Marginal Structural Models and Causal Inference in Epidemiology :

AIDS Clinical Trial Group Randomized Trial 002 compared the effect of high-dose with low-dose 3-azido-3-deoxythymidine (AZT) on the survival of AIDS patients. Embedded within the trial was an essentially uncontrolled observational study of the effect of prophylaxis therapy for pneumocystis carinii pneumonia on survival. In this paper, we estimate the causal effect of prophylaxis therapy on survival by using the method of G-estimation to estimate the parameters of a structural nested failure time model (SNFTM). Our SNFTM relates a subject's observed time of death and observed prophylaxis history to the time the subject would have died if, possibly contrary to fact, prophylaxis therapy had been withheld. We find that, under our assumptions, the data are consistent with prophylaxis therapy increasing survival by 16% or decreasing survival by 18% at the alpha = 0.05 level. The analytic approach proposed in this paper will be necessary to control bias in any epidemiologic study in which there exists a time-dependent risk factor for death, such as pneumocystis carinii pneumonia history, that (A1) influences subsequent exposure to the agent under study, for example, prophylaxis therapy, and (A2) is itself influenced by past exposure to the study agent. Conditions A1 and A2 will be true whenever there exists a time-dependent risk factor that is simultaneously a confounder and an intermediate variable.