A multiple reader scoring system for Nasal Potential Difference parameters

Abstract

Background: Nasal Potential Difference (NPD) is a biomarker of CFTR activity used to diagnose CF and monitor experimental therapies. Limited studies have been performed to assess agreement between expert readers of NPD interpretation using a scoring algorithm.

Methods: We developed a standardized scoring algorithm for "interpretability" and "confidence" for PD (potential difference) measures, and sought to determine the degree of agreement on NPD parameters between trained readers.

Results: There was excellent agreement for interpretability between NPD readers for CF and fair agreement for normal tracings but slight agreement of interpretability in indeterminate tracings. Amongst interpretable tracings, excellent correlation of mean scores for Ringer's Baseline PD, Δ_amiloride, and Δ_{Cl-free+Isoproterenol} was observed. There was slight agreement regarding confidence of the interpretable PD tracings, resulting in divergence of the Ringers and Δ_amiloride, and ΔCl_{-free+Isoproterenol} PDs between "high" and "low" confidence CF tracings.

Conclusion: A multi-reader process with adjudication is important for scoring NPDs for diagnosis and in monitoring of CF clinical trials.

Keywords: CFTR; Clinical trial outcomes; Nasal Potential Difference.

Fig. 1

A. Training example of high confidence, interpretable CF tracing demonstrating lack of interfering artifacts, shifts, or catheter displacements with biologically plausible values and absence of missing or incomplete tracing portions. B. Training example of low-confidence, interpretable CF tracing due to excessive artifacts interfering with interpretability but displaying biologically plausible responses and the absence of missing or incomplete portions of the tracings. C. Training example of an uninterruptable CF tracing due to an incomplete chloride portion of the tracing due to catheter displacement with biologically implausible responses to amilioride and ATP controls. D. Training example of an unintepretable CF tracing due to excessive artifacts affecting the signal-to-noise ratio throughout with biologically implausible responses to amilioride and ATP controls.

Fig. 2

A. Histogram showing higher level of agreement of “interpretability” for CF and non-CF amongst readers (n = 40 CF and non-CF tracings and n = 20 “indeterminate” tracings) reveals that CF and non-CF tracings display larger levels of complete agreement by readers regarding “interpretability” B. Histogram showing higher levels of agreement of “confidence” for sodium measures for CF and non-CF tracings amongst readers (n = 40 CF and non-CF tracings and n = 20 “indeterminate” tracings). C. Histogram showing higher level of agreement of “confidence” for chloride measures CF and non-CF tracings amongst readers (n = 40 CF and non-CF tracings and n = 20 “indeterminate” tracings).