. 2023 Oct 5;3(1):138.

doi: 10.1038/s43856-023-00360-3.

Precision subclassification of type 2 diabetes: a systematic review

Shivani Misra^#^{1

2}, Robert Wagner^#^{3

4

5}, Bige Ozkan^{6

7}, Martin Schön^{4

5

8}, Magdalena Sevilla-Gonzalez^{9

10

11}, Katsiaryna Prystupa^{4

5}, Caroline C Wang⁶, Raymond J Kreienkamp^{10

12

13

14}, Sara J Cromer^{10

11

12

13}, Mary R Rooney^{6

15}, Daisy Duan¹⁶, Anne Cathrine Baun Thuesen¹⁷, Amelia S Wallace^{6

15}, Aaron Leong^{10

11

12

18}, Aaron J Deutsch^{10

11

12

13}, Mette K Andersen¹⁷, Liana K Billings^{19

20}, Robert H Eckel²¹, Wayne Huey-Herng Sheu^{22

23

24}, Torben Hansen¹⁷, Norbert Stefan^{5

25

26}, Mark O Goodarzi²⁷, Debashree Ray^{15

28}, Elizabeth Selvin^{6

15}, Jose C Florez^{10

11

12

13}; ADA/EASD PMDI; James B Meigs^{10

11

18}, Miriam S Udler^{10

11

12

13}

Collaborators, Affiliations

Collaborators

ADA/EASD PMDI:
Deirdre K Tobias, Jordi Merino, Abrar Ahmad, Catherine Aiken, Jamie L Benham, Dhanasekaran Bodhini, Amy L Clark, Kevin Colclough, Rosa Corcoy, Sara J Cromer, Jamie L Felton, Ellen C Francis, Pieter Gillard, Véronique Gingras, Romy Gaillard, Eram Haider, Alice Hughes, Jennifer M Ikle, Laura M Jacobsen, Anna R Kahkoska, Jarno L T Kettunen, Raymond J Kreienkamp, Lee-Ling Lim, Jonna M E Männistö, Robert Massey, Niamh-Maire Mclennan, Rachel G Miller, Mario Luca Morieri, Jasper Most, Rochelle N Naylor, Bige Ozkan, Kashyap Amratlal Patel, Scott J Pilla, Sridaran Raghaven, Martin Schön, Zhila Semnani-Azad, Magdalena Sevilla-Gonzalez, Pernille Svalastoga, Wubet Worku Takele, Claudia Ha-Ting Tam, Anne Cathrine B Thuesen, Mustafa Tosur, Caroline C Wang, Jessie J Wong, Jennifer M Yamamoto, Katherine Young, Chloé Amouyal, Maxine P Bonham, Mingling Chen, Feifei Cheng, Tinashe Chikowore, Sian C Chivers, Christoffer Clemmensen, Dana Dabelea, Adem Y Dawed, Aaron J Deutsch, Laura T Dickens, Linda A DiMeglio, Monika Dudenhöffer-Pfeifer, Carmella Evans-Molina, María Mercè Fernández-Balsells, Hugo Fitipaldi, Stephanie L Fitzpatrick, Stephen E Gitelman, Mark O Goodarzi, Jessica A Grieger, Marta Guasch-Ferré, Nahal Habibi, Chuiguo Huang, Arianna Harris-Kawano, Heba M Ismail, Benjamin Hoag, Randi K Johnson, Angus G Jones, Robert W Koivula, Aaron Leong, Gloria K W Leung, Ingrid M Libman, Kai Liu, S Alice Long, William L Lowe Jr, Robert W Morton, Ayesha A Motala, Suna Onengut-Gumuscu, James S Pankow, Maleesa Pathirana, Sofia Pazmino, Dianna Perez, John R Petrie, Camille E Powe, Alejandra Quinteros, Rashmi Jain, Mathias Ried-Larsen, Zeb Saeed, Vanessa Santhakumar, Sarah Kanbour, Sudipa Sarkar, Gabriela S F Monaco, Denise M Scholtens, Wayne Huey-Herng Sheu, Cate Speake, Maggie A Stanislawski, Nele Steenackers, Andrea K Steck, Norbert Stefan, Julie Støy, Rachael Taylor, Sok Cin Tye, Gebresilasea Gendisha Ukke, Marzhan Urazbayeva, Bart Van der Schueren, Camille Vatier, John M Wentworth, Wesley Hannah, Sara L White, Gechang Yu, Yingchai Zhang, Shao J Zhou, Jacques Beltrand, Michel Polak, Ingvild Aukrust, Elisa de Franco, Sarah E Flanagan, Kristin A Maloney, Andrew McGovern, Janne Molnes, Mariam Nakabuye, Pål Rasmus Njølstad, Hugo Pomares-Millan, Michele Provenzano, Cécile Saint-Martin, Cuilin Zhang, Yeyi Zhu, Sungyoung Auh, Russell de Souza, Andrea J Fawcett, Chandra Gruber, Eskedar Getie Mekonnen, Emily Mixter, Diana Sherifali, Robert H Eckel, John J Nolan, Louis H Philipson, Rebecca J Brown, Liana K Billings, Kristen Boyle, Tina Costacou, John M Dennis, Jose C Florez, Anna L Gloyn, Maria F Gomez, Peter A Gottlieb, Siri Atma W Greeley, Kurt Griffin, Andrew T Hattersley, Irl B Hirsch, Marie-France Hivert, Korey K Hood, Jami L Josefson, Soo Heon Kwak, Lori M Laffel, Siew S Lim, Ruth J F Loos, Ronald C W Ma, Chantal Mathieu, Nestoras Mathioudakis, James B Meigs, Shivani Misra, Viswanathan Mohan, Rinki Murphy, Richard Oram, Katharine R Owen, Susan E Ozanne, Ewan R Pearson, Wei Perng, Toni I Pollin, Rodica Pop-Busui, Richard E Pratley, Leanne M Redman, Maria J Redondo, Rebecca M Reynolds, Robert K Semple, Jennifer L Sherr, Emily K Sims, Arianne Sweeting, Tiinamaija Tuomi, Miriam S Udler, Kimberly K Vesco, Tina Vilsbøll, Stephen S Rich, Paul W Franks

Affiliations

¹ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. s.misra@imperial.ac.uk.
² Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, UK. s.misra@imperial.ac.uk.
³ Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
⁴ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.
⁵ German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
⁶ Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
⁹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Diabetes Unit, Division of Endocrinology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Pediatrics, Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
¹⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁶ Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Division of General Internal Medicine, Massachusetts General Hospital, 100 Cambridge St 16th Floor, Boston, MA, USA.
¹⁹ Division of Endocrinology, Diabetes and Metabolism, NorthShore University Health System, Skokie, IL, USA.
²⁰ Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
²¹ Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
²² Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli County, Taiwan, ROC.
²³ Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
²⁴ Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
²⁵ University Hospital of Tübingen, Tübingen, Germany.
²⁶ Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich, Neuherberg, Germany.
²⁷ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁸ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

^# Contributed equally.

PMID: 37798471
PMCID: PMC10556101
DOI: 10.1038/s43856-023-00360-3

Precision subclassification of type 2 diabetes: a systematic review

Shivani Misra et al. Commun Med (Lond). 2023.

. 2023 Oct 5;3(1):138.

doi: 10.1038/s43856-023-00360-3.

Authors

Collaborators

ADA/EASD PMDI:
Deirdre K Tobias, Jordi Merino, Abrar Ahmad, Catherine Aiken, Jamie L Benham, Dhanasekaran Bodhini, Amy L Clark, Kevin Colclough, Rosa Corcoy, Sara J Cromer, Jamie L Felton, Ellen C Francis, Pieter Gillard, Véronique Gingras, Romy Gaillard, Eram Haider, Alice Hughes, Jennifer M Ikle, Laura M Jacobsen, Anna R Kahkoska, Jarno L T Kettunen, Raymond J Kreienkamp, Lee-Ling Lim, Jonna M E Männistö, Robert Massey, Niamh-Maire Mclennan, Rachel G Miller, Mario Luca Morieri, Jasper Most, Rochelle N Naylor, Bige Ozkan, Kashyap Amratlal Patel, Scott J Pilla, Sridaran Raghaven, Martin Schön, Zhila Semnani-Azad, Magdalena Sevilla-Gonzalez, Pernille Svalastoga, Wubet Worku Takele, Claudia Ha-Ting Tam, Anne Cathrine B Thuesen, Mustafa Tosur, Caroline C Wang, Jessie J Wong, Jennifer M Yamamoto, Katherine Young, Chloé Amouyal, Maxine P Bonham, Mingling Chen, Feifei Cheng, Tinashe Chikowore, Sian C Chivers, Christoffer Clemmensen, Dana Dabelea, Adem Y Dawed, Aaron J Deutsch, Laura T Dickens, Linda A DiMeglio, Monika Dudenhöffer-Pfeifer, Carmella Evans-Molina, María Mercè Fernández-Balsells, Hugo Fitipaldi, Stephanie L Fitzpatrick, Stephen E Gitelman, Mark O Goodarzi, Jessica A Grieger, Marta Guasch-Ferré, Nahal Habibi, Chuiguo Huang, Arianna Harris-Kawano, Heba M Ismail, Benjamin Hoag, Randi K Johnson, Angus G Jones, Robert W Koivula, Aaron Leong, Gloria K W Leung, Ingrid M Libman, Kai Liu, S Alice Long, William L Lowe Jr, Robert W Morton, Ayesha A Motala, Suna Onengut-Gumuscu, James S Pankow, Maleesa Pathirana, Sofia Pazmino, Dianna Perez, John R Petrie, Camille E Powe, Alejandra Quinteros, Rashmi Jain, Mathias Ried-Larsen, Zeb Saeed, Vanessa Santhakumar, Sarah Kanbour, Sudipa Sarkar, Gabriela S F Monaco, Denise M Scholtens, Wayne Huey-Herng Sheu, Cate Speake, Maggie A Stanislawski, Nele Steenackers, Andrea K Steck, Norbert Stefan, Julie Støy, Rachael Taylor, Sok Cin Tye, Gebresilasea Gendisha Ukke, Marzhan Urazbayeva, Bart Van der Schueren, Camille Vatier, John M Wentworth, Wesley Hannah, Sara L White, Gechang Yu, Yingchai Zhang, Shao J Zhou, Jacques Beltrand, Michel Polak, Ingvild Aukrust, Elisa de Franco, Sarah E Flanagan, Kristin A Maloney, Andrew McGovern, Janne Molnes, Mariam Nakabuye, Pål Rasmus Njølstad, Hugo Pomares-Millan, Michele Provenzano, Cécile Saint-Martin, Cuilin Zhang, Yeyi Zhu, Sungyoung Auh, Russell de Souza, Andrea J Fawcett, Chandra Gruber, Eskedar Getie Mekonnen, Emily Mixter, Diana Sherifali, Robert H Eckel, John J Nolan, Louis H Philipson, Rebecca J Brown, Liana K Billings, Kristen Boyle, Tina Costacou, John M Dennis, Jose C Florez, Anna L Gloyn, Maria F Gomez, Peter A Gottlieb, Siri Atma W Greeley, Kurt Griffin, Andrew T Hattersley, Irl B Hirsch, Marie-France Hivert, Korey K Hood, Jami L Josefson, Soo Heon Kwak, Lori M Laffel, Siew S Lim, Ruth J F Loos, Ronald C W Ma, Chantal Mathieu, Nestoras Mathioudakis, James B Meigs, Shivani Misra, Viswanathan Mohan, Rinki Murphy, Richard Oram, Katharine R Owen, Susan E Ozanne, Ewan R Pearson, Wei Perng, Toni I Pollin, Rodica Pop-Busui, Richard E Pratley, Leanne M Redman, Maria J Redondo, Rebecca M Reynolds, Robert K Semple, Jennifer L Sherr, Emily K Sims, Arianne Sweeting, Tiinamaija Tuomi, Miriam S Udler, Kimberly K Vesco, Tina Vilsbøll, Stephen S Rich, Paul W Franks

Affiliations

¹ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. s.misra@imperial.ac.uk.
² Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, UK. s.misra@imperial.ac.uk.
³ Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
⁴ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.
⁵ German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
⁶ Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
⁹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Diabetes Unit, Division of Endocrinology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Pediatrics, Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
¹⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁶ Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Division of General Internal Medicine, Massachusetts General Hospital, 100 Cambridge St 16th Floor, Boston, MA, USA.
¹⁹ Division of Endocrinology, Diabetes and Metabolism, NorthShore University Health System, Skokie, IL, USA.
²⁰ Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
²¹ Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
²² Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli County, Taiwan, ROC.
²³ Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
²⁴ Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
²⁵ University Hospital of Tübingen, Tübingen, Germany.
²⁶ Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich, Neuherberg, Germany.
²⁷ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁸ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

^# Contributed equally.

PMID: 37798471
PMCID: PMC10556101
DOI: 10.1038/s43856-023-00360-3

Abstract

Background: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.

Methods: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.

Results: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.

Conclusion: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

Plain language summary

In people with type 2 diabetes there may be differences in the way people present, including for example, their symptoms, body weight or how much insulin they make. We looked at recent publications describing research in this area to see whether it is possible to separate people with type 2 diabetes into different subgroups and, if so, whether these groupings were useful for patients. We found that it is possible to group people with type 2 diabetes into different subgroups and being in one subgroup can be more strongly linked to the likelihood of developing complications over others. This might mean that in the future we can treat people in different subgroups differently in ways that improves their treatment and their health but it requires further study.

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Conflict of interest statement

The authors declare the following conflicts of interest. S.M. has investigator-initiated funding from DexCom, has received speaker fees (donated to institution) from Sanofi for a scientific talk over which she had full control of content and serves on the Board of Trustees for the Diabetes Research & Wellness Foundation (UK); R.W. declares lecture fees from Novo Nordisk, Sanofi and Eli Lilly. He served on an advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi, Eli Lilly, and NovoNordisk; S.J.C. reports a close family member employed by a Johnson & Johnson company; R.H.S. reports fees from Novo Nordisk and Amgen; L.K.B. has received consulting honoraria from Bayer, Novo Nordisk, Sanofi, Lilly, and Xeris; W.H.H.S. reported as Advisor and/or Speaker for AstraZeneca, Bayer HealthCare, Boehringer Ingelheim Pharmaceuticals., Daiichi-Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda Pharmaceutical Company; N.S. is Senior Associate Editor of Diabetes and has received speaking honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer and Sanofi for scientific talks over which he had full control of content; M.G. has served on an advisory board for Nestle Health Science; E.S. is a Deputy Editor of Diabetes Care and a member of the editorial board of Diabetologia and receives payments from Wolters Kluwer for chapters and laboratory monographs in UpToDate on measurements of glycemic control and screening tests for type 2 diabetes; J.C.F. has received speaking honoraria from AstraZeneca and Novo Nordisk for scientific talks over which he had full control of content; J.B.M. is an Academic Associate for Quest Inc. Diagnostics R&D; M.U. reports an unpaid collaborator with AstraZeneca. All other authors have no disclosures. A.L. reports a close family member employed by Merck & Co., Inc.

Figures

**Fig. 1. PRISMA systematic review attrition diagram.**
A This shows the flow diagram for simple approaches to subclassification and B Complex approaches.

**Fig. 2. Schematic overview of approaches used to subclassify type 2 diabetes.**
The figure summarises simple approaches that have been taken to subclassify type 2 diabetes and complex approaches. HbA1c glycated haemoglobin, BMI body mass index, GAD-65 glutamic acid decarboxylase-65 antibodies.

**Fig. 3. Main characteristics of diabetes clusters derived using a modified set of clustering variables, compared to original ‘Alhqvist’ clusters.**
Clustering variables denoted in blue are consistent across the different studies, those in black are unique to the particular study outlined. A greyed-out box indicates that the indicated diabetes cluster was replicated from the Ahlqvist study, a dark blue box indicates a new diabetes cluster. GAD, glutamic decarboxylase antibody; BMI, body mass index; HDL, high-density lipoprotein cholesterol; HOMA2-IR/B, homoeostasis model assessment-2 insulin resistance/beta cell function. SAID, severe autoimmune diabetes; SIDD, severe insulin-deficient diabetes; SIRD, severe insulin resistant diabetes; MOD, mild obesity-related diabetes; MARD, mild age-related diabetes.

See this image and copyright information in PMC

Update of

Systematic review of precision subclassification of type 2 diabetes.
Misra S, Wagner R, Ozkan B, Schön M, Sevilla-Gonzalez M, Prystupa K, Wang CC, Kreienkamp RJ, Cromer SJ, Rooney MR, Duan D, Thuesen ACB, Wallace AS, Leong A, Deutsch AJ, Andersen MK, Billings LK, Eckel RH, Sheu WH, Hansen T, Stefan N, Goodarzi MO, Ray D, Selvin E, Florez JC; ADA/EASD PMDI; Meigs JB, Udler MS. Misra S, et al. medRxiv [Preprint]. 2023 Apr 20:2023.04.19.23288577. doi: 10.1101/2023.04.19.23288577. medRxiv. 2023. Update in: Commun Med (Lond). 2023 Oct 5;3(1):138. doi: 10.1038/s43856-023-00360-3. PMID: 37131632 Free PMC article. Updated. Preprint.

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1. ElSayed NA, et al. 2. Classification and diagnosis of diabetes: standards of care in diabetes-2023. Diabetes Care. 2023;46:S19–S40. - PMC - PubMed
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1. Prando R, et al. Is type 2 diabetes a different disease in obese and nonobese patients? Diabetes Care. 1998;21:1680–1685. - PubMed

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Precision subclassification of type 2 diabetes: a systematic review

Collaborators

Affiliations

Precision subclassification of type 2 diabetes: a systematic review

Authors

Collaborators

Affiliations

Abstract

Plain language summary

Conflict of interest statement

Figures

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources