Purpose: Vitamin B deficiency has been identified as a risk factor for vascular events. However, the reduction of vascular events was not shown in large randomized controlled trials evaluating B-Vitamin therapy. There is an important requirement to develop sensitive biomarkers to be used as efficacy targets for B-Vitamin therapy as well as other dietary treatments and lifestyle regimes that are being developed. Carotid vessel-wall-plus-plaque thickness change (VWT-Change) measured from 3D ultrasound has been shown to be sensitive to atorvastatin therapies in previous studies. However, B-Vitamin treatment is expected to confer a smaller beneficial effect in carotid atherosclerosis than the strong dose of atorvastatin. This paper introduces a sensitive atherosclerosis biomarker based on the weighted mean VWT-Change measurement from 3D ultrasound with a purpose to detect statistically significant effect of B-Vitamin therapy. Methods: Of the 56 subjects analyzed in this study, 27 were randomized to receive a B-Vitamin tablet daily and 29 received a placebo tablet daily. Participants were scanned at baseline and 1.9 ± 0.8 yr later. The 3D VWT map at each scanning session was computed by matching the outer wall and lumen surfaces on a point-by-point basis. The 3D annual VWT-Change maps were obtained by first registering the 3D VWT maps obtained at the baseline and follow-up scanning sessions, and then taking the point-wise difference in VWT and dividing the result by the years elapsed from the baseline to the follow-up scanning session. The 3D VWT-Change maps constructed for all patients were mapped to a 2D carotid template to adjust for the anatomic variability of the arteries. A weight at each point of the carotid template was assigned based on the degree of correlation between the VWT-Change measurements exhibited at that point and the treatment received (i.e., B-Vitamin or placebo) quantified by mutual information. The weighted mean of VWT-Change for each patient, denoted by ΔVWT-Weighted, was computed according to this weight. T-tests were performed to compare the sensitivity of ΔVWT-Weighted with existing biomarkers in detecting treatment effects. These biomarkers included changes in intima-media thickness (IMT), total plaque area (TPA), vessel wall volume (VWV), unweighted average of VWT-Change (ΔVWT-) and a previously described biomarker, denoted by ΔVWT-S, that quantifies the mean VWT-Change specific to regions of interest identified by a feature selection algorithm. Results: Among the six biomarkers evaluated, the effect of B Vitamins was detected only by ΔVWT-Weighted in this cohort (P=4.4×10-3). The sample sizes per treatment group required to detect an effect as large as exhibited in this study were 139, 178, 41 for ΔVWV, ΔVWT- and ΔVWT-Weighted respectively. Conclusion: The proposed weighted mean of VWT-Change is more sensitive than existing biomarkers in detecting treatment effects. This measurement tool will allow for many proof-of-principal studies to be performed for various novel treatments before a more costly study involving a larger population is held to validate the results.

Additional Metadata
Keywords B-Vitamin treatment, Carotid atherosclerosis, Mutual information, Three-dimensional ultrasound, Vessel-wall-plus-plaque thickness (VWT)
Persistent URL dx.doi.org/10.1002/mp.12507
Journal Medical Physics
Citation
Cheng, J. (Jieyu), Ukwatta, E.M, Shavakh, S. (Shadi), Chow, T.W.S. (Tommy W. S.), Parraga, G. (Grace), Spence, J.D. (J. David), & Chiu, B. (Bernard). (2017). Sensitive three-dimensional ultrasound assessment of carotid atherosclerosis by weighted average of local vessel wall and plaque thickness change. Medical Physics. doi:10.1002/mp.12507