Diagnostic accuracy of cerebrospinal fluid and blood biomarkers for the differential diagnosis of sporadic Creutzfeldt-Jakob disease: a (network) meta-analysis

ObjectiveTo conduct a systematic review of cerebrospinal fluid (CSF) and blood biomarkers as diagnostic tests for sporadic Creutzfeldt-Jakob disease (sCJD) in a specialised care setting and to compare diagnostic accuracies in a network meta-analysis (NMA). MethodsWe searched Medline, Embase, and the Cochrane Library for diagnostic studies of sCJD biomarkers. Risk of bias was assessed with the QUADAS-2 tool. We used a generalised bivariate model to conduct individual biomarker meta-analyses, and to estimate between-study variability. To investigate sources of heterogeneity, we performed subgroup analyses based on QUADAS-2 quality and clinical criteria. For the NMA, we applied a Bayesian beta-binomial ANOVA model. The study protocol was registered at PROSPERO (CRD42019118830). ResultsOut of 2,976 publications screened, we included 16 studies, which investigated 14-3-3{beta} Western blot (n=13), 14-3-3{gamma} ELISA (n=3), NfL (n=1), NSE (n=1), p-tau181/t-tau ratio (n=2), RT-QuIC (n=6), S100B (n=3), t-tau (n=12), and t-tau/A{beta}42 ratio (n=1) in CSF. No included study investigated blood biomarkers. Many diagnostic studies excluded had strong limitations in study design. In the NMA, RT-QuIC (0.93; 95% CI [0.87, 0.96]) and NfL (0.94 [0.81, 0.99]) were the most sensitive biomarkers. RT-QuIC was the most specific biomarker (0.96 [0.86, 0.99]), and had the highest balanced accuracy (0.94). Heterogeneity in accuracy estimates was high between studies, especially for specificity. ConclusionsOur NMA identified RT-QuIC as the overall most accurate biomarker, partially confirming current guidelines. The severe shortcomings identified in many diagnostic studies for sCJD biomarkers need to be addressed in future studies in the field.