This may have resulted in underestimating the effect of TB on mortality by ignoring the effect that TB may have had on mortality through its mediation on CD4 cell counts.[20] Marginal structural models have been introduced to estimate the causal effect of a time-dependent exposure in the presence of time-dependent covariates that may be simultaneously confounders and intermediate variables.[61] In 3 out of 15 studies marginal structural models were constructed[8], [11], [20] and TB status varied in time. The gene discussed is CD4; the disease is tuberculosis.