Conventional diffusion MRI (dMRI) techniques, such as DTI and DKI, are sensitive to pathology but lack specificity. In brain white matter, the “Standard Model” framework of dMRI may provide specificity to microstructural changes. Generally, clinical dMRI is noisy and limited, making SM estimation challenging. Thus, different constraints and techniques have been introduced to robustly extract SM parametric maps. Here, we employ a large clinical dataset of Multiple Sclerosis patient data (N = 134) and noise propagation experiments to study the sensitivity and specificity of these techniques.