Background: Many methods under the umbrella of inter-rater agreement (IRA) have been proposed to evaluate how well two or more medical experts agree on a set of outcomes. The objective of this work was to assess key IRA statistics in the context of multiple raters with binary outcomes. Methods: We simulated the responses of several raters (2–5) with 20, 50, 300, and 500 observations. For each combination of raters and observations, we estimated the expected value and variance of four commonly used inter-rater agreement statistics (Fleiss’ Kappa, Light’s Kappa, Conger’s Kappa, and Gwet’s AC1). Results: In the case of equal outcome prevalence (symmetric), the estimated expected values of all four statistics were equal. In the asymmetric case, only the estimated expected values of the three Kappa statistics were equal. In the symmetric case, Fleiss’ Kappa yielded a higher estimated variance than the other three statistics. In the asymmetric case, Gwet’s AC1 yielded a lower estimated variance than the three Kappa statistics for each scenario. Conclusion: Since the population-level prevalence of a set of outcomes may not be known a priori, Gwet’s AC1 statistic should be favored over the three Kappa statistics. For meaningful direct comparisons between IRA measures, transformations between statistics should be conducted.

In advanced non-small cell lung cancer (NSCLC), patients with actionable genomic alterations may derive additional clinical benefit from targeted treatment compared to cytotoxic chemotherapy. Current guidelines recommend extensive testing with next generation sequencing (NGS) panels. We investigated the impact of using a targeted NGS panel (TruSight Tumor 15, Illumina) as reflex testing for NSCLC samples at a single institution. Molecular analysis examined 15 genes for hotspot mutation variants, including AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET and TP53 genes. Between February 2017 and October 2020, 1460 samples from 1395 patients were analyzed. 1201 patients (86.1%) had at least one variant identified, most frequently TP53 (47.5%), KRAS (32.2%) or EGFR (24.2%). Among these, 994 patients (71.3%) had clinically relevant variants eligible for treatment with approved therapies or clinical trial enrollment. The incremental cost of NGS beyond single gene testing (EGFR, ALK) was CAD $233 per case. Reflex upfront NGS identified at least one actionable variant in more than 70% of patients with NSCLC, with minimal increase in testing cost. Implementation of NGS panels remains essential as treatment paradigms continue to evolve.