ROUGH DRAFT authorea.com/105679

# Reviewer 1

• I am pleased with the changes in the paper, however I would like a more direct answer to the previously stated question on repositioning consistency, since gradient-nonlinearity induced volume changes are dependent on positioning inside scanner.

The previously stated question was:

• It is mentioned in the Methods section that repositioning consistency of each site’s scanning procedure was captures, however there is no metric in the results section focusing explicitly on that (i.e consistency of the subject position). It would be important to compare it to the consistency of subject positioning in Caramanos 2010 , since it will affect assumption on ability to correct gradient-distortions caused variations with a scaling factor derived from different acquisition.

We would like to thank Reviewer 1 for the feedback and will address this concern by reporting the consistency of Z-positioning in relation to (Caramanos 2010). In (Caramanos 2010), researchers found that variations in z-position affected the percent brain volume change (PBVC) measurements of a longitudinal SIENA pipeline significantly. Specifically, they compared results of “accurate as possible” repositioning with a 50mm displacement repositioning, and found significant differences between measurements. When comparing the “accurate as possible” repositioning to the phantom-corrected result, the absolute error was much lower than that of the 50mm displacement. They calculated an average Z-displacement of 4.3 mm (-9.0 to 21.1). We ran rigid-body-registration to calculate the Z-translations for each subject at each site in our dataset. Overall, our average absolute Z-displacement across all sites was $$3.5mm \pm 3.7mm$$, which falls within the range of the “as accurate as possible” repositioning from (Caramanos 2010). Our average Z-shift, for each site separately is provided in the supplemental materials.

The following text was added to the methods:

“By repositioning in our study, a realistic measure of test-retest variability, which includes the repositioning consistency of each site’s scanning procedure, was captured. Because gradient distortion effects correspond to differences in z-positioning (Caramanos 2010), the average translation in the Z-direction between the two runs of each subject at each site was estimated with a rigid body registration.”

And in the results we report:

“In addition, the average translation in the Z-direction across all sites was $$3.5mm \pm 3.7mm$$, which falls within the accuracy range reported by (Caramanos 2010). The repositioning Z-translation measurements for each site separately is reported in the supplemental materials.”

• Second minor concern is the description of the acquisition sequences - in the section 3.1 you should specify the type of sequence used (MP-RAGE) and the units of measurements (ms). Also, this section should describe acquisition parameters of the MS cohort (currently described in section 3.3)

We have added units to tables 1-4 to be more precise (ms for TR, TE and TI, mm for FOV and voxel size, degrees $$^\circ$$ for the flip angle, and T for the field strength). We also moved the description of the 3D-FLASH sequence acquisition parameters to the acquisition section of 3.1, and specified that all images were T1-weighted 3D-MPRAGE sequences.

# Reviewer 2

• Authors are to be commended for a detailed response to reviewers and significant changes in manuscript.