Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

doi:10.1136/gutjnl-2021-324243

Meta-Analysis

. 2022 May;71(5):1006-1019.

doi: 10.1136/gutjnl-2021-324243. Epub 2021 May 17.

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

Ferenc Emil Mózes¹, Jenny A Lee², Emmanuel Anandraj Selvaraj^{1

3

4}, Arjun Narayan Ajmer Jayaswal¹, Michael Trauner⁵, Jerome Boursier^{6

7}, Céline Fournier⁸, Katharina Staufer^{5

9

10}, Rudolf E Stauber¹¹, Elisabetta Bugianesi¹², Ramy Younes¹³, Silvia Gaia¹², Monica Lupșor-Platon¹⁴, Salvatore Petta¹⁵, Toshihide Shima¹⁶, Takeshi Okanoue¹⁶, Sanjiv Mahadeva¹⁷, Wah-Kheong Chan¹⁷, Peter J Eddowes^{18

19}, Gideon M Hirschfield²⁰, Philip Noel Newsome^{18

21

22}, Vincent Wai-Sun Wong²³, Victor de Ledinghen^{24

25}, Jiangao Fan²⁶, Feng Shen²⁶, Jeremy F Cobbold^{3

4}, Yoshio Sumida²⁷, Akira Okajima²⁸, Jörn M Schattenberg²⁹, Christian Labenz²⁹, Won Kim³⁰, Myoung Seok Lee³¹, Johannes Wiegand³², Thomas Karlas³², Yusuf Yılmaz^{33

34}, Guruprasad Padur Aithal^{19

35}, Naaventhan Palaniyappan^{19

35}, Christophe Cassinotto³⁶, Sandeep Aggarwal³⁷, Harshit Garg³⁷, Geraldine J Ooi³⁸, Atsushi Nakajima³⁹, Masato Yoneda³⁹, Marianne Ziol⁴⁰, Nathalie Barget⁴¹, Andreas Geier⁴², Theresa Tuthill⁴³, M Julia Brosnan⁴³, Quentin Mark Anstee⁴⁴, Stefan Neubauer¹, Stephen A Harrison¹, Patrick M Bossuyt², Michael Pavlides^{45

3

4}; LITMUS Investigators

Collaborators, Affiliations

Collaborators

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

Affiliations

¹ Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³ Translational Gastroenterology Unit, University of Oxford, Oxford, Oxfordshire, UK.
⁴ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁶ Laboratoire HIFIH, UPRES EA 3859, SFR ICAT 4208, Universite d'Angers, Angers, Pays de la Loire, France.
⁷ Service d'Hepato-Gastroenterologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, Pays de la Loire, France.
⁸ Echosens SA, Paris, Île-de-France, France.
⁹ Department of Visceral Surgery and Medicine, Inselspital University Hospital Bern, Bern, Switzerland.
¹⁰ Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
¹¹ Department of Internal Medicine, Medical University of Graz, Graz, Austria.
¹² Medical Sciences, University of Turin, Torino, Italy.
¹³ Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany.
¹⁴ Department of Ultrasonography, University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj Napoca, Romania.
¹⁵ Section of Gastroenterology and Hepatology, PROMISE, Palermo, Italy.
¹⁶ Hepatology Center, Saiseikai Suita Hospital, Suita, Osaka, Japan.
¹⁷ Faculty of Medicine, Department of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia.
¹⁸ NIHR Biomedical Research Centre, University of Birmingham, Birmingham, UK.
¹⁹ NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, Nottinghamshire, UK.
²⁰ Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.
²¹ Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
²² Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
²³ Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, Hong Kong.
²⁴ Centre d'Investigation de la Fibrose Hépatique, Hopital Haut-Leveque, Pessac, France.
²⁵ INSERM1053, Universite de Bordeaux, Talence, Aquitaine, France.
²⁶ Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²⁷ Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
²⁸ Department of Gastroenterology, Koseikai Takeda Hospital, Kyoto, Japan.
²⁹ Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University Mainz, Mainz, Rhineland-Palatinate, Germany.
³⁰ Department of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, South Korea.
³¹ Department of Radiology, Seoul National University Seoul Metropolitan Government Boramae Medical Center, Dongjak-gu, Seoul, The Republic of Korea.
³² Department of Medicine II, Leipzig University Medical Center, Leipzig, Sachsen, Germany.
³³ Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey.
³⁴ Institute of Gastroenterology, Marmara University, Istanbul, Turkey.
³⁵ Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
³⁶ Diagnostic and Interventional Radiology, University Hospital Centre Montpellier, Montpellier, Languedoc-Roussillon, France.
³⁷ Department of Surgical Disciplines, AIIMS, New Delhi, Delhi, India.
³⁸ Department of Surgery, Monash University, Prahran, Victoria, Australia.
³⁹ Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Kanagawa, Japan.
⁴⁰ Service d'Anatomie Pathologique et Centre de Ressources Biologiques, Hopital Jean Verdier, Paris, France.
⁴¹ Centre de Ressources Biologiques, Hopitaux Universitaires Paris-Seine-Saint-Denis, Bondy, Île-de-France, France.
⁴² Division of Hepatology, University Hospital Wurzburg, Wurzburg, Bayern, Germany.
⁴³ Internal Medicine Research Unit, Pfizer Inc, Cambridge, Massachusetts, USA.
⁴⁴ Translational and Clinical Research Institute, Faculty of Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.
⁴⁵ Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK michael.pavlides@cardiov.ox.ac.uk.

PMID: 34001645
PMCID: PMC8995830
DOI: 10.1136/gutjnl-2021-324243

Meta-Analysis

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

Ferenc Emil Mózes et al. Gut. 2022 May.

. 2022 May;71(5):1006-1019.

doi: 10.1136/gutjnl-2021-324243. Epub 2021 May 17.

Authors

Collaborators

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

Affiliations

¹ Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³ Translational Gastroenterology Unit, University of Oxford, Oxford, Oxfordshire, UK.
⁴ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁶ Laboratoire HIFIH, UPRES EA 3859, SFR ICAT 4208, Universite d'Angers, Angers, Pays de la Loire, France.
⁷ Service d'Hepato-Gastroenterologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, Pays de la Loire, France.
⁸ Echosens SA, Paris, Île-de-France, France.
⁹ Department of Visceral Surgery and Medicine, Inselspital University Hospital Bern, Bern, Switzerland.
¹⁰ Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
¹¹ Department of Internal Medicine, Medical University of Graz, Graz, Austria.
¹² Medical Sciences, University of Turin, Torino, Italy.
¹³ Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany.
¹⁴ Department of Ultrasonography, University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj Napoca, Romania.
¹⁵ Section of Gastroenterology and Hepatology, PROMISE, Palermo, Italy.
¹⁶ Hepatology Center, Saiseikai Suita Hospital, Suita, Osaka, Japan.
¹⁷ Faculty of Medicine, Department of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia.
¹⁸ NIHR Biomedical Research Centre, University of Birmingham, Birmingham, UK.
¹⁹ NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, Nottinghamshire, UK.
²⁰ Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.
²¹ Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
²² Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
²³ Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, Hong Kong.
²⁴ Centre d'Investigation de la Fibrose Hépatique, Hopital Haut-Leveque, Pessac, France.
²⁵ INSERM1053, Universite de Bordeaux, Talence, Aquitaine, France.
²⁶ Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²⁷ Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
²⁸ Department of Gastroenterology, Koseikai Takeda Hospital, Kyoto, Japan.
²⁹ Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University Mainz, Mainz, Rhineland-Palatinate, Germany.
³⁰ Department of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, South Korea.
³¹ Department of Radiology, Seoul National University Seoul Metropolitan Government Boramae Medical Center, Dongjak-gu, Seoul, The Republic of Korea.
³² Department of Medicine II, Leipzig University Medical Center, Leipzig, Sachsen, Germany.
³³ Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey.
³⁴ Institute of Gastroenterology, Marmara University, Istanbul, Turkey.
³⁵ Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
³⁶ Diagnostic and Interventional Radiology, University Hospital Centre Montpellier, Montpellier, Languedoc-Roussillon, France.
³⁷ Department of Surgical Disciplines, AIIMS, New Delhi, Delhi, India.
³⁸ Department of Surgery, Monash University, Prahran, Victoria, Australia.
³⁹ Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Kanagawa, Japan.
⁴⁰ Service d'Anatomie Pathologique et Centre de Ressources Biologiques, Hopital Jean Verdier, Paris, France.
⁴¹ Centre de Ressources Biologiques, Hopitaux Universitaires Paris-Seine-Saint-Denis, Bondy, Île-de-France, France.
⁴² Division of Hepatology, University Hospital Wurzburg, Wurzburg, Bayern, Germany.
⁴³ Internal Medicine Research Unit, Pfizer Inc, Cambridge, Massachusetts, USA.
⁴⁴ Translational and Clinical Research Institute, Faculty of Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.
⁴⁵ Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK michael.pavlides@cardiov.ox.ac.uk.

PMID: 34001645
PMCID: PMC8995830
DOI: 10.1136/gutjnl-2021-324243

Abstract

Objective: Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.

Design: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.

Results: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m²; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy.

Conclusion: Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

Keywords: biostatistics; clinical decision making; fatty liver; hepatic fibrosis.

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Conflict of interest statement

Competing interests: AG reports personal fees from AbbVie, personal fees from Alexion, personal fees from Bayer, personal fees from BMS, personal fees from CSL Behring, personal fees from Gilead, grants and personal fees from Intercept, personal fees from Ipsen, personal fees from Merz, grants and personal fees from Novartis, personal fees from Pfizer, personal fees from Sanofi-Aventis, personal fees from Sequana, grants and personal fees from Falk, personal fees from MSD, during the conduct of the study. ANAJ reports other from Perspectum, during the conduct of the study. CF reports other from Echosens, during the conduct of the study. JFC reports personal fees from AstraZeneca, personal fees from Novo Nordisk, personal fees from Intercept, personal fees from Alnylam, during the conduct of the study. JB reports other from Pfizer, during the conduct of the study. JMS reports personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from Echosens, personal fees from Genfit, personal fees from Gilead Sciences, personal fees from Intercept Pharmaceuticals, personal fees from Madrigal, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from Sanofi, personal fees from Falk Foundation, personal fees from MSD, grants from Gilead Sciences, during the conduct of the study. JW reports grants from Echosens, during the conduct of the study. Dr. Pavlides reports other from Perspectum, during the conduct of the study. MT reports personal fees from Bristol-Myers Squibb, personal fees from Falk Foundation, personal fees from Gilead, personal fees from Intercept, personal fees from Merck Sharp & Dohme, personal fees from Albireo, personal fees from Boehringer Ingelheim, personal fees from BiomX, personal fees from Falk Pharma GmbH, personal fees from GENFIT, personal fees from Jannsen, personal fees from Novartis, personal fees from Phenex, personal fees from Regulus and Shire, grants from AbbVie, grants from Falk, grants from Gilead, grants from Intercept, grants from Albireo, grants from CymaBay, grants from Merck Sharp & Dohme, grants from Takeda, during the conduct of the study; in addition, MT has a patent norUDCA issued. PNN reports personal fees from Bristol-Myers Squibb, personal fees from Gilead, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Novo Nordisk, personal fees from Poxel, grants from Pharmaxis, grants from Boehringer Ingelheim, grants from Echosens, grants from Novo Nordisk, during the conduct of the study. QMA reports grants from AbbVie, grants and personal fees from Allergan/Tobira, grants from AstraZeneca, grants from GlaxoSmithKline, grants from Glympse Bio, grants and personal fees from Novartis Pharma, grants and personal fees from Pfizer, grants from Vertex, personal fees from Abbott Laboratories, personal fees from Acuitas Medical, personal fees from Blade, personal fees from BNN Cardio, personal fees from Cirius, personal fees from CymaBay, personal fees from EcoR1, personal fees from Eli Lilly, personal fees from Galmed, personal fees from Genfit, personal fees from Gilead, personal fees from Grunthal, personal fees from HistoIndex, personal fees from Indalo, personal fees from Imperial Innovations, personal fees from Intercept Pharma Europe, personal fees from Inventiva, personal fees from IQVIA, personal fees from Janssen, personal fees from Kenes, personal fees from Madrigal, personal fees from MedImmune, personal fees from Metacrine, personal fees from NewGene, personal fees from NGMBio, personal fees from North Sea Therapeutics, personal fees from Novo Nordisk, personal fees from Poxel, personal fees from ProSciento, personal fees from Raptor Pharma, personal fees from Servier, personal fees from Viking Therapeutics, personal fees from Abbott Laboratories, personal fees from BMS, personal fees from Clinical Care Options, personal fees from Falk, personal fees from Fishawack, personal fees from Integritas Communications, personal fees from MedScape, other from IMI2 LITMUS consortium, during the conduct of the study. SH reports grants and personal fees from Akero, grants and personal fees from Axcella, grants and personal fees from Cirius, grants and personal fees from CiVi Biopharma, grants and personal fees from CymaBay, grants and personal fees from Galectin, grants from Galmed, grants and personal fees from Genfit, grants and personal fees from Gilead Sciences, grants and personal fees from Hepion Pharmaceuticals, grants and personal fees from Hightide Therapeutics, grants and personal fees from Intercept, grants and personal fees from Madrigal, grants and personal fees from Metacrine, grants and personal fees from NGM Bio, grants and personal fees from North Sea Therapeutics, grants and personal fees from Novartis, grants and personal fees from Novo Nordisk, grants and personal fees from Poxel, grants and personal fees from Sagimet, grants and personal fees from Viking, personal fees from Altimmune, personal fees from Alentis, personal fees from Arrowhead, personal fees from Canfite, personal fees from Echosens, personal fees from Enyo, personal fees from Fibronostics, personal fees from Foresite Labs, personal fees from Fortress Biotech, personal fees from HistoIndex, personal fees from Kowa, personal fees from Prometic, personal fees from Ridgeline, personal fees from Terns, during the conduct of the study. SM reports personal fees from Echosens, during the conduct of the study. SN reports other from Perspectum, during the conduct of the study. SP reports personal fees from AbbVie, personal fees from Gilead, personal fees from Intercept, personal fees from Pfizer, during the conduct of the study. TK reports grants from Echosens, during the conduct of the study. TT reports other from Pfizer, during the conduct of the study. VdL reports personal fees from Bristol-Myers Squibb, personal fees from Gilead Sciences, personal fees from AbbVie, personal fees from Pfizer, personal fees from Echosens, personal fees from Intercept Pharmaceuticals, personal fees from MSD, personal fees from Myr-Pharma, personal fees from Supersonic Imagine, personal fees from Tillotts, during the conduct of the study. Dr. Wong reports personal fees from AbbVie, personal fees from 3V-BIO, personal fees from Allergan, personal fees from Boehringer Ingelheim, personal fees from Center for Outcomes Research in Liver Diseases, grants and personal fees from Gilead, personal fees from Intercept, personal fees from Echosens, personal fees from Hanmi Pharmaceutical, personal fees from Novartis, personal fees from Pfizer, personal fees from Merck, personal fees from Novo Nordisk, personal fees from Perspectum, personal fees from ProSciento, personal fees from Sagimet Biosciences, personal fees from TARGET PharmaSolutions, personal fees from Terns, personal fees from BMS, during the conduct of the study. WK reports personal fees from Samil, personal fees from Boehringer Ingelheim, personal fees from Ildong, personal fees from LG Chemistry, personal fees from Gilead Sciences, personal fees from HK inno.N, personal fees from GreenCross, personal fees from Bukwang, personal fees from Standigm, personal fees from PharmaKing, personal fees from KOBIOLABS, personal fees from Eisai, personal fees from Zydus, personal fees from Novo Nordisk, grants from Gilead, grants from Ildong, grants from GreenCross, grants from Bukwang, grants from PharmaKing, grants from Roche, grants from Galmed, grants from Novartis, grants from Pfizer, grants from Springbank, grants from Altimmune, grants from MSD, grants from BMS, grants from Dicerna, grants from Enyo, grants from Hitachi-Aloka, other from KOBIOLABS, other from Lepidyne, during the conduct of the study. YY reports grants from Biocodes, grants and personal fees from Gilead Sciences, personal fees from Bilim Pharmaceuticals, personal fees from Pharmactive Pharmaceutical, personal fees from Sanovel Pharmaceuticals, personal fees from Galmed, personal fees from Zydus, personal fees from Novo Nordisk, during the conduct of the study. MP, ANAJ and SN are shareholders of Perspectum, Oxford, UK. CF is employed by Echosens, France. MT received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Jannsen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz. SP was speaker and/or Advisor for AbbVie, Gilead, Intercept and Pfizer. PNN received grant and research support from Pharmaxis, Boehringer Ingelheim, Echosens and Novo Nordisk and consulting fees from BMS, Boehringer Ingelheim, Gilead, Novo Nordisk, Pfizer, and Poxel on behalf of the University of Birmingham. VL reports consultancy for AbbVie, BMS, Echosens, Gilead Sciences, Intercept Pharmaceuticals, MSD, Myr-Pharma, Pfizer, Supersonic Imagine and Tillotts. SM received honorarium fees from Echosens. JFC received consultancy, advisory board, and speaker fees from Astra Zeneca, NovoNordisk, Intercept and Alnylam. JMS reports consultancy for BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Pfizer, Roche, Sanofi; received research funding from Gilead Sciences and was on the speakers bureau for Falk Foundation MSD Sharp & Dohme GmbH. WK has served as a speaker and consultant of Gilead, Boehringer-Ingelheim, Samil, Ildong, LG Chemistry, HK inno.N, GreenCross, Bukwang, Standigm, PharmaKing, KOBIOLABS, Eisai, Zydus, and Novonordisk, received grants from Gilead, Ildong, GreenCross, Bukwang, Pharmaking, Roche, Galmed, Novartis, Pfizer, Springbank, Altimmune, MSD, BMS, Dicerna, Enyo, and Hitachi-Aloka, and owns stocks in KOBIOLABS and Lepidyne. TK and JW received unrestricted research grants from Echosens, Paris France. TK participated in a clinical advisory board meeting. YY received research grant from Biocodex, Gilead Sciences, speaker fees for Gilead Sciences, Bilim Pharmaceuticals, Pharmactive Pharmaceutical, Sanovel Pharmaceuticals, and served as advisory board member for Galmed, Zydus, NovoNordisk. AG reports consultancy for AbbVie, Alexion, Bayer, BMS, CSL Behring, Gilead, Intercept, Ipsen, Merz, Novartis, Pfizer, Sanofi-Aventis, Sequana; received research funding from Intercept, Falk, Novartis and was on the speakers bureau for AbbVie, Alexion, BMS, CSL Behring, Falk Foundation, Gilead, Intercept, MSD, Merz, Novartis, Sequana. VWSW has served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. He has also received a research grant from Gilead Sciences for fatty liver research. QMA is coordinator of the IMI2 LITMUS consortium and he reports research grant funding from Abbvie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer Ltd., Vertex; consultancy on behalf of Newcastle University for Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Blade, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Servier, Viking Therapeutics; and speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, MedScape. SAH has research grants from Akero, Axcella, Cirius, CiVi Biopharma, Cymabay, Galectin, Galmed, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, Viking. He has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Canfite, Cirius, CiVi, Cymabay, Echosens, Enyo, Fibronostics, Foresite Labs, Fortress Biotech, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Prometic, Ridgeline, Sagimet, Terns, and Viking.

Figures

**Figure 1**
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart illustrating the identification and selection process for studies finally included in this individual patient data meta-analysis. IPD, individual patient data; LSM, liver stiffness measurement; VCTE, vibration controlled transient elastography.

**Figure 2**
Distribution of sensitivities and specificities over the possible threshold ranges for liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) (A), Fibrosis-4 Index (FIB-4) (B) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) (C) when considering the diagnosis of advanced fibrosis. Insets show the distribution of cut-offs identified from the literature. Horizontal dashed lines are representing the minimum acceptable criteria for considering a test as having high sensitivity (≥80%) and high specificity (≥80%).

**Figure 3**
Sankey diagrams showing the distribution of patients in true positive, true negative, false positive, false negative and indeterminate groups for a sequential combination of Fibrosis-4 Index (FIB-4) and liver stiffness measurement,(LSM) by vibration controlled transient elastography (VCTE) when using different thresholds for each testing tier. A lower threshold was used to rule out patients without advanced fibrosis and an upper threshold ruled in patients with advanced fibrosis when applying both tests (A). In an alternative model, a lower threshold was used to rule out patients without advanced fibrosis, but the upper threshold ruled in only patients with cirrhosis (B, C). Two different pairs of thresholds were chosen for this hybrid strategy: the lower cut-off for both FIB-4 and LSM by VCTE were determined from the literature; upper cut-offs were both determined as corresponding to 95% specificity in detecting cirrhosis (B) or both corresponding to 98% specificity in detecting cirrhosis (C). In the application of the algorithm described in (A) 33% of patients would need to have a liver biopsy for the diagnosis of cirrhosis (those in the indeterminate group to rule out advanced fibrosis and those in the rule in group to identify cirrhosis). With the application of an upper cut-off to rule in cirrhosis without the need of biopsy, only patients in the indeterminate group need to have a biopsy. The latter strategy results in fewer patients undergoing biopsy (18% and 24% depending on the threshold used). Tables next to each panel contain the number and proportion of patients in each of the true positive (TP), true negative (TN), false positive (FP) and false negative (FN) groups for FIB-4 and LSM by VCTE.

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Comment in

Non-invasive tests and advanced chronic liver disease in NAFLD: two steps forward and one step back?
Majumdar A, Tsochatzis EA. Majumdar A, et al. Gut. 2022 Jun;71(6):1236-1237. doi: 10.1136/gutjnl-2021-325994. Epub 2021 Sep 14. Gut. 2022. PMID: 34521766 No abstract available.

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References

1. Younossi Z, Anstee QM, Marietti M, et al. . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11–20. 10.1038/nrgastro.2017.109 - DOI - PubMed
1. Loomba R, Wong R, Fraysse J, et al. . Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther 2020;51:1149–59. 10.1111/apt.15679 - DOI - PubMed
1. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) . EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Obes Facts 2016;9:65–90. 10.1159/000443344 - DOI - PMC - PubMed
1. Thampanitchawong P, Piratvisuth T. Liver biopsy:complications and risk factors. World J Gastroenterol 1999;5:301–4. 10.3748/wjg.v5.i4.301 - DOI - PMC - PubMed
1. Ratziu V, Charlotte F, Heurtier A, et al. . Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898–906. 10.1053/j.gastro.2005.03.084 - DOI - PubMed

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[1] Younossi Z, Anstee QM, Marietti M, et al. . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11–20. 10.1038/nrgastro.2017.109 - DOI - PubMed

[2] Younossi Z, Anstee QM, Marietti M, et al. . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11–20. 10.1038/nrgastro.2017.109 - DOI - PubMed

[3] Loomba R, Wong R, Fraysse J, et al. . Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther 2020;51:1149–59. 10.1111/apt.15679 - DOI - PubMed

[4] Loomba R, Wong R, Fraysse J, et al. . Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther 2020;51:1149–59. 10.1111/apt.15679 - DOI - PubMed

[5] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) . EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Obes Facts 2016;9:65–90. 10.1159/000443344 - DOI - PMC - PubMed

[6] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) . EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Obes Facts 2016;9:65–90. 10.1159/000443344 - DOI - PMC - PubMed

[7] Thampanitchawong P, Piratvisuth T. Liver biopsy:complications and risk factors. World J Gastroenterol 1999;5:301–4. 10.3748/wjg.v5.i4.301 - DOI - PMC - PubMed

[8] Thampanitchawong P, Piratvisuth T. Liver biopsy:complications and risk factors. World J Gastroenterol 1999;5:301–4. 10.3748/wjg.v5.i4.301 - DOI - PMC - PubMed

[9] Ratziu V, Charlotte F, Heurtier A, et al. . Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898–906. 10.1053/j.gastro.2005.03.084 - DOI - PubMed

[10] Ratziu V, Charlotte F, Heurtier A, et al. . Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898–906. 10.1053/j.gastro.2005.03.084 - DOI - PubMed

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Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

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Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

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