Test-Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial

Maria A Parker, Dongseok Choi, Laura R Erker, Mark E Pennesi, Paul Yang, Elvira N Chegarnov, Peter N Steinkamp, Catherine L Schlechter, Claire-Marie Dhaenens, Saddek Mohand-Said, Isabelle Audo, Jose Sahel, Richard G Weleber, David J Wilson, Maria A Parker, Dongseok Choi, Laura R Erker, Mark E Pennesi, Paul Yang, Elvira N Chegarnov, Peter N Steinkamp, Catherine L Schlechter, Claire-Marie Dhaenens, Saddek Mohand-Said, Isabelle Audo, Jose Sahel, Richard G Weleber, David J Wilson

Abstract

Purpose: The goal of this analysis was to determine the test-retest variability of functional and structural measures from a cohort of patients with advanced forms of Stargardt Disease (STGD) participating in the SAR422459 (NCT01367444) gene therapy clinical trial.

Methods: Twenty-two participants, aged 24 to 66, diagnosed with advanced forms of STGD, with at least one pathogenic ABCA4 mutation on each chromosome participating in the SAR422459 (NCT01367444) gene therapy clinical trial, were screened over three visits within 3 weeks or less. Functional visual evaluations included: best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, semiautomated kinetic perimetry (SKP) using isopters I4e, III4e, and V4e, hill of vision (HOV) calculated from static visual fields (SVF) by using a 184n point centrally condensed grid with the stimulus size V test target. Retinal structural changes such as central macular thickness and macular volume were assessed by spectral-domain optical coherence tomography (SD-OCT). Repeatability coefficients (RC) and 95% confidential intervals (CI) were calculated for each parameter using a hierarchical mixed-effects model and bootstrapping.

Results: Criteria for statistically significant changes for various parameters were found to be the following: BCVA letter score (8 letters), SKP isopters I4e, III4e, and V4e (3478.85; 2488.02 and 2622.46 deg2, respectively), SVF full volume HOV (VTOT, 14.62 dB-sr), central macular thickness, and macular volume (4.27 μm and 0.15 mm3, respectively).

Conclusions: This analysis provides important information necessary to determine if significant changes are occurring in structural and functional assessments commonly used to measure disease progression in this cohort of patients with STGD. Moreover, this information is useful for future trials assessing safety and efficacy of treatments in STGD.

Translational relevance: Determination of variability of functional and structural measures in participants with advanced stages of the STGD is necessary to assess efficacy and safety in treatment trials involving STGD patients.

Keywords: OCT; Stargardt Disease; kinetic perimetry; static perimetry; test variability; visual acuity.

Figures

Figure 1
Figure 1
Representative images that demonstrate FAF (A, C) and the fundus appearance (B, D) from 42-year-old patient (A and B) and 40-year-old patient (C and D) with advanced STGD both associated with the homozygote mutation on ABCA4 (missense). Image A demonstrates FAF phenotype type A with central hypofluorescence surrounded by a ring of hyperfluorescence. Image C demonstrates FAF phenotype type B with only central hypofluorescence without surrounding hyperfluorescence.
Figure 2
Figure 2
Change in BCVA measured at initial (1) and follow-up visits (2 and 3). The red solid lines show the RC estimated by bootstrapping model (8.05 letter score). The data points represent 44 eyes from 22 participants. The blue dotted lines show the lower and upper 95% CI bound (9.52 and 6.63 letters score).
Figure 3
Figure 3
Change in HOV static perimetry VTOT (A), SKP I4e (B), SKP III4e (C), and SKP V4e (D) measured at initial (1) and follow-up visits (2 and 3). The data points represent 44 eyes from 22 participants. The red solid lines show the RC estimated by bootstrapping model and the blue dotted lines show the lower and upper 95% CI bound (18.49 and 11.09 dB-sr).
Figure 4
Figure 4
Representative images showing intervisit variability of static perimetry from 25-year-old patient with advanced Stargardt disease associated with the homozygote mutation on ABCA4 (deletion) by using the volume of the HOV model between session 1 (A), 2 (B), and 3 (C). (D) Shows the custom 184n grid pattern for the session 1 on the same patient; (E) generated incremental color coded plot for the session 1 on the same patient.
Figure 5
Figure 5
Change in CMT (A) and MV (B) measured at initial (1) and follow-up visits (2 and 3). The data points represent 20 eyes from 10 participants. The red solid lines show the RC estimated by the bootstrapping model and the blue dotted lines show the lower and upper 95% CI bound.

References

    1. Allikmets R,, Shroyer NF,, Singh N,, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997; 277: 1805–1807.
    1. Allikmets R,, Singh N,, Sun H,, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997; 15: 236–246.
    1. Lewis RA,, Shroyer NF,, Singh N,, et al. Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR in Stargardt disease. Am J Hum Genet. 1999; 64: 422–34.
    1. Burke TR,, Tsang SH. Allelic and phenotypic heterogeneity in ABCA4 mutations. Ophthalmic Genet. 2011; 32: 165–174.
    1. Maugeri A,, Klevering BJ,, Rohrschneider K,, et al. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet. 2000; 67: 960–966.
    1. Westeneng-van Haaften SC,, Boon CJ,, Camiel JF,, et al. Clinical and genetic characteristics of late-onset Stargardt's disease. Ophthalmology. 2012; 119: 1199–1210.
    1. Lambertus S,, Van Huet RA,, Bax NM,, et al. Early-onset stargardt disease: phenotypic and genotypic characteristics. Ophthalmology. 2015; 122: 335–344.
    1. Fishman GA,, Stone EM,, Grover S,, et al. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol 1999; 117: 504–10.
    1. Fishman GA. Fundus flavimaculatus: a clinical classification. Arch Ophthalmol. 1976; 94: 2061–2067.
    1. Noble KG,, Carr RE. Stargardt's disease and fundus flavimaculatus. Arch Ophthalmol. 1979; 97: 1281–1285.
    1. Sun H,, Smallwood PM,, Nathans J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet. 2000; 26: 242–246.
    1. Saad L,, Washington I. Can vitamin A be improved to prevent blindness due to age-related macular degeneration, Stargardt disease and other retinal dystrophies? Adv Exp Med Biol. 2016; 854; 355–361.
    1. Lee HJ,, Kim MS,, Jo YJ,, Kim JY. Ganglion cell-inner plexiform layer thickness in retinal diseases: repeatability study of spectral-domain optical coherence tomography. Am J Ophthalmol. 2015; 160: 283–289.
    1. Wadhwani M,, Bali SJ,, Satyapal R,, et al. Test-retest variability of retinal nerve fiber layer thickness and macular ganglion cell-inner plexiform layer thickness measurements using spectral-domain optical coherence tomography. J Glaucoma. 2015; 24: 109–115.
    1. Jeffrey BG,, Cukras CA,, Vitale S,, et al. Test-retest intervisit variability of functional and structural parameters in X-linked retinoschisis. Transl Vis Sci Technol. 2014; 3 (5): 5.
    1. Bittner AK,, Iftikhar MH,, Dagnelie G. Test-retest, within-visit variability of Goldmann visual fields in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2011; 52: 8042–8046.
    1. Kim LS,, McAnany JJ,, Alexander KR,, et al. Intersession repeatability of humphrey perimetry measurements in patients with retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2007; 48: 4720–4724.
    1. Fishman GA,, Chappelow AV,, Anderson RJ,, et al. Short-term inter-visit variability of ERG amplitudes in normal subjects and patients with retinitis pigmentosa. Retina. 2005; 25: 1014–1021.
    1. Tosha C,, Gorin MB,, Nusinowitz S. Test-retest reliability and inter-ocular symmetry of multi-focal electroretinography in Stargardt disease. Curr Eye Res. 2010; 35: 63–72.
    1. Cideciyan AV,, Swider M,, Aleman TS,, et al. Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials. Invest Ophthalmol Vis Sci. 2012; 53: 841–852.
    1. Lois N,, Holder GE,, Bunce C,, et al. Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol. 2001; 119: 359–369.
    1. Kurz-Levin MM,, Halfyard AS,, Bunce C,, et al. Clinical evaluation in bull's-eye maculopathy. Arch Ophthalmol. 2002; 120: 567–575.
    1. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology. 1991; 98: 741–756.
    1. Weleber RG,, Smith TB,, Peters D,, et al. VFMA: topographic analysis of sensitivity data from full-field static perimetry. Transl Vis Sci Technol. 2015; 4 (2): 14.
    1. Krebs I,, Smretschining E,, Moussa S,, et al. Quality and reproducibility of retinal thickness measurements in two spectral-domain optical coherence tomography machines. Invest Ophthalmol Vis Sci. 2011; 52: 6925–6933.
    1. Strauss RW,, Muñoz B,, Wolfson Y,, et al. Assessment of estimated retinal atrophy progression in Stargardt macular dystrophy using spectral-domain optical coherence tomography [published online ahead of print November 14 2015]. Br J Ophthalmol. doi: .
    1. Laird NM,, Ware JH. Random effects models for longitudinal data. Biometrics. 1982; 38: 963–974.
    1. Grover S,, Fishman GA,, Gilbert LD,, et al. Reproducibility of visual acuity measurements in patients with retinitis pigmentosa. Retina. 1997; 17: 3.
    1. Arditi A,, Cagenello R. On the statistical reliability of letter-chart visual acuity measurements. Invest Ophthalmol Vis Sci. 1993; 34: 120–129.
    1. Vanden Bosch ME,, Wall M. Visual acuity scored by the letter-by-letter or probit methods has lower retest variability than the line assignment method. Eye (Lond). 1997; 11: 411–417.
    1. Grobbel J,, Dietzsch J,, Johnson CA,, et al. Normal values for the full visual field, corrected for age- and reaction time, using semiautomated kinetic testing on the Octopus 900 perimeter. Transl Vis Sci Technol. 2016; 5 (2): 5.
    1. Nakatani Y,, Hiqashide T,, Ohkubo S,, et al. Evaluation of macular thickness and peripapillary retinal nerve fiber layer thickness for detection of early glaucoma using spectral domain optical coherence tomography. J Glaucoma. 2011; 20: 252–259.

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