Abstract
In diabetes and other chronic lifelong diseases, it is not always known with certainty how chronic correlated non-fatal disease processes co-develop over time. It is also not obvious how to analyze this
complex multivariate statistical problem. This thesis reviews and proposes methods that allow for the
simultaneous modelling of several such processes. In a tutorial setting, it is shown that multistate and
joint modelling approaches are useful for the overall research objective. Multistate models are found to
be particularly applicable for questions surrounding the order and timing of disease-related processes.
However, they require discretization of outcome data and possibly a very complex state space when
more than two processes are modelled. In contrast, joint models can account for variations of continuous biomarkers over time and are particularly designed for modelling complex multivariate association
structures. It would therefore be useful to combine elements of multistate and joint models, and the
next part of the thesis develops this framework. Shared random effects can be used to link multistate
and longitudinal processes, but most existing approaches assume that the multistate transition times
are exactly observed. This renders them unsuitable for interval cohort studies, which are one of the
most popular study designs for questions surrounding the natural history of complications. In interval
cohort studies, participants are intermittently observed at regular intervals and are thus subject to mixed
observation schemes where certain events are interval-censored and others are exactly observed. A novel
shared random effects joint model for a longitudinal outcome and a multistate process under a mixed observation scheme is thus proposed. An appropriate likelihood function is defined and the model is fitted
using a maximum likelihood framework with adaptive Gaussian quadrature. The model is assessed using
simulation studies and is applied to 30-year data from the Diabetes Control and Complications Trial
and Epidemiology of Diabetes Interventions and Complications study. The model is then extended to
accommodate multiple longitudinal outcomes via Bayesian estimation using Hamiltonian Monte Carlo.
In the end, it is shown that the novel joint multistate model gives greater insight into the natural history
of a full complications process.