diseases of the digestive system. Gastroenterology, 3. Good health, Real-time polymerase chain reaction, Biomarker, MicroRNA, Non-alcoholic fatty liver disease, Sequencing, Liver biopsy, ACID, Biomarker (medicine), 030211 gastroenterology & hepatology, Life Sciences & Biomedicine, Research Article, EXPRESSION, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Population, Gastroenterology and Hepatology, SAF, steatosis–activity–fibrosis, VALIDATION, ER, endoplasmic reticulum, 03 medical and health sciences, cDNA, complementary DNA, Internal medicine, ALT, alanine aminotransferase, Gastroenterologi, Internal Medicine, medicine, NAFL, non-alcoholic fatty liver, ALGORITHM, FIB-4, fibrosis-4, education, 030304 developmental biology, PCA, principal component analysis, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, FC, fold change, medicine.disease, digestive system diseases, FLIP, fatty liver inhibition of progression, Ct, cycle threshold, Steatosis, qPCR, quantitative PCR, business
Abstract

Background & Aims Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy., Graphical abstract, Highlights • Serum miRNA was sequenced in 183 NAFLD cases of varying severity and 10 population controls. • Plasma levels of miR-193a-5p were significantly increased in patients with advanced fibrosis, high NAS scores, or high SAF scores. • Other miRNAs including miR378d and miR378e were also significantly increased in certain comparisons. • The findings for miR-193a-5p were replicated in a cohort of 372 additional NAFLD cases.

Published
2022

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