CD4 and substance abuse: Our analysis based on the DAG revealed that age, employment, CD4 nadir, psychotropic drug use, substance abuse, central nervous system integrity (represented by cerebrospinal fluid (CSF) glucose, CSF total protein, HIV viral load in plasma and CSF) were potential confounders of the relationship between NCI and HRQoL (S1 Fig) while depression was identified as a mediator [22].