Addressing Multiplicity in Retinal Sensitivity Analysis: An Alternative Approach to Assessing Gene Therapy Efficacy in Inherited Retinal Diseases.

PURPOSE: The purpose of this study was to propose an alternative statistical approach that addresses the issue of multiplicity in microperimetry data analysis, offering a more balanced and sensitive measure of the efficacy of gene therapy in inherited retinal diseases (IRDs).

METHODS

We analyzed microperimetry data from a phase II trial of AGTC-501 in patients with X-linked retinitis pigmentosa (XLRP). The Macular Integrity Assessment (MAIA; CenterVue, Padova, Italy) device was used to evaluate test-retest repeatability. A binomial model was used to calculate the probability of ≥7 decibel (dB) improvements due to chance alone across a 68-locus grid. We proposed an alternative approach to detect changes using a threshold of ≥7 loci with ≥7 dB mean improvement.

RESULTS

Test-retest repeatability analysis showed a probability of < 5% for observing pointwise improvements ≥7 dB between 2 baseline visits. Applying the binomial distribution model, we found that the probability of observing improvements ≥7 dB in at least 7 unspecified loci purely by chance was 5.3%.

CONCLUSIONS

The proposed approach provides a balanced way to address multiplicity while maintaining reasonable statistical significance. Using ≥7 unspecified loci as the criterion for assessing sensitivity changes, offers a comprehensive assessment that can detect genuine treatment effects without being overly conservative.

TRANSLATIONAL RELEVANCE: This alternative statistical method has the potential to improve the evaluation of retinal sensitivity changes in gene therapy trials for IRDs, providing a more accurate measure of therapeutic efficacy and enhancing clinical decision making.