Series length used during trend analysis affects sensitivity to changes in progression rate in the ocular hypertension treatment study

Abstract

Purpose: Trend analysis techniques to detect glaucomatous progression typically assume a constant rate of change. This study uses data from the Ocular Hypertension Treatment Study to assess whether this assumption decreases sensitivity to changes in progression rate, by including earlier periods of stability.

Methods: Series of visual fields (mean 24 per eye) completed at 6-month intervals from participants randomized initially to observation were split into subseries before and after the initiation of treatment (the "split-point"). The mean deviation rate of change (MDR) was derived using these entire subseries, and using only the window length (W) tests nearest the split-point, for different window lengths of W tests. A generalized estimating equation model was used to detect changes in MDR occurring at the split-point.

Results: Using shortened subseries with W = 7 tests, the MDR slowed by 0.142 dB/y upon initiation of treatment (P < 0.001), and the proportion of eyes showing "rapid deterioration" (MDR <-0.5 dB/y with P < 5%) decreased from 11.8% to 6.5% (P < 0.001). Using the entire sequence, no significant change in MDR was detected (P = 0.796), and there was no change in the proportion of eyes progressing (P = 0.084). Window lengths 6 ≤ W ≤ 9 produced similar benefits.

Conclusions: Event analysis revealed a beneficial treatment effect in this dataset. This effect was not detected by linear trend analysis applied to entire series, but was detected when using shorter subseries of length between six and nine fields. Using linear trend analysis on the entire field sequence may not be optimal for detecting and monitoring progression. Nonlinear analyses may be needed for long series of fields. (ClinicalTrials.gov number, NCT00000125.).

Figure 1.

Box-and-whisker plots of the change in MDR occurring at the split-point, for different lengths of shortened window W. For each box, the central horizontal line represents the median value, the box covers the interquartile range, and the whiskers extend to the maximum and minimum values. The gray horizontal line indicates zero difference in MDR.

Figure 2.

The series of VF test results for a sample participant in the Delayed Treatment Cohort. The vertical gray line represents the first visit at which the subject was receiving treatment. The blue lines show the rate of change of mean deviation from linear regression over the entire sequences, before the split-point and commencing at least 9 months after the split-point. The red lines show the equivalent rates of change derived using the shortened sequences, that is the last seven fields before the split-point and the first seven fields at least 9 months after the split-point. Before the split-point, the red line is steeper than the blue line, showing that use of the shortened sequence makes trend analysis more sensitive to the rapid rate of change that occurred over this period. A change in rate is apparent at treatment onset using the shortened sequence, but not using the entire sequence. Note that when the split-point was caused by the subject reaching an endpoint, all confirmation fields were included in the Before_W sequence.