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Cut point validation vs. real-world performance: the ultra-low cut point dilemma
Lindsay Denhoff1, Cansu Dernek2, Liam Heins3
1Bioanalytical Laboratories, ICON plc, Whitesboro, NY, USA.
Bioanalysis
|May 16, 2026
Summary
Ultra-low cut points (ULCPs) in antidrug antibody (ADA) assays, derived from outlier removal, do not compromise assay reliability. Validated ULCPs are suitable for assessing immunogenicity with modern assay platforms.
Area of Science:
- Pharmacology
- Immunology
- Analytical Chemistry
Background:
- Cut point determination is crucial for validating antidrug antibody (ADA) assays and assessing immunogenicity.
- Outlier removal, using methods like Tukey's test, can lead to ultra-low cut points (ULCPs), raising concerns about assay reliability and false positives.
Purpose of the Study:
- To evaluate the impact of ultra-low cut points (ULCPs) on the performance and reliability of ADA assays.
- To assess whether ULCPs, when appropriately validated, compromise the assessment of immunogenic responses.
Main Methods:
- Analysis of ADA studies from two contract research organizations that utilized ULCPs.
- Evaluation of assay performance and reliability in the context of modern, highly sensitive assay platforms and reagents.
Main Results:
- Ultra-low cut points (ULCPs), defined as signal-to-noise ratios ≤1.10, were analyzed in ADA studies.
- Findings indicate that ULCPs do not inherently reduce ADA assay performance or reliability, even with modern platforms.
Conclusions:
- The use of ultra-low cut points (ULCPs) is supported when statistically justified and appropriately validated.
- ULCPs can be reliably employed in ADA assay development and validation without compromising the assessment of immunogenicity.
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