Study design
We performed a cost-effectiveness study based on routine care data. After optimising the personalised strategy by setting its risk margin, results for personalised and Dutch guideline screening strategies were compared with annual screening in terms of differences in costs and the number of delayed STR diagnoses. Then, a comparison between the personalised and Dutch guideline screening strategies was performed.
Study population
To study the impact of different diabetic retinopathy screening intervals on development of STR, we used the Hoorn Diabetes Care System (DCS) cohort, a dynamic primary care cohort of people with type 2 diabetes in the Netherlands [19]. Data were available over the period from the beginning of 1998 up to the end of 2017. There were 13,959 people in the total cohort, with a varying date of entry and exit, resulting in patient follow-up varying between 0 and 18 years. Inclusion criteria for the current study were: (1) at least one measurement of a grade of retinopathy available; (2) having no STR at baseline; and (3) at least 5 years of follow-up available. The latter criterion was based on the maximal screening interval that the Aspelund et al model would predict, i.e. 5 years [12]. For all participants, we used patient-level results from all routine clinical and laboratory measurements that were available. The measurements in the cohort included, but were not limited to, systolic BP (SBP), diastolic BP, HbA1c, BMI, cholesterol level and triacylglycerol, date of diagnosis of type 2 diabetes, ethnic group, and fundus photography including retinopathy grades. The retinopathy grades were reported according to the EURODIAB scale, which ranges from 0 to 5 [20]: grade 0 means no retinopathy; grade 1 is ‘minimal non-proliferative retinopathy’; grade 2 is ‘moderate non-proliferative retinopathy’; grade 3 is ‘severe non-proliferative retinopathy’; grade 4 is ‘photocoagulated retinopathy’; and grade 5 is ‘proliferative retinopathy’. According to the Dutch guideline, grades 3–5 were considered STR, and usually, patients with these grades were referred to an ophthalmologist for treatment [13, 16]. The study has been approved by the Medical Ethical Review Committee of the VU University Medical Center, Amsterdam. Individuals were informed about the use of their data and were offered an opt-out. Data were used anonymously.
Imputation for missing values
Missing explanatory variables (duration of diabetes, HbA1c and SBP) were imputed by the mean value conditional on retinopathy grade. For missing values of the dependent variable of retinopathy grade, a different approach was followed. First, we used information from adjacent measurements in the same individual for interpolation, and if the grades before and after the missing value were the same, we filled out the missing value with that grade. If grades differed, a uniform distribution between the two adjacent grades was assumed, and a random draw from this distribution was applied and rounded to an integer value. Second, for patients with STR missing the time to develop STR, two extreme scenarios were used to reflect a broad range of possible outcomes, i.e. slow and fast STR progression assumptions. In the slow STR progression assumption, STR was assumed to have developed at the last possible time point. In the fast STR progression assumption, STR was assumed to have developed at the first possible time point. Fast STR progression was taken as a base assumption for imputation and slow STR progression assumption used for sensitivity analysis.
Duration of diabetes, HbA1c and SBP were missing for 1.0%, 1.7% and 2.0%, respectively, of all records. Retinopathy grades of participants without STR showed 12.2% missing values over all the records. Of these, 10.1% had the same grades before and after the missing value, while for the remaining 2.1%, grades differed. For 22% of participants with STR, some retinopathy grades were missing, and needed to be imputed.
Data analysis
In order to perform cost-effectiveness analysis, first, we needed to optimise the screening model [12] to determine the personalised diabetic retinopathy screening strategy. To do so, a preset risk margin (i.e. the risk of developing STR given a certain screening interval) was assumed. Subsequently, different intervals using a personalised diabetic retinopathy screening model were simulated, and the clinical outcomes and costs of these screening intervals were calculated.
Determining personalised screening intervals
To estimate personalised screening intervals, we used the model previously developed by Aspelund et al [12]. A brief description of Aspelund’s model is provided in electronic supplementary material (ESM) Methods. In short, this model predicts the time to develop STR based on individual patient characteristics which include mean blood glucose or HbA1c, SBP, presence of retinopathy, sex, and duration of diabetes. In the original publication, the personalised intervals for screening using Aspelund’s model were determined based on a preset fixed risk margin of 3.2%. This risk margin was derived from the proportion of people that developed STR in their first year of the screening programme in the original dataset used by Aspelund et al [12], and basically reflected patients’ current real-world STR risk. Of note, in our analysis, we varied this risk margin between 0.0% and 4.0% and applied the corresponding personalised screening interval in our simulation. Before comparison with the other two strategies, we optimised the risk margin from the perspective of costs per case of delayed diagnosis, as explained below.
One to 3 year screening interval recommended by the Dutch guideline
In the Dutch diabetic retinopathy guideline, people with diabetes are divided into two subgroups: those without previously known retinopathy and those already having a low retinopathy grade at baseline. The recommended diabetic retinopathy screening intervals are based on the retinopathy grade. If the individual does not have retinopathy at the first visit, then the next screening visit is after 2 years. If after 2 years still no retinopathy is present, the screening interval is increased to 3 years. If the individual has mild retinopathy (grades 1–2), then the screening interval will be annual, and in severe cases (grades 3–5) patients should be referred to an ophthalmologist [6].
Clinical outcomes
The clinical outcome was the number of delayed STR diagnoses. This was calculated by counting the number of patients for whom the personalised screening model that was simulated predicted longer intervals than the observed time to STR diagnosis (based on the real-world longitudinal DCS cohort follow-up). In the present study, we did not consider quality-adjusted life years (QALYs) as an outcome since an estimate of QALYs would require elaborate modelling which would introduce more uncertainty in the study.
Costs
We considered the healthcare perspective for the main cost analysis, while we added productivity losses and travel costs in a sensitivity analysis. Discount rates of 1.5% and 4.0% were applied to effects and costs, respectively, in line with Dutch health economic guideline recommendations [21]. We did not include treatment costs, since all patients with retinopathy will eventually be treated in each of the three different strategies, with only slight differences in the timing of treatment. Price levels used were for 2015.
For the maximum screening costs, the tariff of a large Dutch commercial laboratory was used [22]. For the minimum screening costs, a calculation based on micro-costing was applied [23]. Screening costs ranged from €15.25 to €41.07. Travel costs ranged from €1.58 to €14.19 [23]. Productivity losses were estimated to vary from €2.63 to €16.62 [24]. For all cost types, a gamma distribution was fitted to the minimum and maximum cost estimates to reflect the uncertainty. The details of costs are shown in ESM Table 1.
Determination of the best risk margin for personalised screening
To determine the best risk margin for use with the Aspelund model, risk margins were varied from 0 to 4, and for each risk margin the savings per case with a delayed STR diagnosis were assessed using a stepwise approach. For each 0.1% increase in the risk margin, we calculated the incremental cost saving and compared these to the additional delayed STR diagnoses. The incremental cost saving per delayed STR diagnosis was computed as the ratio of differences in costs to differences in delayed STR diagnoses for each risk margin as compared with the previous risk margin. The best risk margin was considered to be the one with the lowest number of delayed STR cases at which incremental savings per delayed STR case would peak.
Sensitivity analysis
In order to capture the uncertainty around the study sample and around the costs of screening, we conducted bootstrapping (1000 simulations) from the study sample and varied costs over their full ranges.
Bootstrapping with 1000 simulations was performed for the fast and slow progression assumptions. In the first step, the best risk margin in each iteration was determined. Then, for the mean over the iterations of the best risk margin, probabilistic sensitivity analysis using different cost estimates for healthcare perspective (screening cost) and societal perspective (travel cost and productivity loss) was conducted with 1000 iterations, again varying the sample using bootstrapping techniques, but now also varying the costs.
All analyses were performed with the statistical software package R (version 3.6.1) (www.rproject.org) [25] in combination with Microsoft Excel 2010 for Windows.