Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method

Abstract

Drug-induced liver injury (DILI) is largely a diagnosis of exclusion and is therefore challenging. The US Drug-Induced Liver Injury Network (DILIN) prospective study used two methods to assess DILI causality: a structured expert opinion process and the Roussel-Uclaf Causality Assessment Method (RUCAM). Causality assessment focused on detailed clinical and laboratory data from patients with suspected DILI. The adjudication process used standardized numerical and descriptive definitions and scored cases as definite, highly likely, probable, possible, or unlikely. Results of the structured expert opinion procedure were compared with those derived by the RUCAM approach. Among 250 patients with suspected DILI, the expert opinion adjudication process scored 78 patients (31%) as definite, 102 (41%) as highly likely, 37 (15%) as probable, 25 (10%) as possible, and 8 (3%) as unlikely. Among 187 enrollees who had received a single implicated drug, initial complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five-category RUCAM scale (P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearman's r = 0.42, P = 0.0001). Importantly, the RUCAM approach substantially shifted the causality likelihood toward lower probabilities in comparison with the DILIN expert opinion process.

Conclusion: The structured DILIN expert opinion process produced higher agreement rates and likelihood scores than RUCAM in assessing causality, but there was still considerable interobserver variability in both. Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed.

Fig. 1

Overview of the DILIN causality adjudication process. A flow diagram of the different steps in the entire causality process is shown.

Fig. 2

Correlation of the RUCAM and DILIN causality scores. A box and whisker plot of the RUCAM score at each level of the DILIN expert opinion score is shown. There is a general relationship between the two scales (r = 0.42 in absolute value), although there is considerable variability in the RUCAM score at each DILIN score. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]