Title: Super-additive associations between parity and education level on mortality from
cardiovascular disease and other causes: The Japan Collaborative Cohort Study
Version: 0 Date: 26 Nov 2021
Reviewer's report:
This is an interesting paper on the interaction between parity and education of women on
mortality. Specifically, the authors used >40K women and focused on the additive interaction
between parity and education level on mortality associated with stroke, coronary heart disease,
total cardiovascular disease, cancer, non-cardiovascular disease and non-cancer causes, and all-
causes in Japanese women. I think that this paper is relevant to the journal’s scope and hence
deserves publication; nevertheless, the authors should address the following comments
1) Title: The title is a bit misleading, better to rephrase “Super-additive associations between
parity and education level on mortality from cardiovascular and other causes: The Japan
Collaborative Cohort Study”.
Better to replace the word “effect” to “association” or “relationship” through, as the authors
used an observational design and it might be challenging to assess causal inferences due to
unmeasured confounding
2) Abstract: Given that the authors put emphasis on the interaction on the additive scale in the
title, they should report interaction on the additive scale in the abstract as well. In other words,
it would be better if they didn’t report interaction on the multiplicative scale in the abstract and
instead report on the additive scale.
3) Introduction: I strongly support the use of additive interaction in this study. However,
the authors should build the case for focusing on deviations from additivity rather than
multiplicativity of the associations. In other words, they should mention that the study of
interaction on the additive scale is more important from a public health standpoint, because,
in this context, two risk factors are independent, when the number of disease cases is also
independent on whether they act jointly or not.
The authors may refer to the paper
Rothman KJ, Greenland S, Walter AM. Concepts of interaction. Am J Epidemiol.
1980;112:467–470
4) Method: The authors mention: “We calculated P-values for RERI-indicated additive
interactions”. This is not very clear. They authors should be more specific and mention that they
used the delta-method (this is what they present in the Appendix)
5) Methods: The authors mention: “RERI reflects the excess risk due to interaction, relative to
the risk without exposure”. Not quite accurate, because the authors have two exposures, so better
to rephrase “RERI reflects the excess risk due to interaction of nulliparity and low education,
relative to the risk of parity combined with high educational level”
6) Tables:
In Table 1, the authors should remove the column p for trend; it is uninformative and in any
case, we would not anticipate any trend.
Moreover, the author do not report at all Cis and p-values of multiplicative interactions in the
Tables, even if they report it in the abstract and the discussion. My recommendation to improve
the tables is the following
Table 3 should be deleted (too few information) and table 2 should be rearranged, so that the
message is clearer.
The new Table 2 should contain Total mortality, CVD mortality, cancer mortality and non-
cancer & non-CVD mortality (i.e. remove stroke and coronary heart disease mortality). At the
same time, the new Table 2 should contain two extra columns; one for the RERI and one for the
I=eb3 for multiplicative interaction along with the corresponding 95% confidence intervals.
The new Table 3 may contain stroke and coronary heart disease mortality. Again, the new Table
3 should contain two extra columns; one for the RERI and one for the I=ea3 for multiplicative
interaction along with the corresponding 95% confidence intervals.
7) The authors should mention in the discussion that multiplicative associations imply super-
additive associations, refer to the papers
Katsoulis M, Gomes M, Bamia C. Moving from two- to multi-way interactions among binary
risk factors on the additive scale. Biostat Epidemiol. 2020;4(1):282-293
and
VanderWeele TJ, Knol M. A tutorial on interaction. Epidemiol Methods. 2014;3(1):33–72
and rephrase their arguments based on that fact.