A novel device for accurate and efficient testing for vision-threatening diabetic retinopathy

Abstract

Aims: To evaluate the performance of the RETeval device, a handheld instrument using flicker electroretinography (ERG) and pupillography on undilated subjects with diabetes, to detect vision-threatening diabetic retinopathy (VTDR).

Methods: Performance was measured using a cross-sectional, single armed, non-interventional, multi-site study with Early Treatment Diabetic Retinopathy Study 7-standard field, stereo, color fundus photography as the gold standard. The 468 subjects were randomized to a calibration phase (80%), whose ERG and pupillary waveforms were used to formulate an equation correlating with the presence of VTDR, and a validation phase (20%), used to independently validate that equation. The primary outcome was the prevalence-corrected area under the receiver operating characteristic (ROC) curve for the detection of VTDR.

Results: The area under the ROC curve was 0.86 for VTDR. With a sensitivity of 83%, the specificity was 78% and the negative predictive value was 99%. The average testing time was 2.3 min.

Conclusions: With a VTDR prevalence similar to that in the U.S., the RETeval device will identify about 75% of the population as not having VTDR with 99% accuracy. The device is simple to use, does not require pupil dilation, and has a short testing time.

Keywords: Diabetic eye exam; Diabetic macular edema; Diabetic retinopathy; ERG; Pupillography; Retinal diagnostic test.

Figure 1

Representative raw data from the RETeval device from two subjects, one with and one without VTDR. The top plot shows the timing difference between the subject with VTDR (red line) and the subject without VTDR (blue line) for the 32 Td·s flicker ERG. In this steady-state response, the flashes occurred at time = 0, ±35.33 ms, ± 70.66 ms, etc. The vertical grid lines show the implicit time between the flash and the eye’s peak electrical response to be about 30 ms for the subject without VTDR, faster than the 38 ms for the subject with VTDR. The middle plot shows the amplitude difference for the 16 Td·s flicker ERG, where the horizontal grid lines show the peak-to-peak amplitude for the subject without VTDR was 26 μV, larger than the 23 μV for the subject without VTDR. The bottom plots show the difference in pupillary response between a 4 Td·s and 32 Td·s flickering stimulus for the subject with VTDR (bottom left) and without VTDR (bottom right). The time scale for the pupillary response is from the onset of the flickering light (0 seconds) to 5 seconds. The grid lines show that after initial transients, the pupil size for the subject with VTDR was 2.45 mm with the brighter 32 Td·s flicker stimulus, and was a slightly larger 2.66 mm with the dimmer 4 Td·s flicker stimulus. The subject without VTDR had a larger change in pupil diameter between the two stimuli: 3.10 mm vs 1.89 mm. These changes in pupil size are summarized by the ratio of the pupil areas. The subject without VTDR had a pupil area ratio of 2.7 (= 3.10² / 1.89²), larger than the 1.2 for the subject with VTDR.

Figure 2

Dependence of RETeval measurements on diabetic retinopathy severity level. Plots show the mean and standard error of the mean for three measurements and the overall RETeval measurement (DR Score) for each severity group. Severity group definitions and the number of subjects in each group can be found in Table 1. BE and WE stand for “best eye” and “worst eye” respectively.

Figure 3

Receiver operating characteristic (ROC) curves for the calibration phase, validation phase, and prevalence-corrected overall result. The cutoff values from Table 3 are labeled on the prevalence-adjusted curve.