Prevalence of diabetic retinopathy in children and young people living with diabetes: protocol for a systematic review

Introduction The frequency of diabetes mellitus in childhood is increasing. Thus, more children and young people are at risk of developing diabetic retinopathy and diabetes related visual impairment. However, there is no consensus on optimal screening strategies for the paediatric population reflecting the lack of clarity about the current burden of disease in this group. We aim to estimate the prevalence of diabetic retinopathy in children and young people living with types 1 or 2 diabetes, and to investigate potential sources of heterogeneity in this figure so as to inform screening strategies for this population. Methods and analysis PubMed and EMBASE will be searched from 1995 to 2016 using the OvidSP platform with no language restriction. Additionally, manual review of the references lists of included articles will be conducted. Two investigators will independently screen titles and abstracts for potential eligibility. Studies which report prevalence of diabetic retinopathy among general populations of children and young people with types 1 or 2 diabetes will be included. Pooled prevalence estimates of diabetic retinopathy reported in studies with sample size greater than 200 participants will be calculated by the random effect model. Forest plots will be used to summarise individual and pooled estimates of the prevalence. Heterogeneity between studies will be assessed using the I2 statistic and explored through meta-regressions and subgroup analyses if the necessary data are available. Ethics and dissemination Ethics approval is not required as this is a review of anonymised published data. We will report the findings of this systematic review in a peer-reviewed journal, and share it with the relevant professionals including health authorities through our Diabetic Eye disease in Childhood Study collaborative network. Clinical trail registration PROSPERO (CRD42017067178).

Introduction The frequency of diabetes mellitus in childhood is increasing.Thus, more children and young people are at risk of developing diabetic retinopathy and diabetes related visual impairment.However, there is no consensus on optimal screening strategies for the paediatric population reflecting the lack of clarity about the current burden of disease in this group.We aim to estimate the prevalence of diabetic retinopathy in children and young people living with types 1 or 2 diabetes, and to investigate potential sources of heterogeneity in this figure so as to inform screening strategies for this population.Methods and analysis PubMed and EMBASE will be searched from 1995 to 2016 using the OvidSP platform with no language restriction.Additionally, manual review of the references lists of included articles will be conducted.Two investigators will independently screen titles and abstracts for potential eligibility.Studies which report prevalence of diabetic retinopathy among general populations of children and young people with types 1 or 2 diabetes will be included.Pooled prevalence estimates of diabetic retinopathy reported in studies with sample size greater than 200 participants will be calculated by the random effect model.Forest plots will be used to summarise individual and pooled estimates of the prevalence.Heterogeneity between studies will be assessed using the I 2 statistic and explored through metaregressions and subgroup analyses if the necessary data are available.Ethics and dissemination Ethics approval is not required as this is a review of anonymised published data.We will report the findings of this systematic review in a peer-reviewed journal, and share it with the relevant professionals including health authorities through our Diabetic Eye disease in Childhood Study collaborative network.clinical trail registration PROSPERO (CRD42017067178).
bAckground Diabetic retinopathy is the most common preventable cause of visual impairment in young adults. 1 The rising prevalence of childhood type 1 and type 2 diabetes 2-4 has led to a significant increase in the number of children and young people at risk of visual loss.
Microvascular retinal damage is a marker of general vascular health, indicative of a need for greater diabetic disease control.The more advanced, but still asymptomatic, stages of diabetic retinopathy require additional ophthalmic intervention to reduce the risk of irreversible visual loss.][10][11][12] Variable estimates of the prevalence of diabetic retinopathy may be due in part to heterogeneity between study populations, diagnostic methods or definitions of diabetic retinopathy used in the studies. 13 14onsensus about screening strategies for the

Prevalence of diabetic retinopathy in children and young people living with diabetes: protocol for a systematic review
][17] The aim of this systematic review is to estimate the prevalence of diabetic retinopathy in children and young people living with type 1 or type 2 diabetes, and to investigate potential sources of heterogeneity such as study sample characteristics (eg, age, diabetes type and duration, and glycaemic control), diagnostic methods and definition of diabetic retinopathy to inform screening strategies for the paediatric population.

MEthods/dEsIgn
The systematic review will be performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with this protocol written according to the PRISMA-P checklist. 18The PRISMA-P checklist can be found as online supplementary additional file 1.The study has been registered on PROSPERO (CRD42017067178).

data sources and searches
The PubMed and EMBASE databases will be searched using the OvidSP platform.We will also manually review the references lists of identified articles.The search strategy (table 1) will include terms related to children or young people, diabetes, diabetic retinopathy, prevalence and diagnostic tests, and there will be no language restrictions.We will exclude studies published before January 1995 as older studies are likely to have been conducted prior to the publication of the Diabetes Control and Complications Trial, which demonstrated decreased risk of diabetic retinopathy development or progression with tighter glycaemic control than that previously used in routine clinical practice, and may have led to significant changes in disease management and natural history. 19udy eligibility criteria We will include studies which report prevalence estimates of diabetic retinopathy among general populations of children and young people with diabetes mellitus, or studies from which the prevalence data may be derived (table 2).Eligible studies will be those which meet the following criteria.► Participants Individuals aged under 18 years living with types 1 or 2 diabetes.Studies with median/mean age of the sample greater than 25 years or which include participants older than 30 years will be excluded.► Disease measure Report of the clinical examination method used to determine diabetic retinopathy status, and description of either retinal findings or grade of retinopathy using any grading systems which can be correlated to retinopathy features seen at the ophthalmic examination.This will allow comparison between the different grading systems used in screening programmes and Open Access clinical practice.Included grading systems will be displayed in a supplementary table along with the systematic review's results.
Prevalence will be calculated using two cut-offs, any diabetic retinopathy and sight-threatening diabetic retinopathy, that is, grades of retinopathy that require prompt ophthalmic management to reduce the risk of irreversible visual impairment.Any diabetic retinopathy will be defined as background retinopathy or more severe disease.Sight-threatening diabetic retinopathy 20 will be primarily defined as proliferative diabetic retinopathy or clinically significant maculopathy oedema, that is, retinal thickening at or within 500 µm of the centre of the macula, and/or hard exudates at or within 500 µm of the centre of the macula, if associated with thickening of the adjacent retina, and/or a zone or zones of retinal thickening one disc area in size, any part of which is within one disc diameter of the centre of the macula. 21Additionally, a secondary analysis using a more inclusive definition of sight-threatening diabetic retinopathy, that is, including severe non-proliferative diabetic retinopathy, will be conducted using the available data.Conference abstracts with sufficient data on disease measure to determine eligibility will be included.

study selection
The search results will be extracted and managed using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA).Two independent investigators (MIB, ALS) will screen titles and abstracts, and then apply the eligibility criteria to full-text articles.Disagreements will be resolved by consensus following discussion.Arbitration by a third author (JSR) will be sought whenever necessary.

data extraction
Two investigators (MIB, ALS) will extract the data using a standardised form.The following data items will be extracted: first author, year of publication, design, country, year of study conduction, sample size, diabetes type, age at examination, diabetes duration, HbA1c, diagnostic test, diabetic retinopathy definition, number of any diabetic retinopathy cases, severity of diabetic retinopathy cases.If a study reports multiple prevalence estimates over time, the first prevalence estimate, that is, the estimate which is reported with baseline sample clinical characteristics, will be selected as the most informative measure.Characteristics of children and young people with sight-threatening diabetic retinopathy will be also extracted.Authors will be contacted if data in the original publication is unclear.

Assessment of risk of bias in included studies
The risk of bias will be assessed with an adapted version of the tool developed by Hoy and colleagues 22 (online Supplementary additional file 2).The sample will be considered representative of the target population (ie, 'general' population) when all children and young people registered in a paediatric diabetes clinic, or living in a specified catchment area were potentially eligible for the study.Sources of information will be classified as appropriate where diabetic retinopathy status is assessed during the study (cross-sectional and prospective studies) or where prospective databases such as diabetic retinopathy screening registers are used.
data synthesis A comprehensive table for summary of findings with narrative description of all eligible studies will be reported.However, only studies with a sample size equal or greater than 200 participants will be included in the meta-analysis.Small studies will be excluded to reduce variability due to imprecise estimates.Pooled prevalence estimates of any diabetic retinopathy and of sight-threatening diabetic retinopathy will be calculated by random effect model meta-analysis.Forest plots will be used to summarise individual and pooled estimates of the prevalence.Heterogeneity between studies will be assessed using the I 2 statistic (values of 25%, 50% and 75% will be considered low, medium and high heterogeneity, respectively) 23 and will be further explored through meta-regressions and subgroup analyses considering the following covariates: sample median/mean age, median/mean diabetes duration, type of diabetes, median/mean HbA1c, diagnostic test, and year of study conduction.All analyses will be performed with R statistical software V.3.3.2., and p values<0.05 will Open Access be used as the threshold for statistical significance.Assessment of meta-bias(es) is not planned, as preliminary searches of registered protocols have indicated that it is unlikely that eligible epidemiological studies are prospectively registered.As this systematic review is not investigating the evidence underpinning an intervention, confidence in the cumulative evidence cannot be calculated or assessed using the Grading of Recommendations Assessment, Development and Evaluation.The strength of the body of evidence will be examined through the assessment of risk of bias within included studies.dIscussIon Diabetic retinopathy is, in the early stages, an important marker of disease control, and in the later stages, a preventable cause of visual impairment and blindness.The burden of childhood diabetes is increasing, but there is a paucity of synthesised data on the prevalence and natural history of childhood diabetic retinopathy.This systematic review, using a clinically impactful taxonomy to calculate the prevalence of diabetic retinopathy, will provide currently unavailable prevalence estimates to inform screening policy and practice for children and young people living with diabetes.

Table 2
Inclusion and exclusion criteria