The Advantage of Discordance: An Example Using the Highly Subjective Nuclear Grading of Breast Cancer

Discordance among multiple assessments has been a reason to criticize a biomarker. But, if different assessments are all relevant, the meaning of discordance requires explanation. As an example, for 1085 breast cancers, a low (score 1), intermediate (score 2) or high nuclear grade (NG) (score 3) was assigned in years 2013, 2015, 2016. Year apart readings allowed for memory lapse of prior readings. For each cancer, scores for NG2013, NG2015, NG2016 were added together to yield sum score nuclear grade (SSNG) with range 3 to 9. SSNG was used to find if discrepancy between NG readings carried information for patient outcome. Discrepancies were inherent with SSNG=4, 5, 7 or 8. Time-dependent receiver operator curves were central for evaluating discordance as related to patient outcome. Area under curves for SSNG, and the component NGs, in stage 1, stage 2, and stage 3 cancers were, respectively: SSNG: 70, 68, 75; NG2013: 70, 63, 71; NG2015: 67, 65, 74; and NG2016: 65, 66, 68. The area under curves of SSNG was not significantly lower than any of the components from which it was derived. This is despite discordant readings having been incorporated into SSNG. Among the 3 readings, 50.1% were discordant, yet only 2.1% were low/high discrepancy. Concordance in high-grade assignment (SSNG=9) corresponded to poor prognosis. If morphologic features are midway between 2 predefined levels it is sensible that separate readings will be distributed between adjacent levels. Shown has been how an "in-between" level helps predict survival then discordance discovery offers classification. Discordance discovery can conceivably be embraced for real-world applications.