Modelling wound area in studies of wound healing interventions

Experimental studies of wound healing often use survival analysis and time to event outcomes or differences in wound area at a specific time point. However, these methods do not use a potentially large number of observations made over the course of a trial and may be inefficient. A model-based approach can leverage all trial data, but there is little guidance on appropriate models and functional forms to describe wound healing. We derive a general statistical model and review a wide range of plausible mathematical models to describe wound healing. We identify a range of possible derived estimands and their derivation from the models. Using data from a trial of an intervention to promote ulcer healing in patients affected by leprosy that included three measurement methods repeated across the course of the study, we compare the goodness-of-fit of the models using a range of methods and estimate treatment effects and healing rate functions with the best-fitting models. Overall, we included 5,581 ulcer measurements of 1,578 unique images from 130 patients. We examined the performance of a range of models. The square root, log square root, and log quadratic models were the best fitting models across all outcome measurement methods. The estimated treatment effects magnitude and sign varied by time post-randomisation, model type, and outcome type, but across all models there was little evidence of effectiveness. The estimated effects were significantly more precise than non-parametric alternatives. For example, estimated differences from the three outcome measurements at 42-days post-randomisation were − 0.01 cm2 (-0.77, 0.74), -0.44 cm2 (-1.64, 0.76), and 0.11 cm2 (-0.87, 1.08) using a non-parametric method versus − 0.03 cm2 (-0.14, 0.06), 0.06 cm2 (-0.05, 0.17), and 0.03 cm2 (-0.07, 0.17) using a square-root model. Model-based analyses can dramatically improve the precision of estimates but care must be taken to carefully compare and select the best fitting models. The (log) square-root model is strongly recommended reflecting advice from a century ago.