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Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization

Name: Αlpha¹ Rigor Record — Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization
Item: Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization
Rating: 59
Author: Αlpha¹

Wang X, Chen Q, Liu Y, Sun J, Li J, Zhao P, Cai L, Liu W, Yang Z, Wang Z, Lv H.

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Αlpha¹ Rigor Review — 2.5★ (Weak), 0 critical, 6 high issues for “Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization”

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Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · August 5, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

2.5 / 5

Weak — serious problems found

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ReportingBiological variables not met−0.5★
ReportingData & code availability not met−0.5★
ReportingStudy design partially met−0.25★
ReportingStatistical analysis partially met−0.25★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.15.0Source: full text

Not verified in this report

References were not verified against Crossref/OpenAlex.
Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Problems surfaced6 types

Biological variables not reported
Data and code not shared
Statistical reporting gaps (tests, assumptions, effect sizes)
Study-design details incomplete (controls, blinding, power)
Internal contradictions in the reported numbers
Other integrity concern

This Αlpha¹ Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The paper is a Mendelian randomization study with a clear scientific premise and adequate reporting of methods and limitations. However, it lacks demographic details for the study populations, does not provide exact p-values or confidence intervals in the text, and has a vague data availability statement with no code sharing.

The evaluation was based on three independent AI reviewer runs and a copyedit pass. Ethical approvals were not applicable as the study uses public summary data. The reviewers diverged on study design (pass vs. warn) and statistical analysis (pass vs. warn); the synthesized statuses reflect the preponderance of evidence.

11 major claims checked against the paper's own evidence: all adequately supported.

2 integrity concerns flagged (0 high).

Reporting

Eight Dimensions3 pass · 2 warn · 2 fail

The introduction reviews the literature on brain aging, highlighting the heterogeneity and limitations of cross-sectional studies. It clearly states the rationale for using MR to overcome confounding and reverse causation. The paper also discusses how MR addresses the limitations of prior research.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific foundation by citing prior research on brain aging and the limitations of observational studies, and provides a logical rationale for using Mendelian randomization.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“Cross-sectional studies alone are insufficient to chart the dynamic changes in brain aging. ... observational studies have various confounding factors and biases, which are almost inevitable.”

direct quote[Introduction, paragraph 4]

“MR is a method that utilizes genome-wide association study (GWAS) data to analyse and mitigate discrepancies in epidemiological research.”

PASSReviewer 2· 95% conf

The paper establishes a clear scientific foundation, citing prior work on brain aging and limitations of observational studies, and justifies the use of Mendelian randomization.

Evidence

direct quote[Introduction, paragraph 2]

“A large number of imaging-related studies are dedicated to revealing age-related changes, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) or the Rotterdam study”

direct quote[Introduction, paragraph 3]

“Therefore, Mendelian randomization (MR) was used to explore the causal relationship between age (aging) and brain morphometric changes on neuroimaging.”

direct quote[Introduction, paragraph 2]

“In addition, observational studies have various confounding factors and biases, which are almost inevitable.”

PASSReviewer 3· 90% conf

The paper clearly establishes its scientific foundation by citing prior research on brain aging, acknowledging limitations of observational studies, and providing a rationale for using Mendelian randomization.

Evidence

direct quote[Introduction, paragraph 2]

“A large number of imaging-related studies are dedicated to revealing age-related changes, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) or the Rotterdam study”

direct quote[Introduction, paragraph 3]

“If we base our understanding of age-related brain changes on neurodegenerative diseases alone, the regional changes in brain atrophy caused by these diseases will be more extensive, which cannot explain why these changes are completely caused by aging. There are many risk factors related to aging and brain health status, so it is difficult to eliminate the influence of confounding factors and explore the causal link between aging and brain alterations.”

direct quote[Strength and limitations]

“Although more and more studies are using MR analysis, this method itself is imperfect. The use of test hypotheses cannot avoid the generation of false positive results, which can lead to phenomena that do not match the facts”

The paper uses two-sample MR with IVW as primary analysis, MR-PRESSO for outlier removal, and sensitivity analyses. However, no a priori power calculation is reported, and the inclusion/exclusion criteria for the GWAS datasets are not explicitly stated. Outlier handling via MR-PRESSO is described. Randomization, blinding, and other experimental design elements are not applicable to this MR study.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsN/A

outlier handlingADEQUATE

randomization unitN/A

inclusion exclusionNOT REPORTED

randomization methodN/A

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The study design is appropriate for a Mendelian randomization analysis, with clear inclusion/exclusion criteria for SNPs and sensitivity analyses to address pleiotropy and heterogeneity.

Evidence

paraphrase[MR statistical analysis, paragraph 1]

“Exposure factors were filtered using a threshold of 5 × 10^-8”

paraphrase[MR statistical analysis, paragraph 1]

“SNPs and outliers associated with brain imaging, as identified by MR-PRESSO ... were excluded.”

direct quote[MR statistical analysis, paragraph 1]

“heterogeneity was evaluated, and multiple effects were tested using three distinct techniques: IVW, MR-Egger and weighted median regression.”

WARNReviewer 2· 85% conf

The study design is appropriate for MR, but key elements like power analysis and inclusion/exclusion criteria are not reported, and only outlier handling is adequately described.

Evidence

direct quote[Materials and methods, MR statistical analysis]

“SNPs and outliers associated with brain imaging, as identified by MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), were excluded.”

absence[Materials and methods]

No power analysis is reported.

absence[Materials and methods]

Inclusion/exclusion criteria for the GWAS datasets are not stated.

WARNReviewer 3· 80% conf

The study design lacks a priori power analysis and explicit inclusion/exclusion criteria for the MR analysis, but outlier handling via MR-PRESSO is adequately reported.

Evidence

absence[Materials and methods]

No power analysis reported.

absence[Materials and methods]

No inclusion/exclusion criteria for the MR analysis described.

direct quote[Materials and methods, MR statistical analysis]

“SNPs and outliers associated with brain imaging, as identified by MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), were excluded.”

The paper states that the age GWAS includes both males and females, but no demographics are provided for the brain imaging GWAS from UK Biobank. Age, weight, health status, and race/ethnicity are not reported. Since the study relies on publicly available summary statistics, the original cohort characteristics are not described, which limits assessment of generalizability and potential confounding.

Sub-criteria

demographicsNOT REPORTED

sex reportedINADEQUATE

sex justifiedN/A

age weight healthNOT REPORTED

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 65% conf

The paper does not report key demographic and health characteristics of the participants in the brain imaging GWAS, which are essential for understanding the study population.

Evidence

paraphrase[GWAS statistics of brain imaging derived phenotypes, paragraph 1]

“The paper describes the UK Biobank as a major prospective epidemiological study but does not provide age, sex, or health status of the participants used in the imaging GWAS.”

FAILReviewer 2· 90% conf

The paper does not report key biological variables such as age, sex, and health status for the brain imaging GWAS sample, and only briefly mentions sex for the age GWAS.

Evidence

direct quote[Materials and methods, GWAS statistics for age]

“In the GWAS for age, the sample size was 11 856 individuals, including both males and females”

absence[Materials and methods]

Age, weight, and health status of participants are not reported.

absence[Materials and methods]

No demographics (race/ethnicity, comorbidities) are reported for the brain imaging GWAS.

WARNReviewer 3· 70% conf

Sex is reported for the age GWAS, but age distribution and other demographics are not provided for the study participants.

Evidence

direct quote[Materials and methods, GWAS summary statistics for age]

“In the GWAS for age, the sample size was 11 856 individuals, including both males and females”

absence[Materials and methods, GWAS summary statistics for age]

Age distribution not reported.

paraphrase[Materials and methods, GWAS summary statistics for age]

“The paper mentions European genetic background but no other demographics.”

The paper uses only publicly available summary statistics from the UK Biobank and MRC-IEU. No individual-level data were accessed. The UK Biobank has its own ethics approval, but the current study does not generate new subject data, making ethics sub-criteria not applicable.

Sub-criteria

iacuc statementN/A

informed consentN/A

irb ethics statementN/A

regulatory complianceN/A

Per reviewer (3) — the votes behind the verdict

N/AReviewer 1· 90% conf

This study uses only publicly available, de-identified GWAS summary statistics, so no new ethical approval is required. The original data source (UK Biobank) has ethics approval.

Evidence

direct quote[GWAS statistics of brain imaging derived phenotypes, paragraph 1]

“The UK Biobank is a major prospective epidemiological study that includes multimodal brain imaging, genetics and sustained health outcomes, which is approved by the Northwest Multi-Centre Research Ethics Committee.”

N/AReviewer 2· 95% conf

The study is a secondary analysis of publicly available GWAS summary data, so no new ethics approval is required. The paper mentions the UK Biobank's ethics approval.

Evidence

direct quote[Materials and methods, GWAS statistics of brain imaging derived phenotypes]

N/AReviewer 3· 95% conf

The study uses public GWAS summary statistics, so no additional ethical approval is required; the UK Biobank data source has its own ethics approval.

Evidence

direct quote[Materials and methods, GWAS statistics of brain imaging derived phenotypes]

paraphrase[Materials and methods]

“The study uses publicly available GWAS summary statistics from UK Biobank and MRC-IEU.”

The paper reports the use of R version 4.2.1 and the 'TwoSampleMR' package for statistical analysis. It also references the Oxford Brain Imaging Genetics web server. No antibodies, cell lines, or other wet-lab reagents were used, so those criteria are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedN/A

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study identifies the key software tools used (R version 4.2.1 and the TwoSampleMR package), and no other biological or chemical resources are applicable.

Evidence

paraphrase[MR statistical analysis, paragraph 2]

“All statistical analyses including MR and data visualization were performed using the ‘TwoSampleMR’ (https://github.com/MRCIEU/TwoSampleMR) in R (version 4.2.1).”

PASSReviewer 2· 95% conf

The software tools used are adequately identified, and no other biological or chemical resources are applicable.

Evidence

direct quote[Materials and methods, MR statistical analysis]

“All statistical analyses including MR and data visualization were performed using the ‘TwoSampleMR’ ( https://github.com/MRCIEU/TwoSampleMR ) in R (version 4.2.1).”

PASSReviewer 3· 90% conf

The only key resource used is software, which is adequately identified with version and repository URL.

Evidence

paraphrase[Materials and methods, MR statistical analysis]

“All statistical analyses including MR and data visualization were performed using the ‘TwoSampleMR’ (https://github.com/MRCIEU/TwoSampleMR) in R (version 4.2.1).”

The paper names the IVW, MR-Egger, and weighted median methods. It reports p-values only as thresholds (P < 0.05) rather than exact values. Effect sizes (β) are reported but not always with confidence intervals; the forest plots show CIs, but the text does not. The software is identified. The paper does not report sample sizes for each outcome in the imaging GWAS, and the assumptions of the instrumental variable methods are not explicitly discussed, though pleiotropy and heterogeneity are tested. No individual data points are presented.

Sub-criteria

tests namedADEQUATE

exact p valuesNOT REPORTED

effect sizes ciINADEQUATE

data presentationNOT REPORTED

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

While the statistical methods are named and sensitivity analyses are performed, the paper does not report exact p-values or consistently provide confidence intervals for effect sizes, and assumptions are not explicitly verified.

Evidence

paraphrase[Results, paragraphs 1-3]

“Results with a bilateral P-value of <0.05 were assessed to determine statistical significance.”

direct quote[Results, paragraph 1]

“a positive trend of increasing white matter hyperintensities (WMHs) with advancing age was found (IVW, β = 0.151, P < 0.05).”

WARNReviewer 2· 80% conf

Statistical tests are named and software identified, but assumptions are only partially verified, exact p-values are not reported, effect sizes lack confidence intervals, and data presentation is incomplete.

Evidence

direct quote[Materials and methods, MR statistical analysis]

“In MR analysis, heterogeneity was evaluated, and multiple effects were tested using three distinct techniques: IVW, MR-Egger and weighted median regression.”

direct quote[Results, paragraph 1 and throughout]

“Results with a bilateral P -value of <0.05 were assessed to determine statistical significance.”

direct quote[Results, paragraph 1]

“a positive trend of increasing white matter hyperintensities (WMHs) with advancing age was found (IVW, β = 0.151, P < 0.05).”

PASSReviewer 3· 85% conf

Statistical tests are named, assumptions are verified with sensitivity analyses, and effect sizes are presented with confidence intervals in forest plots. However, p-values are reported only as thresholds (<0.05) rather than exact values.

Evidence

direct quote[Materials and methods, MR statistical analysis]

“In MR analysis, heterogeneity was evaluated, and multiple effects were tested using three distinct techniques: IVW, MR-Egger and weighted median regression.”

direct quote[Materials and methods, MR statistical analysis]

“To comprehensively evaluate pleiotropy in the MR test, the MR Egger intercept test and retention analysis were applied. Cochran’s Q test was used in each MR analysis to detect heterogeneity between exposure and outcome”

paraphrase[Results]

“Results with a bilateral P-value of <0.05 were assessed to determine statistical significance.”

The paper states that data are available from the corresponding author on reasonable request, which is considered inadequate. No repository deposit or accession numbers are provided for the GWAS summary statistics used. The code is limited to referencing the TwoSampleMR package; no custom scripts are shared. The paper also references the UK Biobank brain imaging website but does not provide a direct link to the specific data used.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

The data availability statement is vague, no data are deposited in a repository, no accession numbers are provided, and no custom code is shared.

Evidence

direct quote[Data Availability Statement]

“The datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.”

paraphrase[GWAS statistics of brain imaging derived phenotypes, paragraph 1]

“The paper refers to the Oxford Brain Imaging Genetics web server but does not provide accession numbers for the summary statistics.”

FAILReviewer 2· 90% conf

The data availability statement is vague ('available on reasonable request'), no repository deposit or accession numbers are provided, and custom code is not shared.

Evidence

direct quote[Data Availability Statement]

“The datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.”

absence[Data Availability Statement]

No repository deposit or accession numbers are provided.

absence[Materials and methods]

No custom code is shared.

FAILReviewer 3· 90% conf

The data availability statement is vague ('on reasonable request'), no data are deposited in a repository, no accession numbers are provided, and custom code is not shared.

Evidence

direct quote[Data Availability Statement]

“The datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.”

absence[Data Availability Statement]

No repository deposit or accession numbers.

absence[Materials and methods]

No custom code repository.

The paper includes a STROBE-MR statement, comprehensive methods, results, and a dedicated limitations section. All pre-specified outcomes are reported, including negative results for microbleeds. Funding sources and conflicts of interest are stated.

Sub-criteria

funding coiADEQUATE

trial registrationN/A

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The paper follows the STROBE-MR reporting guideline, describes methods adequately, reports all outcomes including null results, discusses limitations, and provides funding information, though a conflict of interest statement is missing.

Evidence

direct quote[Materials and methods, paragraph 1]

“In this study, we followed the principles of the STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomization) statement”

direct quote[Strength and limitations, paragraph 2]

“However, there are inevitably some limitations: (i) although more and more studies are using MR analysis, this method itself is imperfect.”

direct quote[Results, paragraph 4]

“For cerebral microbleeds (SWI display), we did not find positive results (IVW, P > 0.05).”

PASSReviewer 2· 85% conf

The paper follows STROBE-MR guidelines, reports all outcomes, discusses limitations, and provides proportional conclusions, but methods completeness and funding/COI statements are lacking.

Evidence

direct quote[Materials and methods, paragraph 1]

“In this study, we followed the principles of the STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomization) statement”

direct quote[Discussion, Strength and limitations]

“However, there are inevitably some limitations: (i) although more and more studies are using MR analysis, this method itself is imperfect.”

absence[End of manuscript]

No conflicts-of-interest statement is provided.

PASSReviewer 3· 90% conf

Methods are detailed, STROBE-MR is followed, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are provided.

Evidence

direct quote[Materials and methods]

“In this study, we followed the principles of the STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomization) statement”

paraphrase[Strength and limitations]

“However, there are inevitably some limitations: (i) although more and more studies are using MR analysis, this method itself is imperfect...”

paraphrase[Funding]

“This work was supported by Grant No. 61931013 from the National Natural Science Foundation of China, No. [2015] 160 from Beijing Scholars Program...”

13 copyedit issues flagged: mostly clarity, grammar, consistency.

Reproducibility

3 data/code links checked; 3 live.

No trial/study registration detected. Reporting guideline cited: STROBE.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

In a post-publication audit, the paper is moderately robust but has notable reporting gaps. An informed reader should weigh the missing participant demographics and the lack of exact p-values and confidence intervals in the text. The authors should consider issuing a correction or supplement to address the data and code availability statement, and to provide demographic details for the GWAS samples.

1.
HIGHdata code
Replace the vague data availability statement ('available on reasonable request') with a concrete repository link (e.g., Zenodo, Figshare) or managed-access platform with conditions, and deposit the GWAS summary statistics used.
The current statement is insufficient for reproducibility and would not meet the standards of most journals; a correction or supplement is warranted.
2.
HIGHdata code
Deposit the custom analysis scripts (e.g., R code for SNP selection, MR-PRESSO, and visualization) in a public repository (e.g., GitHub, Zenodo) with a persistent identifier.
Without code, the analysis cannot be fully reproduced, undermining the study's robustness.
3.
HIGHrigor
Report the demographic characteristics (age, sex distribution, health status, race/ethnicity) of the participants in the UK Biobank brain imaging GWAS sample in the Methods section.
Missing demographics limit assessment of generalizability and potential confounding, and are essential for interpreting the study's applicability.
4.
HIGHstatistics
Provide exact p-values (e.g., p = 0.023) instead of thresholds (P < 0.05) for all reported results in the text and tables.
Threshold-only p-values obscure the strength of evidence and are considered imprecise reporting; exact values allow readers to assess significance appropriately.
5.
HIGHstatistics
Include 95% confidence intervals for all causal effect estimates (β) in the Results text, not just in forest plots.
Confidence intervals convey precision and are standard for reporting effect sizes; their absence in the text is a notable gap.
6.
HIGHreporting
Add a formal conflicts-of-interest statement (e.g., 'The authors declare no competing interests') in the Declarations section.
A missing COI statement is a standard reporting requirement and its absence may raise concerns about undisclosed conflicts.
7.
MEDIUMrigor
Report a power analysis or sample size justification for the MR analysis, including expected effect sizes and number of SNPs, in the Methods section.
A power analysis helps assess whether the study was adequately powered to detect the hypothesized effects.
8.
MEDIUMrigor
State the inclusion/exclusion criteria for the GWAS datasets used (e.g., UK Biobank, MRC-IEU) in the Methods section.
Explicit dataset selection criteria are needed to understand the study population and potential biases.
9.
MEDIUMstatistics
Address multiple testing across the many outcomes and brain regions tested, e.g., by applying a Bonferroni or FDR correction, or by clearly stating that the results are exploratory.
Without correction, the risk of false positives is elevated, and readers should be informed of this limitation.
10.
MEDIUMcopyedit
Correct typographical errors: change 'intragalarine' to 'intracalcarine' and 'occidental' to 'occipital' in the Results section.
Typographical errors in anatomical terms could mislead readers and undermine precision.
11.
MEDIUMcopyedit
Standardize the abbreviation for white matter hyperintensities to 'WMHs' throughout the manuscript (currently sometimes 'WHMs').
Inconsistent abbreviations cause confusion and should be harmonized.
12.
LOWreporting
Clarify the potential impact of sample overlap between the exposure and outcome GWAS in the limitations section.
The two-sample MR design assumes no sample overlap; the paper should discuss whether this assumption is violated and the potential consequences.

Full text (31,928 chars)Analyzed: Aug 5, 2026

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