Title: Expression of inflammatory states in response to psychological distress in breast cancer
survivors and its relationship to subjective memory function complaints
Version: 4 Date: 17 Jan 2025
Reviewer's report:
This study of 104 breast cancer survivors who had completed chemotherapy examined the
association of psychological distress with self-reported cognitive complaints (assessed with the
PRMQ), cognitive deficits (screened with the MMSE) and inflammatory markers (e.g., IL-1#,
NLR, GLR, SII), finding that distress showed a small correlation with cognitive complaints and
higher inflammation, but not with cognitive deficits. The manuscript suffers from several issues
regarding the interpretation of results. In addition, the choice of mediation analysis for these
cross-sectional data is questionable. In the current state, basic criteria for scientific publication
are not fulfilled.
Major issues:
1. The main issue is the interpretation of the PRMQ results. Since it is a self-report questionnaire,
it measures subjective cognitive complaints, but not cognitive deficits, cognitive impairment or
cognitive function. The only measure of cognitive impairment that was used was the MMSE,
which showed no significant difference between the NPD and PD groups. Thus the interpretation
of results should be rephrased throughout the manuscript and any results based on the PRMQ
should only be referred to as (subjective) cognitive complaints, not cognitive impairment or
memory function. Accordingly, the title needs to be changed as well.
2. Another major issue is the choice of mediation analysis on cross-sectional data. This
modelling should only be used on cross-sectional data if there is a strong hypothesis regarding
the direction of effects. However, given the variables used, no such strong hypotheses can be
claimed. Subjective cognitive complaints and psychological distress can affect each other in both
directions. E.g. patients with depressive symptoms who also report high levels of psychological
distress typically judge their cognitive performance as worse than they actually perform in
objective cognitive assessments. Conversely, cognitive impairment is highly distressing so that
patients with subjective cognitive complaints are more likely to report elevated psychological
distress than patients who do not notice any cognitive deficits. With regards to the inflammatory
markers that were analyzed, the connections are less clear cut. However, hypotheses in
either direction appear plausible: patients with chronic inflammation are more likely to be
distressed, but also, vice versa, patients with chronic distress will likely have an altered immune
response. For these reasons, cross-sectional data are not suited to infer mediating or even
causal relationships. I would therefore recommend to remove the mediation analysis from the
manuscript.
There are several minor issues that also need to be addressed:
1. It is unclear why the DT was analyzed as a dichotomized rather than a continuous variable.
Splitting the DT score implies two distinct categories, which arguably are not present in the data.
In addition, some of the variance is lost by dichotomizing the variable.
2. The interpretation of correlations is incorrect. E.g., the correlation between IL-1ß and DT
is described as a strong correlation, but r is only 0.378, which corresponds to a medium sized
correlation (Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences (2nd ed.).
Hillsdale, NJ: Lawrence Erlbaum Associates.)
3. As remarked by the other reviewers, phrasings like “influences” are inappropriate for cross-
sectional analyses, especially in the results section. Please use neutral, descriptive language
(“associated”, “correlated”) throughout the manuscript.