Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy

Abstract Background Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so‐called “new vessels,” at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high‐risk characteristics (HRC) PDR (HRC‐PDR), which is defined by the presence of NVD more than one‐fourth to one‐third disc area in size plus vitreous haemorrhage or pre‐retinal haemorrhage, or vitreous haemorrhage or pre‐retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight‐threatening PDR stage. Objectives To determine risk factors for the development of PDR and HRC‐PDR in people with diabetes and DR. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication. Selection criteria We included prospective or retrospective cohort studies and case‐control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non‐proliferative diabetic retinopathy (NPDR) or PDR with less than HRC‐PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full‐text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong. Data collection and analysis Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta‐analyses in clinically relevant groups using a random‐effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta‐analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework. Main results We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty‐five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case‐control studies. Twenty‐three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years. We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies. There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta‐analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low‐ (LDL) and high‐ (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC‐PDR. Authors' conclusions Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight‐threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.


Population
Male and female adults ≥ 18 years of age of any ethnicity with DR (NPDR), diagnosed as per standard clinical protocol

Index prognostic factors
Broad review of prognostic factors associated with the development of PDR.
Specific prognostic factors of interest will include, but not be restricted to, routinely collected patient demographics and information, such as age, gender, ethnicity, socio-economic status, and smoking habits; frequently obtained standard clinical data, such as comorbidities (presence/absence of cardiovascular disease, cerebrovascular disease, nephropathy and specifically chronic kidney failure (defined as estimated glomerular filtration rate (GFR) of < 60 mL/min/1.73m 2 ), peripheral neuropathy and specifically foot ulcers, amputation), body mass index (BMI), neck/ waist circumference, glycated haemoglobin, blood pressure, low-density lipoprotein, high-density lipoprotein, triglycerides, and functional and structural retinal biomarkers in the prognostic context of the development and progression of PDR.Prognostic factors will be considered in the absence of treatment for DR.
It is expected that prognostic factors will generally be measured at the time participants enter the study, and indeed after the diagnosis of DR.If measures of prognostic factors are available at other Cochrane Database of Systematic Reviews time points, and these coincide in more than one study, we may consider investigating them, additionally, at other time points.
Studies evaluating risk factors requiring invasive procedures to be measured (e.g.aqueous or vitreous samples to measure growth factors in these fluids) not performed in routine clinical practice will be excluded.

Outcomes
Progression from DR (NPDR) to any stage of PDR.Participants who have received laser PRP for the treatment of PDR will be considered to have progressed to the outcome of PDR.
Timing 3 years (± 2 years), 8 years (± 2 years), or lifelong, if available.If not, other time points will be accepted and presented.PDR can occur very rapidly -in days -or take months or years to develop.We will also determine over what time period the outcomes are predicted by the risk factors investigated.

Secondary objectives
To assess prognostic risk factors for predicting the progression of PDR from less than HRC-PDR to HRC-PDR.

Population
Male and female adults ≥ 18 years of age of any ethnicity with less than HRC-PDR, diagnosed as per standard clinical protocol

Index prognostic factors
We anticipate that less information will be available regarding prognostic factors associated with progression from PDR to HRC-PDR.Prognostic factors of interest will include, but not be restricted to, routinely collected patient demographics and information, such as age, gender, ethnicity, socio-economics, and smoking habits; frequently obtained standard clinical data, such as comorbiidities (presence/absence of cardiovascular disease, cerebrovascular disease, nephropathy and specifically chronic kidney failure (defined as estimated GFR of < 60 mL/min/1.73m 2 ), peripheral neuropathy and specifically foot ulcers, amputation), BMI, neck/waist circumference, glycated haemoglobin, blood pressure, low-density lipoprotein, high-density lipoprotein, triglycerides, and functional and structural retinal biomarkers in the prognostic context of the development and progression of HRC-PDR.The scope of this review will not extend to the evaluation of the effect of treatment on progression to HRC-PDR, and as such, prognostic factors will be considered in the absence of previous treatment for PDR.
It is expected that prognostic factors will generally be measured at the time participants enter the study, and indeed after the diagnosis of less than HRC-PDR.If measures of prognostic factors are available at other time points, and these coincide in more than one study, we may consider investigating them additionally at other time points.Prognostic factors requiring invasive procedures to be measured (e.g.aqueous or vitreous samples to measure growth factors in these fluids) not performed in routine clinical practice will not be considered.

Health condition
Diabetes mellitus (DM) is a chronic metabolic disease characterised by elevated blood glucose levels which, over time, lead to multiorgan dysfunction.The global prevalence of diabetes is estimated to be 9 Retinal ischaemia (also referred to as retinal capillary nonperfusion) is considered to be the main catalyst for the occurrence of PDR.PDR is characterised by the development of abnormal new blood vessels (so-called new vessels), with or without accompanying fibrous tissue (i.e.fibromuscular membranes), at the optic disc (new vessels in the disc (NVD)) or elsewhere in the retina (new vessels elsewhere (NVE)).The ischaemic retina triggers the release of growth factors, including vascular endothelial growth factor (VEGF), which promote the growth of these new vessels in a futile attempt to restore vascular supply to the retina.However, new vessels are fragile and o en rupture leading to haemorrhages inside the eye (so-called vitreous haemorrhages

Moment of prognostication
The moment of prognostication is any time a er an individual has been diagnosed as having diabetes and DR, and prior to the occurrence of PDR.

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Clinical context
Although many people develop DR, few will progress to the stage of PDR.However, all individuals with DR require lifelong followup, and Diabetic Eye Screening Services and Eye Health Services are currently finding it impossible to contend with the demand.A concerning report revealed that lack of capacity within hospital eye services resulted in permanent sight loss in patients of all ages due to delayed appointments (Foot 2017).The Liverpool Risk Calculation Engine study group determined that implementing individualised screening intervals based on standard clinical data would facilitate more e ective management of resources into targeting high-risk groups (Eleuteri 2017).Identifying prognostic factors signalling risk of visual loss would thus be extremely beneficial in the enhancement and development of predictive models to optimise resources.

Description of the prognostic/predictive model(s)/ factor(s)
This systematic review will focus on identifying prognostic factors for progression to PDR and to HRC-PDR.Information on some of the risk factors entertained is provided below.
Diabetes duration appears to be a key predictor of the development and progression of DR, independent of glycaemic control (Fong 2003).For example, in individuals with T1D, PDR is not usually observed for the first 10 years of disease, but there is a rapid increase in incidence, to approximately 60%, by 20 years of disease duration (Klein 2008).
The Diabetes Control and Complications Trial (DCCT) provided evidence that rigorous glycaemic control delays development and progression of DR in T1D (Diabetes Control and Complications Group 1998).Similarly, the UK Prospective Diabetes Studies (UKPDS) (Turner 1998) was pivotal in establishing the beneficial e ect of regulating glycaemic levels in people with T2D.A metaanalysis of 16 RCTs found that the risk of retinopathy progression was lower a er two years of intensive glucose control.However, it concluded that progression to and within NPDR is clinically di erent from progression to PDR, but not all studies separate these stages.In those that did, long-term intensive glucose control significantly reduced retinopathy progression to PDR (odds ratio 0.44 (95% confidence interval (CI) 0.22 to 0.87), P = 0.018; test for heterogeneity, P = 0.991) (Wang 1993).
A Cochrane Review assessed the e ects of intensive versus conventional glycaemic control on long-term diabetic complications in people with T1D, and aimed to determine whether near normo-glycaemic values are beneficial.The review confirmed that tight blood sugar control significantly reduces the risk of developing retinopathy (23/371 (6.2%) versus 92/397 (23.2%); risk ratio 0.27 (95% CI 0.18 to 0.42); P < 0.001; 768 participants; 2 trials; high-quality evidence).However, the beneficial e ect of tight blood sugar control seems to become weaker once retinopathy is present (Fullerton 2014).A recent review consisting of five RCTs with large sample sizes and long-term follow-up found that in people with worse-than-moderate NPDR, intensive glycaemic control may not confer any benefits in terms of progression (Liu 2020).
International evidence-based clinical practice guidelines recognise the benefit of glycaemic control (Fred Hollows Foundation 2015).However, current management approaches do not fully prevent progression to PDR, and there is no glycaemic threshold below which protection is certain (Diabetes Control and Complications Group 1993).
The current evidence on the e ect of hypertension on progression to and within PDR seems unclear.Although, the Wisconsin Epidemiological Study of Diabetic Retinopathy (Klein 1998), determined hypertension to be associated with progression to PDR in people with T1D and the UKPDS, Turner 1998, identified a corresponding relationship in those with T2D, other studies failed to corroborate these findings.In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study, intensive blood pressure control did not have a significant e ect on retinopathy progression (Chew 2014).A Cochrane Review of 15 RCTs including participants with T1D and T2D conducted mainly in North America and Europe determined an association between reduced blood pressure and prevention of DR for up to four to five years (Do 2015).However, the review concluded that the available evidence did not support a benefit of intervention on blood pressure on progression to PDR or moderate/severe visual loss a er five years of follow-up.A recent meta-analysis similarly concluded that intensive blood pressure control reduced relative risk of incidence of DR by 17% in T2D (Zhou 2018a).However, the available data were insu icient to confirm a relative risk reduction for DR progression or incidence of PDR.
The e ect of cholesterol on the progression of DR also remains uncertain.A recent systematic review and meta-analysis of observational studies exploring associations between serum lipids and the occurrence of DR found a slightly higher low-density lipoprotein cholesterol in cases with DR (Zhou 2018b).The review identified that in a large population-based, longitudinal, observational study of people with pre-existing DR at baseline, poor control of total cholesterol was associated with a higher incidence of sight-threatening retinopathy a er adjusting for potential confounders.Poor control of triglycerides was also associated with progression to PDR, and this was greater when all lipid types were abnormal (Srinivasan 2017).There is currently no Cochrane Review evaluating the relationship between cholesterol and DR.Although definitive evidence is lacking regarding the e ect of optimal control of blood lipids on reducing the incidence and progression of DR, it is advisable in terms of benefits to overall health.Cochrane Database of Systematic Reviews generalised DR progression using data from screening programmes where the majority of people included had no DR or only mild NPDR.To our knowledge, there are currently no systematic reviews on prognostic factors for the development of PDR and its progression.
This review aims to identify factors conferring increased risk of PDR and HRC-PDR in people with diabetes once retinopathy is present.

Health outcomes
This review will consider the prognostic factors associated with the development of PDR and progression from less than HRC-PDR to HRC-PDR.PDR and HRC-PDR are thus the health outcomes to be investigated.
As ).The study found that the age-standardised prevalence of DR decreased over time from 2.6% to 2.2%, whilst the age-standardised prevalence of severe DR remained stable at 0.1%.The incidence also remained stable at one event per 10,000 person-years (Mathur 2017).This suggests that despite improved medical management of DM, the threat of PDR and its complications remain a significant problem.
The time horizon for the evaluation of health outcomes in this review will be 3 years (± 2 years), 8 years (± 2 years), or lifelong, if available.If not, other time points will be acceptable and presented.

Why it is important to do this review
We are undertaking this review to gather evidence on prognostic factors for the development and progression of PDR.This information is essential for ophthalmologists and other healthcare professionals for the counselling and management of people with diabetes and thus for patients and their families.Our findings will help clinicians to provide advice to their patients regarding modifiable risk factors, to determine in a more personalised manner the interval required for the purpose of monitoring their disease, and to consider early intervention in high-risk groups.Due to the increasing prevalence of diabetes and the limited resources of healthcare systems, tailoring health care in an individualised manner seems essential, avoiding the need to review patients in low-risk groups too o en and guaranteeing prompt and close evaluation of those who are at high risk.
This prognostic review may help to identify targets for new interventions that aim to modify the course of the disease.Furthermore, the findings may guide the design and analysis of future interventional clinical trials, and will highlight areas where further research is required.
To our knowledge, there are currently no systematic reviews on prognostic factors specifically for the development of PDR and its progression to high-risk PDR.A systematic review on prognostic prediction models for DR progression was published recently (Haider 2019).The aim of this review was to summarise the performance of existing models in predicting progression of retinopathy and their applicability for higher-risk DR patients under hospital care to predict the need for treatment or loss of vision.Based on their findings, the authors identified the need for an accurate model that can determine patients' individual risk of progression to treatment stage or loss of vision.They determined that this knowledge will allow for a more appropriate use of resources and further optimisation of services, especially for individuals with a higher risk of progression (Haider 2019).This Cochrane Review will provide evidence-based information on risk factors for the development and progression of PDR that can be used for the development of future prognostic models.

O B J E C T I V E S Primary objectives
To assess prognostic factors for predicting the occurrence of PDR in individuals with diabetic retinopathy.

Population
Male and female adults ≥ 18 years of age of any ethnicity with DR (NPDR), diagnosed as per standard clinical protocol

Index prognostic factors
Broad review of prognostic factors associated with the development of PDR.
Specific prognostic factors of interest will include, but not be restricted to, routinely collected patient demographics and information, such as age, gender, ethnicity, socio-economic status, and smoking habits; frequently obtained standard clinical data, such as comorbidities (presence/absence of cardiovascular disease, cerebrovascular disease, nephropathy and specifically chronic kidney failure (defined as estimated glomerular filtration rate (GFR) of < 60 mL/min/1.73m 2 ), peripheral neuropathy and specifically foot ulcers, amputation), body mass index (BMI), neck/ waist circumference, glycated haemoglobin, blood pressure, low-density lipoprotein, high-density lipoprotein, triglycerides, and functional and structural retinal biomarkers in the prognostic con- Cochrane Database of Systematic Reviews text of the development and progression of PDR.Prognostic factors will be considered in the absence of treatment for DR.
It is expected that prognostic factors will generally be measured at the time participants enter the study, and indeed after the diagnosis of DR.If measures of prognostic factors are available at other time points, and these coincide in more than one study, we may consider investigating them, additionally, at other time points.
Studies evaluating risk factors requiring invasive procedures to be measured (e.g.aqueous or vitreous samples to measure growth factors in these fluids) not performed in routine clinical practice will be excluded.

Outcomes
Progression from DR (NPDR) to any stage of PDR.Participants who have received laser PRP for the treatment of PDR will be considered to have progressed to the outcome of PDR.
Timing 3 years (± 2 years), 8 years (± 2 years), or lifelong, if available.If not, other time points will be accepted and presented.PDR can occur very rapidly -in days -or take months or years to develop.We will also determine over what time period the outcomes are predicted by the risk factors investigated.

Secondary objectives
To assess prognostic risk factors for predicting the progression of PDR from less than HRC-PDR to HRC-PDR.

Population
Male and female adults ≥ 18 years of age of any ethnicity with less than HRC-PDR, diagnosed as per standard clinical protocol

Index prognostic factors
We anticipate that less information will be available regarding prognostic factors associated with progression from PDR to HRC-PDR.Prognostic factors of interest will include, but not be restricted to, routinely collected patient demographics and information, such as age, gender, ethnicity, socio-economics, and smoking habits; frequently obtained standard clinical data, such as comorbiidities (presence/absence of cardiovascular disease, cerebrovascular disease, nephropathy and specifically chronic kidney failure (defined as estimated GFR of < 60 mL/min/1.73m 2 ), peripheral neuropathy and specifically foot ulcers, amputation), BMI, neck/waist circumference, glycated haemoglobin, blood pressure, low-density lipoprotein, high-density lipoprotein, triglycerides, and functional and structural retinal biomarkers in the prognostic context of the development and progression of HRC-PDR.The scope of this review will not extend to the evaluation of the effect of treatment on progression to HRC-PDR, and as such, prognostic factors will be considered in the absence of previous treatment for PDR.
It is expected that prognostic factors will generally be measured at the time participants enter the study, and indeed after the diagnosis of less than HRC-PDR.If measures of prognostic factors are available at other time points, and these coincide in more than one study, we may consider investigating them additionally at other time points.Prognostic factors requiring invasive procedures to be measured (e.g.aqueous or vitreous samples to measure growth factors in these fluids) not performed in routine clinical practice will not be considered.

Outcomes
Progression from PDR to HRC-PDR.Participants who received laser PRP for the treatment of PDR will be considered to have progressed to the outcome of PDR.Cochrane Database of Systematic Reviews PDR can occur very rapidly -in days -or take months or years to develop.We will also determine over what time period the outcomes are predicted by the risk factors investigated.

Investigation of sources of heterogeneity between studies
We anticipate between-study heterogeneity relating to two key areas.
1. Clinical heterogeneity including the e ect of di erent comorbidities, medications, and interventions in study cohorts.Di erences in how outcomes are measured, such as diagnoses of PDR (clinical examination versus supported by imaging/imaging technologies used) and how progression is defined.2. Methodological heterogeneity generated from di erent study designs, and how robustly studies are conducted with regard to risk of bias and approach to analysis.
We will explore the e ects of these aspects of heterogeneity if a meta-analysis is conducted.

Inclusion criteria
Eligible study designs will include prospective or retrospective cohort and case-control longitudinal studies involving patients who have not had previous treatment for DR; as well as randomised controlled trials (RCTs) evaluating therapeutic interventions to prevent the progression of DR where there is a control, untreated arm.We will also include studies based on longitudinal registry data.It is a mandatory requirement that relevant studies must evaluate prognostic factors involved specifically in the development and progression of PDR, as opposed to generalised progression of retinopathy.
Studies investigating general microvascular complications of diabetes but including a subset of data related to factors involved in the development of PDR will be eligible for inclusion, if information on this group (PDR) is specifically given.

Exclusion criteria
We will exclude case reports, as they will introduce selection bias, and editorials/letters to editor not containing primary data.We will not include cross-sectional studies, as this is a less appropriate study design for the evaluation of prognostic factors for the development or progression of disease.

Targeted population
The target population will consist of adults (≥ 18 years of age) of any gender with NPDR or PDR with less than HRC-PDR, diagnosed as per standard clinical practice.Studies involving participants of all ethnicities, geographical locations, and socio-economic status will be eligible for inclusion.Any appropriate studies including a subset of relevant participants will be considered as potentially eligible if data from this subset are given separately.

Types of prognostic/predictive factor(s) or model(s)
This review will consider prognostic factor studies only.Specific prognostic factors of interest will include, but are not restricted to, routinely collected patient demographics and information, such as age, gender, ethnicity, socio-economic status, and smoking habits; frequently obtained standard clinical data, such as comorbidities (presence/absence of cardiovascular disease, cerebrovascular disease, nephropathy and specifically chronic kidney failure (defined as estimated GFR of < 60 mL/min/1.73m 2 ), peripheral neuropathy and specifically foot ulcers, amputation), BMI, neck/ waist circumference, glycated haemoglobin, blood pressure, lowdensity lipoprotein, high-density lipoprotein, triglycerides, and functional and structural retinal biomarkers in the prognostic context of the development and progression of PDR.
We will exclude studies evaluating prognostic factors involving invasive procedures that cannot be practically undertaken in a clinical setting (such as aqueous/vitreous sampling) and are thus unlikely to be translatable to routine clinical practice.
It is expected that prognostic factors will generally be measured at the time participants enter the study, and indeed a er the diagnosis of DR or PDR.If measures of prognostic factors are available at other time points, and these coincide in more than one study, we may consider investigating them additionally at other time points.

Development of PDR
The development of PDR will be determined by the presence of retinal new vessels, either at the disc (NVD) or elsewhere in the retina (NVE) as determined by fundus examination, fundus photography, or fundus fluorescein angiography.We will consider participants requiring laser treatment for PDR specifically to have progressed to the outcome of PDR.

Development of HRC-PDR
Progression from less than HRC-PDR to HRC-PDR.HRC-PDR is defined according to the ETDRS as: i) NVD > 1/4 to 1/3 disc area; ii) NVD of any extent or NVE if associated with the presence of vitreous haemorrhage or pre-retinal haemorrhage.These features may be assessed by clinical examination or by the grading of ophthalmic images, both fundus photography and fundus fluorescein angiograms.Participants requiring laser treatment for HRC-PDR specifically will be considered as having progressed to the outcome of HRC-PDR.
The time horizon for the evaluation of health outcomes in this review will be 3 years (± 2 year), 8 years (± 2 years), or lifelong, if available.If not, other time points will be accepted and presented.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy (Protocol)
Copyright © 2020 The Cochrane Collaboration.Published by John Wiley & Sons, Ltd.

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Electronic searches
The Cochrane Eyes and Vision Information Specialist will search the following electronic databases.A search has been developed around the following components, "prognostic factors", "proliferative diabetic retinopathy", and "development and progression".There will be no restrictions to language or year of publication. •

Searching other sources
We will supplement the search by screening the reference lists of eligible articles.We will not include grey literature sources in the review, as we do not expect these to be su iciently informative to justify the extra resources required in conducting the searches.

Selection of studies
Two review authors, independently and masked to each other's initial decisions, will review titles and abstracts of studies identified by the electronic searches and classify them as potentially eligible or ineligible.We will use online review management so ware for this purpose (Covidence).Any discrepancies will be resolved by discussion or by consultation with a third review author if necessary.We will obtain the full-text articles of potentially eligible studies, and two review authors will independently classify them as included or excluded.Any discrepancies will be resolved by discussion or by consultation with a third review author if necessary.We will report the selection process of studies in a PRISMA flow diagram and document reasons for exclusion of the studies excluded a er full-text review.

Data extraction and management
To account for heterogeneity amongst studies, data extraction will involve two stages.The first stage will consist of a mapping exercise to categorise eligible studies according to their design, prognostic factors evaluated, time points of prognostic factor measurements and outcomes, and type of analysis/e ect estimates.We will enter information into a pilot-tested spreadsheet specifically designed for this purpose.
In the second stage, we will extract data for each prognostic factor of interest from relevant studies which have been identified by stage one as having common factors appropriate for meta-analysis.
Two review authors will independently undertake data extraction.Any disagreements will be resolved by discussion or with the involvement of a third review author if necessary.We will use the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS-PF) to guide data extraction (Appendix 4).
We will extract and enter the following data, if available, according to the following categories.

Cochrane Database of Systematic Reviews
Two review authors will independently assess risk of bias, with any discrepancies arbitrated by a third review author.
We will assess each 'Risk of bias' domain as low, moderate, or high, and detail our reasoning for such assessments.

Measures of association or predictive performance measures to be extracted
For each factor of interest, we will extract estimates of prognostic e ect such as hazard ratios, risk ratios, odds ratios, or mean di erences with a measure of their uncertainty (standard errors, variances, or confidence intervals).We will collect adjusted prognostic e ect estimates preferentially, and document the set of adjustment factors used.

Dealing with missing data
We will contact study authors if further information or clarification is required.When time-to-event analyses were performed, and adjusted hazard ratio estimates and their uncertainty are unavailable, if the summary statistics reported permit, we will attempt to derive unadjusted estimates and their standard errors following guidance described by Tierney and colleagues (Tierney 2007).

Assessment of heterogeneity
We anticipate there will be statistical heterogeneity due to clinical and methodological di erences between studies.Since the I 2 statistic can be problematic in certain situations (Rücker 2008), we will quantify heterogeneity using Tau 2 .Where there is an appropriate number of studies included in a meta-analysis, we will also present 95% prediction intervals.

Assessment of reporting deficiencies
We will assess small-study e ects using contour-enhanced funnel plots when 10 or more studies are included in a meta-analysis.We anticipate variation in e ect measures, length of follow-up, etc., and therefore expect to include few studies in each meta-analysis.Consequently, we do not plan to perform funnel plot asymmetry tests given the low power of such tests when studies are few (Debray 2018).

Data synthesis Data synthesis and meta-analysis approaches
We will conduct meta-analysis (i.e.report a weighted average of the individual study measures of association) in clinically relevant groups using a random-e ects approach.We will stratify by di erent time points of outcomes and meta-analyse hazard ratios, odds ratios, and risk ratios separately for each prognostic factor and outcome.Similarly, unadjusted and adjusted associations will be reported separately.Our primary analyses will focus on adjusted estimates.If we determine that conducting a meta-analysis is inappropriate due to heterogeneity, we will present a narrative or tabulated summary.We will use 95% confidence intervals throughout.

Sensitivity analysis
We will perform sensitivity analyses to explore the impact of the following factors (when applicable) on e ect sizes by excluding: • studies at high risk of bias in one or more domains; • retrospective studies.

Conclusions and 'Summary of findings'
We will prepare a 'Summary of findings' table assessing the certainty of the evidence using GRADE modified for prognostic factor studies (Foroutan 2020).We will use the table to clearly identify factors that influence the development of PDR and progression to HRC-PDR and our confidence in the estimates of e ect.

A C K N O W L E D G E M E N T S
stated above, PDR is diagnosed by the presence of NVD on or within 1-disc diameter, or NVE.HRC-PDR is defined according to the ETDRS as NVD > 1/4 to 1/3 disc area, NVD of any extent, or NVE if associated with the presence of vitreous haemorrhage or preretinal haemorrhage.Alarmingly, many people with diabetes can progress to the sightthreatening stage of PDR without developing any obvious prior warning symptoms.The DRS found that approximately 50% of people with PDR who do not receive timely treatment will become legally blind within five years (Diabetic Retinopathy Study Research Group 1981).The ETDRS was important in establishing that PRP treatment can be deferred in patients with NPDR or PDR until high-risk characteristics develop (Diabetic Retinopathy Study Research Group 1991).The study also identified that only 50% of eyes assigned to deferral of treatment (until HRC-PDR ensued) progressed to HRC-PDR a er seven years of follow-up.
A large cohort study of 7.7 million patients contributing to the Clinical Practice Research Datalink evaluated population trends in the 10-year incidence and prevalence of DR in the UK from 2004 to 2014, by diabetes type, age, sex, ethnicity, deprivation, region, and calendar year (Mathur 2017

Assessment of risk of bias in included studies
Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy (Protocol)Copyright © 2020 The Cochrane Collaboration.Published by John Wiley & Sons, Ltd.