CD4 and chronic obstructive pulmonary disease: Typical examples include the evolution of CD4 cell count or HIV-RNA viral load levels in HIV-infected individuals, prostate-specific antigen (PSA) levels in prostate cancer patients, BMI evolution in children, respiratory parameters in chronic obstructive pulmonary disease (COPD) patients, etc. A typical example of a mixed linear model with restricted cubic splines can be found in the work of Mallon PW et al. [29].