Joint modeling of HIV data in multicenter observational studies: A comparison among different approaches

Disease process over time results from the combination of event history information and longitudinal process. Commonly, separate analyses of longitudinal and survival outcomes are performed. However, discharging the dependence between these components may cause misleading results. Separate analyses are difficult to interpret whenever one deals with observational retrospective multicenter cohort studies where the biomarkers are poorly monitored over time, while the survival component may be affected by several sources of bias, such as multiple endpoints, multiple time-scales, and informative censoring. We discuss how joint modeling of longitudinal and survival data represents an effective strategy to incorporate all information simultaneously and to provide valid and efficient inferences, thus allowing to produce a better insight into the biological mechanisms underlying the phenomenon under study. Accounting for the whole dynamics of the disease process is crucial in retrospective longitudinal studies. In this work, we present different approaches for modeling longitudinal and time-to-event data, retrieved from 648 HIV-infected patients enrolled in the Italian cohort of the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) study, one of the largest AIDS collaborative cohort studies. In particular, we evaluate CD4 lymphocyte evolution over time (from the date of seroconversion) and overall survival, CD4 being one of the most important immunologic biomarker for HIV progression. Besides a standard separate modeling approach, we consider two alternative joint models: the traditional joint model and the joint latent class mixed model. Advantages and disadvantages of the different approaches are discussed. To compare the performances of these models, cross-validation procedures are also performed.