Aims To investigate myopic maculopathy in Chinese children with high myopia and its association with choroidal and retinal changes.
Methods This cross-sectional study included Chinese children aged 4–18 years with high myopia. Myopic maculopathy was classified by fundus photography and retinal thickness (RT) and choroidal thickness (ChT) in the posterior pole were measured by swept-source optical coherence tomography. A receiver operation curve was used to determine the efficacy of fundus factors in classifying myopic maculopathy.
Results In total, 579 children aged 12.8±3.2 years with a mean spherical equivalent of −8.44±2.20 D were included. The proportions of tessellated fundus and diffuse chorioretinal atrophy were 43.52% (N=252) and 8.64% (N=50), respectively. Tessellated fundus was associated with a thinner macular ChT (OR=0.968, 95% CI: 0.961 to 0.975, p<0.001) and RT (OR=0.977, 95% CI: 0.959 to 0.996, p=0.016), longer axial length (OR=1.545, 95% CI: 1.198 to 1.991, p=0.001) and older age (OR=1.134, 95% CI: 1.047 to 1.228, p=0.002) and less associated with male children (OR=0.564, 95% CI: 0.348 to 0.914, p=0.020). Only a thinner macular ChT (OR=0.942, 95% CI: 0.926 to 0.959, p<0.001) was independently associated with diffuse chorioretinal atrophy. When using nasal macular ChT for classifying myopic maculopathy, the optimal cut-off value was 129.00 µm (area under the curve (AUC)=0.801) and 83.85 µm (AUC=0.910) for tessellated fundus and diffuse chorioretinal atrophy, respectively.
Conclusion A large proportion of highly myopic Chinese children suffer from myopic maculopathy. Nasal macular ChT may serve as a useful index for classifying and assessing paediatric myopic maculopathy.
Trial registration number NCT03666052.
- Child health (paediatrics)
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Myopic maculopathy is one of the main causes of irreversible blindness in adults, but it has rarely been studied in highly myopic children. Consequently, the characteristics of paediatric myopic maculopathy are unclear.
WHAT THIS STUDY ADDS
More than half of highly myopic Chinese children may suffer from myopic maculopathy. Nasal macular choroidal thickness (ChT) was closely associated with the severity of myopic maculopathy.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The prevalence of myopic maculopathy was high in Chinese children with high myopia, raising special concern. Nasal macular ChT may be a useful index for evaluating the severity of paediatric myopic maculopathy.
Myopia is a common eye disease worldwide.1 The prevalence of myopia and high myopia is particularly high in countries and regions in East and Southeast Asia, such as China, Hong Kong, Korea, Japan and Singapore, with a strong and developed education system.1–5 Current predictions indicate that nearly 5 billion people worldwide will have myopia by 2050 and that 1 billion will be highly myopic.6 Myopia and high myopia are also the main causes of visual impairment and blindness in the world,7–9 and impose an increasingly heavy economic burden.
High myopia is often accompanied by diverse pathological changes, but these changes may vary between children and adults due to the varied course and severity of the condition. For example, the reported prevalence of posterior staphyloma and chorioretinal atrophy is lower in children than in adults.10 11 In addition, the prevalence and severity of myopic maculopathy are much higher in adults than in children,12 as its progression rate.13 14 Nevertheless, a recent study also reported a high prevalence of myopic maculopathy, even in children with myopia and a progression rate of nearly 20%.15 Therefore, recognition of the early signs of pathological changes in childhood may be critical for the early prediction, diagnosis and treatment of severe pathological changes later in life. Nevertheless, studies focused on the relationship between myopic maculopathy and chorioretinal changes in children are limited.
According to previous studies, children with high myopia may present with thinning of the retina and choroid in the posterior pole.16–18 However, the relationships with myopic maculopathy have not been further discussed. One study has suggested that peripapillary diffuse chorioretinal atrophy temporal to the peripapillary region in childhood could develop into advanced myopic chorioretinal atrophy in adulthood.19 However, the children included in that study had attended a high myopia clinic very early in life and may not be representative of the general condition. Nevertheless, these discoveries have suggested that both the choroid and retina in the posterior pole play important roles in the development of high myopia and that significant changes in the choroid and retina may be early signs of myopic maculopathy in childhood, which deserves further exploration. Therefore, the aim of the present study was to explore paediatric myopic maculopathy and its relationship with choroidal and retinal changes in the posterior pole in a large population of highly myopic Chinese children.
Materials and methods
High myopia registration study: the Shanghai Child and Adolescent Large-scale Eye Study (SCALE-HM) is a prospective, examiner-masked study. As we described in our previously published methodology paper, the database of the SCALE study (a city wide, school-based study covering over one million children in Shanghai and the methodology of which has been published elsewhere20) was used to select participants of the current study. The detailed protocol has been described in our previous methodological article.21 Prior to the commencement of the study, the study rationale was explained to all children and their parents/guardians. Written informed consent was obtained from all parents/guardians and from children aged 12 or older, while oral consent was obtained from children younger than 12. Children who met the diagnostic criteria of high myopia, had no organic eye diseases, were in good general condition and resided in Shanghai were included in the study. Children with organic eye diseases, including strabismus, moderate–severe ptosis, congenital cataract or glaucoma, fundus diseases other than myopia-related fundus lesions and other cases not suitable for the study were excluded. Those who had undergone intraocular or refractive surgeries were also excluded.
In the current study, children and adolescents aged 4–18 years were included in the final analysis. Because myopia develops with age, children with differing myopic levels were enrolled based on their ages. Based on the progression of myopia in children, we set our definition of high myopia and the range of refractive error as follows: for children aged between 4 and 5 years old, at least one eye of spherical equivalent (SE, defined as spherical power+0.5×cylindrical power)≤−0.5 D was included; for those aged between 6 and 8 years old, at least one eye of SE≤−3.0 D was included; for those aged between 9 and 12 years old, at least one eye of SE≤−5.0 D was included; and for those aged≥13 years old, at least one eye of SE≤−6.0 D was included.21 Before measuring refractive status, cycloplegia was performed according to the protocol in our methodology article.21
Given that some family members of the highly myopic children were also suffered from myopia or high myopia, these family members were also allowed to have comprehensive ocular examinations together with these highly myopic children and the examinational data were recorded in the data system. During data analysis, data from these myopic family members were excluded from the output dataset due to their age. Finally, a total of 735 subjects applied to participate in the study from 2018 to 2019, and 126 subjects were excluded due to age and the mean age of these excluded participants were 49.0 years (ranging from 20 to 78 years old). Among the remaining participants with required age, 30 participants were further excluded due to their refractive status. Among these 30 participants, 2 participants were aged between 4 and 5 years old with SE of +0.38 D; 4 participants were aged between 6 and 8 years old with a mean SE of −0.81 D (ranging from −2.00 D to +0.50 D); 12 participants were aged between 9 and 12 years old with a mean SE of −2.32 D (ranging from −4.88 D to +0.63 D); and 12 participants were older than or equal to 13 years with a mean SE of −3.89 D (ranging from −5.88 D to +0.63 D). The image quality was strictly controlled by both the examiner and the inspector, and the examinations were repeated if the quality was below the standard. Therefore, no subject was further excluded due to poor image quality during data analysis. Totally, 579 subjects met the eligibility criteria and were enrolled in the final analysis.
Fundus grading was performed independently by two experts (JD, TC) in the field based on fundus photographs and facilitated by optical coherence tomography (OCT) images.22 23 The experts were masked to the personal information of the participants. Any discrepancy between the two experts was recorded and discussed later by an expert panel. The META-analysis for Pathologic Myopia (META-PM) classification system for myopic maculopathy was used in this study; therefore, myopic maculopathy was classified as ‘no myopic retinal degenerative lesion’ (category 0), ‘tessellated fundus’ (category 1, well-defined choroidal vessels that can be observed clearly around the fovea as well as around the arcade vessels), ‘diffuse chorioretinal atrophy’ (category 2, yellowish white atrophic lesions in the posterior pole), ‘patchy chorioretinal atrophy’ (category 3, well-defined, greyish white lesions) and ‘macular atrophy’ (category 4, a well-defined, round greyish white or whitish chorioretinal atrophic lesion that is centred on the central fovea).24 Three ‘plus’ lesions, namely lacquer cracks, myopic choroidal neovascularisation and Fuchs spots, were also assessed. This definition has been adopted widely in studies of high myopia and was discussed in the recent International Myopia Institute (IMI) report.25 A vision-threatening condition occurring in people with myopia, usually high myopia, that comprises diffuse or patchy macular atrophy with or without lacquer cracks, macular Bruch’s membrane defects, choroidal neovascularisation, and Fuchs spot was also called myopic macular degeneration according to the IMI report.25
Measurements of choroidal thickness (ChT) and retinal thickness (RT) in the posterior pole
Fundus structural changes were assessed using fundus photography and swept-source OCT (SS-OCT, DRI OCT Triton, Topcon, Tokyo, Japan) in both the macular and the peripapillary regions. The OCT examination was performed between 10:00 and 15:00 each day to minimise the influence of diurnal variation. Spherical power, cylindrical power, axial length (AL) and cornea curvature radius were input into the OCT system before image collection. Littmann’s method was used by the OCT system to compensate for magnification factors. A signal strength≥60 and image quality≥90 were required for each qualified OCT image. Each SS-OCT examination included 12 radial scan lines focused on the centre of the fovea or the optic disc. Each scan line was 9 mm long and was separated from the adjacent lines by 15°. Sixteen B-scan OCT images were obtained on each scan line and were averaged with built-in software to create an averaged image. The automatic segmentation was carefully inspected, and manual correction was performed when the software misjudged the borderlines.16
The thickness of each fundus layer was measured using SS-OCT (online supplemental figure 1). The Early Treatment Diabetic Retinopathy Study (ETDRS) grid was overlaid to define the sectors in both the macular and peripapillary regions. The diameters for the inner, middle and outer circles of the ETDRS grid were 1, 3 and 6 mm, respectively, and the inner ring (also called the parafoveal region in the macula) and the outer ring (also called the perifoveal region in the macula) were further divided into four quadrants—the temporal, superior, nasal and inferior sectors. In the macular region, all nine sectors of the grid were applied; however, in the peripapillary region, only four sectors in the outer ring were used in the final analysis.16
Statistical analysis was performed using SPSS (V.22.0) and R (R core team, 2020). Continuous variables were described as the mean±SD, while categorical variables were described as counts (proportions). Intergroup differences were assessed with t-tests or analysis of variance, and the Bonferroni method was used for post hoc tests. Multivariate regression analysis was performed to determine the independent factors of myopic maculopathy.
Three main analyses were performed. First, the severity of myopic maculopathy was described based on the fundus photographs. Second, the SS-OCT measurements in each sector of the macular and peripapillary regions were compared among children with different levels of myopic maculopathy. Third, the distribution of ChT and RT was compared across different levels of myopic maculopathy, and multivariate regression analysis was performed to determine the independent factors for myopic maculopathy. A multicategory receiver operating characteristic (ROC) curve was used to determine the cut-off values of ChT for different myopic maculopathy categories.26 27 The mean nasal macular ChT was adopted, calculated as the weighted average of the parafoveal nasal ChT and perifoveal nasal ChT, with weights of 8 and 27 (based on their area), respectively. The hypervolume under the manifold (HUM) was calculated in multicategory ROC analysis to correspond to the accuracy of the whole classification. The area under the curve (AUC) was used to assess the accuracy of prediction in two-by-two classifications. Statistical significance was defined as p<0.05 (two tailed).
General characteristics of the participants
The study included 579 children and adolescents (271 boys and 308 girls) with a mean age of 12.8±3.2 years. Their general characteristics are shown in table 1. The parameters of the bilateral eyes were moderately to highly correlated (R values ranging from 0.59 to 0.86) (online supplemental figure 2). Therefore, only the right eyes were included for analysis. For the involved right eyes, the mean AL and SE were 26.65±1.16 mm and −8.44±2.20 D, respectively.
The proportions of tessellated fundus and diffuse chorioretinal atrophy were 43.52% (N=252) and 8.64% (N=50), respectively. No severe atrophic myopic maculopathy (ie, patchy chorioretinal atrophy and macular atrophy), myopic traction maculopathy or neovascular myopic maculopathy were present. The demographics and basic clinical characteristics of the three groups are shown in table 2. The distribution of tessellated fundus and diffuse chorioretinal atrophy by age is depicted in figure 1. In general, children with older age and longer AL tended to have higher rates of myopic maculopathy. The proportion of diffuse chorioretinal atrophy in children younger than 7 years old was extremely high, and this may be a unique clinical characteristic of early onset high myopia.
Significant choroidal thinning with limited retinal changes in the peripapillary region
Table 3 and figure 2A–2C show the thickness of each fundus layer in the peripapillary region. The ChT became significantly thinner in all four sectors of the peripapillary region in children with more severe myopic maculopathy (all p values<0.001). This tendency was most noticeable in the temporal sector (127 µm vs 59 µm, a 53.5% decrease in ChT) and least pronounced in the nasal sector (148 µm vs 90 µm, a 39.2% decrease in ChT) when comparing the groups without myopic maculopathy and those with diffuse chorioretinal atrophy (figure 2F). A similar thinning tendency was observed between the groups without myopic maculopathy and those with tessellated fundus (figure 2D) and between the groups with tessellated fundus and those with diffuse chorioretinal atrophy (figure 2E).
By contrast, the RT remained similar across different levels of myopic maculopathy. The RT became slightly thinner in the superior and nasal sectors (p=0.021 and 0.003, respectively) in children with more severe myopic maculopathy and remained similar in the inferior and temporal sectors (p=0.134 and 0.369, respectively) in children with different categories of myopic maculopathy. The retinal nerve fibre layer thickness (RNFLT) became thinner in the nasal sector (p=0.001) and thicker in the temporal sector (p<0.001) in the peripapillary region with more severe myopic maculopathy (table 3).
Significant thinning of the retina and choroid in the macular region
The distribution of macular RT and ChT for different severities of myopic maculopathy is shown in table 4. Similar to the peripapillary region, the choroid in the macular region also became significantly thinner in children as the severity of myopic maculopathy increased (figure 2A–2C, all Ps<0.001), with a 40%–60% decrease in ChT observed when comparing the groups without myopic maculopathy with those with diffuse chorioretinal atrophy (figure 2F) and a 20%–30% decrease comparing the groups without myopic maculopathy with those with tessellated fundus (figure 2D). This tendency was most pronounced in the nasal sectors and least pronounced in the temporal sectors. Combining the discoveries in the peripapillary region, the ChT became thinner most significantly in the area between the fovea and the optic disc, and this thinning tendency then weakened towards the more peripheral area (figure 2D–2F).
The macular RT decreased slightly in children with a greater degree of myopic maculopathy, with a 7 μm to 15 µm decrease in each sector when compared with the groups without myopic maculopathy with those with diffuse chorioretinal atrophy (all Ps<0.05, table 4). Additionally, for the layers inside the retina, such as the combined thickness of the ganglion cell layer and the inner plexiform layer (GCL+) and the RNFL, the distribution of each layer thickness was similar for the different degrees of myopic maculopathy.
Associated factors of myopic maculopathy, ChT and RT
Factors associated with the severity of myopic maculopathy are shown in table 5. Deletion of variables with collinearity revealed that thinner macular ChT, thinner macular RT, longer AL, female gender and older age were independently associated with the presence of tessellated fundus when compared with children without myopic maculopathy, and only thinner macular ChT was independently associated with the presence of diffuse chorioretinal atrophy when compared with children with tessellated fundus. Given the close association of fundus changes in the nasal macular area and myopic maculopathy, the associations between nasal ChT, RT and myopia maculopathy categories were also analysed (online supplemental table 1) and gave results similar to those observed in the whole macular area.
Macular ChT was positively correlated with SE and negatively correlated with the grade of myopic maculopathy in all nine sectors, while gender and IOP were marginally associated with central foveal ChT. The macular RT was positively correlated with age and negatively correlated with the grade of myopic maculopathy in all nine sectors. The SE was positively correlated with RT in most of the parafoveal and perifoveal sectors, and males tended to have thicker RT in the central foveal and parafoveal sectors. The details of the associated factors of the macular ChT and RT are provided in online supplemental table 2.
In the peripapillary region, ChT was positively correlated with SE and age and negatively correlated with the grade of myopic maculopathy in all four sectors. The peripapillary RT was positively correlated with age in all four sectors. The peripapillary RT in the inferior, nasal and superior sectors were negatively correlated with the grade of myopic maculopathy. SE was a common influencing factor of the peripapillary RT in the nasal, superior and temporal sectors and was marginally associated with inferior peripapillary RT. Detailed information about the influencing factors of the peripapillary ChT and RT are shown in online supplemental table 3.
Cut-off values of nasal macular ChT for three myopic fundus gradings
The HUM of the multicategory ROC analysis for the whole classification was 0.714, which was statically higher than the non-informative value of 1/6 (figure 3A). The AUC values for two-by-two classification among groups 0 and 1, groups 1 and 2, and groups 0 and 2 (where 0 refers to the group without myopic maculopathy, 1 refers to the group with tessellated fundus and 2 refers to the group with diffuse chorioretinal atrophy) were 0.801, 0.910 and 0.982, respectively (figure 3B–3D). The cut-off values for nasal macular ChT for classifying tessellated fundus and diffuse chorioretinal atrophy were 129.00 µm and 83.85 µm, respectively.
The results of this large-scale study of Chinese children with high myopia revealed that more than half could suffer from myopic maculopathy, in agreement with another recent study.15 The choroid was significantly thinner and the retina was only slightly thinner in children with more severe myopic maculopathy. Thinner macular ChT and RT, longer AL, female gender and older age were independently associated with tessellated fundus, whereas only thinner macular ChT was independently associated with diffuse chorioretinal atrophy. The cut-off values for nasal macular ChT for classifying tessellated fundus and diffuse chorioretinal atrophy were 129.00 and 83.85 µm.
The distribution pattern of ChT differed from that described by previous studies performed in myopic children, where peripapillary ChT was reported as thinnest in the inferior sector in children.16 28 29 This may be due to that the optic fissure located inferiorly is the last part to close during ocular development.30 In the current study, the thinnest peripapillary ChT was observed in the temporal sector in the groups with tessellated fundus and diffuse chorioretinal atrophy, suggesting a significant thinning of the choroid in the area between the macula and the optic disc. The current findings also indicated a significantly thinner ChT for all the peripapillary sectors in eyes with more severe myopic maculopathy. A similar tendency was reported in highly myopic young adults with higher myopic degree.31 However, in our previous study, children with higher myopic degree tended to have a thinner peripapillary ChT only at the temporal and inferior sectors.16 These differences may be due to differences in the severity and course of myopia.
Two previous studies that found a relationship between ChT and myopic maculopathy gradings reported that the cut-off value of ChT that predicted the presence of peripapillary diffuse choroidal atrophy was 56.5 µm at a distance of 3000 µm nasal to the fovea in adults and 60 µm at a distance of 2500 µm nasal to the fovea in children.22 23 These previous findings indicated that the ChT between the fovea and the optic disc shows the most significant thinning with the development of myopic maculopathy, suggesting that the mean macular nasal ChT could be an excellent predictor of myopic maculopathy in children. Therefore, in our current study, mean macular nasal ChT values of 129.00 and 83.85 µm were adopted to classify the presence of tessellated fundus and diffuse chorioretinal atrophy, respectively, and the AUC values were quite good. Given that tessellated fundus and diffuse chorioretinal atrophy may involve a relatively wide area in the posterior pole, especially in the area nasal to the fovea, the use of mean macular nasal ChT may be superior to a ChT measurement taken at a single point.
Previously reported influencing factors of ChT have included thinning of the choroid with an increased degree of myopia and AL in the macula.17 32 However, the results due to age differences were not uniform, probably due to the growth and development of the eyeballs.16 17 33–35 Similar to our previous study,16 age was not an independent factor of ChT in most macular sectors in the present study. Another of our previous study also suggested no relationship between age and ChT in children with SE≤−2.00 D,36 suggesting that the protective effect of physiologic choroidal growth with age against myopia-related choroidal atrophy vanished in the macula, whereas the severity of myopia became the main determinant of macular ChT among children with high myopia.
Unlike the case for macular ChT, age was positively correlated with peripapillary ChT in the present study. As we expected, the protective effect of age appeared to fade, first in the macular region in childhood and then in the peripapillary region with ageing, in agreement with previous studies that have found a negative correlation between age and peripapillary ChT in adults.37 Confirmation of this correlation will require long-term follow-up studies in the future to decipher the development process and determine the cut point.
Unlike the significant changes in ChT, the changes in RT were limited. Similar results were observed in our previous follow-up study.38 The retinal thinning was also more obvious in the macular region, suggesting an uneven thinning process of the retina in highly myopic children. Retinal thinning in the macula was closely associated with the severity of myopic maculopathy, regardless of age, suggesting that highly myopic children with significant myopic fundus changes may have a tendency to develop retinal atrophy, even at a relatively young age. Nevertheless, retinal atrophy is more common in high myopes with older age and a longer course, and follow-up studies are needed in the future to determine the developmental processes that lead to these retinal atrophic changes.
The strength of this study was that myopic maculopathy was explored in a relatively large sample size of the paediatric population, as this has been rarely performed according to a literature search. Moreover, the changes in the choroid and retina in the posterior pole were analysed in depth in children with different levels of myopic maculopathy, another aspect that has rarely been reported. Despite these discoveries, the current study also had several limitations. First, the causal relationships between myopic maculopathy and ChT and RT changes cannot be determined by the cross-sectional data. Therefore, a long-term follow-up study (set at once per year) will be necessary. Second, the number of children with severe myopic maculopathy was small, and the data for advanced myopic fundus changes were limited. Therefore, more children with severe myopic fundus changes should be included. Third, this study was performed in Chinese children aged 4–18; therefore, the results may not be applicable to children of other ethnicities and age groups. Fourth, a small portion of the included children developed myopia at a very young age (younger than 7 years old). Congenital elements may therefore play an important role in these subjects, and their inclusion may have caused potential bias when they were analysed together with children whose disease is mainly environmental in origin. Nevertheless, the influence was very limited due to the small sample size of those patients (N=22, 3.8%). The influence of congenital and environmental factors was complicated, and both may have contributed together to the development of myopic maculopathy. Undeniably, genes play important roles in these young myopic children, but the role of environmental factors, especially the prevalence of early education and decreased outdoor activities, should also be given full consideration. Therefore, excluding children who had purely congenital myopia was difficult based on the cross-sectional study design. In addition, myopia driven by either congenital or environmental factors may show significant chorioretinal changes. These lesions may keep changing and may progress into pathological myopia later in life. For this reason, we included all the patients in an attempt to determine the relationship between myopic maculopathy and chorioretinal changes in children, regardless of the exact aetiology, with the view that this is actually controlled by both genes and environmental factors together in most cases. During follow-up research, subjects with an early onset history and congenital factors can be analysed separately to determine if myopic maculopathy progression differs from that more likely to be school myopia. We will also examine myopia-related genes in our future studies, as this may be helpful in distinguishing subjects who are more likely to have congenital myopia.
In conclusion, the prevalence of myopic maculopathy was high in children with high myopia, and this raises special concern. The ChT in the posterior pole was closely associated with the severity of myopic maculopathy, and the nasal macular ChT can serve as a useful index for classifying myopic maculopathy. Further long-term follow-up studies with larger sample sizes will be needed in the future to confirm our findings and speculations.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
Patient consent for publication
This study involves human participants. This study was approved by the Shanghai General Hospital Ethics committee and adhered to the tenets of the Declaration of Helsinki (ClinicalTrials.gov Identifier: NCT03666052). Participants gave informed consent to participate in the study before taking part.
We gratefully acknowledge the expert guidance and help provided by the following individuals: Jidong Chen, Mengli Luan, Huijuan Zhao, Haifeng Gan, Tianwei Qian and Yupeng Xu. We also gratefully acknowledge the valuable contribution and support of the district-level eye disease control and prevention branch centres, community health service centres; enrolled kindergartens, primary and secondary schools and the child participants and their caregivers.
Contributors JD and Xian Xu contributed equally as cofirst authors. JD, Xian Xu designed the study, collected, analysed and interpreted the data, drafted and revised the manuscript. C-WP, ZZ, GB and JC designed the study, analysed and interpreted the data, drafted and revised the manuscript. JW. JY and TC designed the study, collected and analysed the data and revised the manuscript. MH, X-WH, SY, YF, KL, HZ and Xun Xu designed the study, analysed and interpreted the data and revised the manuscript. BZ designed the study, collected and interpreted the data and revised the manuscript. XH designed the study, collected, analysed and interpreted the data, drafted and revised the manuscript, and also he is the guarantor.
Funding National Key R&D Program of China (No.2021YFC2702100, No.2021YFC2702104, No.2019YFC0840607); Excellent Discipline Leader Cultivation Program of Shanghai Three Year Action Plan on Strengthening Public Health System Construction (No.GWV-10.2-XD09); National Natural Science Foundation of China (No.81900911, No.82003562); ORBIS International (No award/grant number).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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