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. Author manuscript; available in PMC: 2014 Sep 1.
Published in final edited form as: Retina. 2013 Sep;33(8):1700–1707. doi: 10.1097/IAE.0b013e3182845c39

Plus disease diagnosis in retinopathy of prematurity: vascular tortuosity as a function of distance from optic disc

Katie M Keck 1, Jayashree Kalpathy-Cramer 2, Esra Ataer-Cansizoglu 3, Sheng You 3, Deniz Erdogmus 3, Michael F Chiang 1,4
PMCID: PMC3759352  NIHMSID: NIHMS505395  PMID: 23538582

Abstract

Purpose

To examine vascular tortuosity as a function of distance from the optic disc in infants with retinopathy of prematurity (ROP).

Methods

34 wide-angle retinal images from infants with ROP were reviewed by 22 experts. A reference standard for each image was defined as the diagnosis (plus vs. not plus) given by the majority of experts. Tortuosity, defined as vessel length divided by straight-line distance between vessel endpoints, was calculated as a function of distance from the disc margin for arteries and veins using computer-based methods developed by the authors.

Results

Mean cumulative tortuosity increased with distance from the disc margin, both in 13 images with plus disease (p=0.007 for arterial tortuosity (n=62 arteries), p<0.001 for venous tortuosity (n=58 veins) based on slope of best fit line by regression), and in 21 images without plus disease (p<0.001 for arterial tortuosity (n=94 arteries), p<0.001 for venous tortuosity (n=85 veins)). Images with plus disease had significantly higher vascular tortuosity than images without plus disease (p<0.05), up to 7.0 disc diameters from the optic disc margin.

Conclusions

Vascular tortuosity was higher peripherally than centrally, both in images with and without plus disease, suggesting that peripheral retinal features may be relevant for ROP diagnosis.

Keywords: Medical informatics, Pediatric ophthalmology, Retina, Retinopathy of prematurity

INTRODUCTION

Retinopathy of prematurity (ROP) is a vasoproliferative disease occurring in low birth-weight infants. During the past several decades, major progress in ROP diagnosis and treatment has occurred. An international classification system has been developed as a standard for describing clinical characteristics of ROP.1,2 This system has provided an infrastructure to support multicenter clinical trials. In particular, the Cryotherapy for ROP (CRYO-ROP) and Early Treatment for ROP (ETROP) trials have established that treatment with cryotherapy or laser photocoagulation can significantly improve structural and functional outcomes in infants with severe disease.3,4 Yet despite this progress, ROP continues to be a leading cause of childhood blindness worldwide.5

“Plus” disease, which is defined as arterial tortuosity and venous dilation in the posterior pole greater than or equal to that of a standard published photograph selected by expert consensus in the 1980s, is a key component of the ROP international classification system.1,2 According to the CRYO-ROP and ETROP trials, presence of plus disease is the most critical factor for diagnosis of treatment-requiring disease.3,4 Therefore, accurate and consistent diagnosis of plus disease is crucial. However, there are several limitations regarding this definition of plus disease. Studies have suggested inconsistency in clinical diagnosis, even among experts.6–8 The standard published photograph has a larger magnification and narrower field of view than clinical evaluation tools such as indirect ophthalmoscopy and wide-angle photography, and this difference in perspective may cause difficulty for ophthalmologists.9,10 Vessels in the standard published photograph have varying degrees of tortuosity and dilation, creating uncertainty regarding which vessels clinicians should focus on during clinical examination. Finally, although plus disease is defined solely based on appearance of the posterior retinal vessels, it is possible that other factors such as peripheral retinal features and the rate of vascular change may contribute to actual clinical diagnosis by experts.11 In fact, it has recently been shown that wide-field images are associated with more consistent plus disease diagnosis than medium-field or narrow-field images, and that peripheral retinal features may contribute useful diagnostic information.10 Understanding these factors will improve the accuracy and consistency of plus disease diagnosis.

To address these limitations, computer-based image analysis methods have been applied to provide more objective and quantitative plus disease diagnosis.12–19 Studies have suggested that some semi-automated systems have potential to identify plus disease with comparable or better accuracy than experts.7,16,20 However, an important gap in knowledge with regard to plus disease is that the retinal field of view which should be processed by these systems is not known. This is in part because the true clinical significance of peripheral vs. posterior retinal vascular changes has not been established, and in part because previous studies involving computer-based image analysis have examined different fields of view.7,11–20 Understanding the retinal field of view required for plus disease diagnosis has implications for both clinical diagnosis and design of computer-based systems.

The purpose of this study is to examine retinal vascular tortuosity as a function of distance from the optic disc. This will be done using computer-based quantification of retinal vascular tortuosity in wide-angle images captured by a commercially-available camera. Tortuosity is used because it is a key element of plus disease diagnosis.12,14,18 and because it is independent of differences in image magnification. Vascular dilation, another component of plus disease, is not evaluated in this study because it is dependent on differences in image magnification.

METHODS

This study was reviewed by the Institution Review Board at Oregon Health & Science University (Portland, OR), and was exempted because it involved computer-based analysis of an existing set of de-identified retinal images.

Image Selection

Thirty-four wide-angle retinal images were selected for this study. These images were obtained from premature infants during routine ROP care using a commercially-available camera with a 130-degree lens (RetCam; Clarity Medical Systems, Pleasanton, CA). Each image included a clear view of the optic disc and the vascular arcades, and reflected some vascular changes compared to baseline examination in the opinion of the authors. Each image was independently reviewed using a web-based system by 22 established ROP experts, who provided a diagnosis (plus vs. not plus). A reference standard for each image was defined as the diagnosis given by the majority of these 22 experts. Twenty-two expert responses were submitted for 18/34 (53%) images, 21 responses were submitted for 14/34 (41%) images, and 20 responses were submitted for 2/34 (6%) images (6%).6 Any visible peripheral ROP was cropped out of images to avoid biasing reviewers, but images were not otherwise manipulated or processed.

Computer-Based Image Analysis

Using graphics editing software (Photoshop CS5; Adobe Systems, San Jose, CA), a “mask” outlining each vessel was manually created for each wide-angle retinal image by the authors, and each vessel was classified as either an artery or vein by consensus of two authors (KMK, MFC). A representative example of this process is shown in Figure 1. The center of the optic disc and the optic disc margin were marked in each vessel mask.

Figure 1. Representative examples of wide-angle retinal images obtained from infants with ROP and corresponding vessel mask.

Figure 1

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Examples shown represent (A) expert consensus diagnosis of plus disease and (B) expert consensus diagnosis of not plus disease.

Each vessel mask was then prepared for analysis using computational software (Matlab 7.10; MathWorks, Natick, MA). First, a “skeleton” of the mask was constructed, in which the vessels were reduced to a one-pixel width tree. Next, end points and bifurcation points of the vessels were marked. Each portion of the vessel between an end point and a bifurcation, or between a bifurcation and another bifurcation, was termed a “branch.” A computer-based algorithm was developed and implemented by the authors to identify and trace the main vessel in each of the four quadrants by selecting the thickest branch at each bifurcation, and to calculate vascular tortuosity as a function of distance from the optic disc margin in disc diameters. Tortuosity was defined as length of the vessel divided by length of a straight line connecting the vessel ends.

Data Analysis

Mean tortuosity of each vessel was calculated as a function of distance in disc diameters (DD). The average DD of all images (based on average of horizontal and vertical dimensions in pixels) was used to standardize all computations. This was calculated using two different methods: (1) Cumulative tortuosity (e.g. between 0–0.5 DD from disc margin, 0–1.0 DD, 0–1.5 DD, etc.). The optic disc margin was chosen as the reference point because it was often difficult to evaluate vessels overlying the optic disc. (2) Instantaneous tortuosity (e.g. between 0–0.5 DD from disc margin, 0.5–1.0 DD, 1.0–1.5 DD, etc.).

Arteries and veins were analyzed separately. Mean values of tortuosity from all vessels in each image were compared between: (1) arteries in images with plus disease and images without plus disease; (2) veins in images with plus disease and images without plus disease; (3) arteries and veins in images with plus disease; and (4) arteries and veins in images without plus disease. These quantitative tortuosity values were compared among images with vs. without plus disease, as determined by the reference standard from expert consensus defined above. Statistical software (Graphpad QuickCalcs; Graphpad Software Inc., La Jolla, CA) was used to perform comparisons using an unpaired t-test. Linear regression analysis was performed to determine the trend of tortuosity with increasing distance from the optic disc.

RESULTS

Summary of Image Vessels and Reference Standard

Of the 34 images, 13 (38 %) represented “plus” disease and 21 (62%) represented “not plus” disease based on the consensus reference standard. From 13 images with plus disease, 62 arteries and 58 veins were analyzed. From 21 images without plus disease, 94 arteries and 85 veins were analyzed. The mean (range) number of vessels analyzed per image was 4.59 (1–7) arteries and 4.21 (2–6) veins.

Computer-Based Analysis: Arterial Tortuosity

Figure 2A shows that images with plus disease had significantly higher mean cumulative arterial tortuosity than images without plus disease up to 3.5 DD from the disc margin (p<0.05). In addition, mean cumulative arterial tortuosity for images with and without plus disease increased with distance from the optic disc margin. Linear regression analysis showed that there was a small positive slope of the best fit line (p=0.007 among images with plus disease, p<0.001 among images without plus disease).

Figure 2. Comparison of mean arterial tortuosity as a function of distance from the optic disc margin among images with and without plus disease.

Figure 2

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Thirty-four wide-angle retinal images were analyzed, including 13 images with plus disease (n=62 arteries) and 21 images without plus disease (n=94 arteries). Results are displayed as (A) cumulative arterial tortuosity and (B) instantaneous arterial tortuosity for images with and without plus disease. Statistically significant differences in mean arterial tortuosity are shown between images with plus and without plus disease. Difference between plus vs. not plus significant at *p<0.05, †p<0.005, and ‡p<0.001.

Figure 2B shows that images with plus disease had significantly higher mean instantaneous arterial tortuosity than images without plus disease up to 2.0 DD from the disc margin (p<0.05). In addition, mean instantaneous arterial tortuosity for images with and without plus disease decreased with distance from the disc margin. Linear regression analysis showed that there was a negative slope of the best fit line (p<0.001 among images with plus disease, p<0.001 among images without plus disease).

Computer-Based Analysis: Venous Tortuosity

Figure 3A shows that images with plus disease had significantly higher mean cumulative venous tortuosity than images without plus disease up to 7.0 DD from the optic disc margin (p<0.05). In addition, mean cumulative venous tortuosity for images with and without plus disease increased with distance from the disc margin. Linear regeression analysis showed that there was a positive slope of the best fit line (p<0.001 among images with plus disease, p<0.001 among images without plus disease).

Figure 3. Comparison of mean venous tortuosity as a function of distance from the optic disc margin among images with and without plus disease.

Figure 3

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Thirty-four wide-angle retinal images were analyzed, including 13 images with plus disease (n=58 veins) and 21 images without plus disease (n=85 veins). Results are displayed as (A) cumulative venous tortuosity and (B) instantaneous venous tortuosity for images with and without plus disease. Statistically significant differences in mean venous tortuosity are shown between images with plus and without plus disease. Difference between plus vs. not plus significant at *p<0.05, †p<0.005, and ‡p<0.001.

Figure 3B shows that images with plus disease had significantly higher mean instantaneous venous tortuosity than images without plus disease up to 6.5 DD from the disc margin (p<0.05). Mean instantaneous venous tortuosity was similar with distance from the disc margin based on linear regression analysis (p=0.06 among images with plus disease, p=0.08 among images without plus disease).

Computer-Based Analysis: Arteries vs. Veins

Mean values of tortuosity were also compared in arteries vs. veins in all study images. Images with plus disease had significantly higher mean cumulative tortuosity in arteries than in veins, up to 2.5 DD from the optic disc margin (Figure 4A). Images without plus disease also had significantly higher mean cumulative tortuosity in arteries than in veins, up to 4.5 DD from the optic disc margin (Figure 4B).

Figure 4. Comparison of mean cumulative tortuosity as a function of distance from optic disc margin between arteries and veins among images with and without plus disease.

Figure 4

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Thirty-four wide-angle retinal images were analyzed, including 13 images with plus disease (n=62 arteries and 58 veins) and 21 images without plus disease (n=94 arteries and 85 veins). Results are displayed as (A) cumulative tortuosity for images with plus disease and (B) cumulative tortuosity for images without plus disease. Statistically significant differences in mean vascular tortuosity are shown between arteries and veins. Difference between plus vs. not plus significant at *p<0.05, †p<0.005, and ‡p<0.001.

DISCUSSION

This study was designed to examine vascular tortuosity as a function of distance from the optic disc in wide-angle retinal images from premature infants with vs. without plus disease. The key findings are that: (1) there is an increase in vascular tortuosity as a function of distance from the optic disc margin, both in images with and without plus disease; (2) vascular tortuosity is significantly higher in images with plus disease than in those without plus disease, up to several disc diameters from the optic disc margin; and (3) arterial tortuosity is significantly higher than venous tortuosity, both in images with and without plus disease, up to several disc diameters from the optic disc margin.

In this study, mean vascular tortuosity was higher peripherally than centrally, both in images with plus and without plus disease (Figures 2A and 3A). A representative image illustrating these differences is shown in Figure 5. Plus disease is defined by a standard narrow-field photograph that displays central vessels extending less than 1.0 DD from the optic disc center superiorly, and approximately 2.0 DD inferiorly. However, findings from this study suggest that peripheral retinal features such as tortuosity may also be relevant for plus disease diagnosis. In related studies, we have shown that plus disease diagnosis is more consistent from wide-field (e.g. 80° or more) images than from medium-field (e.g. 40°–50°) or narrow-field (e.g. 20°–30°) images, and that the large magnification and narrow field of view of the standard published photograph may cause confusion for ophthalmologists.9,10 Taken together, these findings suggest that the notion of plus disease being based solely on central retinal vascular features may be an over-simplification.

Figure 5.

Figure 5

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Representative example of increased peripheral vascular tortuosity, compared to central vascular tortuosity, in a study image with plus disease.

Another key finding from this study is that arterial tortuosity was higher than venous tortuosity, both in images with and without plus disease (Figure 4). We found that arterial tortuosity was significantly higher centrally in images with plus disease than in images without plus disease. However, we also found that venous tortuosity, which is not included in the formal definition of plus disease, was significantly higher centrally as well as peripherally in images with plus disease than in images without plus disease. This is consistent with findings previously published by Gelman et al., suggesting that increased venous tortuosity is associated with plus disease.7 This may have implications for clinical ROP diagnosis and education.6,21–22 We note that previous studies involving computer-based image analysis systems for plus disease diagnosis have evaluated vascular tortuosity without distinguishing between arteries and veins.12,14,18,20,23 One possible reason is that arteries and veins are not always easy to distinguish. For example, Johnston et al. reported that experts did not agree when distinguishing retinal arteries from veins approximately 17% of the time.24 Based on all of these findings, further studies to clarify the role of venous vs. arterial tortuosity in plus disease diagnosis will be useful. In particular, venous tortuosity may be useful for plus disease diagnosis.

Two different methods were defined in this study to calculate vascular tortuosity. The reference point for each main vessel was first defined as its starting point on the optic disc margin. Then, each main vessel was divided into equal segments based on linear distance to the reference point (i.e. 0–0.5 DD, 0.5–1.0 DD, etc.). In the first method, “cumulative tortuosity” was defined as the tortuosity of the vessel from the reference point to the segment’s end-point (e.g. 0–2.0 DD). Cumulative tortuosity was intended to represent the overall nonlinearity of a vessel in a typical real-world system, in which the optic disc margin is easily demarcated. In the second method, “instantaneous tortuosity” was defined as the tortuosity of the segment from its starting point to its end-point (e.g. 1.5–2.0 DD). Instantaneous tortuosity was intended to represent the curving of vessels in specific local areas of the retina. While cumulative vascular tortuosity increased peripherally in images with and without plus disease (p=0.007 from linear regression analysis) (Figures 2A and 3A), instantaneous arterial tortuosity decreased (p=<0.001) and instantaneous venous tortuosity remained unchanged (p=0.06 to p=0.08) with increasing distance from the optic disc based on the p-value of the slope of the line (Figures 2B and 3B). These differences between “cumulative” and “instantaneous” tortuosity are presumably related to differences between overall vs. local vascular nonlinearities, as well as second-order curving effects of vessels. In the future, better metrics to measure overall curvature of vessels will need to be defined and validated.

Accurate and consistent identification of plus disease is essential for appropriate clinical management as the presence of plus disease has been shown to be the most critical marker for identifying treatment-requiring ROP.3,4 Yet, several studies have suggested significant diagnostic inconsistencies, even among experts.6–8 Potential reasons for disagreement include subjective observations of vascular tortuosity and dilation during examination, different understandings of the amount of abnormality required for plus disease, and confusion due to differences in image magnification.9 Variable interpretations of the significance of peripheral retinal features including vascular tortuosity and dilation as well as vascular branching patterns, may contribute to disagreement to the extent that experts may place greater emphasis on certain peripheral features when characterizing plus disease. Further studies to determine the exact retinal features used by experts when diagnosing plus disease will be helpful.

Computer-based image analysis methods have been developed as a way to provide more objective and quantitative plus disease diagnosis. Yet, the retinal field of view that should be processed by these systems has not been standardized. Some studies have performed image analysis using a narrow-angle field of view comparable to the standard published photograph, which includes only the central retina.12,14,20 Others have used medium-angle or wide-angle fields of view, which include peripheral vessels, with the rationale that experts may have difficulty diagnosing plus disease based solely on the appearance of central vessels.15,16,18 We feel that findings from the current study suggest that computer-based image analysis systems for plus disease diagnosis should process a standard field of view well beyond that of the published photographic definition.3

Several details regarding the computer-based analysis methods used in this study warrant further discussion. Vessels in each image were identified using a manual process in which authors reviewed and outlined arteries and veins using software drawing tools (Figure 1). Computer tools have been developed for semi-automated segmentation of retinal vessels in ROP, but these systems have been shown to perform imperfectly and to require manual correction by experts.15,25,26 Although segmentation algorithms are improving,27 the decision was made to perform manual vessel identification for this study to remove a potential confounding factor caused by segmentation errors. Furthermore, a computer-based algorithm was then used to calculate vascular tortuosity of the main vessel in each quadrant of each image, which was defined as the thickest branch at each bifurcation point. It is possible that including all vessel branches may have altered the computed values of mean vascular tortuosity, and that this may have systematically affected either the central or peripheral tortuosity values more. However, analysis on multiple vascular branches would be technically difficult because tortuosity was defined for this study based on the start and end points of the vessels – this would be difficult to compute because branches occur at unpredictable locations. Therefore, the decision was made to calculate tortuosity values only for the main vascular branch in each quadrant for simplicity and reproducibility. Future research examining the impact of vascular branching pattern on ROP and plus disease diagnosis will be informative.

Further study limitations include: (1) This study evaluated a limited number of vessels in a limited number of wide-angle retinal images from infants being examined for ROP. More complete analysis of vascular tortuosity as a function of field of view will be informative, but will require collection of much larger data sets with expert interpretations. (2) The reference standard for each image was defined as the diagnosis given by the majority of experts. We recognize that this may be an imperfect reference standard because of potential diagnostic inconsistency among experts.6,8,28 However, we have previously explored different methods of defining reference standard for plus disease, and found that they appear to produce very similar results.7 (3) Similarly, the reference standard was defined purely based on appearance of wide-angle retinal images without additional clinical data or opportunities to visualize peripheral disease. It is possible that these factors may be considered by examiners during real-world diagnosis. However, we note that the definition of plus disease involves only the central retina, without consideration of peripheral ROP features such as stage.3 Furthermore, multiple published studies have shown that image-based ROP diagnosis agrees very closely with ophthalmoscopic diagnosis.29–37 (4) Pre-plus disease was not included as a third diagnostic category in this study, because our anecdotal impression is that there is often significant variability among experts regarding the definition of pre-plus disease. Future studies incorporating pre-plus disease into these analyses may be useful. (5) Finally, the wide-angle images used in this study represent projections of the spherical retinal structure onto a flat plane. For that reason, the distances from the optic disc measured in this study might not reflect the exact anatomic distances.

In summary, our findings that peripheral vascular tortuosity is higher than central vascular tortuosity in wide-angle retinal images suggests that peripheral retinal features may be important for diagnosis of clinically-significant disease. This may have implications for the standard photographic definitions of plus disease as well as the future development of computer-based image analysis systems.

Summary Statement.

This study examines vascular tortuosity as a function of distance from the optic disc in infants with ROP. The key finding is that vascular tortuosity is higher peripherally compared to centrally, both in images with and without plus disease, suggesting that peripheral features may be relevant for ROP diagnosis.

Acknowledgments

MFC is supported by grant EY19474 from the National Institutes of Health (Bethesda, MD). KMK and MFC are supported by unrestricted departmental funding from Research to Prevent Blindness (New York, NY). JKC is supported by grant 4R00LM009889 from the National Library of Medicine (Bethesda, MD).

Footnotes

No authors have financial conflicts of interest. MFC is an unpaid member of the Scientific Advisory Board for Clarity Medical Systems (Pleasanton, CA).

Presented in part at the 2012 Association for Research in Vision and Ophthalmology conference (Fort Lauderdale, FL).

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