Global, regional and national burden due to retinoblastoma in children aged younger than 10 years from 1990 to 2021

doi:10.21203/rs.3.rs-4702408/v1

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Global, regional and national burden due to retinoblastoma in children aged younger than 10 years from 1990 to 2021

https://doi.org/10.21203/rs.3.rs-4702408/v1

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Background

Retinoblastoma (RB), an aggressive intraocular malignant neoplasm, is a significant contributor to the global disease burden in early childhood. To date, there has been no analysis of global burden and trends in RB among children. This study provides the incidence, mortality and disability-adjusted life years (DALYs) of RB among 0–9 years old children by age, sex, location, and sociodemographic index (SDI) level between 1990 and 2021, aiming to provide novel and robust information for health policy, allocation of medical resources and strategies for fighting RB.

Methods

Data were retrieved from newly released Global Burden of Disease (GBD) study. The measures were estimated both as numerical counts and age-standardised rates per 100,000 population. Joinpoint regression analysis was used to do a rigorous examination on the temporal trends, estimated as the average annual percentage change (AAPC). Spearman’s correlation test was used to examine the relationship between SDI and the burden of RB by location and year.

Results

Globally, the age-standardised incidence rate (ASIR), age-standardised mortality rate (ASMR), and age-standardised DALYs rate (ASDR) for RB among young children in 2021 were 0.09 [95% uncertainty interval (UI): 0.05 to 0.13], 0.04 (95%UI: 0.03 to 0.06), and 3.65 (95%UI: 2.21 to 4.96), respectively. Despite an overall increasing trend [AAPC: 0.62; 95% confidence interval (CI): 0.42 to 0.82], the incidence rate of RB demonstrated a significant decrease from 2019 to 2021, whereas overall downward trends were observed in terms of mortality and DALYs rate for RB. Trends in ASIR varied across regions, and the increased trends of ASIR of RB was highest in East Asia. Among all GBD regions, only Southern Sub-Saharan Africa exhibited increasing trends of mortality and DALYs rate. Gender comparisons showed negligible differences in ASIR, ASMR and ASDR in 2021. Moreover, the highest disease burden was noted in early neonatal (0–6 days), and 2–4 years old children at global and regional levels. The SDI-based analysis showed that the incidence rate of RB increased along with the increase in SDI level. In addition, the associations reflected a significantly negative correlation between the SDI level and ASMR as well as ASDR of RB among children aged 0–9 years.

Conclusions

RB related incidence, mortality, and DALYs varied across age and locations from 1990 to 2021. Evaluating spatiotemporal trends over time underscores the impact of health policies and substantial public health measures on the control of RB.

Retinoblastoma

Children

Global burden of disease

Incidence

Mortality

Disability-adjusted life years

Retinoblastoma (RB) is the most common malignant tumor in childhood, with an incidence rate of 1/15,000 to 1/20,000, and approximately 8,000 children each year worldwide [1]. Globally, the incidence of RB is responsible for about 6% of all cancers in children younger than 5 years [2, 3]. Moreover, there is a substantial variation, up to 50-fold, in the incidence of RB across different populations. Recent study indicates that the incidence of RB is highest in Africa and Asia [4]. Within Asia, the highest incidence was observed in Jordan, while India leads in incidence rates, closely followed by China in the Asia-Pacific region [5]. Whilst prior research has pointed to a higher incidence rate in women, the scientific community has yet to reach a consensus regarding the influence of sex on disease incidence [6]. The mortality from RB is estimated to be fewer than 5% in high-income countries, while it can reach up to 70% in African countries [7]. Evidence from the Surveillance, Epidemiology, and End Results (SEER) database has indicated a decline in both five- and ten-year relative survival rates of RB from 2000 to 2018 in the United States [8]. Although this trend may be associated with the highly localized therapies used in advanced disease, distinguishing the exact factors responsible for this unanticipated reduction in survival rates presents a challenging task. These findings underscore the importance of maintaining vigilant surveillance on this disease. Epidemiological data is pivotal in implementing effective disease prevention, and informing medical resource allocation to address this substantial yet under-examined child health challenge. However, comprehensive epidemiological profiling of RB, especially regarding disease burden metrics like disability-adjusted life years (DALYs) and its spatio-temporal distribution characteristics, remains lacking.

The Global Burden of Disease (GBD) dataset is considered the largest and most comprehensive study undertaken to present a broad view of health loss from hundreds of diseases, injuries, and risk factors. It provides a unique platform to compare the magnitude of diseases, injuries, and risk factors across different age groups, sexes, locations, and timeframes. Recently, GBD 2021 estimates has been produced, which provides updated estimates for 371 diseases and injuries incidence, prevalence, mortality and burden in 204 countries and territories and 811 subnational locations, 1990–2021 [9–11].

Utilizing the most recent data from the GBD 2021, current study provides an all-encompassing evaluation of the global incidence, mortality, and DALYs of RB from 1990 to 2021. The intention behind these findings is to furnish indispensable information to government and healthcare policymakers, allowing them to discern priority sectors for the prevention and control of RB. This, in turn, will aid in the development of more impactful policies and the reasonable distribution of resources.

Study population and data collection

This was a prospective study that used data from the GBD 2021 using the Global Health Data Exchange (GHDx) results tool, which employed a consistent and comparable approach to extensively determine the population, fertility, disease prevalence, and mortality across 204 countries and territories. Detail methods are presented in the appendix of the GBD 2021 capstone papers [10, 11]. Briefly, GBD 2021 synthesises a large and growing number of data input sources including surveys, censuses, vital statistics, and other health-related data sources. The data from these sources are used to estimate morbidity; illness, and injury; and attributable risk for 204 countries and territories from 1990 to 2021; mortality deaths are estimated from 1980 to 2021. The input sources are accessible through an interactive citation tool available in the GHDx. Citations for specific GBD components, causes and risks, and locations can be found through the Data Input Sources Tool in GHDx (https://ghdx.healthdata.org/gbd-2021). This tool allows users to view and access GHDx records for input sources and export a comma-separated value (CSV) file that includes metadata, citations, and information about where the data were used in GBD. As required by GATHER, additional metadata for input sources are available through the citation tool as well. Data on the incidence, mortality, and DALYs of RB were extracted from the GBD 2021.

We defined the study population as younger children aged 0–9 years, because GBD 2021 only provided the most recent estimates of the burden of RB among these population. Furthermore, ages in the range 0–9 years were divided into seven GBD age groups as 0–6 days, 7–27 days, 1–5 months, 6–11 months, 12–23 months, and 2–4 years, and 5–9 years.

Definition

According to GBD 2021, RB is defined by the International Statistical Classification of Diseases (ICD) by the Tenth Revision (ICD-10) as codes (C69.2-C69.22), and ICD-9 as code (190.5).

The Sociodemographic Index (SDI) is a composite indicator of background social and economic conditions that influence health outcomes in each location. In short, it is the geometric mean of 0 to 1 indices of total fertility rate for those younger than 25 years old, mean education for those 15 years old and older, and lag-distributed income per capita.

In current study, years lived with disability (YLDs) were derived by taking the prevalence of varying severity levels and multiplying them against their corresponding disability weights. Additionally, years of life lost (YLLs) were computed by multiplying the number of deaths in each age bracket by the remaining life expectancy for that age group. The DALYs is a summary measure that quantifies the overall burden of disease, which were the sum of YLLs and YLDs. One DALYs can be regarded as the loss of 1 year in total health. The detail estimates on RB related incidence, mortality and DALYs were presented in supplementary methods. All above measures were presented as counts and rates per 100,000 population. The 95% uncertainty interval (UI) was derived by using the 2.5th and 97.5th percentiles of an ordered set of 1000 draws. Age-standardised populations were calculated by using the GBD world population age standard.

Data analysis

In the present study, we described the number and analysed the age-standardised rate of incidence, mortality, and DALYs of RB by age, sex, and location. Moreover, we employed the Joinpoint regression analysis model which is a statistical methodology widely used in epidemiological studies to examine temporal changes in disease prevalence or mortality. This model expertly identifies and quantitatively describes significant turning points in the time-series data related to the estimate of RB at global, regional, and national levels. The model assisted in determining the annual percent change (APC) and its corresponding 95% confidence interval (CI) to outline indicator trends over defined time periods. Additionally, for a comprehensive evaluation of the observed trends, the average annual percent change (AAPC) was also computed, encapsulating consolidated trend data over the study duration from 1990 to 2021. Statistically, an APC or AAPC estimate, with its 95% CI lower limit surpassing zero, indicates an increasing trend in the specified interval. Conversely, an APC or AAPC estimate with a 95% CI upper limit less than zero indicates a decreasing trend. If the 95% CI for the APC or AAPC includes zero, it suggests that the trend has remained stable. Finally, Spearman’s correlation test was used to evaluate the association between SDI with the burden of RB by location and year. Significance level was set at a p-value less than 0.05. All analyses were performed using R software (version 4.2.2).

Ethical considerations

This study used publicly available data from the GBD study, which is ethically approved by the Institutional Review Board at the University of Washington. No personal identifying information was used in the analysis.

Role of the funding source

The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Global level

In 2021, the worldwide number of incidences of RB was 6274.97 (95% UI: 3854.96 to 8381.78), while this number was 4673.52 (95% UI: 3033.33 to 5953.1) in 1990, with an increase of 34% (95% UI: 5–64%) from 1990 to 2021 (Table 1). Additionally, the global age-standardised incidence rate (ASIR) of RB were 0.08 per 100,000 population (95% UI: 0.05 to 0.10) in 1990 (Table 1). This rate has increased to be 0.09 per 100,000 population (95% UI: 0.06 to 0.13), with an AAPC of 0.62 (95% CI: 0.42 to 0.82) between 1990 and 2021 (Table 1). The number of deaths due to RB was 2762.04 (95% UI: 1666.28 to 3760.79) in 2021, with an age-standardised mortality rate (ASMR) of 0.04 per 100,000 population (95% UI: 0.03 to 0.06) (Table 1), showing a decrease trend with AAPC to be -0.70 (95% CI: -0.87 to -0.53) from 1990 to 2021 (Table 1). Furthermore, the global disability-adjusted life years (DALYs) for RB in 2021 was 243204.27 (95% UI: 147357.66 to 330473.92) (Table 1), with an age-standardised DALYs rate (ASDR) of 3.65 per 100,000 population (95% UI: 2.21 to 4.96), which showed with downward trend by -0.69 (95% CI: -0.86 to -0.52) between 1990 and 2021 (Table 1).

Table 1

Incidence, deaths and DALYs of retinoblastoma in children aged younger than 10 years in 1990 and 2021, and change from 1990 to 2021
	Number, (95% UI)		1990–2021 Percentage change (95% UI)	ASR, per 100,000 population (95% UI)		AAPC (95% CI)
	1990	2021	1990–2021 Percentage change (95% UI)	1990	2021	AAPC (95% CI)
By sex groups
Both sexes
Incidence	4673.52 (3033.33 to 5953.1)	6274.97 (3854.96 to 8381.78)	0.34 (0.05 to 0.64)	0.08 (0.05 to 0.10)	0.09 (0.05 to 0.13)	0.62 (0.42 to 0.82)
Deaths	3179.83 (1819.02 to 4172.8)	2762.04 (1666.28 to 3760.79)	-0.13 (-0.34 to 0.14)	0.05 (0.03 to 0.07)	0.04 (0.03 to 0.06)	−0.70 (−0.87 to−0.53)
DALYs	279066.14 (159656.45 to 365149.79)	125385.75 (65266.11 to 180824.51)	-0.13 (-0.34 to 0.14)	4.54 (2.60 to 5.94)	3.65 (2.21 to 4.96)	−0.69 (−0.86 to−0.52)
Boys
Incidence	2410.74 (1435.95 to 3243.18)	3252.15 (1846.39 to 4461.52)	0.35 (0.02 to 0.75)	0.08 (0.05 to 0.10)	0.09 (0.05 to 0.13)	0.64 (0.51 to 0.76)
Deaths	1650.42 (810.15 to 2308.05)	1424.66 (739.58 to 2057.8)	-0.14 (-0.4 to 0.23)	0.05 (0.03 to 0.07)	0.04 (0.02 to 0.06)	−0.73 (−0.86 to −0.60)
DALYs	144682.66 (71222.75 to 202318.81)	117818.52 (55125.56 to 168087.88)	-0.13 (-0.4 to 0.23)	4.57 (2.25 to 6.39)	3.64 (1.90 to 5.26)	−0.72 (−0.84 to−0.59)
Girls
Incidence	2262.78 (1270.54 to 3052.55)	3022.82 (1487.72 to 4248.09)	0.34 (0.02 to 0.66)	0.08 (0.04 to 0.10)	0.09 (0.06 to 0.13)	0.67 (0.46 to 0.88)
Deaths	1529.4 (656.66 to 2123.4)	1337.38 (623.07 to 1913.08)	-0.13 (-0.34 to 0.12)	0.05 (0.02 to 0.07)	0.04 (0.02 to 0.06)	−0.68 (−0.85 to−0.51)
DALYs	134383.48 (57787.02 to 186200.84)	243204.27 (147357.66 to 330473.92)	-0.12 (-0.33 to 0.13)	4.51 (1.94 to 6.25)	3.67 (1.72 to 5.22)	−0.67 (−0.84 to−0.50)
By age groups
0–6 days
Incidence	23.06 (15.33 to 30.17)	25.04 (15.34 to 34.53)	0.09 (-0.14 to 0.37)	0.91 (0.6 to 1.19)	1.02 (0.63 to 1.41)	0.41 (0.14 to 0.67)
Deaths	15.61 (8.88 to 20.97)	10.49 (5.68 to 14.68)	-0.33 (-0.49 to -0.12)	0.61 (0.35 to 0.83)	0.43 (0.23 to 0.60)	-1.17 (-1.28 to -1.06)
DALYs	1418.01 (808.18 to 1905.77)	957.75 (521 to 1336.61)	-0.32 (-0.49 to -0.11)	55.85 (31.83 to 75.06)	39.07 (21.25 to 54.53)	-1.15 (-1.26 to -1.04)
7–27 days
Incidence	8.8 (6.34 to 11.47)	12.08 (8.39 to 16.25)	0.37 (0.08 to 0.71)	0.12 (0.08 to 0.15)	0.17 (0.12 to 0.22)	1.18 (0.64 to 1.72)
Deaths	5.28 (3.26 to 6.99)	3.41 (2.03 to 4.74)	-0.35 (-0.5 to -0.15)	0.07 (0.04 to 0.09)	0.05 (0.03 to 0.06)	-1.33 (-1.61 to -1.04)
DALYs	480.36 (296.95 to 635.44)	314.07 (187.7 to 435.01)	-0.35 (-0.5 to -0.14)	6.4 (3.96 to 8.47)	4.31 (2.57 to 5.96)	-1.32 (-1.54 to -1.10)
1–5 months
Incidence	231.07 (134.43 to 312.56)	296.98 (178.25 to 409.91)	0.29 (-0.07 to 0.69)	0.42 (0.25 to 0.57)	0.55 (0.33 to 0.76)	0.88 (0.68 to 1.09)
Deaths	170.01 (86.15 to 242.59)	131.12 (74.33 to 183.28)	-0.23 (-0.48 to 0.05)	0.31 (0.16 to 0.44)	0.24 (0.14 to 0.34)	-0.83 (-1.02 to -0.64)
DALYs	15393.24 (7802.02 to 21955.64)	11939.99 (6781.94 to 16641.38)	-0.22 (-0.47 to 0.05)	28.19 (14.29 to 40.21)	22.21 (12.62 to 30.96)	-0.81 (-1.00 to -0.63)
6–11 months
Incidence	278.59 (149.26 to 389.08)	368.96 (201.51 to 535.63)	0.32 (-0.11 to 0.87)	0.44 (0.24 to 0.62)	0.58 (0.32 to 0.85)	0.97 (0.63 to 1.31)
Deaths	218.91 (102.9 to 319.8)	206.75 (110.5 to 320.65)	-0.06 (-0.39 to 0.41)	0.35 (0.16 to 0.51)	0.33 (0.17 to 0.51)	-0.19 (-0.34 to -0.04)
DALYs	19712.3 (9289.83 to 28738.34)	18679.1 (9982.31 to 28941.33)	-0.05 (-0.39 to 0.41)	31.23 (14.72 to 45.54)	29.56 (15.8 to 45.8)	-0.19 (-0.34 to -0.04)
12–23 months
Incidence	645.31 (438.94 to 834.22)	1025.57 (567.3 to 1431.33)	0.59 (0.16 to 1.17)	0.52 (0.35 to 0.67)	0.80 (0.44 to 1.11)	1.37 (1.06 to 1.67)
Deaths	365.18 (207.56 to 488.87)	306.37 (175.64 to 426.52)	-0.16 (-0.37 to 0.12)	0.29 (0.17 to 0.39)	0.24 (0.14 to 0.33)	-0.66 (-0.76 to -0.56)
DALYs	32718.9 (18659.3 to 43657.83)	27727.51 (15953.59 to 38599.01)	-0.15 (-0.37 to 0.13)	26.26 (14.97 to 35.03)	21.59 (12.42 to 30.06)	-0.63 (-0.74 to -0.52)
2–4 years
Incidence	2836.22 (1789.75 to 3719.09)	3649.43 (2169.18 to 5110.76)	0.29 (-0.03 to 0.64)	0.77 (0.49 to 1.01)	0.91 (0.54 to 1.27)	0.42 (0.26 to 0.58)
Deaths	2027.79 (1150.11 to 2694.44)	1781.16 (1068.08 to 2501.36)	-0.12 (-0.36 to 0.19)	0.55 (0.31 to 0.73)	0.44 (0.26 to 0.62)	-0.72 (-0.92 to -0.52)
DALYs	177718.26 (101267.82 to 236068.53)	156337 (93921.64 to 219378.25)	-0.12 (-0.36 to 0.19)	48.35 (27.55 to 64.22)	38.79 (23.3 to 54.43)	-0.72 (-0.92 to -0.52)
5–9 years
Incidence	650.46 (444.37 to 842.39)	896.91 (573.03 to 1233.99)	0.38 (0.1 to 0.68)	0.11 (0.08 to 0.14)	0.13 (0.08 to 0.18)	0.54 (0.02 to 1.07)
Deaths	377.04 (214.99 to 514.5)	322.74 (189.68 to 426.58)	-0.14 (-0.35 to 0.07)	0.06 (0.04 to 0.09)	0.05 (0.03 to 0.06)	-0.97 (-1.22 to -0.71)
DALYs	31625.07 (18113.11 to 43127.48)	27248.84 (16117.81 to 35912.42)	-0.14 (-0.35 to 0.08)	5.42 (3.1 to 7.39)	3.97 (2.35 to 5.23)	-0.95 (-1.20 to -0.70)
AAPC, average annual percent change; ASR, age-standardised rate; CI, confidence interval; DALYs, Disability-Adjusted Life Years; UI, uncertainty interval.

Joinpoint regression analyses showed an increasing trend in incidence between 1990 and 2019 in the children younger than 10 years old, but the most pronounced decrease between 2019 and 2021 [APC: -8.89, P < 0.05]. As shown in Figure S1, the ASMR of RB decreased slowly from 1990 to 2002, followed by two significant rapid declines from 2014 to 2019 (APC = -1.94, P < 0.05) and from 2019 to 2021 (APC = -3.58, P < 0.05). A similar trend was observed in the ASDR, with the most notable decrease occurring from 2019 to 2021 (APC = -3.72, P < 0.05).

Regional level

In 2021, the highest ASIR of RB was observed in regions with a high-middle SDI, at 0.13 per 100,000 population (95% UI: 0.07 to 0.19) (Table S1). Geographically, the ASIR was highest in Eastern Sub-Saharan Africa, at 0.20 per 100,000 population (95% UI: 0.12 to 0.31), followed by Andean Latin America, at 0.18 per 100,000 population (95% UI: 0.10 to 0.30), and Western Europe at 0.17 per 100,000 population (95% UI: 0.12 to 0.21) (Table S1). Interestingly, relative high-income regions demonstrated obviously lower ASIRs, including Caribbean at 0.01 per 100,000 population (95% UI: 0.01 to 0.02), Oceania at 0.02 per 100,000 population (95% UI: 0.01 to 0.05), and Australasia at 0.02 per 100,000 population (95% UI: 0.01 to 0.03) (Table S1). During the period from 1990 to 2021, changes in the ASIR varied across different regions. A significant increasing trend was also observed in regions with a high-middle SDI, with an AAPC of 2.08 (95% CI: 1.29 to 2.87). In contrast, those regions with low SDI experienced the largest downward trend, with an AAPC of -0.73 (95% CI: -0.86 to -0.60). Nevertheless, regions with a high SDI showed a stable change of ASIR (AAPC: -0.26, 95% CI: -0.78 to 0.26) (Table S1). Geographically, the East Asia showed the highest increasing trend at 3.16 (95% CI: 2.53 to 3.79). Australasia exhibited the most significant downward trend, with an AAPC at -3.52 (95% CI: -6.26 to -0.69), followed by Caribbean at -3.25 (95% CI: -5.26 to -1.19), and High-income North America at -2.06 (95% CI: -3.12 to -0.98) Table S1).

The ASMR of RB was found to be highest in regions with a low SDI, recorded at 0.09 per 100,000 population (95% UI: 0.05 to 0.13), and lowest in High SDI regions in 2021 (Table S1). The most significant decreasing trend of ASMR was observed in high SDI regions with an AAPC of -3.44 (95% CI: -4.24 to -2.63) (Table S1). Geographically, the regions with the highest ASMR were Eastern Sub-Saharan Africa at 0.17 per 100,000 population (95% UI: 0.11 to 0.26), Western sub-Saharan Africa at 0.08 per 100,000 population (95% UI: 0.03 to 0.12), and Southern Sub-Saharan Africa at 0.04 per 100,000 population (95% UI: 0.02 to 0.07) (Table S1). It is noteworthy that from 1990 to 2021, the Southern Sub-Saharan Africa experienced the most significant upward trend in ASMR, with an AAPC to be 0.98 (95% CI: 0.40 to 1.57). In contrast, other regions exhibited downward trends, with Australasia (AAPC: -6.95, 95% CI: -9.34 to -4.50), the Southern Latin America (AAPC: -5.02, 95% CI: -6.10 to -3.93), and Central Europe (AAPC: -4.16, 95% CI: -5.54 to -2.76) showing the most pronounced declines (Table S1).

In terms of burden due to RB, the highest ASDR were observed in regions with low SDI at 7.80 per 100,000 population (95% UI: 4.70 to 11.24) in 2021 (Table S1), while regions with high SDI showed the lowest ASDR of RB at 0.26 per 100,000 population (95% UI: 0.20 to 0.32). Geographically, the regions with the highest ASDR were Eastern Sub-Saharan Africa at 14.67 per 100,000 population (95% UI: 9.70 to 22.54), Western sub-Saharan Africa at 6.69 per 100,000 population (95% UI: 2.81 to 10.58), and Andean Latin America at 3.73 per 100,000 population (95% UI: 2.31 to 6.08) (Table S1). Of note, almost regions showed downward trends of disease burden from 1990 to 2021. Of which, the most notable reductions were observed in Australasia (AAPC: -6.00, 95% CI: -9.21 to -2.68), Southern Latin America (AAPC: -4.78, 95% CI: -5.84 to -3.71), and Central Europe (AAPC: -3.93, 95% CI: -5.31 to -2.53) (Table S1). Conversely, only Southern Sub-Saharan Africa showed a significant upward trend of ASDR, with AAPC to be 1.00 (95% CI: 0.42 to 1.58) (Table S1).

National level

The country-specific distribution of ASIR is detailed in Fig. 1 and Table S2. Notably, Tokelau (1.19 per 100,000 population; 95% UI: 0.25 to 3.86), Kenya (0.51 per 100,000 population; 95% UI: 0.27 to 0.83), Malawi (0.44 per 100,000 population; 95% UI: 0.17 to 0.89), Portugal (0.44 per 100,000 population; 95% UI: 0.30 to 0.54), and Finland (0.37 per 100,000 population; 95% UI: 0.23 to 0.51) have the highest ASIR in 2021 (Fig. 1D and Table S2). From 1990 to 2021, variations in the change of the ASIR were observed across countries. Of note, Tokelau (AAPC: 19.13, 95% CI: 14.98 to 23.42), Armenia (AAPC: 13.08, 95% CI: 12.32 to 13.84), and Cook Islands (AAPC: 9.34, 95% CI: 8.18 to 10.51) experienced the most substantial relative increases in ASIR (Table S2). Conversely, Cuba (AAPC: -8.30, 95% CI: -12.69 to -3.67), Kuwait (AAPC: -8.29, 95% CI: -10.52 to -6.00), and Lithuania (AAPC: -7.89, 95% CI: -9.39 to -6.36) ranked as the top three countries with the highest decreasing trends in ASIR of RB.

In 2021, Malawi (0.40 per 100,000 population; 95% UI: 0.16 to 0.88), Tokelau (0.37 per 100,000 population; 95% UI: 0.08 to 1.23), and Kenya (0.36 per 100,000 population; 95% UI: 0.20 to 0.57) had the highest ASMR (Fiure 1E and Table S2). From 1990 to 2021, the countries with the largest increases in ASMR were Tokelau (AAPC: 15.27, 95% CI: 11.06 to 19.64), Armenia (AAPC: 9.61, 95% CI: 8.52 to 10.71), and Georgia (AAPC: 7.30, 95% CI: 4.89 to 9.77) (Table S2). Conversely, the countries with the most significant decreases in ASMR were Kuwait (AAPC: -10.80, 95% CI: -12.91 to -8.64), Cuba (AAPC: -10.64, 95% CI: -15.20 to -5.83), and Lithuania (AAPC: -10.22, 95% CI: -11.63 to -8.80) (Table S2). Similar results were found in terms of DALYs. Therefore, more results about RB related DALYs were shown in Fig. 1 and Tables S2.

By age and gender patterns

In our findings, although the cases of incident RB and its mortality were higher in boys than those in girls, the ASIR and ASMR as well as ASDR were similar between different genders in children aged 0–9 years (Table 1). The ASIR for RB has increased from 1990 to 2021 in both boys and girls, with an AAPC of 0.64 (95% CI: 0.51 to 0.76) in boys, and 0.67 (95% CI: 0.46 to 0.88) in girls. However, the number of mortalities was slightly higher, while the DALYs were lower in boys as compared to girls. Moreover, both the ASMR and ASDR declined for boys and girls from 1990 to 2021. The AAPC of ASMR for boys is -0.73 (95% CI: -0.86 to -0.60), and for females is -0.68 (95%CI: -0.85 to -0.51). The AAPC of ASDR for boys is -0.72 (95% CI: -0.84 to -0.59), and for females is -0.67 (95% CI: -0.84 to -0.50) (Table 1). Regionally, the largest disparities in incidence, mortality, and DALYs rates between sexes were observed in high income Asia pacific, and Southern Sub-Saharan Africa (Fig. 2).

In terms of age, the highest incidence in 2021 was in the age group of less than 6 days, at 1.02 per 100,000 population (95%UI: 0.63 to 1.41), followed by 2–4 years old 0.91 per 100,000 population (95%UI: 0.54 to 1.27), and 12–23 months old 0.80 per 100,000 population (95%UI: 0.44 to 1.11) (Table 1, Fig. 3). However, the lowest incidence in 2021 was in the age group of 5–9 years old at 0.13 per 100,000 population (95%UI: 0.08 to 0.18). The results of the incidence rates for RB increased in all seven age groups during study period, with the greatest increase in those 12–23 months of age [AAPC: 1.37 (95% CI: 1.06 to 1.67)]. The description of incidence, mortality, and DALYs rate of RB by age at different SDI levels were shown in Fig. 4. In 2019, the mortality rate was highest in the 2–4 years age group [0.44 per 100,000 population (95%UI: 0.26 to 0.62)], followed by 0–6 days group [0.43 per 100,000 population (95%UI: 0.23 to 0.60)], but lowest in the 7–27 days and 5–9 years age group (Table 1). All age groups showed downward trends of mortality rates during this period, with the highest decline in children aged 7–27 days as AAPC to be -1.33 (95%CI: -1.61 to -1.04). The DALYs rate analysis revealed a trend similar to that of the mortality, with DALYs decreasing with all age groups (Table 1). Globally, the largest disparities in incidence, mortality, and DALYs rates between sexes were both observed in 0–6 days children (Fig. 3).

By SDI

The variations in ASIR, ASMR and ASDR of RB among children across SDI by GBD regions are shown in Figures S2-4. Spearman rank order correlation analyses showed a positive correlation between SDI level and ASIR of RB in children aged 0–9 years old (r = 0.154, P < 0.01; Figure S2A). In term of mortality, a significant negative correlation was observed between SDI level and ASMR (r = -0.669, P < 0.01; Figure S3A). For the burden of RB, the ASDR of RB were significantly associated with SDI level (r = -0.665, P < 0.01; Figure S4A). Of the 204 countries and territories whose association with the 2019 SDI was recognised, while there was no significant negative association between the SDI and ASIR of RB (r = -0.021, P = 0.77). Tokelau and Kenya were significantly higher than expected (Figure S2). Moreover, following a similar pattern to the association of mortality and SDI (r = -0.535, P < 0.01), there was a marked adverse correlation between DALYs and SDI (r = -0.531, P < 0.01) (Figures S3 and S4).

RB is the most frequent intraocular tumor, accounting for 3% of all childhood cancers, which represents a significant public health challenge worldwide. There has been some research showing concern about RB in children, while the burden of RB was still unclear worldwide. Notably, the present study offers the first-time critical evaluation of the disease burden of RB and introduces an innovative assessment of its temporal trends in children aged 0–9 years, empowering regional governments to implement suitable preventative measures for RB in children. Enhancing the prevention and treatment of RB in children carries significant public health importance in diminishing the global disease burden.

In 2021, the global ASIR for RB has significantly increased compared to 1990, but the overall ASMR and ASDR have shown noticeable downward changes. According to the World Health Organization (WHO) Guide for Effective Programmes in Cancer Control, programs are recommended for ‘early diagnosis’ (target children with common symptoms) American Academy of Ophthalmic Oncologists and Pathologists (AAOOP) has formulated clear guidelines for detection of RB in children ‘at risk’ for disease and these are practiced widely [12]. Some other countries including Canada, Mexico, United Kingdom, Kenya, India, Australia, and New Zealand promote ‘early diagnosis’ projects mainly using red reflex examination in neonates, infants, and children [13]. The promotion in “early diagnosis” was one driver of the increase in the number of new RB cases and patients. RB can be inherited [14], and more than nine out of every ten sufferers surviving into adulthood in developed countries [15, 16], thus, extended survival of inherited patients may also lead to an increase in morbidity. Besides, improvements in therapeutic and health care were the most important factors contributing to the decrease in deaths and DALYs associated with RB [17]. Interestingly, Joinpoint regression indicated that there was a significant decline in global ASIR of RB from 2019 to 2021. This shift may be associated with the intensification of RB management policies by global health organizations and governments around the time of 2019 [18]. Enhancing awareness among healthcare professionals along with incorporating data from refugee populations are vital steps towards advancing our understanding of disease epidemiology [19]. In addition, it is important to note that the emergence of the COVID-19 pandemic at the end of 2019 and into early 2020 has influenced the implementation of prevention and treatment strategies for RB. This could potentially decrease the epidemiological trend of RB incidence in the near term [20–23].

We noticed that high SDI regions had higher incidence but lower mortality and burden from RB. This may result from the more common high-energy activities in high SDI regions. Generally, high SDI regions also have better medical education and doctor training and could offer better medical services to reduce burden. Moreover, social relationships and social status are also powerful determinants of individual health, and high SDI regions could provide more social supports and welfare, contributing to better recovery. The welfare and social policies in high SDI regions could, to a great extent, diminish the considerable financial gap between people with and without a disability. On the contrary, the higher mortality and burden in low-SDI regions may result from the lacking cancer screening system and poor health care conditions.

From 1990 to 2021, despite a rapid rise in the incidence of RB among children aged 0–9 years in East Asia countries including China, South Korea, and North Korea, a decline in mortality and disease burden has been observed. Contrastingly, Southern Sub-Saharan Africa including Namibia, and South Africa emerges as a region warranting heightened attention, with its incidence, mortality, and disease burden escalating worldwide. Notably, this region possesses the second-highest rank of rising global incidence and is the only region where ASMR and ASDR are on an upward trend. This highlights low SDI region exhibiting an increase in mortality rates and burden of disease. Furthermore, within populous regions characterized by elevated birth rates, such as Asia and Africa, the frequency and repercussions of RB are substantively pronounced, contributing significantly to the worldwide disease burden [15]. Countries demonstrating high incidence rates of RB have also reported the most substantial mortality rates; approximately 40 to 70% of affected individuals succumb to the disease. Comparatively, mortality rates range between 3 to 5% in regions such as Europe, Canada, and the USA [24, 25]. In developing nations, mortality rate remains exceedingly high, accounting for 95% of total cases [26]. This is primarily attributed to delayed intervention resulting from tardy diagnoses. Factors such as impoverishment, lack of understanding or awareness of the disease's ramifications impede timely access to healthcare services [27]. Some countries conducting early diagnosis, e.g., Canada and Australia, showed significant decline trends in incidence, mortality, and DALYs. Although there is higher ASIR in Kenya in 2021, its ASMR and ASDR showed a downward trend from 1990 to 2021. Therefore, implementing an early screening protocol is essential to mitigate the burden caused by RB across both developed and developing Furthermore, we found that the number of incidences and deaths from RB in boys in 2021 was slightly higher than that of girls, but the burden was lower than that of girls. There are no significant gender differences in the morbidity, mortality and burden rates of RB. Similarly, a previous review involving 4,351 new RB cases in 2017 suggested that there was no sex predilection associated with RB. However, sex differences existed in specific countries, such as Asia, and India, which may be probably related to gender discrimination [28]. In contrast with our findings, previous retrospective population-based cohort study using the Taiwan National Health Insurance Research Database (1998–2011) indicated that there were more cases of male than female children [29]. Moreover, the RB incidence rate during 2000–2009 among boys in SEER 18 was significantly higher than that among girls [30]. Following (SEER) data 2000–2017 indicated that increased cumulative incidence (CMI) of RB was observed among male children and they had excess mortality compared to female children, which may be explained in part by male X-linkage [31]. However, there are no updated evidence on the sex disparity of RB based on worldwide population.

To the best of our knowledge, there is no evidence on the epidemiologic characteristics of RB among different age groups in detail. Compared with GBD 2019 with relatively broad grouping of 1–4-year-old children, all estimates for age groups younger than 5 years were further disaggregated into those aged 0–6 days, 7–27 days, 1–5 months, 6–11 months, 12–23 months, and 2–4 years in GBD 2021. Globally, we found higher morbidity, mortality and disease burden in early neonatal age (0–6 days) and children aged 2–4 years compared with other age groups. This may provide an opportunity to make targeted recommendations regarding the health services, and caregiver needs vary considerably within these age groups.

RB continues to pose a significant health challenge for low- and middle-income countries. However, high SDI regions also exhibited a relative higher incidence of disease, which may be due to the prenatal screening and diagnosis of RB procedure in developed regions and changes in newborn growth [32]. In addition, the present study found the inverse association between the SDI with mortality and burden of RB. Several factors may explain the higher ASMR and ASDR of RB in low SDI regions. Apart from potential shortcomings in social-economic background, low SDI regions might have worse medical, and public childhood healthcare conditions, which increases the disease burden [33–35].

The strengthen of current study first demonstrated the most comprehensive global trends of the incidence and mortality of RB among children younger than 10 years, including regional, sex-based, and SDI-based estimates. However, this study is limited to the general defects of GBD study. First, the GBD project estimates the impact of different health conditions by combining information about morbidity and premature mortality. However, the methodologies employed can be subject to biases and uncertainties, and the results may not align entirely with individual call detail records statistics or other sources of health information. Second, the accuracy of GBD estimates can be limited by the availability and quality of data, particularly in regions with poor health information systems. These estimates, therefore, might not fully capture the health condition or disease's scope or its variability across different populations. The process of synthesizing such sparse and unevenly distributed data is complex and can lead to substantial uncertainty in the findings. Another potential limitation includes difficulty in accounting for co-morbidity and the complexity of multiple health conditions in individuals. Finally, GBD database did not estimate data on the type of RB such as unilateral and bilateral disease. Even so, the GBD 2021 study has indeed made a considerable contribution to global health by providing comprehensive and comparable estimates of the burden of RB for global, regional, and national decision-making.

Although there has been a general increase in the incidence rate of childhood-onset RB from 1990 to 2021, a significant decline was observed since 2019. Furthermore, there was a significant decline in the mortality and DALYs rate of RB in the period of 1990 to 2021. Of note, East Asia exhibited the most significant rise in the incidence rate of RB among children aged 0–9 years old. Moreover, there was decline trends in most regions, while Southern Sub-Saharan Africa only showed a significant increase in the mortality and DALYs rate of RB. In 2021, boys had slightly higher incidences, mortalities, but lower DALYs compared with girls. Early neonatal (0–6 days), and 2-4year-old children were found to have the largest incidence, mortality and DALYs rate of RB. There was also marked heterogeneity between individual regions with different SDI levels. Countries with high SDI generally exhibited a greater incidence rate of RB, while lower in mortality and DALYs rate among children aged 0–9 years old.

Data sharing statement

The datasets analyzed during the current study are available through the GBD Results Tool (http://ghdx.healthdata.org/gbd-results-tool).

Declaration of interests

The other authors declare no competing interests.

Ethics approval and consent to participate

The protocol for this study was exempted by the Research Ethics Committee of the Guangdong Provincial People’s Hospital (KY-Q-2022-495-01) because of the public availability of the data.

Consent for publication

Not applicable.

Funding

This study was funded by GDPH Supporting Fund for Talent Program (KY0120220263), LiaoNing Revitalization Talents Program (XLYC2203192), National Natural Science Foundation of China (82271125, 81870663 and 82171075), Guangdong Basic and Applied Basic Research Foundation (2023B1515120028), the launch fund of Guangdong Provincial People’s Hospital for NSFC (8217040449, 8227040339 and 8217040546), the Science and Technology Program of Guangzhou (20220610092), the Outstanding Young Talent Trainee Program of Guangdong Provincial People’s Hospital (KJ012019087), the GDPH Scientific Research Funds for Leading Medical Talents and Distinguished Young Scholars in Guangdong Province (KJ012019457), and Personalized Medical Incubator Project, The fund for Precison Medicine Research and Industry Development in SIMQ (2023-31).

Author Contribution

All estimates presented in this article were provided by the GBD core team. CL, LYZ, LL, XHY, and XHY have verified the underlying data. CL, LL, JHJ, GYH, JZ, and MXZ provided data or critical feedback on data sources. CL and LL developed methods or computational machinery. CL, LJZ, JZ, YW, XH, CYC, and LL provided critical feedback on methods or results. All authors contributed to the drafting of the work or revised the article critically for important intellectual content. LL, HHY, and XHY contributed to managing the overall research enterprise. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The corresponding authors attest that all listed authors meet authorship criteria and that no others who meet the criteria have been omitted. LL and XHY are the guarantors.

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Global, regional and national burden due to retinoblastoma in children aged younger than 10 years from 1990 to 2021

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Study population and data collection

Definition

Data analysis

Ethical considerations

Role of the funding source

Results

Global level

Regional level

National level

By age and gender patterns

By SDI

Discussion

Conclusion

Declarations

Data sharing statement

Declaration of interests

Funding

Author Contribution

References

Additional Declarations

Supplementary Files

Status:

Version 1