The percentage flow-mediated dilation index: A large-sample investigation of its appropriateness, potential for bias and causal nexus in vascular medicine

The percentage flow-mediated dilation index (FMD%) scales the increase in arterial diameter (D-diff) as a constant proportion of baseline artery diameter (D-base). We have demonstrated, albeit with small samples, that the scaling properties of FMD% can lead to biased inferences on endothelial dysfunction. Therefore, we aimed to investigate the underlying rationale and potential bias of FMD% using a selection of new examples from the large (n = 3499) and diverse Multi-Ethnic Study of Atherosclerosis (MESA). In this dataset, we found that smaller values of D-diff are associated with larger values of D-base, which contradicts the scaling properties of FMD%. Consequently, FMD% over-scales' and naturally generates an even stronger negative correlation between itself and D-base. Using a data simulation, we show that this FMD%-D-base correlation can be a statistical artefact due to inappropriate scaling. The new examples we present from MESA indicate that FMD% biases the differences in flow-mediated response between men and women, Framingham risk score categories, and diseased and healthy people. We demonstrate how FMD%, as an exposure for predicting cardiovascular disease, is confounded by its dependency on D-base, which itself could be clinically important. This critical review, incorporating an allometric analysis of a large dataset, suggests that the FMD% index has a less-than-clear rationale, can itself generate the D-base-dependency problem, provides biased estimates of differences in the flow-mediated response, complicates the interpretation of the flow-mediated protocol and clouds the causal pathway to vascular disease. These interpretative problems can be resolved by applying accepted allometric principles to the flow-mediated response.