Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Vessel Tortuosity Cutoff Values Using the Modified ROPtool May Predict Need for Treatment in Retinopathy of Prematurity

Itsara Lertjirachai, MD; Maxwell S. Stem, MD; Stavros N. Moysidis, MD; Nicole Koulisis, MD; Antonio Capone, MD; Kimberly A. Drenser, MD, PhD; Michael T. Trese, MD

Abstract

BACKGROUND AND OBJECTIVE:

To quantify vessel tortuosity among infants with retinopathy of prematurity (ROP).

PATIENTS AND METHODS:

This was a retrospective study including 61 RetCam images from 33 infants. The laser treatment (LT) group included 17 infants who underwent laser for ROP. The no-treatment (NT) group included 16 infants. The modified ROPtool was used to calculate mean vessel tortuosity (MVT) and highest vessel tortuosity (HVT) for the participants and for the standard plus disease photograph from the Early Treatment for Retinopathy of Prematurity (ETROP) study.

RESULTS:

The median MVT was 1.226 versus 1.056 for the LT and NT groups, respectively (P < .001). The median HVT was 1.346 versus 1.088 (P < .001). An MVT of 1.124 was 96.7% sensitive and 100% specific for identifying infants with treatment-requiring ROP. Both MVT and HVT cutoff values correctly captured plus disease in the standard ETROP trial photograph.

CONCLUSION:

The modified ROPtool can be used to identify infants who have treatment-requiring ROP with a high level of sensitivity and specificity.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:215–220.]

Abstract

BACKGROUND AND OBJECTIVE:

To quantify vessel tortuosity among infants with retinopathy of prematurity (ROP).

PATIENTS AND METHODS:

This was a retrospective study including 61 RetCam images from 33 infants. The laser treatment (LT) group included 17 infants who underwent laser for ROP. The no-treatment (NT) group included 16 infants. The modified ROPtool was used to calculate mean vessel tortuosity (MVT) and highest vessel tortuosity (HVT) for the participants and for the standard plus disease photograph from the Early Treatment for Retinopathy of Prematurity (ETROP) study.

RESULTS:

The median MVT was 1.226 versus 1.056 for the LT and NT groups, respectively (P < .001). The median HVT was 1.346 versus 1.088 (P < .001). An MVT of 1.124 was 96.7% sensitive and 100% specific for identifying infants with treatment-requiring ROP. Both MVT and HVT cutoff values correctly captured plus disease in the standard ETROP trial photograph.

CONCLUSION:

The modified ROPtool can be used to identify infants who have treatment-requiring ROP with a high level of sensitivity and specificity.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:215–220.]

Introduction

Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness.1 If ROP is not detected and treated at an early stage, it can progress rapidly and lead to unfavorable outcomes.2,3

The multicenter trial of Early Treatment for Retinopathy of Prematurity (ETROP)4 demonstrated that laser is an effective therapy for ROP and defined the clinical criteria for initiating treatment. The most important clinical indicator of treatment-requiring ROP is the presence of plus disease, which is defined as posterior pole venous dilation and vascular tortuosity.5 However, determining the presence or absence of plus disease can be highly subjective.6,7 The ability to quantify plus disease would be an important step toward standardizing ROP treatment decision-making in cases where a skilled examiner is not immediately available.

The modified ROPtool (developed at the University of North Carolina, Chapel Hill, and Duke University, licensed by FocusROP) is a computer software program that can be used to trace retinal vessels in fundus photographs; from these tracings, the software can quantify vessel tortuosity. Herein, we used the modified ROPtool to quantify vessel tortuosity among infants with treatment-requiring ROP and those who never required treatment. From these groups, we determined vessel tortuosity scores that could be used to predict the need for ROP treatment. We also analyzed the standard photographs in the ETROP study to determine if the cutoff values obtained from the modified ROPtool could be used to detect plus disease in these standard photographs.

Patients and Methods

Data Acquisition

This retrospective study was approved by the Western Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. Fundus images were obtained with the RetCam3 (Natus Medical Incorporated, Pleasanton, CA) during the routine ROP screening program in the neonatal intensive care unit (NICU) at William Beaumont Hospital in Royal Oak, Michigan. Images taken between August 2014 and December 2017 were reviewed, and only high-quality images were included.

We classified the images into two groups. Group 1 consisted of infants who were determined to need laser treatment for ROP (LT group). The decision to treat was made by one of our three experts (KAD, AC, MTT). All of the infants in Group 1 had documented evidence of plus disease in the medical record. For each child, we analyzed only the images taken on the day that the decision was made to initiate treatment for ROP. Infants in Group 2 were photographed weekly with the RetCam3 up to 42 weeks postmenstrual age (PMA) in the NICU and never required treatment for ROP (NT group). Posterior pole images in Group 2 were randomly selected for analysis. Each child in Group 2 had retinal images taken weekly between 32 weeks and 38 weeks PMA; thus, each infant in Group 2 had 14 posterior pole images (seven from each eye) to choose from. One of these 14 posterior pole images was selected randomly for each infant in Group 2, and the modified ROPtool was used to analyze each of the selected images.

A standard photograph from the ETROP study was also reviewed. We then applied the Modified ROPtool to this photograph in order to determine whether the tool could accurately detect plus disease as defined by the ETROP study.

Modified ROPtool

To use the modified ROPtool, the operator first clicks on the superior, inferior, nasal, and temporal borders of the optic nerve and then on the center of the macula (fovea). The program then defines the posterior pole as a circle with a radius extending from the center of the optic nerve to the fovea. This circle is divided electronically into four sectors or quadrants. Within each sector, the most tortuous major vessels are selected. The program creates a straight line along the path of each vessel from its origin at the optic nerve to its terminus at the edge of the posterior pole. It then generates a smooth curve that approximates the path of each vessel and measures the total length of this smooth curve. The tortuosity values are calculated as the ratio of the total length of the vessel (as determined by the smooth curve) to the length of the straight line. For example, if the total length of the vessel is 10% longer than that of the straight line, then the tortuosity value is 1.10. In each sector, the tortuosity value is based on the most tortuous arteriole or venule.8 The mean vessel tortuosity (MVT) and highest vessel tortuosity (HVT) scores were calculated for each eye.

Statistical Analysis

All statistical analyses were performed using IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, NY). Categorical data were analyzed using the Chi-square test. Normality was assessed with the Kolmogorov-Smirnov test. Normally distributed variables were analyzed with Student's t-test, and the Mann-Whitney U test was used to compare outcomes that were not normally distributed. For all statistical tests, a P value of less than .05 was considered statistically significant. Receiver operating characteristic (ROC) curves were formulated to assess cutoff values that predicted the need for ROP treatment and optimized sensitivity and specificity.

Results

Baseline Characteristics

Patient characteristics are summarized in Table 1. Sixty-one images from 33 infants were included in the analysis. The LT group consisted of 30 images from 17 babies, whereas the NT group had 31 images from 16 infants. In the LT group, the median gestational age (GA) was 24 weeks, and the median birth weight (BW) was 686 grams. A slight minority of patients (n = 14, 46.7%) were male. Most patients (n = 24, 80%) were white; four (13.3%) were African-American, and two (6.7%) were other. The median postmenstrual age (PMA) of the selected images in the LT group was 36 weeks. In the NT group, the median GA was 25 weeks and the median BW was 835 grams. Most patients (n = 18, 58.1%) were male, and 25 infants (80.6%) were white. The median PMA of the selected images in the NT group was 35 weeks.

Summary of Baseline Characteristics

Table 1:

Summary of Baseline Characteristics

Tortuosity Measurement

Retinal vessels in infants who required treatment for ROP were significantly more tortuous than the vessels in babies who did not undergo ROP treatment (Table 2). In the LT group, the median of the MVT score was 1.226, and the corresponding value in the NT group was 1.056 (P < .001). The median of the HVT score in the LT group was 1.346 compared to 1.088 in the NT group (P < .001). From the standard photograph of the ETROP study,9 the MVT and the HVT scores were 1.195 and 1.252, respectively.

Comparison of Vessel Tortuosity Between LT and NT Groups

Table 2:

Comparison of Vessel Tortuosity Between LT and NT Groups

Tortuosity Cutoff Values

ROC curves were generated to find threshold values for initiating treatment for ROP. For both the MVT and HVT scores, the area under the ROC curves (AUCs) were generated (Table 3). An MVT score of 1.124 had a 96.7% sensitivity and 100% specificity for identifying infants in need of ROP treatment (Figure 1), and an HVT score of 1.145 was 96.7% sensitive and 80.7% specific (Figure 2). These cutoff values also successfully captured the presence of plus disease in the standard photographs from the ETROP study.

Cut-Off Values With Sensitivity and Specificity for Identifying Infants With Treatment-Requiring ROP

Table 3:

Cut-Off Values With Sensitivity and Specificity for Identifying Infants With Treatment-Requiring ROP

Receiver operating characteristic (ROC) curve of mean vessel tortuosity (MVT) for all patients. The sensitivity was 96.7%, and the specificity was 100% for a MVT score of 1.124. The area under the ROC curve (AUC) was 0.994.

Figure 1.

Receiver operating characteristic (ROC) curve of mean vessel tortuosity (MVT) for all patients. The sensitivity was 96.7%, and the specificity was 100% for a MVT score of 1.124. The area under the ROC curve (AUC) was 0.994.

Receiver operating characteristic (ROC) curve of highest vessel tortuosity (HVT) for all patients. The sensitivity was 96.7%, and the specificity was 80.7% for a HVT score of 1.145. The area under the ROC curve (AUC) was 0.967.

Figure 2.

Receiver operating characteristic (ROC) curve of highest vessel tortuosity (HVT) for all patients. The sensitivity was 96.7%, and the specificity was 80.7% for a HVT score of 1.145. The area under the ROC curve (AUC) was 0.967.

Discussion

This study demonstrates the ability of the modified ROPtool to quantify vascular tortuosity among preterm infants with and without treatment-requiring ROP. Specifically, the MVT and HVT scores generated from the modified ROPtool analysis can be used to help the physician identify infants with treatment-requiring ROP with a high degree of sensitivity and specificity. As plus disease is often a subjective diagnosis, the quantification of vessel tortuosity may help to guide clinical decision-making for novice ROP examiners.

Unsurprisingly, infants in the LT group exhibited a lower GA and BW compared to infants in the NT group who did not undergo laser treatment for ROP. Several studies have previously reported that both low GA and low BW are risk factors for the development of ROP. A computerized risk model developed from the CRYO-ROP study found that combining these factors into a single indicator of prematurity can be used to predict an unfavorable visual outcome.10 Lundgren et al.11 similarly found that low GA and low BW are risk factors for the development of treatment-requiring ROP.

The quantification of plus disease in ROP has been reported using different analytic techniques.12–15 The ROPtool is one program that has been used by investigators in several studies. For example, Wallace et al.16,17 previously performed a pilot study using the ROPtool to quantify plus disease. They found that the ROPtool inter-user agreement between two experts was 95%, compared to a 90% agreement rate when using subjective investigator judgment. We have also previously reported the ROPtool's validity and reliability for quantification of plus disease.18 Our previous study showed that cutoff tortuosity values from fundus images had excellent sensitivity and good specificity compared to a consensus among three experts taken as the gold standard for the identification of plus disease.

ROP can advance rapidly if there is a delay in diagnosis or treatment. A highly sensitive test is crucial so that potential patients are not missed. The current study shows that threshold MVT and HVT scores are both highly sensitive indicators of plus disease, correctly identifying 96.7% of infants who ultimately required laser. Also, the cutoff values used in our analysis correctly captured plus disease in the standard photographs from the ETROP study, further validating these tortuosity values as metrics of treatment-requiring ROP. Although the definition of plus disease also includes vessel dilation in addition to tortuosity, previous studies have shown that tortuosity by itself, when quantified with the ROP tool, is sufficient for the identification of plus disease.19,20

The main strength of this study is that we had both a control group and a treatment group, which allowed us to identify meaningful differences in HVT and MVT scores across the two groups. Additionally, we determined threshold values for the HVT and MVT scores that are both sensitive and specific for identifying infants with treatment-requiring ROP. With this methodology, the findings from this study can be applied to clinical practice. However, the study has several limitations that should be acknowledged. Its small sample size and retrospective nature preclude us from eliminating all potential sources of bias in the study.

In conclusion, the modified ROPtool software can be used to quantify vessel tortuosity, and thus the degree of plus disease, by creating indices such as the MVT and HVT scores. These measures are both sensitive and specific for identifying babies with treatment-requiring ROP. Thus, the modified ROPtool may be a useful adjunct for clinicians when deciding whether to initiate treatment for infants with ROP.

References

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Summary of Baseline Characteristics

Laser Treatment, N = 30No Treatment, N = 31P Value

Median Gestational Age (Weeks)2425.02a

(IQR)(23, 26)(24, 26)

Median Birth Weight (Grams)686835

(IQR)(501, 797)(650, 930).002a

Gender, Male (%)14 (46.7%)18 (58.1%).37b

Race.005b
  White (%)24 (80%)25 (80.6%)
  African-American (%)4 (13.3%)0 (0%)
  Others (%)2 (6.7%)6 (19.4%)

Median PMA at Selected Image Analysis3635

(IQR)(33, 36)(34, 35).17a

Eye, Right (%)16 (53.3%)16 (51.6%).89b

Comparison of Vessel Tortuosity Between LT and NT Groups

Laser Treatment, N = 30No Treatment, N = 31P Value
Median of Mean Tortuosity1.2261.056< .001a
(IQR*)(1.148, 1.273)(1.052, 1.080)
Median of Highest Tortuosity1.3461.088< .001 a
(IQR)(1.268, 1.426)(1.061, 1.114)

Cut-Off Values With Sensitivity and Specificity for Identifying Infants With Treatment-Requiring ROP

AUC95% CIP ValueCut-Off PointSensitivitySpecificity
Mean Tortuosity0.9940.98,1< .0011.12496.7%100.00%
Highest Tortuosity0.9670.93,1< .0011.14596.7%80.7%
Authors

From Associated Retinal Consultants, PC, William Beaumont Hospital, Royal Oak, Michigan (IL, MSS, SNM, NK, ACJ, KAD, MTT); and the Department of Ophthalmology, Srinakharinwirot University, Bangkok, Thailand (II).

Drs. Capone, Drenser, and Trese are equity owners of ROPtool, developed at the University of North Carolina, Chapel Hill, and Duke University, and licensed by FocusROP. The remaining authors report no relevant financial disclosures.

Address correspondence to Michael T. Trese, MD, Neuroscience Center Building, 3555 W. 13 Mile Road Suite LL-20, Royal Oak, MI 48073; email: mgjt46@aol.com.

Received: May 15, 2018
Accepted: November 02, 2018

10.3928/23258160-20190401-03

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