Multisite longitudinal calibration of HR-pQCT scanners and precision in osteogenesis imperfecta

For high-resolution peripheral quantitative computed tomography (HR-pQCT) to be used in longitudinal multi-center studies to assess disease and treatment effects, data must be aggregated across multiple timepoints and scanners. This requires an understanding of the factors contributing to scanner precision, and multi-scanner cross-calibration procedures, especially for clinical populations with severe phenotypes, like osteogenesis imperfecta (OI). To address this, we first evaluated single- and multi-center short- and long-term precision errors of standard HR-pQCT parameters. Two imaging phantoms were circulated among 13 sites (7 XtremeCT and 6 XtremeCT2) and scanned in triplicate at 3 timepoints/site. Additionally, duplicate in vivo radial and tibial scans were acquired in 29 individuals with OI. Secondly , we investigated subject- and scanner-related factors that contribute to precision errors using regression analysis. Thirdly , we proposed a reference site selection criterion for multisite cross-calibration and demonstrated the external validity of phantom-based calibrations. Our results show excellent short-term single-site precision in both phantoms ( CV % < 0.5%) and in density, microarchitecture and finite element parameters of OI participants ( CV % = 0.75 to 1.2%). In vivo reproducibility significantly improved with ( i ) cross sectional area image registration versus no registration and ( ii ) scans with no motion artifacts. While reproducibility was similar across OI subtypes and anatomical sites, XtremeCT2 scanners achieved ~2.5% better precision than XtremeCT for trabecular parameters. Finally , we demonstrate that multisite longitudinal precision errors resulting from inconsistencies between scanners can be partially corrected through scanner cross-calibration. This study is the first to assess long-term reproducibility and cross-calibration in a study using first and second generation HR-pQCT scanners. The results presented in this context provide timely guidelines for future use of this powerful clinical imaging modality in multi-center longitudinal clinical trials. • Our study provides short- and long-term reproducibility measurements in the context of a multi-center clinical study reporting HR-pQCT outcomes from different scanner generations and in the osteogenesis imperfecta population. • We provide recommendations on reporting practices, imaging phantom selection and design, and reference site selection criteria. • We present XcalRep, an open-sourced R package ( https://github.com/NMikolajewicz/XcalRep ), that implements methods for cross-calibration and precision analysis of HR-pQCT.