Brain Size: To Adjust or Not Adjust? It's Not a Matter of If, but How

Total intracranial volume (TIV) is a major confounding factor in neuroimaging studies, particularly when studying sex differences in the brain. There are different methods to adjust this effect however their impact is not directly studied and compared. In this study, we sought to evaluate the effect that four of the main methods used in the literature, namely the proportions, the residuals, the power corrected proportions method, and adding TIV as a covariate in a regression analysis, have on the estimation of neuroanatomical sex differences. Leveraging data from the UK Biobank, we employed a matching approach (based on age and TIV in each sex to remove the impact of TIV between sexes) to devise a gold standard as reference for comparing these methods. We further modeled aging trajectories at the regional, vertexwise, and voxelwise level, using raw and adjusted values, and compared the obtained estimates against the gold standard. We found that across the different metrics, adding TIV as a covariate was the best-performing method for removing the effect of TIV, in terms of the correlation the estimates of the different subsamples had with the gold standard and the low degree of over or under estimation. Furthermore, we showed commonly used smoothing of the morphometric measures can result in biased estimation of sex differences in these measures. Finally, we showed that after all adjustment methods, while small in effect size, there still remains some neuroanatomically specific uncorrected effect.