Review for 10.1186/s12876-025-03665-w (2025)

Title: Big Data Analysis of Influenza Vaccination and Liver Cancer Risk in Hypertensive
Patients: Insights from a Nationwide Population-Based Cohort Study
Version: 2 Date: 04 Sep 2024
Reviewer's report:
Abstract:
The word "Methods:" is repeated at the beginning of the Methods section in the Abstract. Please
remove the redundant entry.
In the Results section of the Abstract, "However" should be replaced with "In addition," as it
more appropriately continues the flow of information without implying contrast.
Introduction:
The sentences "However, the World Health Organization estimated that only 20% of patients
with hypertension receive appropriate treatment (2). Hypertension is caused by various factors,
including environmental, genetic, and personal behavioral factors (4). More than 90% of cases
of hypertension are cases of essential hypertension (4)." appear to have limited relevance to the
main topic of this study. I suggest considering their removal or revising them to better align
with the study’s focus.
The phrase "However, the exact mechanism underlying the protective effects of vaccination
remains unknown. Consequently," in the Introduction should be revised to clarify that the study
does not aim to investigate these mechanisms. Perhaps, rephrasing to something like, "While
the exact mechanisms remain unknown, this study focuses on..." would be clearer.
Methods:
The study cohort includes 206,077 patients diagnosed with hypertension. Considering that
hypertension has a prevalence of 24.1% in Taiwan, is this number appropriate for the study
period?
The reason for excluding "patients who received influenza vaccination within half a year before
the enrollment date" from the study should be explained more clearly.
There is a need to specify the starting point for observing liver cancer occurrence in the Methods
section. The flowchart suggests it starts from the first vaccination date between 2001-2012, but
this should be explicitly stated. Also, for unvaccinated patients, clarify what date was used as
the start point. For patients who received multiple vaccinations, explain how you handled the
analysis of periods when they transitioned from one vaccination status to another.
The grouping for dose-response analysis ("patients who received two or three vaccine doses")
needs clarification: Were these doses received before enrollment, or after? How did you analyze
the periods when patients transitioned from receiving one dose to two or more?
Given the substantial impact of HBV, HCV, and cirrhosis as major comorbidities affecting HCC
risk, I recommend including cirrhosis as a comorbidity and considering subgroup analysis for
these conditions, rather than merely adjusting for them in the propensity score.
Results:
The beginning of the "Baseline characteristics" section in the Results repeats information from
the "Patient selection and definition of the primary endpoint" section in the Methods. Consider
revising to avoid redundancy.
The phrase "it was more significant in women (subdistribution HR = 0.52, 95% CI = 0.39–0.67;
p < 0.001) than in men (subdistribution HR = 0.58, 95% CI = 0.45–0.74; p < 0.001)" suggests
a comparison, but statistical significance between the groups should be tested. Similarly, "those
aged above 65 had significantly more protection than their younger counterparts" and "protective
effect in the subgroup with shorter duration of blood pressure medication use" need statistical
testing to validate these statements.
In Table 2, you analyzed liver cancer incidence by influenza season and non-influenza season,
but the rationale for this division isn't clear in the Methods section. Since liver cancer does not
typically develop over such short periods, please explain why you chose to calculate incidence
rates separately for these seasons. Additionally, the total follow-up duration(10028.9 person-
years) mentioned at the top of the table should match the sum of the follow-up durations(a+b+c
or d+f) for unvaccinated and vaccinated groups (87,208.7 person-years), but it seems to differ.
Please clarify this discrepancy.
In Table 3, how are the number of events, follow-up duration, and incidence rates for the different
vaccination groups (1 dose, 2-3 doses, and #4 doses) presented?