The economic burden of inherited retinal disease in Singapore: a prevalence-based cost-of-illness study

Abstract

Objective

To assess the economic impact of inherited retinal disease (IRD) among Singaporeans.

Methods

IRD prevalence was calculated using population-based data. Focused surveys were conducted for sequentially enrolled IRD patients from a tertiary hospital. The IRD cohort was compared to the age- and gender-matched general population. Economic costs were expanded to the national IRD population to estimate productivity and healthcare costs.

Results

National IRD caseload was 5202 cases (95% CI, 1734–11273). IRD patients (n = 95) had similar employment rates to the general population (67.4% vs. 70.7%; p = 0.479). Annual income was lower among IRD patients than the general population (SGD 19,500 vs. 27,161; p < 0.0001). Employed IRD patients had lower median income than the general population (SGD 39,000 vs. 52,650; p < 0.0001). Per capita cost of IRD was SGD 9382, with a national burden of SGD 48.8 million per year. Male gender (beta of SGD 6543, p = 0.003) and earlier onset (beta of SGD 150/year, p = 0.009) predicted productivity loss. Treatment of the most economically impacted 10% of IRD patients with an effective IRD therapy required initial treatment cost of less than SGD 250,000 (USD 188,000) for cost savings to be achieved within 20 years.

Conclusions

Employment rates among Singaporean IRD patients were the same as the general population, but patient income was significantly lower. Economic losses were driven in part by male patients with early age of onset. Direct healthcare costs contributed relatively little to the financial burden.

Introduction

Inherited retinal diseases (IRDs) are a heterogenous group of Mendelian conditions that lead to variable onset of retinal degeneration with loss of vision that can be limited to central vision, peripheral vision, or both [1]. The majority of IRDs are rare, occurring in less than 0.1% of the population, but unlike more common blinding diseases such as age-related macular degeneration and diabetic retinopathy, IRDs affect predominantly younger individuals. This has resulted in IRDs becoming the most common cause of blindness among working age adults in developed nations over the past decade [2, 3].

With the ongoing development of gene- and cell-based therapies for IRDs [4–6], there is concern about the potentially high costs of treatment for IRDs given the scarcity of individual IRD phenotypes and their causative genotypes [7, 8]. Gene therapy for Leber congenital amaurosis (LCA) caused by RPE65 mutations using voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) exceeds half a million dollars per eye and it remains unclear if this treatment is cost-effective from a societal perspective [7, 9–11]. A series of recent studies have indicated that, despite their rarity, IRDs do create a substantial economic burden on society. Cost of illness studies with data from the Canada, Ireland, the United Kingdom and the United States have estimated IRDs impose an annual financial burden of up to 60 thousand dollars for each affected individual [12, 13], which in the United States amounts to a national annual burden of tens of billions of dollars. These estimates were based on both economic losses and costs due to reduced wellbeing, which alone contributed more than 60% of the financial burden in the United States and Canada. Analyses of registry data from Denmark determined that childhood onset of IRDs can reduce an individual’s lifetime income by one-third [14, 15]. This reduction appeared to be related to reduced educational and employment opportunities. More recent data have shown that healthcare costs for IRD patients were ~40% greater than the general population [16], which was due to increased expenditure for outpatient eye clinic visits, inpatient visits, prescription medication, and primary healthcare.

Singapore is a prosperous Southeast Asian city state with a population of 5.7 million, the majority being ethnic Han Chinese, with smaller populations of Malay and South Indian descent. Healthcare in Singapore is delivered using a mixed model where costs are shared on average almost equally between the user (55%) and government and private health insurance (45%) [17]. The phenotypic and genotypic landscape of IRDs in Singapore remains poorly defined, although recent epidemiological data have shown that the prevalence of retinitis pigmentosa, the most common form of IRD, is ~1 in 1600 in the population [18]. In the current work we used a prevalence-based approach to estimate the size of the IRD population and studied a clinic-based IRD cohort to estimate the economic cost of IRDs in Singapore.

Methods

Enrollment

Adults with IRD were recruited from retina outpatient clinics at the Singapore National Eye Centre (SNEC). SNEC is a tertiary hospital system that manages ~50% of all public sector ophthalmology care, amounting to 340,000 outpatient visits annually [19]. In 2021 there were 307 registered ophthalmologists in Singapore [20], of whom 105 (34.2%) were practicing in SNEC. Intra-hospital referrals are from a general ophthalmology clinic to a retina clinic at SNEC and IRD patients undergo a systematic interview, clinical examination, imaging, psychophysical testing, genotyping, referral to additional medical specialties (e.g., for syndromic disease) and genetic counseling. Enrollment took place between March 2021 and March 2022. Sample size was calculated based on estimated IRD prevalence in Singapore, and we determined that a confidence level of 95% with a 10% margin of error required a sample of 95 cases [21]. This study was approved by the SingHealth Institutional Review Board (SHF-SNEC/920/4) and was performed in accordance with the tenets of the Declaration of Helsinki. Informed consent was obtained for all patients.

Data and measures

IRD prevalence estimates were based on previously published data from the Singapore Epidemiology of Eye Diseases (SEED) population-based cohorts [18, 22]. The prevalence of retinitis pigmentosa (RP) in the Chinese, Malay, and Indian cohorts was 0.09%, 0.03%, and 0.06%, respectively, with an overall prevalence of 0.06% (95% CI, 0.02–0.13). This prevalence estimate was then used to estimate the proportion of all IRDs in Singapore. This was done by taking a sequentially enrolled clinical cohort of IRD patients seen at the Singapore National Eye Centre during the period from March 2021 to March 2022 and determining the proportion of cases that were RP compared to non-RP IRDs. These data were then extrapolated to the general Singapore population based on the proportion of IRD patients with a clinical diagnosis of RP seen in the study center (n = 291 of 500 IRD cases; 58.2%). Population demographics and employment data were collected through the Comprehensive Labour Force Survey obtained from the 2021 Singapore Department of Statistics census [23]. Statistical analyses were performed using GraphPad Prism version 9.0, and Microsoft Excel version 16.

Expected loss of income from the IRD cohort, which represents the productivity loss from being unemployed or earning less, was estimated as the difference in the expected median income between the IRD cohort and the age- and gender-matched general population. A two-part regression model was used to estimate the expected median income, controlling for a quadratic function of age and gender [24]. The first part is a logit model which estimated the probability of being employed and the second a quantile regression model which estimated median income conditional on being employed. The fitted models were used to predict expected median income for the cohort, calculated as the product of probability of being employed and the median income conditional on being employed. This prediction was compared to the expected median income of the corresponding age and gender in the general population.

Mean and standard deviation of the annual per capita IRD burden attributed to productivity loss, carer, and medical costs due to IRD, and spending on assistive technologies were reported. National burden was projected using prevalence estimates from earlier analyses. Monte Carlo simulation (1 million replications) was used to derive standard deviation and 95% percentile intervals. Per capita costs were assumed to follow a gamma distribution, while the number of IRD cases were assumed to follow a negative binomial distribution.

To further investigate which patient characteristics predicted economic loss, we performed linear regressions to estimate the unadjusted and adjusted association between per-patient economic loss and each characteristic. Adjusted associations simultaneously controlled for the presence of other characteristics. Unadjusted and adjusted beta coefficients, confidence intervals, and statistical probabilities were calculated using Wizard 2.0 (Evan Miller, Chicago, USA).

For break-even analysis we used the mean per capita economic losses for the bottom 10% of patients (i.e., those with greatest economic losses), the bottom 50%, and for all patients, as an ongoing annual cost. A 3% discount rate was applied for the future cost of an IRD therapy with a fixed cost at the time of treatment. We assumed financial losses would decline directly in response to the application of IRD treatments of varying efficacy.

Clinical characterization of IRDs

All patients included in the study were seen in the IRD Clinic at SNEC during the period from March 2021 to March 2022.

All subjects underwent clinical evaluation by the treating clinician, including a targeted clinical history, assessment of visual acuity by LogMAR testing with pinhole or manifest refraction, intraocular pressure (IOP), and fundus examination by slit lamp biomicroscopy. Optomap fundus photography and autofluorescence imaging (Optos, Marlborough, Massachusetts), Spectralis macular OCT (Heidelberg Engineering, Heidelberg, Germany), Ishihara color vision testing, and Goldmann kinetic perimetry (Haag-Streit, Koeniz, Switzerland) was performed on all subjects. Electroretinography was performed as an adjunctive test according to ISCEV methodology [25] in cases where the diagnosis was in doubt.

Participant visual acuity was recorded and classified according to World Health Organization categories of central visual impairment [26]. Data obtained for the entire IRD cohort and the subset that participated in the economic survey were compared to ensure equivalent representation using two-tailed Student’s t test for age and the n − 1 chi-squared test of proportions for gender, race, visual acuity, and IRD phenotype.

Patients were interviewed by clinically trained professionals using a targeted questionnaire that assessed visual complaints, employment and income, IRD-related expenses, carer expenses, and psychological status (see Supplementary Information). Survey questions were devised specifically for the study, adapted from previously described instruments [12], or used with permission from the Foundation Fighting Blindness [27].

Results

The prevalence of retinitis pigmentosa (RP) in a Singapore populated-based study was 0.06%, with some variability between races [18]. These data yielded an estimate of 3065 cases of RP and a total of 5202 cases of IRD (95% CI, 1734–11,273) in Singapore. Descriptive statistics of the study sample are shown in Table 1, which compares the study cohort (n = 95) with a larger (n = 500) cohort of IRD patients that were seen in the same center during the same period. Statistically, the study cohort was of similar age (mean 47.9 in the study cohort vs. 51.3 in the larger IRD cohort; p = 0.089), gender (41% females in study cohort and 46.6% in the larger IRD cohort; p = 0.316), ethnic composition, and visual impairment compared to the larger IRD patient cohort. RP was similarly prevalent between the two groups (63.2% in study cohort vs. 58.2% in larger IRD cohort; p = 0.364). A comparison of the study cohort and previously published IRD clinical cohorts showed statistically similar proportions of RP cases between the Singapore cohort and cohorts from other geographic regions (Supplementary Fig. 1). Median age of symptom onset was 32 years (IQR 15–50) and median age at diagnosis was 40 years (IQR, 21–55). Self-reported symptoms of nyctalopia, peripheral vision loss, reduced visual acuity, and reduced color vision were present in 75.8%, 69.5%, 41.1%, and 44.2% of patients, respectively.

Table 1.

Summary and comparative statistics of the Singaporean IRD study cohort.

	Survey group (n = 95)	All IRD clinic patients (n = 500)	p valuea
Mean age (SD)	47.90 (15.6)	51.3 (18.7)	0.089
Female gender (%)	39 (41.0)	233 (46.6)	0.316
Ethnic group (%)
Chinese	83 (87.3)	426 (85.2)	0.673
Malay	6 (6.3)	25 (5.0)
Indian	6 (6.3)	47 (9.4)
Others	0 (0)	2 (0.4)
Central visual acuity (%)
Unimpaired	49 (51.6)	236 (47.2)	0.547
Mild	15 (15.8)	58 (11.6)
Moderate	18 (18.9)	117 (23.4)
Severe	3 (3.2)	25 (5.0)
Blindness	10 (10.5)	64 (12.8)
Retinitis pigmentosa cases (%)	60 (63.2)	291 (58.2)	0.364

^aGroups were compared using the Student’s t test for age, the (n − 1) chi-squared test of proportions for gender and RP proportion, or the Fisher exact test for ethnic group and VA impairment category. VA impairment categories were based on the WHO classification of visual impairment, which classifies vision loss as unimpaired (6/12 or better), mild (worse than 6/12 to 6/18), moderate (worse than 6/18 to 6/60), severe (worse than 6/60 to 3/60), and blindness (worse than 3/60) [26].

Among the 95 individuals that participated in the study, 92 cases (96.8%) had initially presented to and were diagnosed at the study hospital or affiliated hospitals without having previously being seen by external providers. The remaining three cases (3.2%) were initially diagnosed at another hospital but subsequently sought transfer of care to the study hospital.

IRD-related healthcare utilization was modest, with a median of one visit to optometry and ophthalmology clinics per year, and median IRD-related clinical visits of two per year (range 0–12; see Supplementary Table 1). Employment rates were lower among the IRD cohort (67.4%) compared to the age- and gender-matched general population (70.7%), but this was not statistically significant (p = 0.479; Table 2). Surprisingly, the expected median income of employed IRD patients was 26% lower than the age- and gender-matched general population who were employed (Table 2), and this was significant (SGD 39,000 vs. SGD 52,650; p < 0.0001). Similarly, the expected median income of all IRD patients was nearly 30% lower than the general population (SGD 19,500 vs. SGD 27,161; p < 0.0001). Mean patient-reported costs for medical care, assistive technologies, and carer costs due to IRD were SGD 193, 43, and 958 per patient, respectively (Table 3 and Supplementary Fig. 2). Lost productivity due to being unemployed or reduced productivity while employed accounted for 87.9% of the total losses (Table 3). Overall, we estimated the per capita cost of IRD to be SGD 9382 (SD 10,790) per annum. Extrapolated to the predicted number of IRD cases in Singapore, we estimate the national economic losses to be SGD 48.8 million per year.

Table 2.

Employment and income findings for the Singapore clinic IRD cohort.

	IRD cohort (n = 95)			General populationa			Significanceb
	Male (n = 56)	Female (n = 39)	Total	Male	Female	Total
Employed (%)	67.9	66.7	67.4	74.6	65.2	70.7	0.479
Median income among employed (n = 64)	39,000	39,000	39,000	63,780	49,140	52,650	<0.0001
Expected median incomec (n = 95)	6500	19,500	19,500	32,430	27,161	27,161	<0.0001

^aSingapore population taken from the 2021 Singapore Department of Statistics Census data [34]. Median annual income was determined with age and gender-matched data from the national census data. Gender-weighted totals were calculated by weighting the national data to the gender proportions obtained for the IRD cohort. Age-weighted totals were calculated by weighting the national data to the age range proportions for the IRD cohort.

^bComparisons for employment were performed using the (N − 1) chi-squared test [35] to compare employment rates between the IRD cohort with age- and gender-matched data from the Singapore census. Income data were compared using the Mann–Whitney U test to compare median annual income between the IRD cohort with age- and gender-matched data from the Singapore census. Income is shown in Singapore dollars.

^cExpected median income is calculated as the respective median income weighted by the proportion of individuals who are employed and unemployed in each age and gender strata. Unemployed individuals are assigned zero income.

Table 3.

Estimated annual costs associated with IRD.

	Mean cost (SD) per capita in study populationa	Mean cost nationally (SD) in millionsb [95% percentile intervals]
Expected productivity lossa	8188 (10,199)	42.59 (39.00) [1.76–145.90]
Carer costs due to IRD	958 (6200)	4.98 (4.58) [0.18–17.15]
Medical costs	193 (292)	1.00 (0.92) [0.04–3.44]
Assistive technologies	43 (129)	0.22 (0.21) [0.01–0.77]
Total annual costs	9382 (10,790)	48.81 (44.69) [2.01–167.20]

^aExpected productivity loss is defined as the difference in expected median income between an IRD patient and a member of the general population in the same age and gender strata.

^bEstimates are expressed in SGD per capita (study population) and SGD million for the entire estimated national population of Singapore IRD cases (5202 individuals) [18].

We additionally assessed subjective psychological impacts of IRD among the study cohort as patient wellbeing was previously reported to be a significant contributor to financial burden for IRD patients [12]. Self-reported depression (35.8% vs. 6.3%, p < 0.0001) and anxiety (44.2% vs. 1.6%; p < 0.0001) were more prevalent in the IRD study cohort compared to the general population, although these conditions were not more common in the carers of IRD patients (Supplementary Table 2).

The impact of clinical findings on economic losses among the IRD cohort was assessed using linear regression analysis. Male gender (adjusted beta coefficient of SGD 6543; p = 0.003) and earlier age of onset (adjusted beta coefficient of SGD –150; p = 0.009) were significantly associated with reduced income, while no significant association was noted with better eye visual acuity and extent of remaining visual field at the time of study enrollment, or IRD-related depression and anxiety (Table 4).

Table 4.

Male gender and earlier age of onset are significantly associated with economic losses among IRD patients.

Clinical finding	Unadjusteda		Adjusteda
	β coefficient (95% CI)b	p valuec	β coefficient (95% CI)b	p valuec
Male gender (n = 56)	6495 (2255, 10,735)	0.003	6543 (2316, 10,770)	0.003
Age at symptom onset	−173 (−283, −63)	0.002	−150 (−261, −39)	0.009
VA in better eye (logMAR letters)	59 (46, 166)	0.265	44 (−64, 153)	0.418
Horizontal GVF in better eye (° on V4e)	30 (−10, 70)	0.148	38 (−81, 158)	0.527
Vertical GVF in better eye (° on V4e)	28 (−19, 75)	0.237	−23 (−161, 114)	0.735
IRD-related depression (n = 34)	1583 (−2966, 6134)	0.491	1848 (−4539, 8235)	0.567
IRD-related anxiety (n = 42)	−990 (−5389, 3408)	0.656	2394 (−8612, 3823)	0.446

^aUnadjusted estimates come from separate simple linear regressions. Adjusted estimates come from a multiple linear regression model controlling for all patient characteristics.

^bThe β coefficients refer to the lost income due to the presence of the clinical finding based on linear regression analysis. Categorical data were male gender, depression, or anxiety. Continuous variables were age of symptom onset, VA in better eye, and Goldmann visual field (GVF) extent along the central horizontal and vertical meridian. For continuous variables, the β coefficient indicates the amount of income lost (positive values) or gained (negative values) for each unit of increase in the continuous variable. Positive coefficients indicate income lost, and negative coefficients indicate income gained.

^cThe threshold for statistical significance was set at <0.05.

Finally, we performed a break-even analysis for a hypothetical IRD therapy in Singapore to determine the efficacy and treatment cost required to make a future IRD therapy yield a cost saving in terms of regained economic productivity. When only the bottom 10% of patients (i.e., those most economically affected) are treated, a therapy with 100% efficacy and costing SGD 500,000 would yield a cost saving only after 22 years, compared to 1.7 years with the same therapy costing SGD 50,000 (Table 5). If all patients were treated with a 100% effective therapy costing SGD 500,000, a cost saving was not possible, while the same therapy costing SGD 50,000 would achieve a cost saving after 5.8 years. Assuming an intermediate efficacy of 60%, and treating only the bottom 10% of patients, break-even points for treatments costing SGD 50,000, 125,000, 250,000, and 500,000 were reached at 2.8, 7.5, 17.2, and 54.0 years, respectively (Table 5).

Table 5.

Financial break-even analysis of future IRD therapeutics in Singapore.

Treatment cost (SGD)	Treatment efficacy (%)
	20			40			60			80			100
	Bottom 10% treated	Bottom 50% treated	All treated	Bottom 10% treated	Bottom 50% treated	All treated	Bottom 10% treated	Bottom 50% treated	All treated	Bottom 10% treated	Bottom 50% treated	All treated	Bottom 10% treated	Bottom 50% treated	All treated
1 million	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100
500,000	>100	>100	>100	>100	>100	>100	54.0	>100	>100	30.8	>100	>100	22.0	57.0	>100
250,000	>100	>100	>100	30.8	>100	>100	17.2	38.4	>100	12.0	24.1	>100	9.3	17.7	52.4
125,000	30.8	>100	>100	12.0	24.1	>100	7.5	14.0	36.1	5.5	9.9	22.9	4.3	7.7	16.9
50,000	9.3	17.7	52.4	4.3	7.7	16.9	2.8	4.9	10.3	2.1	3.6	7.4	1.7	2.9	5.8

Treatment efficacy was assumed to directly correlate with reduced annual economic losses caused by the IRD, with a one-time treatment model and a cost between SGD 50,000 and 1 million. The hypothetical treatment was applied to the bottom (i.e., greatest economic loss) 10%, 50%, or all IRD patients based on the economic losses calculated for the IRD clinic cohort above. Calculated values represent the number of years post-treatment before the cost savings match the initial cost of treatment. Values of >100 indicate that it would take more than 100 years for cost savings to reach the initial cost of treatment, or that the initial cost of treatment would never be surpassed by cost savings. A discount rate of 3% per year was applied uniformly over the remaining life of the patient following the initial treatment.

Discussion

Until recently, the clinical management of IRD was focused mainly on establishing a clinical diagnosis, determining the pattern of inheritance via clinical and/or molecular means, and providing low vision referrals and counseling to enable informed family planning. With the advent of interventions that may slow or stop the progression of vision loss caused by IRD, there has been a shift in the clinical approach to IRD patients. A major focus of current clinical practice is now focused on whether a patient is suitable for treatment, either in the form of Luxturna treatment for rare cases of biallelic RPE65 mutation, or participation in one of a growing number of clinical trials for other IRDs [5, 28]. Despite this, the high cost of gene-based therapies has meant that low income nations may find it hard to justify subsidizing IRD therapies at the government level, especially given the scarcity of IRDs in the general population. Our findings indicate that despite their scarcity, IRDs contribute a considerable burden that appears to be driven in part by income losses suffered by patients of male gender and early age of onset.

Our findings share some similarities with recently published studies examining the economic burden of IRDs in Western nations, but also some notable differences. Our estimates of IRD prevalence in Singapore (0.101%; 95% CI, 0.033–0.219) were consistent with those used for the previous Western cohort studies (US 95% CI, 0.056–0.133%; Canada 95% CI, 0.056–0.228%) [12, 13]. Work by Kessel et al. using a Danish national registry determined that childhood-onset IRDs reduce lifetime income by one-third and that these patients had 6.6 times the odds of being unemployed compared to the general population [14]. We found a similar reduction of income, but surprisingly, did not observe a significant difference in employment rates between IRD patients and the general population. Our study was comprised of sequentially enrolled IRD clinic patients, the majority of whom had adolescent- or adult-onset disease. It is likely that profound visual impairment or blindness was more prevalent among the childhood-onset IRD cohort examined by Kessel et al. compared to our study cohort due to enrichment of LCA in childhood onset IRDs. This may explain the higher unemployment rates in the Danish cohort. Our finding that earlier age of onset was significantly associated with economic losses also appears to support this conclusion. The additional finding that male gender was associated with greater economic losses appears to be related to underlying gender-based differences in salary, as there were no significant differences in age of symptom onset or visual function between genders in our IRD cohort.

A recent series of cost-of-illness studies for the Canada, Ireland, the United Kingdom, and the United States, estimated annual financial burdens of ~USD 61,000, 32,000, 29,000, and 73,000 per IRD case, respectively [12, 13]. These estimates were substantially higher than our estimate of SGD 9382 (USD 6908), although this at least in part reflects the incorporation of wellbeing into their cost of illness estimates. Removal of this component from the cost of illness estimates results in burdens of USD 21,000, USD 22,000, USD 18,100, and USD 27,000, for Canada, Ireland, UK, and the US, respectively. We do acknowledge that patient wellbeing is negatively impacted by IRD, as demonstrated by higher rates of self-reported depression and anxiety in our IRD cohort, although we did not have local data that could inform the economic cost of these psychological stressors distinct from overall economic losses. Our linear regression analysis indicated that patient-reported depression and anxiety were not significantly associated with income losses in this IRD cohort. Sainohira et al. [29], have previously reported that depression and anxiety were more common among unemployed individuals with RP compared to employed individuals. It is possible that our questions were not sensitive enough to identify the components of anxiety and depression relevant to economic outcomes in our patient cohort, as Sainohira et al. used an battery of questions to characterize the psychological status of their RP cohort [29].

The introduction of gene therapies for IRD management will ostensibly create dramatic increases in the direct healthcare costs for IRD. Recent estimates of the cost effectiveness of Luxturna for RPE65-mediated LCA vary dramatically, ranging from USD 79,000 to 640,000 per quality adjusted life year [7, 30]. Our break-even analysis indicates that an IRD therapy of similar cost to Luxturna, which is currently priced at close to USD 1 million for treatment of both eyes, would be unlikely to achieve future cost savings based on Singapore data presented here, even assuming full efficacy and durability. Conversely, treatment of individuals who are most impacted in terms of economic productivity would yield a cost savings within 10–20 years assuming intermediate to high efficacy and durability, and an initial treatment cost of SGD 50,000–250,000 (USD 37,000–188,000). It is important to note, however, that the current proven durability of Luxturna is only 3 to 4 years [31], and it is presently unknown whether a 10–20-year horizon to achieve a break-even point is achievable with current gene therapy approaches.

We acknowledge several limitations in our study. Prevalence estimates were based on epidemiological work with a population-based cohort that used standard field 50° color fundus photography to identify cases of RP [18]. Cases with peripheral or mild disease and normal fundus appearance would likely have been missed from this screen, resulting in underestimation of case prevalence. It is also difficult to know if IRD cases with late-stage disease and severe visual impairment were less likely to have participated in the population-based SEED study [32, 33], which relied on letters, email, and telephone calls to enroll subjects from the community. Systematic exclusion of such cases would have also resulted in underestimates of IRD prevalence. Moreover, we cannot exclude ascertainment bias affecting the spectrum of IRD cases seen in our clinic. We suspect that a significant proportion of congenital and childhood-onset IRD patients default clinical follow-up following clinical diagnosis by pediatric ophthalmologists due to the lack of efficacious treatment options available. Such cases may be systematically excluded from enrollment at adult retina clinics such as the one used in this work. In this case, the estimates reported here likely underestimate the true economic burden as early onset IRDs such as LCA are frequently more severe than later onset disease. Additionally, we cannot exclude the possibility that certain groups of IRD patients, such as the unemployed, may not attend ophthalmology clinics due to cost concerns and the limited treatment options currently available. This may explain the surprising finding there was no significant difference in employment rates between our IRD cohort and the general population. That said, there is presumably also a group of individuals in the community with sufficiently mild IRD that these individuals remain asymptomatic. Despite these limitations, we did note that the large majority (96.8%) of patients participating in the study were seen at the study hospital as their first contact with an ophthalmology service. In larger countries with decentralized healthcare systems, such as the United States, IRD patients are often seen by private practice ophthalmologists before referral to a larger tertiary eye hospital, potentially resulting in skewing of the resulting patient cohorts. This did not appear to be the case in the current study, and it appears likely that the sampled population is representative of the IRD spectrum among individuals with disease sufficient to warrant clinical presentation.

In conclusion, we found that IRDs in Singapore impose a substantial economic burden, primarily through reduced productivity of employed individuals. With the development of potentially costly genetic therapies, it will be important to balance the initially high economic burden to society against the possibility of substantial long-term benefits brought by improved productivity of treated individuals.

Summary

What was known before

• Inherited retinal diseases (IRDs) are a leading cause of blindness among working age adults, but the economic burden created by IRDs remains poorly understood.

• The anticipated introduction of costly gene- and cell-based therapies for IRD treatment raises questions about the economic relevance of this rare group of conditions.

What this study adds

• The nearly 50 million dollar annual economic burden of IRDs in Singapore was largely the result of reduced productivity by IRD patients. However, employment rates were surprisingly similar between IRD patients and the general population.

• Financial modeling of IRD therapies indicated that a financial break-even point of less than 20 years would only be achieved if treatment was targeted to a subset of economically impacted individuals and if treatment costs were limited to less than SGD 250,000 per individual.

Author contributions

JC, TET, EKF, ELL, CMGC, and BJF were responsible for the study design. RWCT, TET, CMC, RM, HHC, SSKPS, SF, KT, CMGC, and BJF were responsible for patient enrollment and data collection. JC, RWCT, BJHL, and BJF were responsible for data analysis. The manuscript was drafted by JC and BJF, and all authors contributed to critical revision of the manuscript.

Funding

This work was supported by grant SHF-SNEC/0920/4 from the SingHealth Foundation.

Data availability

All relevant data are included in the manuscript and Supplementary.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41433-023-02624-7.