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Background: Many cohort studies and clinical trials use repeated measurements of laboratory markers to track disease progression and to evaluate new therapies. A major problem in the analysis of such studies is that marker data are censored in some patients owing to withdrawal, loss to follow-up, or death. The objective of this paper is to evaluate the impact of selective dropouts attributable to death or disease progression on the estimates of marker change among different groups., Methods: Data on CD4 cell count in human immunodeficiency virus 1-infected individuals from a clinical trial and a cohort study are used to illustrate this problem and a possible solution. Simulation studies are also presented., Results: When the rate of dropout is greater in subjects whose marker status is declining rapidly, commonly used methods, like random effects models, that ignore informative dropouts lead to overoptimistic statements about the marker trends in all compared groups, because subjects with steeper marker drops tend to have shorter follow-up times and hence are weighted less in the estimation of the group rate of the average marker decline., Conclusions: The potential biases attributable to incomplete data require greater recognition in longitudinal studies. Sensitivity analyses to assess the effect of dropouts are important.

Objectives: To assess the practical significance of the following sources of bias for estimates of the AIDS incubation period in a large seroconverter cohort: estimation of the time of seroconversion; presentation with an HIV-related illness; preferential inclusion of survivors; loss to follow-up and analysis cut-off date; the inclusion of Kaposi's sarcoma as an AIDS event; death without an AIDS diagnosis; and representativeness of the HIV population., Methods: Standard non-parametric survival methods were used to estimate the AIDS incubation period distribution. The practical importance of each type of bias was assessed using various sensitivity analyses., Results: The potential sources of bias of most practical importance in this study were the right-censoring strategy and that due to lack of documentation of a negative HIV antibody test. Five different right-censoring strategies gave estimates of the median time to AIDS ranging from 8.1 to 10.8 years for the 1202 individuals enrolled in the UK Register of HIV Seroconverters. HIV-infected persons with a history of a previous antibody negative test which could not be verified appeared to progress to AIDS more rapidly than persons with such verification (Relative risk = 1.8, 95% confidence intervals = 1.3-2.3)., Conclusions: As a number of possible causes of bias can impact on results, care must be taken to document them and control for them wherever possible. In our study, this was particularly relevant in relation to the documentation of a previous HIV antibody negative test and the choice of analysis cut-off dates. As methods may differ between cohorts, comparison of the published results from one cohort with those of another may be misleading.

Background: The Concorde trial compared two policies of therapy with zidovudine (ZVD) in individuals with asymptomatic HIV infection: immediate or deferred ZDV. Participants in both groups could stop their blinded trial therapy for several reasons and/or could start open-label ZDV. The difference in survival and disease progression between the two groups was estimated allowing for treatment changes., Methods: The relationship between latest CD4 count, treatment changes and time to AIDS-related complex (ARC), AIDS or death was investigated using time-updated proportional hazards models, but these models gave seriously biased estimates of the effect of ZDV. Therefore, a method based on the comparison of the randomized groups was used. A model relating a participant's events times to the treatment actually received was used to estimate what would have been observed if the deferred group had not received ZDV before ARS or AIDS, and to explore alternative policies for starting Pneumocystis carinii pneumonia (PCP) prophylaxis., Results: The major treatment changes during the trial were the termination of blinded therapy because of adverse events or personal reasons (575 out of 1749 participants), starting open-label ZDV (745 participants), and starting PCP prophylaxis (613 participants). Starting open-label ZDV and PCP prophylaxis were strongly related to latest CD4 count. The uncorrected hazard ratios for immediate compared with deferred groups were 0.89 for time to ARC, AIDS or death [95% confidence interval (CI), 0.75-1.05], 1.01 for time to AIDS or death (95% CI, 0.82-1.24), and 1.26 for time to death (95% CI, 0.93-1.70). After correction for treatment changes, these hazard ratios were 0.79 (95% CI, 0.57-1.11), 1.01 (95% CI, 0.81-1.26), and 1.37 (95% CI, 0.91-2.08), respectively. Correction for PCP prophylaxis made little difference to the results., Conclusions: Open-label ZDV before ARC or AIDS in the deferred group was likely to have diluted any differences between the immediate and deferred groups. After correction for this dilution, both the estimated benefit of immediate treatment in delaying progression to ARC, AIDS or death and the estimated disadvantage of immediate treatment in accelerating death were somewhat increased, but both remained consistent with chance alone. This study demonstrated the large potential bias inherent in non-randomization-based methods of analysis of clinical trials.