I appreciate the authors’ intent with this innovative proposal but found some of the language to be a bit too vague. I think the proposal could be clearer to other scientists, and thus allow better understanding of the objectives and methods, with revision. For instance, the specific aims of the project are quite broadly stated. Could the investigators be more specific with the explicit intent of these analyses?
In addition, the authors’ proposed statistical analysis could be better defined: “This can be performed either in one step using a regression model with suitable interaction terms between the X’s and the treatment arm Z, or separately for each treatment arm, thus being non-parametric on the form of these interactions. There is no need for the model to be correctly specified to determine an ITR. However, model misspecification may influence the properties of the resulting ITR at two levels. First, a parametric model may put to much constraints on the relationship between predictors and treatment effect, and therefore miss regions of the parameter space where one treatment in superior to the other, or conversely, wrongly identify regions where a treatment would seem beneficial, thus decreasing the benefit of the ITR overall. Second, the model for E(Y(1)|X) and E(Y(0)|X)—and therefore the ITR—and the benefit of this ITR are usually estimated using the same set of data, which leads to over-fitting and over-optimism.” I would recommend writing the statistical analysis section to mirror the explicit research objective statement and to be clear in which is the primary analysis and how it will be performed, which is the secondary analysis and how it will be performed.
Similar to this, the authors explain that they will write 2 articles, one for a statistical audience and a second for a clinical audience. I was confused by this. Will the statistical article report a method that will be developed using the CANTATA-SU data? Or will it report a method developed prior to beginning work with this data? I’d imagine that the clinical article will be a report of the application of the method to this data.

There were several typos throughout the proposal. A close read to correct these errors would be helpful.