Title: Fibrosis status, extrahepatic multimorbidity and all-cause mortality in 53093 women
and 74377 men with metabolic dysfunction associated steatotic liver disease (MASLD) in UK
Biobank
Version: 1 Date: 26 May 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
1. Definition and Operationalization of MASLD
The study uses a proxy definition of MASLD based on FLI #60 and cardiometabolic risk factors,
rather than direct imaging or histological confirmation. While practical in large-scale cohorts,
this approach may result in misclassification bias, especially considering FLI's limitations
in distinguishing MASLD from other steatotic conditions.Acknowledge the potential for
misclassification more explicitly in the limitations. Consider validating MASLD identification
against imaging data for a sub-cohort where available.
2. Use of FIB-4 as a Surrogate for Fibrosis
The FIB-4 score is a useful non-invasive tool, but it lacks sensitivity in early fibrosis
stages and is affected by age. The age stratification partially addresses this, but the tool’s
limited diagnostic accuracy—especially in distinguishing intermediate from advanced fibrosis
—remains a concern.
Authors should elaborate more critically on the limitations of using FIB-4 for fibrosis staging in
a general population cohort and consider presenting sensitivity analyses using alternative non-
invasive fibrosis indices (e.g., NAFLD fibrosis score, APRI).
3. Cross-sectional analysis of Multimorbidity
The analysis linking FIB-4 to multimorbidity is cross-sectional, precluding inference on
temporal or causal relationships. This is especially problematic given age-related confounding
and possible reverse causation (e.g., multimorbidity impacting liver biochemistry).
This limitation should be acknowledged. If feasible, include longitudinal analyses to assess
incident multimorbidity following FIB4 stratification.
4. Interpretation of Mediation by Multimorbidity
The mediation analysis attempting to quantify how much multimorbidity “accounts for”
the FIB-4–mortality association lacks formal causal mediation modeling. Simply comparing
coefficient attenuation may be misleading. Consider using formal mediation analysis
frameworks (e.g., counterfactual-based mediation models) or explicitly limit interpretation to
exploratory purposes.
5. Potential Residual Confounding
Despite extensive adjustment, important clinical variables are missing—such as baseline liver
disease severity beyond FIB-4, medication use (e.g., statins, antihypertensives), and lifestyle
changes over time. These may confound associations with mortality.Acknowledge residual
confounding as a key limitation. If data permits, adjust for medications and changes in covariates
during follow-up.
6. Incomplete Exploration of Sex Differences
The manuscript mentions sex differences but does not sufficiently explore biological or clinical
mechanisms underlying the stronger associations in females. The analyses stop at reporting
interaction terms and hazard ratios. Expand the discussion to consider potential sex-specific
pathophysiological mechanisms or differences in healthcare access/utilization.
7. Limited Generalizability
The UK Biobank cohort is known to be healthier and less ethnically diverse than the general
population, which limits external validity. This issue is not adequately addressed. Acknowledge
this selection bias and discuss its implications for generalizability to broader, more diverse
populations.
8. Presentation and Clarity
The manuscript is dense, and critical definitions (e.g., exact components of the 47 LTCs list)
are only in supplementary materials. The methodology section is particularly verbose and could
hinder reproducibility.
Summarize key LTC categories in the main text or a table. Consider condensing and streamlining
the methods section to improve clarity.
Title: Fibrosis status, extrahepatic multimorbidity and all-cause mortality in 53093 women
and 74377 men with metabolic dysfunction associated steatotic liver disease (MASLD) in UK
Biobank
Version: 1 Date: 26 May 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
1. Definition and Operationalization of MASLD
The study uses a proxy definition of MASLD based on FLI #60 and cardiometabolic risk factors,
rather than direct imaging or histological confirmation. While practical in large-scale cohorts,
this approach may result in misclassification bias, especially considering FLI's limitations
in distinguishing MASLD from other steatotic conditions.Acknowledge the potential for
misclassification more explicitly in the limitations. Consider validating MASLD identification
against imaging data for a sub-cohort where available.
2. Use of FIB-4 as a Surrogate for Fibrosis
The FIB-4 score is a useful non-invasive tool, but it lacks sensitivity in early fibrosis
stages and is affected by age. The age stratification partially addresses this, but the tool’s
limited diagnostic accuracy—especially in distinguishing intermediate from advanced fibrosis
—remains a concern.
Authors should elaborate more critically on the limitations of using FIB-4 for fibrosis staging in
a general population cohort and consider presenting sensitivity analyses using alternative non-
invasive fibrosis indices (e.g., NAFLD fibrosis score, APRI).
3. Cross-sectional analysis of Multimorbidity
The analysis linking FIB-4 to multimorbidity is cross-sectional, precluding inference on
temporal or causal relationships. This is especially problematic given age-related confounding
and possible reverse causation (e.g., multimorbidity impacting liver biochemistry).
This limitation should be acknowledged. If feasible, include longitudinal analyses to assess
incident multimorbidity following FIB4 stratification.
4. Interpretation of Mediation by Multimorbidity
The mediation analysis attempting to quantify how much multimorbidity “accounts for”
the FIB-4–mortality association lacks formal causal mediation modeling. Simply comparing
coefficient attenuation may be misleading. Consider using formal mediation analysis
frameworks (e.g., counterfactual-based mediation models) or explicitly limit interpretation to
exploratory purposes.
5. Potential Residual Confounding
Despite extensive adjustment, important clinical variables are missing—such as baseline liver
disease severity beyond FIB-4, medication use (e.g., statins, antihypertensives), and lifestyle
changes over time. These may confound associations with mortality.Acknowledge residual
confounding as a key limitation. If data permits, adjust for medications and changes in covariates
during follow-up.
6. Incomplete Exploration of Sex Differences
The manuscript mentions sex differences but does not sufficiently explore biological or clinical
mechanisms underlying the stronger associations in females. The analyses stop at reporting
interaction terms and hazard ratios. Expand the discussion to consider potential sex-specific
pathophysiological mechanisms or differences in healthcare access/utilization.
7. Limited Generalizability
The UK Biobank cohort is known to be healthier and less ethnically diverse than the general
population, which limits external validity. This issue is not adequately addressed. Acknowledge
this selection bias and discuss its implications for generalizability to broader, more diverse
populations.
8. Presentation and Clarity
The manuscript is dense, and critical definitions (e.g., exact components of the 47 LTCs list)
are only in supplementary materials. The methodology section is particularly verbose and could
hinder reproducibility.
Summarize key LTC categories in the main text or a table. Consider condensing and streamlining
the methods section to improve clarity.
Please review this paper.
user
Title: Fibrosis status, extrahepatic multimorbidity and all-cause mortality in 53093 women
and 74377 men with metabolic dysfunction associated steatotic liver disease (MASLD) in UK
Biobank
Version: 1 Date: 26 May 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
1. Definition and Operationalization of MASLD
The study uses a proxy definition of MASLD based on FLI #60 and cardiometabolic risk factors,
rather than direct imaging or histological confirmation. While practical in large-scale cohorts,
this approach may result in misclassification bias, especially considering FLI's limitations
in distinguishing MASLD from other steatotic conditions.Acknowledge the potential for
misclassification more explicitly in the limitations. Consider validating MASLD identification
against imaging data for a sub-cohort where available.
2. Use of FIB-4 as a Surrogate for Fibrosis
The FIB-4 score is a useful non-invasive tool, but it lacks sensitivity in early fibrosis
stages and is affected by age. The age stratification partially addresses this, but the tool’s
limited diagnostic accuracy—especially in distinguishing intermediate from advanced fibrosis
—remains a concern.
Authors should elaborate more critically on the limitations of using FIB-4 for fibrosis staging in
a general population cohort and consider presenting sensitivity analyses using alternative non-
invasive fibrosis indices (e.g., NAFLD fibrosis score, APRI).
3. Cross-sectional analysis of Multimorbidity
The analysis linking FIB-4 to multimorbidity is cross-sectional, precluding inference on
temporal or causal relationships. This is especially problematic given age-related confounding
and possible reverse causation (e.g., multimorbidity impacting liver biochemistry).
This limitation should be acknowledged. If feasible, include longitudinal analyses to assess
incident multimorbidity following FIB4 stratification.
4. Interpretation of Mediation by Multimorbidity
The mediation analysis attempting to quantify how much multimorbidity “accounts for”
the FIB-4–mortality association lacks formal causal mediation modeling. Simply comparing
coefficient attenuation may be misleading. Consider using formal mediation analysis
frameworks (e.g., counterfactual-based mediation models) or explicitly limit interpretation to
exploratory purposes.
5. Potential Residual Confounding
Despite extensive adjustment, important clinical variables are missing—such as baseline liver
disease severity beyond FIB-4, medication use (e.g., statins, antihypertensives), and lifestyle
changes over time. These may confound associations with mortality.Acknowledge residual
confounding as a key limitation. If data permits, adjust for medications and changes in covariates
during follow-up.
6. Incomplete Exploration of Sex Differences
The manuscript mentions sex differences but does not sufficiently explore biological or clinical
mechanisms underlying the stronger associations in females. The analyses stop at reporting
interaction terms and hazard ratios. Expand the discussion to consider potential sex-specific
pathophysiological mechanisms or differences in healthcare access/utilization.
7. Limited Generalizability
The UK Biobank cohort is known to be healthier and less ethnically diverse than the general
population, which limits external validity. This issue is not adequately addressed. Acknowledge
this selection bias and discuss its implications for generalizability to broader, more diverse
populations.
8. Presentation and Clarity
The manuscript is dense, and critical definitions (e.g., exact components of the 47 LTCs list)
are only in supplementary materials. The methodology section is particularly verbose and could
hinder reproducibility.
Summarize key LTC categories in the main text or a table. Consider condensing and streamlining
the methods section to improve clarity.
assistant