Title: Investigating genetic links between blood metabolites and preeclampsia
Version: 3 Date: 07 Jan 2024
Reviewer's report:
Dear respected Authors,
I hope this message finds you well. I have completed my review of your manuscript titled
"[Genetically predicted causality between circulating metabolites in human blood and the risk
of preeclampsia]" and would like to commend you on your effort and dedication to this research
topic. Below, please find my notes and suggestions that I believe will help enhance the quality
and clarity of your work.
Title:
1. Lack of Clarity: The title suggests a definitive establishment of causality, which may not
be fully supported by the evidence from a two-sample Mendelian randomization analysis. This
could be misleading as MR studies typically provide evidence that is suggestive rather than
definitive.
2. Precision and Specificity: The title could benefit from greater specificity regarding the nature
of the study. For instance, it could specify that the study is exploratory or that it identifies
potential causal relationships, rather than asserting predicted causality.
3. Length and Complexity: The title is somewhat lengthy and complex, which might reduce its
accessibility and immediate comprehension to a broader readership. A more concise title could
be more impactful.
4. Technical Terminology: While the title is appropriate for a specialized audience, the use
of terms such as "genetically predicted causality" and "circulating metabolites" might be too
technical for readers who are not experts in genetic epidemiology or metabolomics.
Recommendations for Improvement:
1. Consider rephrasing the title to reflect the exploratory nature of the study, such as "Exploring
the Genetic Associations Between Circulating Metabolites and Preeclampsia Risk."
2. Simplify the language to enhance readability while maintaining scientific accuracy, for
example, "Investigating Genetic Links Between Blood Metabolites and Preeclampsia."
3. Introduce a more cautious tone to align better with the limitations of MR studies, possibly
rewording the title to "Potential Genetic Influence on Metabolite Levels and the Risk of
Preeclampsia."
4. If the paper focuses on specific metabolites or pathways, consider including these in the title
to provide more insight into the study's focus, for example, "The Role of Arachidonate and
Citrulline in Preeclampsia: A Genetic Approach."
Abstract:
1. Lack of Specificity in Reporting SNPs: The abstract does not provide specific information
about the single nucleotide polymorphisms (SNPs) used as instrumental variables in the
Mendelian randomization (MR) analysis. The inclusion of more detailed SNP data could
enhance the transparency and reproducibility of the study.
2. Limited Description of Methods: The methods section of the abstract is concise but lacks
detail on the selection criteria for SNPs, the number of SNPs used, and the number of individuals
involved in the GWAS datasets. This information is crucial to evaluate the robustness of the
MR approach.
3. Unclear Definition of "Suggestively Causal": The term "suggestively causally associated" is
used to describe the relationship between metabolites and PE. It is unclear what criteria were
applied to define this level of association, and the term itself lacks precision, potentially leading
to ambiguity in interpretation of the results.
4. Validation Methodology: While the abstract mentions that results were validated using
another metabolite GWAS dataset, it does not describe the methodology or criteria for validation
in sufficient detail for the reader to understand the validation process.
5. Missing Data on Sensitivity Analyses: The abstract refers to sensitivity analyses performed
to test the robustness of the MR results but fails to provide any data or specific findings from
these analyses, which are crucial to understanding the reliability of the causal inferences.
6. Generalization of Metabolic Pathways: While glycolysis/gluconeogenesis and arginine
biosynthesis are mentioned as significantly enriched pathways, the abstract does not discuss the
specific implications of these pathways in the context of PE. Additional detail on how these
pathways could be mechanistically linked to PE would strengthen the conclusions.
7. Overstatement of Conclusions: The final statement of the abstract claims the identification of
a causal relationship between certain metabolites and PE, which may not be fully supported by
the evidence presented, especially given the preliminary nature of the findings and the need for
further research to confirm causality.
8. Lack of Discussion on Clinical Relevance: Although the abstract alludes to the potential
clinical applications of the findings, it does not discuss the practical implications or how these
metabolites could be integrated into current clinical practice for PE.
9. Missing Consideration of Confounders: The abstract does not address potential confounders
that might influence the association between metabolites and PE, nor does it discuss how these
were accounted for in the study design.
10. No Mention of Study Limitations: The abstract should acknowledge the limitations of the
study to provide a balanced view of the research. The absence of such a discussion might lead
to an overestimation of the study's findings.
Introduction:
• Lack of clear research question or hypothesis.
• Insufficient background information or context for the study.
• Failure to appropriately justify the research or explain its significance.
• Inadequate review of the relevant literature or missing key references.
Methods:
• Inadequate description of the study design, making it difficult to reproduce the research.
• Poorly defined or non-standardized procedures and measurements.
• Sample size too small, leading to a lack of statistical power.
• Selection bias due to improper sampling techniques.
• Lack of or insufficient blinding and controls.
• Failure to address ethical concerns or obtain proper approvals.
Statistical Analysis:
• Inappropriate or misapplied statistical methods.
• Lack of transparency in data handling (e.g., missing data treatment, data exclusions).
• Failure to meet assumptions of statistical tests (e.g., normality, independence,
homoscedasticity).
• Over-reliance on p-values without considering effect sizes or confidence intervals.
• Inadequate reporting of statistical results, such as omitting measures of variability or exact p-
values.
• No correction for multiple comparisons when appropriate, raising the risk of Type I errors.
Results:
1. Lack of Clarity: The presentation of data may be confusing or not clearly depicted in tables
and figures.
2. Insufficient Data: There may be a lack of necessary data to support the claims or insufficient
replicates to ensure statistical robustness.
3. Selective Reporting: The authors may appear to report only favorable results while ignoring
data that do not support their hypotheses.
4. No Error Analysis: There may be a lack of error analysis or confidence intervals, making it
difficult to assess the reliability of the data.
Discussion:
1. Overinterpretation of Results: The authors may draw conclusions that are not fully supported
by the data presented.
2. Ignoring Contradictory Evidence: There may be a failure to address or discuss findings in the
literature that contradict their results.
3. Speculative Conclusions: The discussion may include speculation that goes beyond what the
results can substantiate.
4. Lack of Context: The results may not be adequately compared and contrasted with related
studies in the field.
Conclusion:
1. Overstated Claims: The authors may make broad claims that are not justified by the scope of
the research or the data obtained.
2. No Practical Implications: The conclusion may miss an opportunity to discuss the practical
or theoretical implications of the findings.
3. Lack of Recommendations for Future Research: The authors may fail to suggest how their
findings could guide future studies or address remaining questions.
4. Inconsistency: The conclusion may not align well with the stated objectives or the evidence
presented in the results.