Genetics and Traumatic Brain Injury: Findings from an Exome-Based Study of a 50-Patient Case Series

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article “Genetics and traumatic brain injury: findings from an exome-based study of a 50-patient case series” by Alesya S. Gracheva et al. explores the potential genetic predisposition to traumatic brain injury (TBI) by analyzing the exomes of 50 patients undergoing rehabilitation post-TBI. Moderate revision is needed.

1. Introduction (Lines 38-77):

• Lack of Clear Hypothesis and Research Gap: While the introduction provides a broad overview of traumatic brain injury (TBI) and mentions genetic predispositions, it does not have a specific hypothesis that the study aims to test. Additionally, although the authors acknowledge the lack of prior studies on genetic predisposition to TBI, they do not sufficiently emphasize the novelty of their approach compared to existing genetic research on TBI recovery.
• Generalization of Genetic Predisposition: The introduction suggests that traits like intelligence, risk behaviors, and reaction times, which have genetic components, could predispose individuals to TBI. Citations are then provided, but I still believe the wording is too strong. This generalization might lead to a perceived overextension of the study's scope.

2. Methods (Lines 78-215):

• Participant Selection and Exclusion Criteria: The exclusion criteria (e.g., psychiatric disorders, inherited neurological diseases, etc.) are reasonable for managing confounders, but they might also limit the generalizability of the study findings to a broader TBI population, which has such comorbidities. I do not believe there was a discussion on how excluding these patients might impact the interpretation of the results or limit the applicability of the findings.
• Lack of Power Analysis: The study involved only 50 patients, divided into three outcome-based groups. There is no mention of a power analysis to justify this sample size.
• Ambiguity in Control Group Selection: The selection of COVID-19 patients as a control group for validating findings seems arbitrary and lacks justification. The choice is likely fine but should be explained more.

3. Results (Lines 216-413):

• Overemphasis on Statistical Significance: The results section highlights various statistically significant findings but does not critically evaluate their biological relevance or clinical significance. For instance, while differences in genetic variants are statistically significant between TBI and non-TBI groups, the actual effect sizes and potential impact on patient outcomes are not discussed, making it difficult to assess the practical implications of these findings.
• Limited Interpretation of Violin Plots: The use of violin plots to compare neurological scales and SOFA scores among patient groups is great but the interpretation of these plots is limited. A more detailed clinical analysis explaining the meanings would be good.

4. Enrichment Analysis (Lines 267-420):

• Absence of Mechanistic Links: The study identifies numerous genes with rare variants but does not establish mechanistic links between these variants and TBI susceptibility or outcomes.

5. Discussion (Lines 421-504):

• Inadequate Addressing of Study Limitations: While the discussion acknowledges sample size and heterogeneity as limitations, it does not critically assess the impact of these limitations on study findings. For example, how might small sample sizes have affected the detection of significant genetic associations?
• Overgeneralization of Findings: The authors imply a broad applicability but this might be overreaching given the study's sample size, demographic specificity, and exclusion of certain patient groups.

6. Conclusion (Lines 505-516):

• Overemphasis on the Novelty of Genetic Findings: The conclusion highlights the novelty of finding potential genetic predispositions to TBI, but the study’s exploratory nature and the preliminary nature of the findings are downplayed. Emphasizing that these findings are a first step towards understanding genetic influences, rather than definitive evidence, would provide a more balanced perspective.

General Feedback:

• The title is accurate. The abstract effectively summarizes the study’s objectives, methods, and key findings.
• The methods section is detailed with informative figures.

 

Comments on the Quality of English Language

English language is fine but needs minor editing

Author Response

Dear Reviewer,

Please see our answers to your questions in the attached file.

Best regards, Lyubov Salnikova

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Summary of Key Points

Significance of TBI

Traumatic brain injury (TBI) is recognized as a major cause of death and disability worldwide.

Unexplored Genetic Predisposition

The accidental nature of TBIs has meant that the role of genetic predisposition has not been thoroughly investigated.

Non-random Injury Potential

There is a suggestion that TBIs may not occur entirely at random and could be linked to specific physical and mental traits.

Research Methodology

This study examined the exomes of 50 TBI patients, dividing them into three groups based on their rehabilitation outcomes: improved, unchanged, and worsened/deceased. The focus was on identifying rare and potentially functional mutations.

Major Findings

The study found consistent results across three independent patient groups, indicating that rare functional mutations in certain genes might be associated with a genetic susceptibility to TBI. Out of the 50 patients, 44 had rare and potentially harmful mutations in one or more neurogenes.

Limitations and Future Directions

No significant differences were found in the distribution of genes of interest among the patient groups, highlighting the need for further research. This exploratory study offers new insights into the genetic factors influencing TBI risk and is the first to explore potential genetic susceptibility to TBI.

Academic Value Critique

This study provides valuable new insights into the genetic predisposition to traumatic brain injury (TBI), and its academic value can be assessed as follows:

Novelty

The investigation into genetic predisposition to TBI is relatively new, making this study a significant contribution to an emerging field of research.

Methodological Contribution

The use of exome analysis to explore genetic mutations is a novel approach in TBI research, laying the groundwork for understanding how specific genetic mutations may influence susceptibility to TBI.

Clinical Relevance

The suggestion that genetic predisposition may affect TBI risk opens up potential avenues for personalized medicine and preventative strategies in the future.

Consistency of Data

The consistent results obtained from three independent patient groups enhance the reliability of the study’s findings.

Foundation for Future Research

As an exploratory study, it sets the stage for larger-scale studies and reproducibility verification in different populations. This initial effort provides a foundation for future research.

Conclusion

This study represents a pioneering effort to suggest the existence of genetic predisposition to TBI, opening a new research area at the intersection of genetics and trauma medicine. Further research is expected to clarify details, potentially leading to significant advancements in TBI prevention and treatment.

Recommendations for Improvement

1. Addition of Specific Data and Statistical Information

    

   The abstract mentions that 44 out of 50 patients had rare and potentially harmful mutations, but it lacks specific statistical data and details about the types of mutations. Including information on statistical significance and the specific impacts of these mutations would enhance the credibility and transparency of the research.

2. Detailed Description of Patient Groups

    

   While the patients are categorized into three groups (“improved,” “unchanged,” and “worsened/deceased”), there is a lack of specific details regarding the number of patients in each group and the criteria for classification (e.g., the extent of improvement). Providing these details would improve the reproducibility of the study and make it easier to interpret the results.

3. Clarification of Study Limitations and Future Directions

    

   Although the abstract mentions the study’s limitations, it does not specify them in detail (e.g., small sample size, potential biases). Clearly stating these limitations would allow readers to more accurately assess the study’s reliability. Additionally, offering specific suggestions for future research directions (e.g., what additional studies are needed) would clarify the research’s significance and the next steps.

Author Response

Dear Reviewer,

Please see our answers to your questions in the attached file.

Best regards, Lyubov Salnikova

Author Response File: Author Response.pdf