Population‐based cohort validation and replication reveals limited generalizability of cluster‐based
                    MASLD
                    subtypes

Junjie Wu; Weiwei Xu; Guyu Zeng; Junfeng Wang

doi:10.1111/dom.70448

journal article Open Access Jan 07, 2026

Population‐based cohort validation and replication reveals limited generalizability of cluster‐based MASLD subtypes

Junjie Wu

Weiwei Xu

Guyu Zeng Junfeng Wang

Diabetes, Obesity and Metabolism Vol. 28 No. 4 pp. 2735-2743 · Wiley

View at Publisher Save 10.1111/dom.70448

Abstract

Abstract

Aims
MASLD, defined as a steatotic liver disease in the presence of one or more cardiometabolic risk factors and the absence of harmful alcohol intake, exhibits substantial heterogeneity complicating risk stratification. A prior clustering model proposed liver‐specific and cardiometabolic subtypes, yet its generalizability and prognostic relevance remain unclear in the broader population. We aim to validate and replicate the prior approach in a nationally representative U.S. cohort.

Materials and methods
We included 3300 participants with MASLD from NHANES III. For validation, participants were assigned to previously defined clusters using published medoids. For replication, de novo clusters were derived using the Partitioning Around Medoids algorithm. Cox proportional hazards models accounting for the complex survey design of NHANES III were used to estimate hazard ratios for all‐cause, cardiovascular‐related, and diabetes‐related mortality across clusters.

Results
Individual cluster assignments showed limited reproducibility between the validation and replication analyses, although the overall clustering pattern was preserved. Based on clinical profiles, clusters were categorized into cardiometabolic, liver‐specific, and other subtypes. The cardiometabolic cluster consistently showed higher risks in both analyses, while the liver‐specific cluster showed no significant associations.

Conclusions
The subtyping model demonstrated limited generalizability. Nonetheless, the consistent identification of broad cardiometabolic and liver‐specific patterns suggests potential value for risk stratification, pending further validation.

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References

20

[1]

The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review

Zobair M. Younossi, Pegah Golabi, James M. Paik et al.

Hepatology 10.1097/hep.0000000000000004

[2]

10.1016/s2468‐1253(22)00165‐0

[3]

10.1016/s0140‐6736(20)32511‐3

[4]

10.1016/s2213‐8587(22)00003‐1

[5]

10.1136/gutjnl‐2023‐330595

[6]

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease

Paul Angulo, David E. Kleiner, Sanne Dam-Larsen et al.

Gastroenterology 10.1053/j.gastro.2015.04.043

[7]

Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD

Hannes Hagström, Patrik Nasr, Mattias Ekstedt et al.

Journal of Hepatology 10.1016/j.jhep.2017.07.027

[8]

10.1002/hep.23314

[9]

10.1038/s41591‐024‐03283‐1

[10]

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies

Erik von Elm, Douglas G. Altman, Matthias Egger et al.

Journal of Clinical Epidemiology 10.1016/j.jclinepi.2007.11.008

[11]

Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS) (1996)

[12]

National Center for Health Statistics Division of Analysis and Epidemiology.NHANES III Public‐use Linked Mortality Files. Hyattsville Maryland; 2019.https://www.cdc.gov/nchs/data-linkage/mortality-public.htm

[13]

EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)

Frank Tacke, Paul Horn, Vincent Wai-Sun Wong et al.

Journal of Hepatology 10.1016/j.jhep.2024.04.031

[14]

National Center for Health Statistics.Third National Health and Nutrition Examination Survey: Hepatic Steatosis Ultrasound Images Assessment Procedures Manual; 2010.http://www.cdc.gov/nchs/data/nhanes/nhanes3/Hepatic_Steatosis_Ultrasound_Procedures_Manual.pdf

[15]

10.1002/hep.32642

[16]

Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge

William T Friedewald, Robert I Levy, Donald S Fredrickson

Clinical Chemistry 10.1093/clinchem/18.6.499

[17]

10.1016/j.csda.2006.11.025

[18]

10.1002/widm.1444

[19]

10.1038/s41591‐024‐03284‐0

[20]

10.1097/hep.0000000000000

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Citations

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References

Details

Published: Jan 07, 2026
Vol/Issue: 28(4)
Pages: 2735-2743
License: View

Authors

J

Junjie Wu

Utrecht University Utrecht the Netherlands

W

Weiwei Xu

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht the Netherlands

G

Guyu Zeng

National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

J

Junfeng Wang

Department of Epidemiology CAPHRI Care and Public Health Research Institute, Maastricht University Maastricht the Netherlands

Cite This Article

Junjie Wu, Weiwei Xu, Guyu Zeng, et al. (2026). Population‐based cohort validation and replication reveals limited generalizability of cluster‐based MASLD subtypes. Diabetes, Obesity and Metabolism, 28(4), 2735-2743. https://doi.org/10.1111/dom.70448

Population‐based cohort validation and replication reveals limited generalizability of cluster‐based MASLD subtypes

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