Methods

The study protocol has been detailed elsewhere, is available on the PEDIG website ( www.pedig.net ), and is summarized at www.clinicaltrials.gov under the identifier NCT00000170 . A brief summary of the protocol follows.

Primary eligibility criteria for the multicenter randomized trial included age less than 7 years, visual acuity in the amblyopic eye of 20/40 to 20/100, visual acuity in the fellow eye of 20/40 or better, interocular acuity difference of 3 or more logarithm of minimal angle of resolution (logMAR) lines, no myopia (−0.50 diopters [D] or more spherical equivalent refractive error) in either eye, and the presence or history of an amblyopiogenic factor meeting the study-specified criteria for strabismus and/or anisometropia.

After wearing any needed refractive correction for at least 4 weeks, subjects were randomized to either patching (6 hours up to full-time every day at investigator discretion) or atropine (1%, 1 drop once daily) for 6 months. A primary outcome examination was performed 6 months after randomization. Between 6 months and 2 years postrandomization, treatment was at investigator discretion.

At the time of the 2-year visit, parents of subjects from a subset of participating sites (those with more than 5 subjects enrolled and continuing with other PEDIG protocols) were invited to enter a long-term extension phase. All treatment during this phase was prescribed at investigator discretion. Of the 419 subjects in the trial, 188 consented to participate, and 176 completed the age 10–year extension examination. Alignment and visual acuity were measured with correction, if prescribed. Testing at the age 10–year examination included measurement of visual acuity in each eye (measured by a study-certified examiner with the Electronic Early Treatment of Diabetic Retinopathy Study testing protocol), cycloplegic refraction (within the prior 6 months), measurement of ocular alignment using the simultaneous prism and cover test at distance and near fixation, and assessment of random dot stereoacuity using the Preschool Randot. At enrollment, alignment was recorded as either orthotropic, microtropic (1–8 prism diopters [Δ] horizontal tropia), or heterotropic (>8 Δ horizontal tropia) based on the maximum angle measured at distance or near. Visual acuity was measured using the ATS-HOTV protocol on the Baylor Video Acuity Tester (BVAT; Mentor O&O Inc, Norwell, Massachusetts, USA) or Electronic Visual Acuity Tester (EVA).

To be included in the current analyses, subjects needed to meet the following additional criteria: have a cause of amblyopia attributable to anisometropia, strabismus, or both (2 subjects with indeterminate cause were excluded) and have a cycloplegic refraction at or within 6 months of their 10th birthday (age 9.5 to 10.5 years). Sixty-nine subjects without a cycloplegic refraction within this age window were excluded. Of the 176 subjects completing the age 10–year examination, 105 met these additional criteria and were included for analysis. Because subjects were enrolled between age 3 and <7 years, the length of follow-up until the age 10–year examination ranged from 3.1 to 7.3 years (mean of 5.0 years).

Statistical Methods

Subject characteristics for those included in these analyses vs those not included were compared to evaluate potential selection bias. The primary outcome for analysis was total change in spherical equivalent refractive error in the amblyopic eye between baseline and age 10 years. Positive values of change indicated a shift in the positive (more hyperopic) direction, while a negative value indicated a shift in the negative (less hyperopic and more myopic) direction. Change from baseline to age 10 years was evaluated in each eye by computing descriptive statistics and 95% confidence intervals (CI). All additional analyses were adjusted for baseline spherical equivalent refractive error as a potential confounder.

A multivariate linear regression model adjusting for age at randomization, baseline spherical equivalent refractive error, and amblyopia treatment prescribed at randomization was used to evaluate the association of change in spherical equivalent refractive error in each eye with ocular alignment categorization at baseline. Baseline spherical equivalent refractive error and age at randomization were treated as continuous variables (linearity assumptions were evaluated prior to fitting the final model). Ocular alignment at baseline was categorized into 1 of the 3 categories of alignment/misalignment based on the maximum angle of deviation at either distance or near fixation, as either orthotropic (0 Δ), microtropic (1 to 8 Δ), or heterotropic (>8 Δ) ( Table 1 ). To control the type I error rate, pair-wise comparisons between each of the ocular alignment categories were performed using the Tukey-Kramer adjustment for multiple comparisons only if the F test for ocular alignment showed an association. A 95% CI and descriptive statistics were used to evaluate the difference in change in spherical equivalent refractive error between the eyes. Mean change in amblyopic eye spherical equivalent refractive error stratified by baseline amblyopic eye spherical equivalent refractive error and anisometropia at baseline was calculated overall and by each category of baseline ocular alignment to evaluate whether there was an association between change in amblyopic eye refractive error and baseline ocular alignment, controlling individually for baseline amblyopic eye refractive error and baseline anisometropia ( Table 2 ). The effect of tropia status on change in amblyopic eye spherical equivalent refractive error within categories of baseline amblyopic eye spherical equivalent refractive error was examined to evaluate potential interaction. In a separate analysis on each eye, an integer value was assigned to each category of ocular alignment to evaluate trend ( Table 1 , and Supplemental Table , available at AJO.com ). The association between stereoacuity at age 10 years and baseline ocular alignment was evaluated using descriptive statistics and an exact Wilcoxon rank sum test. Analyses were performed using SAS Version 9.1 (SAS Institute, Cary, North Carolina, USA).

TABLE 1

Change in Amblyopic Eye Spherical Equivalent Refractive Error From Baseline to Age 10 Years by Category of Ocular Alignment at Baseline

Category of Ocular Alignment a at Baseline	Change in Amblyopic Eye Spherical Equivalent Refractive Error
	N	Mean b , c	95% Confidence Interval
1: Orthotropia (0 Δ)	47	−1.01 §	(−1.29, −0.72)
2: Microtropia (1–8 Δ)	29	−0.51 §,‡	(−0.88, −0.15)
3: Heterotropia (>8 Δ)	29	−0.21 ‡	(−0.58, 0.17)
P value (baseline ocular alignment score) d	.001

 

Δ = prism diopter; D = diopters.

a Maximum angle of deviation measured in correction, if prescribed, determined using the simultaneous prism and cover test at distance and near fixation.

b Adjusted for baseline amblyopic eye spherical equivalent refractive error, age at randomization, and treatment prescribed at randomization (baseline spherical equivalent refractive error and age at randomization were treated as continuous variables; treatment prescribed was either patching or atropine).

c If the same symbol is listed for any 2 categories of ocular alignment, there is no statistical difference in change in amblyopic eye spherical equivalent refractive error.

d From a model with an ordinal ocular alignment score (1, 2, or 3) with adjustments for baseline amblyopic eye spherical equivalent refractive error, age at randomization, and treatment prescribed at randomization (baseline spherical equivalent refractive error and age at randomization were treated as continuous variables; treatment prescribed was either patching or atropine).

TABLE 2

Change in Amblyopic Eye Spherical Equivalent Refractive Error from Baseline to Age 10 Years by Category of Ocular Alignment at Baseline and Baseline Amblyopic Eye Spherical Equivalent or Baseline Anisometropia

	Alignment at Baseline a
	Change in Amblyopic Eye Spherical Equivalent
	Overall			Ortho (0 Δ)			Micro (1–8 Δ)			Hetero (>8 Δ)
	n	Mean	SD	n	Mean	SD	n	Mean	SD	n	Mean	SD
Amblyopic Eye Spherical Equivalent at Baseline
Overall	105	−0.65	1.02	47	−1.01	1.07	29	−0.55	0.80	29	−0.19	0.94
<2 D	12	−0.36	0.71	2	−1.44	0.80	4	−0.28	0.65	6	−0.06	0.40
2 to <3 D	9	−0.36	0.74	4	−0.38	0.98	1	−0.75	—	4	−0.25	0.65
3 to <4 D	17	−0.53	0.95	7	−0.91	0.90	3	−0.44	0.53	7	−0.20	1.10
4 to <5 D	22	−0.97	1.29	13	−1.32	1.22	4	−0.63	0.88	5	−0.35	1.65
5 to <6 D	16	−0.36	1.24	5	−0.55	1.91	7	−0.63	0.79	4	0.34	0.79
6 to <7 D	16	−0.88	0.76	10	−1.03	0.61	5	−0.70	1.09	1	−0.38	—
≥7 D	13	−0.82	0.88	6	−1.06	0.84	5	−0.48	1.08	2	−0.94	0.27
Anisometropia at Baseline
Overall	105	−0.65	1.02	47	−1.01	1.07	29	−0.55	0.80	29	−0.19	0.94
<0 D	7	−0.45	0.63	1	−0.88	—	2	−0.63	0.88	4	−0.25	0.64
0 to <1 D	40	−0.27	0.91	5	−0.70	0.88	12	−0.27	0.64	23	−0.17	1.03
1 to <2 D	13	−0.67	0.80	7	−0.66	1.02	4	−0.94	0.46	2	−0.19	0.27
2 to <3 D	16	−1.29	1.35	13	−1.24	1.49	3	−1.48	0.49	0	—	—
3 to <4 D	15	−0.90	1.05	9	−1.14	0.97	6	−0.54	1.15	0	—	—
≥4 D	14	−0.85	0.80	12	−0.99	0.76	2	0	0.35	0	—	—

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