Studies of Imprecision, Performance and Measurement Uncertainty in Laboratory Assessment of Thrombotic Thrombocytopenic Purpura

ADAMTS13 activity testing is essential for diagnosing and managing thrombotic thrombocytopaenic purpura (TTP). However, current methods for calibration, measurement uncertainty (MU), verification, and result interpretation are poorly suited to the complexity of ADAMTS13 assays. These tests rely on non-linear calibration models, show high variability between platforms, and lack well-defined analytical performance limits linked to clinical decision points. This research challenges the adequacy of existing standards, including ISO 15189, ISO/TS 20914, and CLSI guidelines, when applied to ADAMTS13. It develops new statistical approaches that better describe assay behaviour and support clinical interpretation. The project also establishes a framework for defining analytical performance specifications (APS) directly linked to clinical risk. This includes ADAMTS13-specific error grids that incorporate uncertainty through guard bands, improving the reliability of results near key clinical thresholds at 10 IU/dL, 20 IU/dL, and 50 IU/dL. Likelihood ratios are calculated across the reportable range, providing clinicians with tools to quantify diagnostic confidence and track disease progression. Verification is restructured using risk-based methods that move beyond protocol-driven processes. This approach connects analytical performance directly to clinical outcomes. The framework developed delivers a more accurate understanding of the limitations and capabilities of ADAMTS13 testing. While focused on ADAMTS13, the methods are applicable to any complex diagnostic assay where current standards fail to link analytical quality with clinical decision-making.