- Email: [email protected]
The Lack of Concordance Between Subretinal Drusenoid Deposits and Large Choroidal Blood Vessels
The Lack of Concordance Between Subretinal Drusenoid Deposits and Large Choroidal Blood Vessels SRITATATH VONGKULSIRI, SOTARO OOTO, SARAH MREJEN, MIHOKO SUZUKI, AND RICHARD F. SPAIDE PURPOSE:
To evaluate the concordance between pseudodrusen as manifested by subretinal drusenoid deposits and large choroidal blood vessels using stereological analysis of spectral-domain optical coherence tomography (SD OCT) images. DESIGN: Retrospective, observational case series. METHODS: The SD OCT images of 31 consecutive patients with the clinical appearance of pseudodrusen from a private-referral retinal clinic were retrospectively reviewed. A grid of 19 evenly spaced vertical lines was randomly superimposed on each SD OCT image using ImageJ to perform systematic uniform random sampling. The main outcome measure was the likelihood of association between subretinal drusenoid deposits and large choroidal vessels. RESULTS: Uniform random systematic sampling of 589 samples found the proportion of geometric probes intersecting subretinal drusenoid deposits to be 0.28, large choroidal vessel 0.65, and both 0.19. This value was nearly identical to the product of the joint probabilities and was within the 95% confidence interval (0.15– 0.21) of the point estimate as calculated by the binomial theorem, indicating mutual independence. The subretinal drusenoid deposits were associated with neither large choroidal vessels nor the intervals in between. CONCLUSIONS: Our results demonstrate that there is no concordance between subretinal drusenoid deposits and large choroidal vessels or the stroma in between. As a consequence, hypotheses postulating that subretinal drusenoid deposits are associated with large choroidal vessels or the choroidal stromal spaces should be abandoned. Stereological techniques are powerful methods used in image evaluation in other fields of study and appear to have utility in analyzing OCT findings of the retina and choroid. (Am J Ophthalmol 2014;158:710–715. Ó 2014 by Elsevier Inc. All rights reserved.)
P
SEUDODRUSEN, FIRST DESCRIBED CLINICALLY AS A
yellowish interlacing macular pattern better seen in blue light fundus photography in 1990,1 is a
Accepted for publication Jul 3, 2014. From Vitreous Retina Macula Consultants of New York and LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York. Inquiries to Richard F. Spaide, Vitreous Macula Retina Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
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strong independent risk factor for late age-related macular degeneration (AMD).2–5 Many terms besides pseudodrusen have been proposed for this clinical entity, including reticular drusen,3,6 reticular pseudodrusen,2 or reticular macular disease.7 Zweifel and associates demonstrated that eyes with pseudodrusen have collections of material in the subretinal space, as seen using spectral-domain optical coherence tomography (SD OCT), that have the size and shape corresponding to the pseudodrusen seen in color fundus photographs, and suggested the term subretinal drusenoid deposits.8 This clinical observation supported previous laboratory observations made of mounds of subretinal material seen in autopsy eyes.9 The SD OCT characteristics of subretinal drusenoid deposits varied from diffuse granular hyperreflective material between the retinal pigment epithelium (RPE) and the ellipsoid zone to conical hyperreflective material sitting on the RPE and breaking through the ellipsoid zone.6,8 There is controversy about pseudodrusen location and patterning. A hypothesis that there is a relationship between pseudodrusen and choroidal vessels first started when Arnold and associates postulated from the histopathologic analysis of 1 eye in which the retina was artifactually lost. The appearance of pseudodrusen was thought to be related to fibrous replacement of the choroidal stroma between a reduced number of choroidal vessels.2 However, the same group later reported the clinicopathologic correlation in a patient with pseudodrusen in a specimen in which the retina was not lost. This patient showed subretinal drusenoid deposits; the authors withdrew their suggestion that pseudodrusen appearance was related to fibrous replacement of the choroid.10 Since Arnold and associates first hypothesized that pseudodrusen resulted from fibrous replacement of the choroidal stroma, multiple imaging studies also proposed that there was some kind of concordance between pseudodrusen and the choroidal vasculature, stating that pseudodrusen were large vessels in the choroid (Haans R, et al. IOVS 2011; ARVO E-Abstract 1782); followed the edges of large vessels11; or followed, but were not located directly over, large choroidal vessels,12 the stroma between vessels,13,14 or the choriocapillaris.7 Although these seem quite disparate, a common element of all these theories is that the patterning of pseudodrusen is in some way controlled by or at least associated with the choroidal vasculature. In all these imaging studies, the hypothesis that there was an association between subretinal drusenoid deposits and choroidal vessels was based on nonrandom selection and
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subjective assessment.7,12–14 Deriving the relationships, or lack thereof, between lesions and nearby structures can lead to better understanding of disease pathogenesis. As such, elucidating the exact relationship between pseudodrusen and the underlying choroidal vasculature is essential in understanding pseudodrusen, a recently recognized manifestation of AMD. In the present study, we used unbiased stereological evaluation to investigate whether or not there is co-localization between pseudodrusen as evidenced by subretinal drusenoid deposits on SD OCT imaging and large choroidal vessels. Stereology is an efficient method that uses geometric probes and inferential statistics to obtain unbiased estimates of quantitative data. Commonly used in microscopy15 and evaluation of neurobiologic specimens,16 it is employed here in an in vivo analysis of SD OCT of the eye.
METHODS SUBJECTS:
This retrospective study was approved by the Western Institutional Review Board and complied with the Health Insurance Portability and Accountability Act of 1996. The SD OCT images showing the detail of the outer retina and the scleral-choroidal interface of 31 consecutive patients with pseudodrusen clearly identified as subretinal drusenoid deposits stage 2 and 3 in SD OCT from a private retinal referral clinic were retrospectively reviewed.
IMAGING DEFINITIONS:
The subretinal drusenoid deposits were defined as isolated mounds of hyperreflective subretinal material in SD OCT scans sufficient to alter the contour of the ellipsoid zone or conical hyperreflective material breaking through the ellipsoid zone, corresponding to subretinal drusenoid deposits stage 2 and 3, respectively, as previously defined.8 The large choroidal blood vessels were identified by a hyperreflective wall and dark center located in the outermost choroidal layer, close to the choroid-sclera junction.17,18
IMAGE ACQUISITION AND PROCESSING:
The SD OCT scans were obtained with the Heidelberg Spectralis (version 1.6.1; Heidelberg Engineering, Heidelberg, Germany), viewed with the Spectralis Viewing Module (version 5.7.0.1; Heidelberg Engineering). The imaging protocols were horizontal-line scan with varied scan size from 15 3 5 degrees to 30 3 20 degrees. The brightness and contrast of selected SD OCT images were manually adjusted with the Spectralis Viewing Module and Adobe Photoshop CS6 Extended (version 13.0.1 x64; Adobe Systems Inc, San Jose, California, USA) to optimize the delineation of subretinal drusenoid deposits and large choroidal vessels. We exported a SD OCT image containing subretinal drusenoid deposits of each subject from the Spectralis Viewing Module as TIFF (Tagged Image File Format; VOL. 158, NO. 4
Adobe Systems, Inc) files for further analysis. The SD OCT images were imported to ImageJ (Java image processing program developed at the National Institutes of Health, Bethesda, Maryland, USA) and were straightened using the segmented line function to line along the curved RPE and using the command Edit > Selection > Straighten. Then a grid of 19 evenly spaced vertical lines was randomly superimposed on each SD OCT image to perform uniform random systematic sampling using the grid plug-in (written by Wayne Rasband; available from the National Institutes of Health at http://rsb.info.nih.gov/ij/plugins/grid.html). DERIVATION OF STEREOLOGY METHOD:
A vertical line probe drawn at random perpendicularly through an OCT section will intersect a structure with a probability determined by the width of the structure in the OCT scan divided by the total width of the OCT scan. This would apply to both subretinal drusenoid deposits and large choroidal vessels. Taken in aggregate, the number of structures times their respective widths divided by the length of the scan defines the length fraction of that aggregate of structures. Let V denote the event of the line intersecting a large choroidal vessel and V that it does not. Let S denote the event of the line intersecting a collection of subretinal drusenoid deposits and S that it does not. The proportion of lines drawn at random that would intersect a large choroidal vessel, P(V), is equal to LV/(LV þ LV), where LV is the length fraction of the choroidal vessels in the section and LV is the length fraction of where the large choroidal vessels are not, or in other words the intervening choroidal stroma. In a similar fashion P(S), the proportion of the probe lines crossing a subretinal drusenoid deposit, is equal to LS/ (LS þ LS), where LS is the length fraction of subretinal drusenoid deposits in the section and LS is the length fraction of the normal intervening sections of outer retina. If we assume they are independent, P(V and S) ¼ P(V)P(S). By setting up a grid of vertical lines through the section, the number of times a line crosses a vessel only, subretinal drusenoid deposits only, neither, or both will be counted. The measured probability of the line going through both the vessel and a subretinal drusenoid deposits is p, which is an estimator for the true proportion P. This process is repeated for each patient; the placement of the lines, although periodically spaced, is offset by a random distance each time. This causes a systematic uniform random sampling. From these measurements the probabilities of crossing a vessel, pV, and subretinal drusenoid deposit, pS, will be calculated. The joint probability, p, as per the null hypothesis, should be pVpS. If this probability is not near zero or 1 then the 95% confidence interval is given by the approximation from the normal distribution pffiffiffiffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffi _p< _ p þ 1:96 pq=n þ 1=2n p 1:96 pq=n 1=2n < where q ¼ 1p; the 1/2n is for continuity correction. If the calculated theoretical joint proportion P(V and S) is within the 95% confidence interval, then the null
SUBRETINAL DRUSENOID DEPOSITS AND LARGE CHOROIDAL VESSELS
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FIGURE 1. Seventy-five-year-old age-related macular degeneration patient with pseudodrusen. Multiple conventional drusen are shown in color fundus photography (Top left) with an area of pseudodrusen in the superior macula. Pseudodrusen are seen on near-infrared scanning laser ophthalmoscopy image (Top right), with some having a target appearance. The spectral-domain optical coherence tomography image was superimposed with evenly spaced 19-vertical-line grid using ImageJ to perform systematic uniform random sampling (Bottom).
hypothesis that P(S) and P(V) are independent cannot be rejected. The numbers of times a line crossing subretinal drusenoid deposit only, large choroidal vessel only, both subretinal drusenoid deposit and large choroidal vessel, or neither were counted manually by 2 independent readers (S.V. and S.O.). Any discrepancy was decided using open adjudication using a third reader (M.S.). Since both the vessels and subretinal drusenoid deposits are more likely to be found in the posterior pole and therefore the center of the B-scan SD OCT image, we also separated the grading into 2 regions for sub-analysis; the analysis of the 11 central lines was called central group and the analysis of the peripheral 4 lines at both edges of the scan was called peripheral group (Figure 1, Bottom). STATISTICAL
ANALYSIS: The data obtained were analyzed with frequency statistics. The concordance of subretinal drusenoid deposits and large choroidal vessels was evaluated using the probability of 2 independent events with the derived method. The aggregate numbers for the stereology analysis were evaluated and secondarily the subset values from the central and peripheral groups were also analyzed.
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RESULTS THIRTY-ONE EYES OF 31 PATIENTS WITH CLINICAL APPEARANCE
of pseudodrusen who had SD OCT images showing the detail of the outer retina and scleral-choroidal interface were included. These 31 patients had a mean age of 82.9 6 7.0 years. A total of 589 lines were analyzed. The number (%) of events of the lines intersecting subretinal drusenoid deposits only, large choroidal vessels only, both, and neither were 51 (8.7%), 274 (46.5%), 111 (18.8%), and 153 (26.0%), respectively. The overall measured probability of the lines intersecting both subretinal drusenoid deposits and large choroidal vessels was 0.19, while probabilities of the lines crossing subretinal drusenoid deposits and those crossing the large choroidal vessels were 0.28 and 0.65, respectively. According to the aforementioned method, if we assume that the subretinal drusenoid deposits and large choroidal vessels are independent: PðS and VÞ ¼ PðSÞPðVÞ 0:19 z0:28 3 0:65 This result met the assumption that the subretinal drusenoid deposits and large choroidal vessels are independent
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with a 95% confidence interval of 0.15–0.21. We also tested the determinations in the central and peripheral groups separately, and neither was significant (data not shown). It is apparent that the same data could be evaluated by a 2 3 2 contingency table. We evaluated the test results and found that the P value was .779 using the x2 test, which also indicates there is no association between large choroidal vessels and subretinal drusenoid deposits.
DISCUSSION IN CONTRAST TO THE CONSENSUS REGARDING THEIR
clinical importance as an independent risk factor for late AMD,2–5 there is an ongoing controversy about the location and patterning of pseudodrusen. Multiple imaging studies claimed there was a concordance between subretinal drusenoid deposits and choroidal vessels.7,12–14 However, the current imaging study is the first to assess the concordance between subretinal drusenoid deposits and large choroidal vessels with an objective methodology. We used unbiased stereological sampling techniques to quantify the interrelationship between pseudodrusen as evidenced by subretinal drusenoid deposits on SD OCT imaging and large choroidal vessels, and we found no significant association. Previous investigators have hypothesized a variety of mutually exclusive associations between the location of pseudodrusen and large choroidal vessels. One possibility for these varying observations is that humans are highly adept at detecting patterns, even if one is not actually present. Palmer stated that the elements located within the perceptually defined region tend to be grouped together and called this the common region principle.19 Perturbations of the arrangements of the groupings or in the elements themselves can be used to make illusory figures, as seen in optical illusions (Figure 2).20 The choroid theories stating that there is a patterning of pseudodrusen that is correlated spatially with choroidal vessels do not agree and are mutually exclusive, even though some were reported by the same groups of authors.2,7,12–14 In 1995, Arnold and associates first found that pseudodrusen lie ‘‘in front of’’ large choroidal vessels, from clinical examination of 100 patients, and that pseudodrusen corresponded to the coarse pattern of large choroidal veins from the pathologic examination of 1 eye where the neurosensory retina was artifactually lost during processing.2 However, they did not demonstrate clinical-pathologic concordance between pseudodrusen appearance, with any imaging technique, and the pattern at the level of the large choroidal veins in the transverse pathologic section.2 In 2011 the same group retracted the claim that pseudodrusen were an appearance arising from the choroid when they reported a case of pseudodrusen being caused by subretinal drusenoid deposits.10 VOL. 158, NO. 4
FIGURE 2. Schematic image shows that the human visual system tends to make patterns or group things even if there are not actually patterns present. It looks like the mounds of material (gray wavy drawing) have a relationship with the larger choroidal vessels (red circles) in the upper drawing. The same thing seems to be true in the lower one. Actually the mounds of gray material in the upper drawing are drawn at random and are flipped 180 degrees to make the lower drawing.
In 2009, Smith and associates found that the pseudodrusen in the affected eyes occurred in analogous regions in color fundus photographs, the blue channel of color fundus photographs, infrared scanning laser ophthalmoscopy (IR-SLO), fundus autofluorescence, and indocyanine green angiographic (ICGA) images.7 To explain the similar regions of involvement with the pseudodrusen appearance in differing imaging modalities, the authors thought the choriocapillaris or inner choroid must be implicated,7 but did not mention other possibilities. In 2011, using a feature of the Heidelberg Spectralis claiming to have point-to-point correlation, Sohrab and associates stated that subretinal deposits on SD OCT did not correspond to pseudodrusen appearance on IR-SLO, but were rather located immediately adjacent to them.14 Barteselli and associates evaluated the accuracy of the claimed point-topoint correlation system of the Heidelberg Spectralis in a model eye and found that the average maximum error in the alignment was 15 6 6 mm, the greatest error was 35 mm, and the error varied with temperature and number of scans and also showed a random variation over time.21 The error in uncalibrated systems in living eyes with pathology, if anything, would likely be greater than in a calibrated system examining model eyes. The range of errors of the correlation feature of the Spectralis overlaps with the range of pseudodrusen radii and thus would be an imperfect tool to test co-localization. Sohrab and associates used the Cirrus HD-OCT and claimed pseudodrusen co-localized to the intervascular choroidal stroma.13,14 However, the Cirrus HD-OCT (which has been shown to be poor at visualization and localization of pseudodrusen22) and the method of determining the location of the pseudodrusen, the methods used in warping images in that study, and any possible statistical analysis were not stated. Querques and associates correlated ICGA and IR-SLO and stated that on ICGA, pseudodrusen appeared to overlie
SUBRETINAL DRUSENOID DEPOSITS AND LARGE CHOROIDAL VESSELS
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the choroidal stroma, ‘‘closely abutting but generally not overlying the large choroidal vessels,’’12 but showed no statistical justification for that statement. Studies published subsequently have shown exact co-localization of pseudodrusen with subretinal deposits using multiple forms of imaging, including flood illuminated23 and scanning laser24 adaptive optics imaging. A limitation of this study is its retrospective design. We studied the patients with the clinical manifestation of subretinal drusenoid deposits, and only isolated nonconfluent stage 2 and 3 subretinal drusenoid deposits8 were in this study. We present the first analysis investigating the colocalization of subretinal drusenoid deposits and large choroidal vessels within the same B-scan SD OCT image, avoiding biases attributable to manual superimposition of
different imaging modalities or to unquantified correlation between images using the Spectralis. The method used to assess the concordance between pseudodrusen and large choroidal vessels in this study is based not on subjective pattern recognition, but rather on stereological analysis using geometric probes and inferential statistics to obtain unbiased estimates of quantitative data. The use of stereological methodology could be applied to other image analysis problems in OCT. Our results demonstrate that there is no concordance between subretinal drusenoid deposits and either the large choroidal vessels or the intervening stroma. As a consequence, hypotheses postulating that subretinal drusenoid deposits are associated with large choroidal vessels or the choroidal stromal spaces should be abandoned.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Sotaro Ooto and Mihoko Suzuki were funded by grant for fellowship study in the United States from Alcon Japan Ltd. Richard F. Spaide receives consultant and royalty payment support from Topcon Inc. This study was supported by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York. Contributions of authors: conception and design (R.F.S., S.V., S.O.); analysis and interpretation (R.F.S., S.V., S.O., M.Z.); writing the article (S.V., S.M., R.F.S., S.O.); critical revision of the article (R.F.S., S.M., S.V.); final approval of the article (R.F.S., S.M., S.V., S.O., M.Z.); data collection (S.V., S.O., M.Z.); provision of materials, patients, or resources (S.V., M.Z., R.F.S.); statistical expertise (R.F.S.); obtaining funding (R.F.S.); literature search (S.V., R.F.S., S.M.).
REFERENCES 1. Mimoun G, Soubrane G, Coscas G. [Macular drusen]. J Fr Ophtalmol 1990;13(10):511–530. 2. Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseudodrusen. A risk factor in age-related maculopathy. Retina 1995;15(3):183–191. 3. Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L. The Wisconsin age-related maculopathy grading system. Ophthalmology 1991;98(7):1128–1134. 4. Klein R, Meuer SM, Knudtson MD, Iyengar SK, Klein BE. The epidemiology of retinal reticular drusen. Am J Ophthalmol 2008;145(2):317–326. 5. Zweifel SA, Imamura Y, Spaide TC, Fujiwara T, Spaide RF. Prevalence and significance of subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular degeneration. Ophthalmology 2010;117(9):1775–1781. 6. Schmitz-Valckenberg S, Steinberg JS, Fleckenstein M, Visvalingam S, Brinkmann CK, Holz FG. Combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging of reticular drusen associated with age-related macular degeneration. Ophthalmology 2010; 117(6):1169–1176. 7. Smith RT, Sohrab MA, Busuioc M, Barile G. Reticular macular disease. Am J Ophthalmol 2009;148(5):733–743.e732. 8. Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 2010;117(2):303–312.e301. 9. Rudolf M, Malek G, Messinger JD, Clark ME, Wang L, Curcio CA. Sub-retinal drusenoid deposits in human retina: organization and composition. Exp Eye Res 2008;87(5): 402–408.
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10. Sarks J, Arnold J, Ho IV, Sarks S, Killingsworth M. Evolution of reticular pseudodrusen. Br J Ophthalmol 2011;95(7): 979–985. 11. Grewal DS, Chou J, Rollins SD, Fawzi AA. A pilot quantitative study of topographic correlation between reticular pseudodrusen and the choroidal vasculature using en face optical coherence tomography. PLoS One 2014;9(3):e92841. http:// dx.doi.org/10.1371/journal.pone.0092841. 12. Querques G, Querques L, Forte R, Massamba N, Coscas F, Souied EH. Choroidal changes associated with reticular pseudodrusen. Invest Ophthalmol Vis Sci 2012;53(3): 1258–1263. 13. Sohrab M, Wu K, Fawzi AA. A pilot study of morphometric analysis of choroidal vasculature in vivo, using en face optical coherence tomography. PLoS One 2012;7(11):e48631. http:// dx.doi.org/10.1371/journal.pone.0048631. 14. Sohrab MA, Smith RT, Salehi-Had H, Sadda SR, Fawzi AA. Image registration and multimodal imaging of reticular pseudodrusen. Invest Ophthalmol Vis Sci 2011; 52(8):5743–5748. 15. Peterson DA. Quantitative histology using confocal microscopy: implementation of unbiased stereology procedures. Methods 1999;18(4):493–507. 16. Schmitz C, Hof PR. Design-based stereology in neuroscience. Neuroscience 2005;130(4):813–831. 17. Branchini LA, Adhi M, Regatieri CV, et al. Analysis of choroidal morphologic features and vasculature in healthy eyes using spectral-domain optical coherence tomography. Ophthalmology 2013;120(9):1901–1908. 18. Mrejen S, Spaide RF. Optical coherence tomography: imaging of the choroid and beyond. Surv Ophthalmol 2013;58(5): 387–429.
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19. Palmer SE. Common region: a new principle of perceptual grouping. Cogn Psychol 1992;24(3):436–447. 20. Palmer SE, Brooks JL, Nelson R. When does grouping happen? Acta Psychol (Amst) 2003;114(3):311–330. 21. Barteselli G, Bartsch DU, Viola F, et al. Accuracy of the Heidelberg Spectralis in the alignment between near-infrared image and tomographic scan in a model eye: a multicenter study. Am J Ophthalmol 2013;156(3):588–592. 22. Switzer DW, Engelbert M, Freund KB. Spectral domain optical coherence tomography macular cube scans and retinal pigment epithelium/drusen maps may fail to display
subretinal drusenoid deposits (reticular pseudodrusen) in eyes with non-neovascular age-related macular degeneration. Eye (Lond) 2011;25(10):1379–1380. 23. Mrejen S, Sato T, Curcio CA, Spaide RF. Assessing the cone photoreceptor mosaic in eyes with pseudodrusen and soft drusen in vivo using adaptive optics imaging. Ophthalmology 2014;121(2):545–551. 24. Zhang Y, Wang X, Rivero ED, et al. Photoreceptor perturbation around subretinal drusenoid deposits revealed by adaptive optics scanning laser ophthalmoscopy. Am J Ophthalmol 2014;158(3):584–596.
LXXI Edward Jackson Memorial Lecture
T
he American Journal of Ophthalmology and Elsevier Inc. will jointly recognize Hans Grossniklaus, MD, MBA, at this year’s American Academy of Ophthalmology meeting in Chicago as the 71st Edward Jackson Memorial Lecturer. Dr Grossniklaus of Emory University in Atlanta, GA, will present his lecture, entitled ‘‘Retinoblastoma: Fifty Years of Progress,’’ on October 19th during the opening session scheduled from 8:30 AM to 10 AM at Hyatt McCormick Place. Dr Grossniklaus is the founding director of the Ocular Oncology and Pathology
VOL. 158, NO. 4
service, director of the L.F. Montgomery Laboratory, and the F. Phinizy Calhoun Jr. Professor of Ophthalmology at Emory Eye Center. He has served on the board of the American Journal of Ophthalmology in a variety of capacities for 20 years, served as president of the American Ophthalmological Society last year, and is currently president of the American Association of Ophthalmic Oncologists and Pathologists. Dr Grossniklaus’ areas of expertise include diagnostic ophthalmic pathology, ocular oncology, ophthalmic pathology research, and translational research.
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To evaluate the concordance between pseudodrusen as manifested by subretinal drusenoid deposits and large choroidal blood vessels using stereological analysis of spectral-domain optical coherence tomography (SD OCT) images. DESIGN: Retrospective, observational case series. METHODS: The SD OCT images of 31 consecutive patients with the clinical appearance of pseudodrusen from a private-referral retinal clinic were retrospectively reviewed. A grid of 19 evenly spaced vertical lines was randomly superimposed on each SD OCT image using ImageJ to perform systematic uniform random sampling. The main outcome measure was the likelihood of association between subretinal drusenoid deposits and large choroidal vessels. RESULTS: Uniform random systematic sampling of 589 samples found the proportion of geometric probes intersecting subretinal drusenoid deposits to be 0.28, large choroidal vessel 0.65, and both 0.19. This value was nearly identical to the product of the joint probabilities and was within the 95% confidence interval (0.15– 0.21) of the point estimate as calculated by the binomial theorem, indicating mutual independence. The subretinal drusenoid deposits were associated with neither large choroidal vessels nor the intervals in between. CONCLUSIONS: Our results demonstrate that there is no concordance between subretinal drusenoid deposits and large choroidal vessels or the stroma in between. As a consequence, hypotheses postulating that subretinal drusenoid deposits are associated with large choroidal vessels or the choroidal stromal spaces should be abandoned. Stereological techniques are powerful methods used in image evaluation in other fields of study and appear to have utility in analyzing OCT findings of the retina and choroid. (Am J Ophthalmol 2014;158:710–715. Ó 2014 by Elsevier Inc. All rights reserved.)
P
SEUDODRUSEN, FIRST DESCRIBED CLINICALLY AS A
yellowish interlacing macular pattern better seen in blue light fundus photography in 1990,1 is a
Accepted for publication Jul 3, 2014. From Vitreous Retina Macula Consultants of New York and LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York. Inquiries to Richard F. Spaide, Vitreous Macula Retina Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
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2014 BY
strong independent risk factor for late age-related macular degeneration (AMD).2–5 Many terms besides pseudodrusen have been proposed for this clinical entity, including reticular drusen,3,6 reticular pseudodrusen,2 or reticular macular disease.7 Zweifel and associates demonstrated that eyes with pseudodrusen have collections of material in the subretinal space, as seen using spectral-domain optical coherence tomography (SD OCT), that have the size and shape corresponding to the pseudodrusen seen in color fundus photographs, and suggested the term subretinal drusenoid deposits.8 This clinical observation supported previous laboratory observations made of mounds of subretinal material seen in autopsy eyes.9 The SD OCT characteristics of subretinal drusenoid deposits varied from diffuse granular hyperreflective material between the retinal pigment epithelium (RPE) and the ellipsoid zone to conical hyperreflective material sitting on the RPE and breaking through the ellipsoid zone.6,8 There is controversy about pseudodrusen location and patterning. A hypothesis that there is a relationship between pseudodrusen and choroidal vessels first started when Arnold and associates postulated from the histopathologic analysis of 1 eye in which the retina was artifactually lost. The appearance of pseudodrusen was thought to be related to fibrous replacement of the choroidal stroma between a reduced number of choroidal vessels.2 However, the same group later reported the clinicopathologic correlation in a patient with pseudodrusen in a specimen in which the retina was not lost. This patient showed subretinal drusenoid deposits; the authors withdrew their suggestion that pseudodrusen appearance was related to fibrous replacement of the choroid.10 Since Arnold and associates first hypothesized that pseudodrusen resulted from fibrous replacement of the choroidal stroma, multiple imaging studies also proposed that there was some kind of concordance between pseudodrusen and the choroidal vasculature, stating that pseudodrusen were large vessels in the choroid (Haans R, et al. IOVS 2011; ARVO E-Abstract 1782); followed the edges of large vessels11; or followed, but were not located directly over, large choroidal vessels,12 the stroma between vessels,13,14 or the choriocapillaris.7 Although these seem quite disparate, a common element of all these theories is that the patterning of pseudodrusen is in some way controlled by or at least associated with the choroidal vasculature. In all these imaging studies, the hypothesis that there was an association between subretinal drusenoid deposits and choroidal vessels was based on nonrandom selection and
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.07.009
subjective assessment.7,12–14 Deriving the relationships, or lack thereof, between lesions and nearby structures can lead to better understanding of disease pathogenesis. As such, elucidating the exact relationship between pseudodrusen and the underlying choroidal vasculature is essential in understanding pseudodrusen, a recently recognized manifestation of AMD. In the present study, we used unbiased stereological evaluation to investigate whether or not there is co-localization between pseudodrusen as evidenced by subretinal drusenoid deposits on SD OCT imaging and large choroidal vessels. Stereology is an efficient method that uses geometric probes and inferential statistics to obtain unbiased estimates of quantitative data. Commonly used in microscopy15 and evaluation of neurobiologic specimens,16 it is employed here in an in vivo analysis of SD OCT of the eye.
METHODS SUBJECTS:
This retrospective study was approved by the Western Institutional Review Board and complied with the Health Insurance Portability and Accountability Act of 1996. The SD OCT images showing the detail of the outer retina and the scleral-choroidal interface of 31 consecutive patients with pseudodrusen clearly identified as subretinal drusenoid deposits stage 2 and 3 in SD OCT from a private retinal referral clinic were retrospectively reviewed.
IMAGING DEFINITIONS:
The subretinal drusenoid deposits were defined as isolated mounds of hyperreflective subretinal material in SD OCT scans sufficient to alter the contour of the ellipsoid zone or conical hyperreflective material breaking through the ellipsoid zone, corresponding to subretinal drusenoid deposits stage 2 and 3, respectively, as previously defined.8 The large choroidal blood vessels were identified by a hyperreflective wall and dark center located in the outermost choroidal layer, close to the choroid-sclera junction.17,18
IMAGE ACQUISITION AND PROCESSING:
The SD OCT scans were obtained with the Heidelberg Spectralis (version 1.6.1; Heidelberg Engineering, Heidelberg, Germany), viewed with the Spectralis Viewing Module (version 5.7.0.1; Heidelberg Engineering). The imaging protocols were horizontal-line scan with varied scan size from 15 3 5 degrees to 30 3 20 degrees. The brightness and contrast of selected SD OCT images were manually adjusted with the Spectralis Viewing Module and Adobe Photoshop CS6 Extended (version 13.0.1 x64; Adobe Systems Inc, San Jose, California, USA) to optimize the delineation of subretinal drusenoid deposits and large choroidal vessels. We exported a SD OCT image containing subretinal drusenoid deposits of each subject from the Spectralis Viewing Module as TIFF (Tagged Image File Format; VOL. 158, NO. 4
Adobe Systems, Inc) files for further analysis. The SD OCT images were imported to ImageJ (Java image processing program developed at the National Institutes of Health, Bethesda, Maryland, USA) and were straightened using the segmented line function to line along the curved RPE and using the command Edit > Selection > Straighten. Then a grid of 19 evenly spaced vertical lines was randomly superimposed on each SD OCT image to perform uniform random systematic sampling using the grid plug-in (written by Wayne Rasband; available from the National Institutes of Health at http://rsb.info.nih.gov/ij/plugins/grid.html). DERIVATION OF STEREOLOGY METHOD:
A vertical line probe drawn at random perpendicularly through an OCT section will intersect a structure with a probability determined by the width of the structure in the OCT scan divided by the total width of the OCT scan. This would apply to both subretinal drusenoid deposits and large choroidal vessels. Taken in aggregate, the number of structures times their respective widths divided by the length of the scan defines the length fraction of that aggregate of structures. Let V denote the event of the line intersecting a large choroidal vessel and V that it does not. Let S denote the event of the line intersecting a collection of subretinal drusenoid deposits and S that it does not. The proportion of lines drawn at random that would intersect a large choroidal vessel, P(V), is equal to LV/(LV þ LV), where LV is the length fraction of the choroidal vessels in the section and LV is the length fraction of where the large choroidal vessels are not, or in other words the intervening choroidal stroma. In a similar fashion P(S), the proportion of the probe lines crossing a subretinal drusenoid deposit, is equal to LS/ (LS þ LS), where LS is the length fraction of subretinal drusenoid deposits in the section and LS is the length fraction of the normal intervening sections of outer retina. If we assume they are independent, P(V and S) ¼ P(V)P(S). By setting up a grid of vertical lines through the section, the number of times a line crosses a vessel only, subretinal drusenoid deposits only, neither, or both will be counted. The measured probability of the line going through both the vessel and a subretinal drusenoid deposits is p, which is an estimator for the true proportion P. This process is repeated for each patient; the placement of the lines, although periodically spaced, is offset by a random distance each time. This causes a systematic uniform random sampling. From these measurements the probabilities of crossing a vessel, pV, and subretinal drusenoid deposit, pS, will be calculated. The joint probability, p, as per the null hypothesis, should be pVpS. If this probability is not near zero or 1 then the 95% confidence interval is given by the approximation from the normal distribution pffiffiffiffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffi _p< _ p þ 1:96 pq=n þ 1=2n p 1:96 pq=n 1=2n < where q ¼ 1p; the 1/2n is for continuity correction. If the calculated theoretical joint proportion P(V and S) is within the 95% confidence interval, then the null
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FIGURE 1. Seventy-five-year-old age-related macular degeneration patient with pseudodrusen. Multiple conventional drusen are shown in color fundus photography (Top left) with an area of pseudodrusen in the superior macula. Pseudodrusen are seen on near-infrared scanning laser ophthalmoscopy image (Top right), with some having a target appearance. The spectral-domain optical coherence tomography image was superimposed with evenly spaced 19-vertical-line grid using ImageJ to perform systematic uniform random sampling (Bottom).
hypothesis that P(S) and P(V) are independent cannot be rejected. The numbers of times a line crossing subretinal drusenoid deposit only, large choroidal vessel only, both subretinal drusenoid deposit and large choroidal vessel, or neither were counted manually by 2 independent readers (S.V. and S.O.). Any discrepancy was decided using open adjudication using a third reader (M.S.). Since both the vessels and subretinal drusenoid deposits are more likely to be found in the posterior pole and therefore the center of the B-scan SD OCT image, we also separated the grading into 2 regions for sub-analysis; the analysis of the 11 central lines was called central group and the analysis of the peripheral 4 lines at both edges of the scan was called peripheral group (Figure 1, Bottom). STATISTICAL
ANALYSIS: The data obtained were analyzed with frequency statistics. The concordance of subretinal drusenoid deposits and large choroidal vessels was evaluated using the probability of 2 independent events with the derived method. The aggregate numbers for the stereology analysis were evaluated and secondarily the subset values from the central and peripheral groups were also analyzed.
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RESULTS THIRTY-ONE EYES OF 31 PATIENTS WITH CLINICAL APPEARANCE
of pseudodrusen who had SD OCT images showing the detail of the outer retina and scleral-choroidal interface were included. These 31 patients had a mean age of 82.9 6 7.0 years. A total of 589 lines were analyzed. The number (%) of events of the lines intersecting subretinal drusenoid deposits only, large choroidal vessels only, both, and neither were 51 (8.7%), 274 (46.5%), 111 (18.8%), and 153 (26.0%), respectively. The overall measured probability of the lines intersecting both subretinal drusenoid deposits and large choroidal vessels was 0.19, while probabilities of the lines crossing subretinal drusenoid deposits and those crossing the large choroidal vessels were 0.28 and 0.65, respectively. According to the aforementioned method, if we assume that the subretinal drusenoid deposits and large choroidal vessels are independent: PðS and VÞ ¼ PðSÞPðVÞ 0:19 z0:28 3 0:65 This result met the assumption that the subretinal drusenoid deposits and large choroidal vessels are independent
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with a 95% confidence interval of 0.15–0.21. We also tested the determinations in the central and peripheral groups separately, and neither was significant (data not shown). It is apparent that the same data could be evaluated by a 2 3 2 contingency table. We evaluated the test results and found that the P value was .779 using the x2 test, which also indicates there is no association between large choroidal vessels and subretinal drusenoid deposits.
DISCUSSION IN CONTRAST TO THE CONSENSUS REGARDING THEIR
clinical importance as an independent risk factor for late AMD,2–5 there is an ongoing controversy about the location and patterning of pseudodrusen. Multiple imaging studies claimed there was a concordance between subretinal drusenoid deposits and choroidal vessels.7,12–14 However, the current imaging study is the first to assess the concordance between subretinal drusenoid deposits and large choroidal vessels with an objective methodology. We used unbiased stereological sampling techniques to quantify the interrelationship between pseudodrusen as evidenced by subretinal drusenoid deposits on SD OCT imaging and large choroidal vessels, and we found no significant association. Previous investigators have hypothesized a variety of mutually exclusive associations between the location of pseudodrusen and large choroidal vessels. One possibility for these varying observations is that humans are highly adept at detecting patterns, even if one is not actually present. Palmer stated that the elements located within the perceptually defined region tend to be grouped together and called this the common region principle.19 Perturbations of the arrangements of the groupings or in the elements themselves can be used to make illusory figures, as seen in optical illusions (Figure 2).20 The choroid theories stating that there is a patterning of pseudodrusen that is correlated spatially with choroidal vessels do not agree and are mutually exclusive, even though some were reported by the same groups of authors.2,7,12–14 In 1995, Arnold and associates first found that pseudodrusen lie ‘‘in front of’’ large choroidal vessels, from clinical examination of 100 patients, and that pseudodrusen corresponded to the coarse pattern of large choroidal veins from the pathologic examination of 1 eye where the neurosensory retina was artifactually lost during processing.2 However, they did not demonstrate clinical-pathologic concordance between pseudodrusen appearance, with any imaging technique, and the pattern at the level of the large choroidal veins in the transverse pathologic section.2 In 2011 the same group retracted the claim that pseudodrusen were an appearance arising from the choroid when they reported a case of pseudodrusen being caused by subretinal drusenoid deposits.10 VOL. 158, NO. 4
FIGURE 2. Schematic image shows that the human visual system tends to make patterns or group things even if there are not actually patterns present. It looks like the mounds of material (gray wavy drawing) have a relationship with the larger choroidal vessels (red circles) in the upper drawing. The same thing seems to be true in the lower one. Actually the mounds of gray material in the upper drawing are drawn at random and are flipped 180 degrees to make the lower drawing.
In 2009, Smith and associates found that the pseudodrusen in the affected eyes occurred in analogous regions in color fundus photographs, the blue channel of color fundus photographs, infrared scanning laser ophthalmoscopy (IR-SLO), fundus autofluorescence, and indocyanine green angiographic (ICGA) images.7 To explain the similar regions of involvement with the pseudodrusen appearance in differing imaging modalities, the authors thought the choriocapillaris or inner choroid must be implicated,7 but did not mention other possibilities. In 2011, using a feature of the Heidelberg Spectralis claiming to have point-to-point correlation, Sohrab and associates stated that subretinal deposits on SD OCT did not correspond to pseudodrusen appearance on IR-SLO, but were rather located immediately adjacent to them.14 Barteselli and associates evaluated the accuracy of the claimed point-topoint correlation system of the Heidelberg Spectralis in a model eye and found that the average maximum error in the alignment was 15 6 6 mm, the greatest error was 35 mm, and the error varied with temperature and number of scans and also showed a random variation over time.21 The error in uncalibrated systems in living eyes with pathology, if anything, would likely be greater than in a calibrated system examining model eyes. The range of errors of the correlation feature of the Spectralis overlaps with the range of pseudodrusen radii and thus would be an imperfect tool to test co-localization. Sohrab and associates used the Cirrus HD-OCT and claimed pseudodrusen co-localized to the intervascular choroidal stroma.13,14 However, the Cirrus HD-OCT (which has been shown to be poor at visualization and localization of pseudodrusen22) and the method of determining the location of the pseudodrusen, the methods used in warping images in that study, and any possible statistical analysis were not stated. Querques and associates correlated ICGA and IR-SLO and stated that on ICGA, pseudodrusen appeared to overlie
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the choroidal stroma, ‘‘closely abutting but generally not overlying the large choroidal vessels,’’12 but showed no statistical justification for that statement. Studies published subsequently have shown exact co-localization of pseudodrusen with subretinal deposits using multiple forms of imaging, including flood illuminated23 and scanning laser24 adaptive optics imaging. A limitation of this study is its retrospective design. We studied the patients with the clinical manifestation of subretinal drusenoid deposits, and only isolated nonconfluent stage 2 and 3 subretinal drusenoid deposits8 were in this study. We present the first analysis investigating the colocalization of subretinal drusenoid deposits and large choroidal vessels within the same B-scan SD OCT image, avoiding biases attributable to manual superimposition of
different imaging modalities or to unquantified correlation between images using the Spectralis. The method used to assess the concordance between pseudodrusen and large choroidal vessels in this study is based not on subjective pattern recognition, but rather on stereological analysis using geometric probes and inferential statistics to obtain unbiased estimates of quantitative data. The use of stereological methodology could be applied to other image analysis problems in OCT. Our results demonstrate that there is no concordance between subretinal drusenoid deposits and either the large choroidal vessels or the intervening stroma. As a consequence, hypotheses postulating that subretinal drusenoid deposits are associated with large choroidal vessels or the choroidal stromal spaces should be abandoned.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Sotaro Ooto and Mihoko Suzuki were funded by grant for fellowship study in the United States from Alcon Japan Ltd. Richard F. Spaide receives consultant and royalty payment support from Topcon Inc. This study was supported by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York. Contributions of authors: conception and design (R.F.S., S.V., S.O.); analysis and interpretation (R.F.S., S.V., S.O., M.Z.); writing the article (S.V., S.M., R.F.S., S.O.); critical revision of the article (R.F.S., S.M., S.V.); final approval of the article (R.F.S., S.M., S.V., S.O., M.Z.); data collection (S.V., S.O., M.Z.); provision of materials, patients, or resources (S.V., M.Z., R.F.S.); statistical expertise (R.F.S.); obtaining funding (R.F.S.); literature search (S.V., R.F.S., S.M.).
REFERENCES 1. Mimoun G, Soubrane G, Coscas G. [Macular drusen]. J Fr Ophtalmol 1990;13(10):511–530. 2. Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseudodrusen. A risk factor in age-related maculopathy. Retina 1995;15(3):183–191. 3. Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L. The Wisconsin age-related maculopathy grading system. Ophthalmology 1991;98(7):1128–1134. 4. Klein R, Meuer SM, Knudtson MD, Iyengar SK, Klein BE. The epidemiology of retinal reticular drusen. Am J Ophthalmol 2008;145(2):317–326. 5. Zweifel SA, Imamura Y, Spaide TC, Fujiwara T, Spaide RF. Prevalence and significance of subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular degeneration. Ophthalmology 2010;117(9):1775–1781. 6. Schmitz-Valckenberg S, Steinberg JS, Fleckenstein M, Visvalingam S, Brinkmann CK, Holz FG. Combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging of reticular drusen associated with age-related macular degeneration. Ophthalmology 2010; 117(6):1169–1176. 7. Smith RT, Sohrab MA, Busuioc M, Barile G. Reticular macular disease. Am J Ophthalmol 2009;148(5):733–743.e732. 8. Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 2010;117(2):303–312.e301. 9. Rudolf M, Malek G, Messinger JD, Clark ME, Wang L, Curcio CA. Sub-retinal drusenoid deposits in human retina: organization and composition. Exp Eye Res 2008;87(5): 402–408.
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10. Sarks J, Arnold J, Ho IV, Sarks S, Killingsworth M. Evolution of reticular pseudodrusen. Br J Ophthalmol 2011;95(7): 979–985. 11. Grewal DS, Chou J, Rollins SD, Fawzi AA. A pilot quantitative study of topographic correlation between reticular pseudodrusen and the choroidal vasculature using en face optical coherence tomography. PLoS One 2014;9(3):e92841. http:// dx.doi.org/10.1371/journal.pone.0092841. 12. Querques G, Querques L, Forte R, Massamba N, Coscas F, Souied EH. Choroidal changes associated with reticular pseudodrusen. Invest Ophthalmol Vis Sci 2012;53(3): 1258–1263. 13. Sohrab M, Wu K, Fawzi AA. A pilot study of morphometric analysis of choroidal vasculature in vivo, using en face optical coherence tomography. PLoS One 2012;7(11):e48631. http:// dx.doi.org/10.1371/journal.pone.0048631. 14. Sohrab MA, Smith RT, Salehi-Had H, Sadda SR, Fawzi AA. Image registration and multimodal imaging of reticular pseudodrusen. Invest Ophthalmol Vis Sci 2011; 52(8):5743–5748. 15. Peterson DA. Quantitative histology using confocal microscopy: implementation of unbiased stereology procedures. Methods 1999;18(4):493–507. 16. Schmitz C, Hof PR. Design-based stereology in neuroscience. Neuroscience 2005;130(4):813–831. 17. Branchini LA, Adhi M, Regatieri CV, et al. Analysis of choroidal morphologic features and vasculature in healthy eyes using spectral-domain optical coherence tomography. Ophthalmology 2013;120(9):1901–1908. 18. Mrejen S, Spaide RF. Optical coherence tomography: imaging of the choroid and beyond. Surv Ophthalmol 2013;58(5): 387–429.
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19. Palmer SE. Common region: a new principle of perceptual grouping. Cogn Psychol 1992;24(3):436–447. 20. Palmer SE, Brooks JL, Nelson R. When does grouping happen? Acta Psychol (Amst) 2003;114(3):311–330. 21. Barteselli G, Bartsch DU, Viola F, et al. Accuracy of the Heidelberg Spectralis in the alignment between near-infrared image and tomographic scan in a model eye: a multicenter study. Am J Ophthalmol 2013;156(3):588–592. 22. Switzer DW, Engelbert M, Freund KB. Spectral domain optical coherence tomography macular cube scans and retinal pigment epithelium/drusen maps may fail to display
subretinal drusenoid deposits (reticular pseudodrusen) in eyes with non-neovascular age-related macular degeneration. Eye (Lond) 2011;25(10):1379–1380. 23. Mrejen S, Sato T, Curcio CA, Spaide RF. Assessing the cone photoreceptor mosaic in eyes with pseudodrusen and soft drusen in vivo using adaptive optics imaging. Ophthalmology 2014;121(2):545–551. 24. Zhang Y, Wang X, Rivero ED, et al. Photoreceptor perturbation around subretinal drusenoid deposits revealed by adaptive optics scanning laser ophthalmoscopy. Am J Ophthalmol 2014;158(3):584–596.
LXXI Edward Jackson Memorial Lecture
T
he American Journal of Ophthalmology and Elsevier Inc. will jointly recognize Hans Grossniklaus, MD, MBA, at this year’s American Academy of Ophthalmology meeting in Chicago as the 71st Edward Jackson Memorial Lecturer. Dr Grossniklaus of Emory University in Atlanta, GA, will present his lecture, entitled ‘‘Retinoblastoma: Fifty Years of Progress,’’ on October 19th during the opening session scheduled from 8:30 AM to 10 AM at Hyatt McCormick Place. Dr Grossniklaus is the founding director of the Ocular Oncology and Pathology
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service, director of the L.F. Montgomery Laboratory, and the F. Phinizy Calhoun Jr. Professor of Ophthalmology at Emory Eye Center. He has served on the board of the American Journal of Ophthalmology in a variety of capacities for 20 years, served as president of the American Ophthalmological Society last year, and is currently president of the American Association of Ophthalmic Oncologists and Pathologists. Dr Grossniklaus’ areas of expertise include diagnostic ophthalmic pathology, ocular oncology, ophthalmic pathology research, and translational research.
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