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Pediatric diabetic retinopathy telescreening
Journal Pre-proof Pediatric diabetic retinopathy telescreening Sasha Strul, MD, Yuxi Zheng, BS, Sapna Gangaputra, MD, MPH, Karishma Datye, MD, Qingxia Chen, PhD, Laura Maynard, BSN, Eric Pittel, MBA, William Russell, MD, Sean Donahue, MD, PhD PII:
S1091-8531(20)30011-2
DOI:
https://doi.org/10.1016/j.jaapos.2019.10.010
Reference:
YMPA 3127
To appear in:
Journal of AAPOS
Received Date: 15 June 2019 Revised Date:
27 October 2019
Accepted Date: 29 October 2019
Please cite this article as: Strul S, Zheng Y, Gangaputra S, Datye K, Chen Q, Maynard L, Pittel E, Russell W, Donahue S, Pediatric diabetic retinopathy telescreening, Journal of AAPOS (2020), doi: https://doi.org/10.1016/j.jaapos.2019.10.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.
Pediatric diabetic retinopathy telescreening Sasha Strul, MD,a,c Yuxi Zheng, BS,a,b Sapna Gangaputra, MD, MPH,a Karishma Datye, MD,d Qingxia Chen, PhD,e Laura Maynard, BSN,f Eric Pittel, MBA,f William Russell, MD,d and Sean Donahue, MD, PhDa Author affiliations: aVanderbilt Eye Institute, Vanderbilt University, Nashville, Tennessee; b Vanderbilt University, School of Medicine, Nashville, Tennessee; cDepartment of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota; d Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University, Nashville, Tennessee; eDepartment of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee; fVanderbilt Eskind Pediatric Diabetes Clinic, Nashville, Tennessee This work was partially supported by an unrestricted grant to the Department of Ophthalmology and Visual Sciences at Vanderbilt University Medical Center from Research to Prevent Blindness, New York, NY, and by the Kids Battle Diabetes Golf Classic and the Care Foundation of America, whose support made possible the purchase non-mydriatic retinal cameras and facilitated expansion of retinal screening to off-campus locations of the Children’s Diabetes Program at Vanderbilt. Presented in part at the 43rd Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, April 2-6, 2017. Submitted June 15, 2019. Revision accepted October 29, 2019. Correspondence: Sasha Strul, MD, 701 25th Ave S #300, Minneapolis, MN 55455 (email: [email protected]). Word count: 2,676 Abstract only: 203
Abstract Purpose To describe the role of telemedicine screening for pediatric diabetic retinopathy (DR) and to identify risk factors for pediatric DR. Methods The medical records of a telemedicine program at a tertiary, academic medical center over 17 months were reviewed retrospectively. Patients visiting an academic pediatric endocrinology clinic who met guidelines underwent telescreening. Presence of pediatric DR and risk factors for retinopathy were evaluated. Results The fundus photographs of 852 patients 10-23 years of age were reviewed. Diabetic retinopathy was noted in 51 (6%). Patients with an abnormal screening photograph were compared to patients with diabetes who had normal screening photographs (n = 64). Older age, longer diabetes duration, type 1 diabetes, and higher average glycated hemoglobin (HbA1c) from the year prior to the photograph were associated with increased risk of retinopathy. Of these, longer duration (P = 0.003) and higher average A1c (P = 0.02) were significant after adjusting for sex, race, and age. Conclusions Our telemedicine program found a higher percentage of diabetic retinopathy screening nonmydriatic photographs than prior studies found through standard ophthalmic examinations. In this relatively small sample size, longer duration of disease and higher average A1c were associated with increased risk of having diabetic retinopathy in our study.
Diabetic retinopathy (DR) is a leading cause of legal blindness among working-age persons worldwide.1 Diabetic retinopathy has been designated as one of the priority eye diseases by WHO, because 7% of people with diabetes are at risk of blindness. This is becoming of greater importance as diabetes mellitus is reaching epidemic proportions globally.2 The Centers for Disease Control estimated that 23.1 million people in the United States were diagnosed with diabetes in 2015, 193,000 of whom were <20 years old.3 Due to this significant risk, global screening guidelines have been developed for early identification of retinopathy. The American Academy of Ophthalmology preferred practice guidelines recommend annual examinations beginning 5 years after onset of type 1 diabetes mellitus (T1DM) and beginning at time of diagnosis of type 2 diabetes mellitus (T2DM).4 The American Diabetes Association (ADA) recommends screening for diabetic retinopathy at age ≥10 years or postpuberty onset (whichever occurs first) in children with diabetes duration of over 3-5 years in children with T1DM, and starting at diagnosis in children with T2DM.5 Early detection is essential to prevent vision loss in the vulnerable and growing population of pediatric patients with diabetes. Telescreening for diabetic retinopathy is a validated and successful method to improve access to care and the time and cost associated with an ophthalmology clinic visit; however, most of the literature comes from screening of adult patients with diabetes.6 The goal of a diabetic retinopathy screening program is to triage patients that need to seek formal ophthalmology examinations and exclude those that have no concerning eye findings. We established a telemedicine program to facilitate screening for diabetic retinopathy in young patients by linking image acquisition with pediatric endocrinology clinical care. Subjects and Methods
Eligible patients visiting the pediatric endocrinology clinic at Vanderbilt University in Nashville, Tennessee, were offered diabetic screening using teleophthalmology, if they met ADA guidelines for DR screening. Specifically, patients with type 1 diabetes of duration ≥5 years and age ≥10 years and patients with type 2 diabetes starting at diagnosis were screened annually. At this clinic, patients with diabetes are scheduled every 3 months for routine follow-up, and retinopathy screening was performed during these routine visits. This screening was considered part of routine diabetes care and received a quality improvement/nonresearch determination from our institutional review board; screening did not require a separate patient consent form. The study complied with requirements of the US Health Insurance Portability and Accountability Act of 1996. A non-mydriatric retinal camera (TRC-NW400; Topcon, Tokyo, Japan) was used to acquire a single 45° image of the posterior pole of both eyes, including the optic nerve head and macula, with resolution of 48 pixels/degree. Images were acquired by medical technicians with minimal training. A trained ophthalmologist received the images remotely for assessment. The images were assessed using the international clinical diabetic retinopathy scale,7 which classifies diabetic retinopathy according to the severity of microaneurysms and hemorrhages in 5 steps: no diabetic retinopathy (no abnormalities), mild nonproliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR).7 A report was generated and sent directly to the endocrine providers with recommendations on referral for full ophthalmic examination if clinically appropriate. The fundus images of all patients who underwent telemedicine screening from December 2015 through early May 2017 were reviewed to determine the prevalence of diabetic retinopathy. A more in-depth review was then performed for patients with an abnormal screening photograph
and a representative, randomly selected sample of 64 patients with diabetes who had normal screening photographs. The following data were collected for these two groups, based on the date of the screening: current age (years), sex, race (white or non-white), ethnicity (Hispanic or non-Hispanic), type of diabetes, duration of diabetes (years), percent glycated hemoglobin (HbA1c) over the year prior to the screening photographs, blood pressure (systolic, diastolic, and mean arterial pressure [MAP]), compliance with scheduled endocrinology clinic visits (physician, nurse practitioner, registered nurse, and dietitian visits) in the year prior to screening, and public insurance (Medicaid or Medicaid-equivalent funded programs) versus private/nonMedicaid insurance. Statistical Analysis Continuous variables were summarized in median and interquartile range and compared between those patients with abnormal photographs and the representative sample of patients with normal photographs using Wilcox rank-sum testing. Categorical variables were summarized in count and frequency and compared using the χ2 test. Logistic regression model was used to simultaneously study the potential risk factors with diabetic retinopathy. Because the valid sample size per parameter was small, the following steps were used to build the final model. We fit an initial model, including sex, race, Medicaid, type of diabetes, and MAP, as well as restricted cubic spline functions of average A1C, duration of diabetes, and age. Based on the ranking of importance, which is the difference between χ2 test statistics of each factor in the initial model and its associated degree of freedom (higher value implies more important), we included the top five factors to allow a sample size of approximately 10 per variable.8 We used penalized logistic regression model to choose optimal penalty with lowest deviance. According to the analysis of variance table, the nonlinear effects of continuous variables with P values of
>0.3 were removed from the model. All analysis was performed with R 3.4.1 (R Core Team, 2013). The two-sided P values of <0.05 were considered statistically significant. Results Over 17 months, non-mydratic fundus photographs of 852 patients aged 10-23 years were acquired. This represents 89% of those eligible for screening based on ADA criteria. Evidence of diabetic retinopathy in at least one eye on fundus photography was found in 51 patients (6%), 3 of whom had either severe NPDR or PDR in one or both eyes; the remaining 48 had mild NPDR. See Figure 1 for the spectrum of diabetic retinopathy noted in our pilot sample. Formal ophthalmology evaluation was recommended for all 51 patients with evidence of diabetic retinopathy. Of these, 22 patients (43%) were examined at our ophthalmology department, 12 of whom had evidence of diabetic retinopathy on dilated ophthalmoscopic examination (55%), with 2 patients requiring urgent treatment for PDR. The time from photograph screening to follow-up examination ranged from 7 days to 1.5 years. The remaining 10 patients had no diabetic retinopathy by the time of examination (time between photographs and clinical examinaiton ranged from 15 days to 8 months). All patients with normal findings on follow-up eye examination had NPDR on their screening photography. A Wilcoxon test was used to compare the average HbA1c values of those who had no DR versus those who had DR on their follow-up examination. The median for the group with DR at follow-up examination was 10.4%, whereas the group without DR at follow-up examination was 11.6%; this was not statistically significantly different with a P value of 0.32. Two patients with an abnormal screening photograph had outside follow-up that was normal by report. We do not have data on the remaining patients who were seen by ophthalmologists outside our group.
We found that age, duration, and type of diabetes, and HbA1c 1 year prior to screening were statistically different between the group of patients with and those without DR on screening photograph (Table 1). Patients with diabetic retinopathy were older (median, 17 years vs 16 years; P = 0.008), had a history of longer duration of diabetes (median, 11 years vs 6.50 years; P < 0.001), had exclusively type 1 diabetes (100% vs 91%; P = 0.02), and had a higher HbA1c (median, 10.2% vs 8.7%; P = 0.003). There was no statistical difference by sex, race, ethnicity, blood pressure, compliance with endocrinology visits, or type of insurance. The final multivariable logistic regression model that adjusted for potential confounders such as sex, race, HbA1c, duration of diabetes, and age found that longer duration of diabetes (P = 0.003) and higher average HbA1c (P = 0.02) were significantly associated with the presence of DR. Female sex (P = 0.24), non-white race (P = 0.12), and older age (P = 0.28) each showed some potential association with an abnormal screen compared to their counterparts, but none was statistically significant (Table 2). Discussion Our pilot study using telescreening during a routine pediatric endocrinology visit identified diabetic retinopathy in 6% of the screened participants over a period of 17 months. In addition to identifying risk factors for diabetic retinopathy, such as T1DM, higher HbA1c in the previous year, and longer duration of diabetes,9 our program reduced the need for a separate eye clinic visit for pediatric patients with diabetes by over 90%. Our capture rate of 89% of diabetic youths eligible for screening likely exceeds national compliance rates.10 Our current knowledge of the prevalence and incidence of DR in youth under 20 years of age is limited. Geloneck and colleagues11 used standard ophthalmoscopic examinations to evaluate 370 children <18 years of age with T1DM or T2DM and found that none of the patients
had any evidence of DR. Tapley and colleagues12 reported the prevalence of pediatric diabetic retinopathy in an Alabama cohort as 3.8%; however, the study included persons with T1DM and T2DM, compared to our study, which was largely T1DM, and the mean duration of diabetes in their cohort was 5.5 years, which was less than the duration of diabetes in our cohort. Both these studies were retrospective reviews from an ophthalmology clinic and are representative of the population seen by the clinic and not generalizable. A recent insurance claims–based database of 2,240 newly diagnosed T1DM and 1,768 T2DM cases under age 21 years who were enrolled in a large US managed-care nationwide network had overall 578 participants (14.4%) with diabetic retinopathy (20.1% T1DM and 7.2% T2DM).13 There are many possible reasons for the difference in DR rates between this recent study and ours. Their study population, which was nationwide, was larger than ours. Importantly, they chose to study only patients who had formal ophthalmology or optometry examination, whereas our goal of improving access and care meant that our study population comprised patients being seen for their regular endocrinology follow-up. Finally, direct comparison of the rates of DR is not possible, given that they report the rate of DR based on any DR diagnosis across their study period of up to 13 years, whereas our study determined the rate based on evidence from a single time point. Despite the high proportion of visual impairment and easily available formal screening programs for diabetic retinopathy, many eligible persons are not following the guidelines for screening.14-17 Of 5,453 newly diagnosed T1DM and 7,233 T2DM patients <21 years of age with health insurance in the United States, only 64.9% with T1DM and 42.2% with T2DM had received an eye examination by 6 years after initial diabetes diagnosis.15 Racial minorities and lower socioeconomic status were associated with lower rates of screening for diabetic
retinopathy.15 Recently, a study of insured patients 10-64 years of age with diabetes found that between 2010 and 2014, of nearly 300,000 patients with type 2 diabetes, almost half did not have an eye examination, and only 15.3% met the ADA recommendations for eye examination frequency.16 Of the study’s nearly 3,000 patients with type 1 diabetes, one-third did not have any eye examinations, and only 26.3% met ADA screening recommendations.16 Our telescreening program was initiated to improve access and compliance with screening for diabetic retinopathy with the ultimate goal of preventing vision loss. Prior to implementing this program, patients were advised to see an ophthalmologist per ADA screening guidelines; however, we have no data on the number of patients who adhered to the guidelines (records from the eye examination were rarely available to the treating endocrinologist). Many patients who had retinal hemorrhages on screening were found to have no hemorrhages at follow-up examination. Microaneurysms have been reported to disappear, especially with good control of diabetes.18 Because microaneurysms may disappear naturally, positive predictive value for mild DR may be affected. For patients with severe visionthreatening DR, we do not expect minor changes to alter the outcome and clinical course. Prior studies have also shown that photographic assessment of fundus photographs is more sensitive at detection of microaneurysms than clinical dilated eye examination.19 This would be especially true for subtle findings, such as single retinal hemorrhages (see Figure 1A). Fluorescein angiography may be the most sensitive modality to detect subtle DR,20 but nonmydriatic photography has the advantage of being noninvasive and of proven efficacy in DR screening. Furthermore, previous reports have shown high concordance between management decisions based on similar telemedicine screening programs for adults with diabetes.6,21-23 Telescreening for ocular disease is cost-effective; it has been successfully implemented in
urban and rural settings in the developing world21 as well as in developed countries.22 Images are interpreted by ophthalmologists, optometrists, or trained allied personnel.21 Alternatively, similar to our model, images are acquired at the primary care clinic or other community setting23 or endocrinology clinics,12 with remote interpretation by an expert,22 will allow for larger numbers to be screened and appropriately referred for further treatment, especially in areas with limited access to eye specialists. We anticipated that easy access to the fundus camera during a routine pediatric endocrinology visit would encourage screening for diabetic retinopathy. Additionally, performing the screening in the diabetes clinic allowed the reading ophthalmologist to communicate results with the treating endocrinologist, who could then communicate directly with patients and recommend additional follow-up as needed. In our pilot study, over 90% of patients had a normal screening photograph and did not need a follow-up eye examination with an ophthalmologist. The pilot telescreening program was provided to patients free of cost. Since December 2017, however, insurance has been covering the cost of these visits. The telescreening visit is much less expensive than a regular eye examination and provides an incentive for patients and for eye care providers to continue screening for diabetic retinopathy. Limitations of this study include our small sample size. The study is not an efficacy study. The lack of follow-up eye examinations for many of those with abnormal screening results and no follow-up eye examination for those with normal screening results makes it impossible to determine sensitivity, specificity, positive predictive value, and negative predictive value of the screening program. Telemedicine for diabetic retinopathy in adults has been proven effective in prior studies, and this was not a goal of our study.
As follow-up by those patients with abnormal screening photographs with eye examinations at our center was 43%, and outside ophthalmology examinations were rarely recorded, it is not possible to determine whether use of telescreening improved patient followthrough with recommended formal eye examinations. As we face a growing population needing diabetic eye care, telescreening provides a viable solution for long-term surveillance. Our study showed promising results for this collaboration of ophthalmologists and endocrinologists treating pediatric patients, especially those with type 1 diabetes of long duration or with high HbA1c should be counseled on completing screening, given the higher risk of diabetic retinopathy.
References 1.
Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol 2007;14:179-83.
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World Health Organization. Global report on diabetes. World Health Organization. http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf. Accessed April 6, 2016.
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Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States. Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
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American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2016.
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American Diabetes Association. Standards of medical care in diabetes—2016: summary of revisions. Diabetes Care 2016;39:S4-S5.
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Cavallerano AA, Cavallerano JD, Katalinic P, et al; Joslin Vision Network Research Team. A telemedicine program for diabetic retinopathy in a Veterans Affairs Medical Center—the Joslin Vision Network Eye Health Care Model. Am J Ophthalmol 2005;139:597-604.
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Wilkinson CP, Ferris FL 3rd, Klein RE, et al; Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110:1677-82.
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Harrell Jr, Frank E. Regression modeling strategies: with applications to linear models,
logistic and ordinal regression, and survival analysis. 2nd ed. New York: Springer; 2015. 9.
Yau JWY, Rogers SL, Kawasaki R, et al; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012 Mar;35:556-64.
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Schoenfeld ER, Greene JM, Wu SY, Leske MC. Patterns of adherence to diabetes vision care guidelines: baseline findings from the Diabetic Retinopathy Awareness Program. Ophthalmology 2001;108:563-71.
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Geloneck MM, Forbes BJ, Shaffer J, Ying GS, Binenbaum G. Ocular complications in children with diabetes mellitus. Ophthalmology 2015;122:2457-64.
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Tapley JL, McGwin G Jr, Ashraf AP, et al. Feasibility and efficacy of diabetic retinopathy screening among youth with diabetes in a pediatric endocrinology clinic: a cross-sectional study. Diabetol Metab Syndr 2015;7:56.
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Wang SY, Andrews CA, Herman WH, Gardner TW, Stein JD. Incidence and risk factors for developing diabetic retinopathy among youths with type 1 or type 2 diabetes throughout the United States. Ophthalmology 2017;124:424-30.
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Lueder GT, Silverstein J; American Academy of Pediatrics Section on Ophthalmology and Section on Endocrinology. Screening for retinopathy in the pediatric patient with type 1 diabetes mellitus. Pediatrics 2005;116:270-73.
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Wang SY, Andrews CA, Gardner TW, Wood M, Singer K, Stein JD. Ophthalmic screening patterns among youths with diabetes enrolled in a large US managed care network. JAMA Ophthalmol 2017;135:432-8.
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Benoit SR, Swenor B, Geiss LS, Gregg EW, Saaddine JB. Eye care utilization among insured people with diabetes in the U.S., 2010-2014. Diabetes Care 2019;42:427-33.
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Witkin SR, Klein R. Ophthalmologic care for persons with diabetes. JAMA 1984;251:2534-7.
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Hellstedt T, Immonen I. Disappearance and formation rates of microaneurysms in early diabetic retinopathy. Br J Ophthalmol 1996;80:135-9.
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Gangaputra S, Lovato JF, Hubbard L, et al; ACCORD Eye Research Group. Comparison of standardized clinical classification with fundus photograph grading for the assessment of diabetic retinopathy and diabetic macular edema severity. Retina 2013;33:1393-9.
20.
Kapsala Z, Anastasakis A, Mamoulakis D, Maniadaki I, Tsilimbaris M. Comparison of digital color fundus imaging and fluorescein angiographic findings for the early detection of diabetic retinopathy in young type 1 diabetic patients. J Fr Ophtalmol 2018;41:39-44.
21.
Thapa R, Bajimaya S, Pradhan E, Paudyal G. Agreement on diabetic retinopathy grading in fundus photographs by allied ophthalmic personnel as compared to ophthalmologist at a community setting in Nepal. Nepal J Ophthalmol 2017;9:43-50.
22.
Rathi S, Tsui E, Mehta N, Zahid S, Schuman JS. The current state of teleophthalmology in the United States. Ophthalmology 2017;124:1729-34.
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Jani PD, Forbes L, Choudhury A, Preisser JS, Viera AJ, Garg S. Evaluation of diabetic retinal screening and factors for ophthalmology referral in a telemedicine network. JAMA Ophthalmol 2017 Jul 1;135:706-14.
Legends FIG 1. Spectrum of diabetic retinopathy noted on fundus photography in 2 patients diagnosed with type 1 diabetes mellitus; both patients were poorly compliant with insulin and blood glucose monitoring. A, Retinal image of a 16-year-old white non-Hispanic young man (diagnosed at 17 months of age). showing mild diabetic retinopathy with single microaneurysm (arrow). HbA1c was 9.3% at time of photograph. B, Retinal image of a 19-year-old white non-Hispanic woman (diagnosed at 4 years of age) showing proliferative diabetic retinopathy with neovascularization of the optic disk. HbA1c was 12.8% at time of photograph.
Table 1. Unadjusted comparison of risk factors between normal (no diabetic retinopathy) a and abnormal screening test (any level of diabetic retinopathy) result Variable Age, years Female, no. (%) White, no. (%) Non-Hispanic, no. (%) Medicaid, no. (%) Type 1 diabetes, no. (%) Duration of diabetes, years Compliance with endocrinology visits, % Blood pressure, mm Hg Systolic Diastolic Mean arterial pressure, mm Hg d Hemoglobin A1c, %
Normal (n = 64) 16 (13-18) 31 (48) 56 (89) 59 (95) 36 (56) 58 (91) 6.5 (5-10) 44 (33-54)
127 (116-136) 72 (67-78) 90 (84-96) 8.7 (7.6-10.4)
Abnormal (n = 51) 17 (15-19) 28 (55) 38 (78) 47 (96) 23 (45) 51 (100) 11 (8-13.5) 46 (30-58)
126 (116-135) 72 (69-79) 91 (86-97) 10.2 (8.7-12.2)
P value b 0.008 c 0.49 c 0.1 0.85c c 0.23 c 0.02 b <0.001 b 0.64 b
0.7 b 0.27 0.34b b 0.003
IQR, interquartile range. a
Results are median (IQR) except as noted. Wilcoxon rank-sum test. c 2 Pearson χ test. d HbA1c calculated from the average of HbA1c measurements across the previous year. b
Table 2. Multivariable logistic regression model assessing risk factors for an abnormal screen (any diabetic retinopathy), adjusting for sex, race, hemoglobin A1C, duration of diabetes, and age Variable Sex (male vs female) Race (others vs white) Hemoglobin A1c (%) Duration of diabetes, years Age, years
OR (95% CI) 0.59 (0.25-1.4) 2.7 (0.77-9.4) 2.2 (1.1-4.4) 3.1 (1.5-6.5) 1.5 (0.73-3.0)
P value 0.24 0.12 0.02 0.003 0.28
S1091-8531(20)30011-2
DOI:
https://doi.org/10.1016/j.jaapos.2019.10.010
Reference:
YMPA 3127
To appear in:
Journal of AAPOS
Received Date: 15 June 2019 Revised Date:
27 October 2019
Accepted Date: 29 October 2019
Please cite this article as: Strul S, Zheng Y, Gangaputra S, Datye K, Chen Q, Maynard L, Pittel E, Russell W, Donahue S, Pediatric diabetic retinopathy telescreening, Journal of AAPOS (2020), doi: https://doi.org/10.1016/j.jaapos.2019.10.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.
Pediatric diabetic retinopathy telescreening Sasha Strul, MD,a,c Yuxi Zheng, BS,a,b Sapna Gangaputra, MD, MPH,a Karishma Datye, MD,d Qingxia Chen, PhD,e Laura Maynard, BSN,f Eric Pittel, MBA,f William Russell, MD,d and Sean Donahue, MD, PhDa Author affiliations: aVanderbilt Eye Institute, Vanderbilt University, Nashville, Tennessee; b Vanderbilt University, School of Medicine, Nashville, Tennessee; cDepartment of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota; d Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University, Nashville, Tennessee; eDepartment of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee; fVanderbilt Eskind Pediatric Diabetes Clinic, Nashville, Tennessee This work was partially supported by an unrestricted grant to the Department of Ophthalmology and Visual Sciences at Vanderbilt University Medical Center from Research to Prevent Blindness, New York, NY, and by the Kids Battle Diabetes Golf Classic and the Care Foundation of America, whose support made possible the purchase non-mydriatic retinal cameras and facilitated expansion of retinal screening to off-campus locations of the Children’s Diabetes Program at Vanderbilt. Presented in part at the 43rd Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, April 2-6, 2017. Submitted June 15, 2019. Revision accepted October 29, 2019. Correspondence: Sasha Strul, MD, 701 25th Ave S #300, Minneapolis, MN 55455 (email: [email protected]). Word count: 2,676 Abstract only: 203
Abstract Purpose To describe the role of telemedicine screening for pediatric diabetic retinopathy (DR) and to identify risk factors for pediatric DR. Methods The medical records of a telemedicine program at a tertiary, academic medical center over 17 months were reviewed retrospectively. Patients visiting an academic pediatric endocrinology clinic who met guidelines underwent telescreening. Presence of pediatric DR and risk factors for retinopathy were evaluated. Results The fundus photographs of 852 patients 10-23 years of age were reviewed. Diabetic retinopathy was noted in 51 (6%). Patients with an abnormal screening photograph were compared to patients with diabetes who had normal screening photographs (n = 64). Older age, longer diabetes duration, type 1 diabetes, and higher average glycated hemoglobin (HbA1c) from the year prior to the photograph were associated with increased risk of retinopathy. Of these, longer duration (P = 0.003) and higher average A1c (P = 0.02) were significant after adjusting for sex, race, and age. Conclusions Our telemedicine program found a higher percentage of diabetic retinopathy screening nonmydriatic photographs than prior studies found through standard ophthalmic examinations. In this relatively small sample size, longer duration of disease and higher average A1c were associated with increased risk of having diabetic retinopathy in our study.
Diabetic retinopathy (DR) is a leading cause of legal blindness among working-age persons worldwide.1 Diabetic retinopathy has been designated as one of the priority eye diseases by WHO, because 7% of people with diabetes are at risk of blindness. This is becoming of greater importance as diabetes mellitus is reaching epidemic proportions globally.2 The Centers for Disease Control estimated that 23.1 million people in the United States were diagnosed with diabetes in 2015, 193,000 of whom were <20 years old.3 Due to this significant risk, global screening guidelines have been developed for early identification of retinopathy. The American Academy of Ophthalmology preferred practice guidelines recommend annual examinations beginning 5 years after onset of type 1 diabetes mellitus (T1DM) and beginning at time of diagnosis of type 2 diabetes mellitus (T2DM).4 The American Diabetes Association (ADA) recommends screening for diabetic retinopathy at age ≥10 years or postpuberty onset (whichever occurs first) in children with diabetes duration of over 3-5 years in children with T1DM, and starting at diagnosis in children with T2DM.5 Early detection is essential to prevent vision loss in the vulnerable and growing population of pediatric patients with diabetes. Telescreening for diabetic retinopathy is a validated and successful method to improve access to care and the time and cost associated with an ophthalmology clinic visit; however, most of the literature comes from screening of adult patients with diabetes.6 The goal of a diabetic retinopathy screening program is to triage patients that need to seek formal ophthalmology examinations and exclude those that have no concerning eye findings. We established a telemedicine program to facilitate screening for diabetic retinopathy in young patients by linking image acquisition with pediatric endocrinology clinical care. Subjects and Methods
Eligible patients visiting the pediatric endocrinology clinic at Vanderbilt University in Nashville, Tennessee, were offered diabetic screening using teleophthalmology, if they met ADA guidelines for DR screening. Specifically, patients with type 1 diabetes of duration ≥5 years and age ≥10 years and patients with type 2 diabetes starting at diagnosis were screened annually. At this clinic, patients with diabetes are scheduled every 3 months for routine follow-up, and retinopathy screening was performed during these routine visits. This screening was considered part of routine diabetes care and received a quality improvement/nonresearch determination from our institutional review board; screening did not require a separate patient consent form. The study complied with requirements of the US Health Insurance Portability and Accountability Act of 1996. A non-mydriatric retinal camera (TRC-NW400; Topcon, Tokyo, Japan) was used to acquire a single 45° image of the posterior pole of both eyes, including the optic nerve head and macula, with resolution of 48 pixels/degree. Images were acquired by medical technicians with minimal training. A trained ophthalmologist received the images remotely for assessment. The images were assessed using the international clinical diabetic retinopathy scale,7 which classifies diabetic retinopathy according to the severity of microaneurysms and hemorrhages in 5 steps: no diabetic retinopathy (no abnormalities), mild nonproliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR).7 A report was generated and sent directly to the endocrine providers with recommendations on referral for full ophthalmic examination if clinically appropriate. The fundus images of all patients who underwent telemedicine screening from December 2015 through early May 2017 were reviewed to determine the prevalence of diabetic retinopathy. A more in-depth review was then performed for patients with an abnormal screening photograph
and a representative, randomly selected sample of 64 patients with diabetes who had normal screening photographs. The following data were collected for these two groups, based on the date of the screening: current age (years), sex, race (white or non-white), ethnicity (Hispanic or non-Hispanic), type of diabetes, duration of diabetes (years), percent glycated hemoglobin (HbA1c) over the year prior to the screening photographs, blood pressure (systolic, diastolic, and mean arterial pressure [MAP]), compliance with scheduled endocrinology clinic visits (physician, nurse practitioner, registered nurse, and dietitian visits) in the year prior to screening, and public insurance (Medicaid or Medicaid-equivalent funded programs) versus private/nonMedicaid insurance. Statistical Analysis Continuous variables were summarized in median and interquartile range and compared between those patients with abnormal photographs and the representative sample of patients with normal photographs using Wilcox rank-sum testing. Categorical variables were summarized in count and frequency and compared using the χ2 test. Logistic regression model was used to simultaneously study the potential risk factors with diabetic retinopathy. Because the valid sample size per parameter was small, the following steps were used to build the final model. We fit an initial model, including sex, race, Medicaid, type of diabetes, and MAP, as well as restricted cubic spline functions of average A1C, duration of diabetes, and age. Based on the ranking of importance, which is the difference between χ2 test statistics of each factor in the initial model and its associated degree of freedom (higher value implies more important), we included the top five factors to allow a sample size of approximately 10 per variable.8 We used penalized logistic regression model to choose optimal penalty with lowest deviance. According to the analysis of variance table, the nonlinear effects of continuous variables with P values of
>0.3 were removed from the model. All analysis was performed with R 3.4.1 (R Core Team, 2013). The two-sided P values of <0.05 were considered statistically significant. Results Over 17 months, non-mydratic fundus photographs of 852 patients aged 10-23 years were acquired. This represents 89% of those eligible for screening based on ADA criteria. Evidence of diabetic retinopathy in at least one eye on fundus photography was found in 51 patients (6%), 3 of whom had either severe NPDR or PDR in one or both eyes; the remaining 48 had mild NPDR. See Figure 1 for the spectrum of diabetic retinopathy noted in our pilot sample. Formal ophthalmology evaluation was recommended for all 51 patients with evidence of diabetic retinopathy. Of these, 22 patients (43%) were examined at our ophthalmology department, 12 of whom had evidence of diabetic retinopathy on dilated ophthalmoscopic examination (55%), with 2 patients requiring urgent treatment for PDR. The time from photograph screening to follow-up examination ranged from 7 days to 1.5 years. The remaining 10 patients had no diabetic retinopathy by the time of examination (time between photographs and clinical examinaiton ranged from 15 days to 8 months). All patients with normal findings on follow-up eye examination had NPDR on their screening photography. A Wilcoxon test was used to compare the average HbA1c values of those who had no DR versus those who had DR on their follow-up examination. The median for the group with DR at follow-up examination was 10.4%, whereas the group without DR at follow-up examination was 11.6%; this was not statistically significantly different with a P value of 0.32. Two patients with an abnormal screening photograph had outside follow-up that was normal by report. We do not have data on the remaining patients who were seen by ophthalmologists outside our group.
We found that age, duration, and type of diabetes, and HbA1c 1 year prior to screening were statistically different between the group of patients with and those without DR on screening photograph (Table 1). Patients with diabetic retinopathy were older (median, 17 years vs 16 years; P = 0.008), had a history of longer duration of diabetes (median, 11 years vs 6.50 years; P < 0.001), had exclusively type 1 diabetes (100% vs 91%; P = 0.02), and had a higher HbA1c (median, 10.2% vs 8.7%; P = 0.003). There was no statistical difference by sex, race, ethnicity, blood pressure, compliance with endocrinology visits, or type of insurance. The final multivariable logistic regression model that adjusted for potential confounders such as sex, race, HbA1c, duration of diabetes, and age found that longer duration of diabetes (P = 0.003) and higher average HbA1c (P = 0.02) were significantly associated with the presence of DR. Female sex (P = 0.24), non-white race (P = 0.12), and older age (P = 0.28) each showed some potential association with an abnormal screen compared to their counterparts, but none was statistically significant (Table 2). Discussion Our pilot study using telescreening during a routine pediatric endocrinology visit identified diabetic retinopathy in 6% of the screened participants over a period of 17 months. In addition to identifying risk factors for diabetic retinopathy, such as T1DM, higher HbA1c in the previous year, and longer duration of diabetes,9 our program reduced the need for a separate eye clinic visit for pediatric patients with diabetes by over 90%. Our capture rate of 89% of diabetic youths eligible for screening likely exceeds national compliance rates.10 Our current knowledge of the prevalence and incidence of DR in youth under 20 years of age is limited. Geloneck and colleagues11 used standard ophthalmoscopic examinations to evaluate 370 children <18 years of age with T1DM or T2DM and found that none of the patients
had any evidence of DR. Tapley and colleagues12 reported the prevalence of pediatric diabetic retinopathy in an Alabama cohort as 3.8%; however, the study included persons with T1DM and T2DM, compared to our study, which was largely T1DM, and the mean duration of diabetes in their cohort was 5.5 years, which was less than the duration of diabetes in our cohort. Both these studies were retrospective reviews from an ophthalmology clinic and are representative of the population seen by the clinic and not generalizable. A recent insurance claims–based database of 2,240 newly diagnosed T1DM and 1,768 T2DM cases under age 21 years who were enrolled in a large US managed-care nationwide network had overall 578 participants (14.4%) with diabetic retinopathy (20.1% T1DM and 7.2% T2DM).13 There are many possible reasons for the difference in DR rates between this recent study and ours. Their study population, which was nationwide, was larger than ours. Importantly, they chose to study only patients who had formal ophthalmology or optometry examination, whereas our goal of improving access and care meant that our study population comprised patients being seen for their regular endocrinology follow-up. Finally, direct comparison of the rates of DR is not possible, given that they report the rate of DR based on any DR diagnosis across their study period of up to 13 years, whereas our study determined the rate based on evidence from a single time point. Despite the high proportion of visual impairment and easily available formal screening programs for diabetic retinopathy, many eligible persons are not following the guidelines for screening.14-17 Of 5,453 newly diagnosed T1DM and 7,233 T2DM patients <21 years of age with health insurance in the United States, only 64.9% with T1DM and 42.2% with T2DM had received an eye examination by 6 years after initial diabetes diagnosis.15 Racial minorities and lower socioeconomic status were associated with lower rates of screening for diabetic
retinopathy.15 Recently, a study of insured patients 10-64 years of age with diabetes found that between 2010 and 2014, of nearly 300,000 patients with type 2 diabetes, almost half did not have an eye examination, and only 15.3% met the ADA recommendations for eye examination frequency.16 Of the study’s nearly 3,000 patients with type 1 diabetes, one-third did not have any eye examinations, and only 26.3% met ADA screening recommendations.16 Our telescreening program was initiated to improve access and compliance with screening for diabetic retinopathy with the ultimate goal of preventing vision loss. Prior to implementing this program, patients were advised to see an ophthalmologist per ADA screening guidelines; however, we have no data on the number of patients who adhered to the guidelines (records from the eye examination were rarely available to the treating endocrinologist). Many patients who had retinal hemorrhages on screening were found to have no hemorrhages at follow-up examination. Microaneurysms have been reported to disappear, especially with good control of diabetes.18 Because microaneurysms may disappear naturally, positive predictive value for mild DR may be affected. For patients with severe visionthreatening DR, we do not expect minor changes to alter the outcome and clinical course. Prior studies have also shown that photographic assessment of fundus photographs is more sensitive at detection of microaneurysms than clinical dilated eye examination.19 This would be especially true for subtle findings, such as single retinal hemorrhages (see Figure 1A). Fluorescein angiography may be the most sensitive modality to detect subtle DR,20 but nonmydriatic photography has the advantage of being noninvasive and of proven efficacy in DR screening. Furthermore, previous reports have shown high concordance between management decisions based on similar telemedicine screening programs for adults with diabetes.6,21-23 Telescreening for ocular disease is cost-effective; it has been successfully implemented in
urban and rural settings in the developing world21 as well as in developed countries.22 Images are interpreted by ophthalmologists, optometrists, or trained allied personnel.21 Alternatively, similar to our model, images are acquired at the primary care clinic or other community setting23 or endocrinology clinics,12 with remote interpretation by an expert,22 will allow for larger numbers to be screened and appropriately referred for further treatment, especially in areas with limited access to eye specialists. We anticipated that easy access to the fundus camera during a routine pediatric endocrinology visit would encourage screening for diabetic retinopathy. Additionally, performing the screening in the diabetes clinic allowed the reading ophthalmologist to communicate results with the treating endocrinologist, who could then communicate directly with patients and recommend additional follow-up as needed. In our pilot study, over 90% of patients had a normal screening photograph and did not need a follow-up eye examination with an ophthalmologist. The pilot telescreening program was provided to patients free of cost. Since December 2017, however, insurance has been covering the cost of these visits. The telescreening visit is much less expensive than a regular eye examination and provides an incentive for patients and for eye care providers to continue screening for diabetic retinopathy. Limitations of this study include our small sample size. The study is not an efficacy study. The lack of follow-up eye examinations for many of those with abnormal screening results and no follow-up eye examination for those with normal screening results makes it impossible to determine sensitivity, specificity, positive predictive value, and negative predictive value of the screening program. Telemedicine for diabetic retinopathy in adults has been proven effective in prior studies, and this was not a goal of our study.
As follow-up by those patients with abnormal screening photographs with eye examinations at our center was 43%, and outside ophthalmology examinations were rarely recorded, it is not possible to determine whether use of telescreening improved patient followthrough with recommended formal eye examinations. As we face a growing population needing diabetic eye care, telescreening provides a viable solution for long-term surveillance. Our study showed promising results for this collaboration of ophthalmologists and endocrinologists treating pediatric patients, especially those with type 1 diabetes of long duration or with high HbA1c should be counseled on completing screening, given the higher risk of diabetic retinopathy.
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Legends FIG 1. Spectrum of diabetic retinopathy noted on fundus photography in 2 patients diagnosed with type 1 diabetes mellitus; both patients were poorly compliant with insulin and blood glucose monitoring. A, Retinal image of a 16-year-old white non-Hispanic young man (diagnosed at 17 months of age). showing mild diabetic retinopathy with single microaneurysm (arrow). HbA1c was 9.3% at time of photograph. B, Retinal image of a 19-year-old white non-Hispanic woman (diagnosed at 4 years of age) showing proliferative diabetic retinopathy with neovascularization of the optic disk. HbA1c was 12.8% at time of photograph.
Table 1. Unadjusted comparison of risk factors between normal (no diabetic retinopathy) a and abnormal screening test (any level of diabetic retinopathy) result Variable Age, years Female, no. (%) White, no. (%) Non-Hispanic, no. (%) Medicaid, no. (%) Type 1 diabetes, no. (%) Duration of diabetes, years Compliance with endocrinology visits, % Blood pressure, mm Hg Systolic Diastolic Mean arterial pressure, mm Hg d Hemoglobin A1c, %
Normal (n = 64) 16 (13-18) 31 (48) 56 (89) 59 (95) 36 (56) 58 (91) 6.5 (5-10) 44 (33-54)
127 (116-136) 72 (67-78) 90 (84-96) 8.7 (7.6-10.4)
Abnormal (n = 51) 17 (15-19) 28 (55) 38 (78) 47 (96) 23 (45) 51 (100) 11 (8-13.5) 46 (30-58)
126 (116-135) 72 (69-79) 91 (86-97) 10.2 (8.7-12.2)
P value b 0.008 c 0.49 c 0.1 0.85c c 0.23 c 0.02 b <0.001 b 0.64 b
0.7 b 0.27 0.34b b 0.003
IQR, interquartile range. a
Results are median (IQR) except as noted. Wilcoxon rank-sum test. c 2 Pearson χ test. d HbA1c calculated from the average of HbA1c measurements across the previous year. b
Table 2. Multivariable logistic regression model assessing risk factors for an abnormal screen (any diabetic retinopathy), adjusting for sex, race, hemoglobin A1C, duration of diabetes, and age Variable Sex (male vs female) Race (others vs white) Hemoglobin A1c (%) Duration of diabetes, years Age, years
OR (95% CI) 0.59 (0.25-1.4) 2.7 (0.77-9.4) 2.2 (1.1-4.4) 3.1 (1.5-6.5) 1.5 (0.73-3.0)
P value 0.24 0.12 0.02 0.003 0.28