Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2024 May 20;19(5):e0303871. doi: 10.1371/journal.pone.0303871

Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: A nationwide population-based study

Yeji Kim 1, Chul Gu Kim 1, Jong Woo Kim 1, Kyungdo Han 2,*, Jae Hui Kim 1,*
Editor: Jiro Kogo3
PMCID: PMC11104591  PMID: 38768233

Abstract

This study aimed to investigate the impact of the cumulative burden of metabolic syndrome (MetS) on the incidence of retinal vein occlusion (RVO) in young adults. We included 1,408,093 subjects aged ≥20 and <40 years without a history of RVO who underwent four consecutive annual health examinations during 2009–2012 from the database of the Korean National Health Insurance Service. The metabolic burden was evaluated based on the cumulative number of MetS diagnoses at each health examination (0–4 times) and the cumulative number of each MetS component diagnosed at each health examination (0–4 times per MetS component). Cox proportional hazards models were used to estimate the risk of RVO according to metabolic burden. The risk of RVO was positively correlated with the cumulative number of MetS diagnoses over the four health examinations. All five MetS components were independently associated with an increased risk of RVO. Subgroup analysis for the impact of MetS on RVO occurrence revealed that MetS had a greater impact on female subjects (P <0.001). Prompt detection of metabolic derangements and their treatment might be important to decrease the risk of RVO in young adults, especially women.

Introduction

Retinal vein occlusion (RVO) is the second most common retinal vascular disease, with an estimated prevalence of 0.4% in branch retinal vein occlusion (BRVO) and 0.08% in central retinal vein occlusion (CRVO) [1, 2]. The incidence of RVO increases with age, frequently seen in people older than 65 years [3, 4]. Traditional risk factors for RVO include advancing age and systemic conditions such as hypertension, arteriosclerosis, diabetes mellitus, hyperlipidemia, vascular cerebral stroke, blood hyperviscosity, and thrombophilia [5]. Advanced age is regarded as a basic risk factor, and metabolic syndromes (MetS), such as hypertension, diabetes mellitus, and hyperlipidemia, and is known as a strong risk factor for RVO [5]. Recently, a nationwide population-based study demonstrated that MetS and each of its diagnostic criteria increase the risk of RVO occurrence [6].

As the incidence of RVO is lower in younger adults, information regarding the risk factors of RVO in the younger population is limited. The etiology of RVO in young patients is likely multifactorial. Previous studies have reported that younger adults were more likely to have nontraditional risk factors, such as physical or psychological stress and hematologic abnormalities [7], whereas other studies have reported that atherosclerotic diseases remain the most commonly associated systemic diseases in patients aged ≤50 years [8]. A substantial increase in the prevalence of MetS has been reported in healthy young adults [9]. In addition, a considerable proportion (7.5–26.2%) of CRVO patients were reported to be under 50 years old [7, 10]. Since visual disturbance in young adults may lead to a significant impact on social participation [11], analyzing the association between MetS and the occurrence of RVO in young patients may have clinical importance.

In the present study, we investigated the association between MetS and the risk of RVO development in young Korean patients through a nationwide, large-scale retrospective cohort study based on the Korean National Health Insurance Database.

Materials and methods

The methods of Ahn et al. were grossly referenced in this study [12]. This study was approved by the Institutional Review Board (IRB) of Kim’s Eye Hospital (Kim’s Eye Hospital IRB; IRB number KEH 2022-04-008), and was conducted according to the principles of the Declaration of Helsinki. The need for informed consent was waived by the IRB of Kim’s Eye Hospital because the study did not include any identifiable information about the subjects. The Korean National Health Insurance Corporation has allowed authors to use the database based on the approved IRB. The data access dates for research purposes were June 2, 2022

Study design and data sources

The data analyzed in this study were derived from the National Health Information Database (NHID), which includes all data from the NHIS covering the entire population of the Republic of Korea. Briefly, all insured Korean adults, except 3% of the population covered by the Medical Aid program, were recommended to undergo standardized biennial medical examinations consisting of detailed surveys of demographics, medical histories, lifestyle questionnaires, vital signs, anthropometric measurements, and laboratory tests. In addition to the regular health examination records, the Korean NHIS collects sociodemographic data, income-based insurance contributions, prescription records, inpatient and outpatient usage, and the date of death of all insured Koreans in the NHID [13, 14].

A total of 1,571,091 adults aged ≥20 and <40 years who underwent four serial health examinations between January 1, 2009, and December 31, 2012, were selected from the NHID. The database was collected over four consecutive years from the first health examination. Individuals with a history of RVO, missing health examination data or covariates, or with a diagnosis of RVO within one year from the last health examination (index date) were excluded (Fig 1). A one-year lag period was implemented to enhance the causality of the study. This was done to mitigate the possibility of delayed RVO diagnoses due to delayed eye examinations and to exclude individuals who received regular checkups over a four-year period and passed away within one year thereafter. By excluding these possibilities, this study aimed to increase the causality of the research, measure exposure over a four-year period, and observe the occurrence of RVO one year after the measurements were taken. The washout period was defined as the period from 2002 until the last health examination was conducted, encompassing a duration of 10 years or more (from 2002 to 2012–2015).

Fig 1. Flow diagram of the selection of the study population from the National Health Information Database.

Fig 1

Open in a new tab

a Patients aged ≥20 years and <40 years who participated in the National Health Insurance Service at least once between 2009 and 2012. b Patients who received a health examination between January 1, 2009, and December 31, 2012 and have subsequently undergone four consecutive examinations thereafter (For example, for 2009, participants who underwent annual health examinations continuously for four years from 2009 to 2012). c Patients diagnosed with retinal vein occlusion (KCD code H34.8 corresponding to ICD-10-clinical modification code 362.35, CRVO, or 362.36, venous tributary (branch) occlusion) during the washout period were excluded. d Patients diagnosed with retinal vein occlusion within one year from the index date were excluded (For example, for 2009, individuals who received annual health examinations from 2009 to 2012 and experienced RVO or passed away in 2013 were excluded). CRVO central retinal vein occlusion.

In national health examinations, waist circumference, blood pressure, and glucose and cholesterol levels are measured annually, with very few cases of missing data. Individuals with missing data were excluded from the analysis, and only those participants who had complete data for all MetS components over a four-year period were enrolled in the study. Ultimately, 1,408,093 adults were included in the analysis.

Evaluation of metabolic syndrome and the influence of cumulative metabolic burden

The MetS was defined using the modified waist circumference criteria of the Korean Society for the Study of Obesity and the guidelines of the National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATP III) as the presence of ≥3 of the following: increased WC [≥90 cm in males or ≥85 cm in females], elevated TG [≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated TG], low HDL-C [<40 mg/dL (1 mmol/L) in males and <50 mg/dL (1.3 mmol/L) in females or drug treatment for low HDL-C], elevated blood pressure [systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or current use of antihypertensives], and impaired fasting glucose [fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or current use of anti-diabetes] [15–17].

At each health examination, the presence of MetS and the number of fulfilled MetS components were calculated. “Metabolic burden” was defined in the following ways during four health examinations: (1) cumulative number of MetS diagnosed at each health examination (0–4 times); and (2) cumulative number of each MetS component diagnosed at each health examination (0–4 times per MetS component).

Covariates, follow-up, and clinical outcomes

The baseline characteristics of the individuals were designated as the data of the last health examination (index date), which comprised sociodemographic data, income-based insurance contributions, laboratory results, anthropometric measurements, comorbidities (diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease), and answers to lifestyle questionnaires. We investigated the risk of new-onset RVO using the Korean Standard Classification of Diseases Version 6 (KCD-6; an adapted version of the International Classification of Disease, Tenth Revision [ICD-10] codes) and inpatient and outpatient records. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. The follow-up period was the time from the index date to the occurrence of RVO or December 31, 2018, whichever occurred first.

Statistical analysis

Data are summarized as mean ± standard deviation for continuous variables and number (%) for categorical variables. One-way analysis of variance and the chi-square test were used to evaluate significant differences in baseline characteristics among groups categorized by the number of MetS components. The incidence rate of RVO was computed by dividing new-onset RVO cases by the total follow-up duration and was presented as per 1000 person-years (PY). The association between MetS status frequency and RVO incidence was estimated using Cox proportional hazards regression models. The risk of RVO according to the number of patients with MetS compared with the non-MetS group was expressed as HRs with 95% CIs. Model 1 represented an unadjusted risk, and Model 2 was adjusted for age and sex. Model 3 was adjusted for age; sex; smoking status (never smoker, ex-smoker, or current smoker); alcohol intake (non-, mild, or heavy drinker, g/day); regular exercise (performing >30 min of moderate physical activity ≥5 times a week or >20 min of vigorous physical activity ≥3 times a week); and low-income level (income in the lower 20% of the entire Korean population of subjects supported by the medical aid program) [18]. Model 4 was additionally adjusted for systolic blood pressure, fasting glucose, the logarithm of TG, and HDL-C levels. A P value of less than 0.05 was considered statistically significant. Data collection and statistical analysis was performed using SAS version 9.4 (SAS Institute, Cary, NC).

Results

Table 1 presents the baseline characteristics of 1,408,093 individuals categorized according to the number of MetS diagnoses over four health examinations. The mean age of the total study population was 32.45 ± 4.11 years, and 1,011,343 (71.8%) were men. The study participants were classified into five groups according to the number of MetS diagnostic criteria met during four consecutive annual health examinations. The number of individuals included in each group was 1,072,217 (76.1%), 165,760 (11.8%), 80,501 (5.7%), 50,712 (3.6%), and 38,903 (2.8%) (0, 1, 2, 3, and 4 times, respectively).

Table 1. Baseline characteristics of the total study population according to the cumulative number of MetS diagnosed at each health examination (0 to 4 times).

Total The number of the presence of the metabolic syndrome p
0 1 2 3 4
No. of participants (%) 1,408,093 (100.0) 1,072,217 (76.1) 165,760 (11.8) 80,501 (5.7) 50,712 (3.6) 38,903 (2.8)
Age (years) 32.45 ± 4.11 32.02 ± 4.16 33.5 ± 3.71 33.91 ± 3.55 34.2 ± 3.47 34.63 ± 3.35 < .0001
Sex < .0001
    Male 1,011,343 (71.8) 703,191 (65.6) 149,321 (90.1) 74,779 (92.9) 47,505 (93.7) 36,547 (93.9)
    Female 396,750 (28.2) 369,026 (34.4) 16,439 (9.9) 5,722 (7.1) 3,207 (6.3) 2,356 (6.1)
Smoking < .0001
    Never smoker 672,683 (47.8) 573,880 (53.5) 53,442 (32.2) 22,564 (28.0) 13,197 (26.0) 9,600 (24.7)
    Ex-smoker 206,809 (14.7) 145,501 (13.6) 29,763 (18.0) 15,238 (18.9) 9,396 (18.5) 6,911 (17.8)
    Current smoker 528,601 (37.5) 352,836 (32.9) 82,555 (49.8) 42,699 (53.0) 28,119 (55.5) 22,392 (57.6)
Alcohol consumptiona < .0001
    Non-drinker 444,733 (31.6) 362,414 (33.8) 41,844 (25.2) 19,140 (23.8) 11,887 (23.4) 9,448 (24.3)
    Mild to moderate drinker 832,667 (59.1) 627,253 (58.5) 101,847 (61.4) 49,433 (61.4) 30,905 (60.9) 23,229 (59.7)
    Heavy drinker 130,693 (9.3) 82,550 (7.7) 22,069 (13.3) 11,928 (14.8) 7,920 (15.6) 6,226 (16.0)
Regular exerciseb 248,553 (17.7) 187,096 (17.5) 30,730 (18.5) 14,802 (18.4) 9,178 (18.1) 6,747(17.3) < .0001
Low incomec 72 (0.0) 54 (0.0) 7 (0.0) 5 (0.0) 4 (0.0) 2 (0.0) < .0001
Comorbidities
    Diabetes mellitus 29,670 (2.1) 7,387 (0.7) 4,494 (2.7) 4,138 (5.1) 4,847 (9.6) 8,804 (22.6) < .0001
    Hypertension 107,787 (7.7) 38,336 (3.6) 21,002 (12.7) 16,247 (20.2) 14,642 (28.9) 17,560(45.1) < .0001
    Dyslipidemia 125,484 (8.9) 59,578 (5.6) 23,902 (14.4) 15,779 (19.6) 12,509 (24.7) 13,716(35.3) < .0001
    CKD 4,993 (0.4) 3,350 (0.3) 604 (0.4) 370 (0.5) 272 (0.5) 397(1.0) < .0001
Laboratory findings
    BMI (kg/m2) 23.58 ± 3.65 22.53 ± 2.97 25.71 ± 3.16 27.22 ± 3.31 28.42 ± 3.45 29.75 ± 3.68 < .0001
    Waist circumference (cm) 79.61 ± 9.99 76.77 ± 8.55 85.72 ± 7.97 89.37 ± 8.06 92.19 ± 8.24 95.31 ± 8.51 < .0001
    Systolic BP (mmHg) 119.07 ± 12.78 116.46 ± 11.69 124.90 ± 11.80 127.95 ± 12.04 130.32 ± 12.56 133.23 ± 13.64 < .0001
    Diastolic BP (mmHg) 74.93 ± 9.19 73.19 ± 8.43 78.66 ± 8.65 80.84 ± 8.99 82.54 ± 9.56 84.72 ± 10.38 < .0001
    Fasting glucose (mg/dL) 92.00 ± 16.06 89.46 ± 11.03 95.81 ± 16.30 99.21 ± 21.09 104.06 ± 28.76 115.26 ± 42.11 < .0001
    Total cholesterol (mg/dL) 189.34 ± 34.10 184.93 ± 31.99 199.84 ± 35.40 205.12 ± 36.44 208.17 ± 37.49 208.97 ± 39.85 < .0001
    HDL cholesterol (mg/dL) 56.08 ± 18.47 58.79 ± 18.44 49.46 ± 16.22 46.71 ± 15.14 44.96 ± 14.05 43.33 ± 15.04 < .0001
    LDL cholesterol (mg/dL) 108.86 ± 32.47 106.03 ± 30.48 116.87 ± 34.93 119.19 ± 36.61 119.73 ± 38.93 117.09 ± 40.87 < .0001
    eGFR (ml/min/1.73m2) 101.68 ± 68.64 102.54 ± 69.76 99.46 ± 67.04 98.73 ± 65.50 97.97 ± 58.14 98.45 ± 62.49 < .0001
    *Triglyceride (mg/dL) 105.81 89.77 155.03 186.14 211.29 243.67 < .0001
(105.70–105.92) (89.68–89.86) (154.64–155.43) (185.48–186.80) (210.37–212.21) (242.47–244.88)
Open in a new tab

Data are presented as mean ± SD or No. (Percentages)

Percentages may not total 100 because of rounding

MetS metabolic syndrome, CKD chronic kidney disease, BMI body mass index, BP blood pressure, HDL high-density lipoprotein, LDL low-density lipoprotein, eGFR estimated glomerular filtration rate

a Alcohol consumption denotes as following

Non-drinker: alcohol consumption 0 g

Mild to moderate drinker: alcohol consumption >0 g to <30 g per day

Heavy drinker: alcohol consumption ≥30 g per day

b Regular exercise denotes performing >30 min of moderate-intensity exercise (e.g., brisk pace walking, tennis doubles, or bicycling leisurely) ≥ 5 times a week or >20 min of vigorous-intensity exercise (e.g., running, climbing, fast cycling, or aerobics) ≥ 3 times a week

c Low income denotes income of the lower 20% among the entire Korean population of subjects supported by the Medical Aid program

*Geometric mean (95% CI)

Accumulation of metabolic burden and the risk of RVO

Table 2 shows the incidence of RVO according to the number of MetS and the number of MetS components during the four health examinations. The cumulative number of MetS diagnoses at each health examination and the risk of RVO showed a positive correlation: adjusted HRs with 95% CIs of groups meeting the diagnostic criteria of MetS 1, 2, 3, and 4 times compared to 0 times were 1.20 (1.03–1.39), 1.35 (1.12–1.63), 1.58 (1.28–1.95), and 1.71 (1.36–2.15), P for trend <0.001). Fig 2A shows the relation.

Table 2. The risk of retinal vein occlusion according to the cumulative number of MetS and each component diagnosed during four health examinations (0 to 4 times).

The number of meeting the component No. of participants RVO IR (1000PY) HR (95% CI)
Model1 Model2 Model3 Model4
Obesity (BMI ≥25)
0 871,556 834 0.20 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 89,802 94 0.22 1.10 (0.89–1.36) 1.06 (0.85–1.31) 1.05 (0.85–1.31) 1.02 (0.82–1.26)
2 70,160 90 0.27 1.36 (1.09–1.68) 1.29 (1.03–1.60) 1.28 (1.03–1.60) 1.22 (0.98–1.52)
3 79,588 85 0.23 1.13 (0.90–1.41) 1.05 (0.84–1.32) 1.05 (0.84–1.32) 0.98 (0.79–1.23)
4 296,987 490 0.35 1.72 (1.54–1.93) 1.55 (1.38–1.75) 1.56 (1.39–1.75) 1.33 (1.18–1.50)
Metabolic syndrome
0 1,072,217 1,014 0.20 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 165,760 222 0.28 1.39 (1.20–1.61) 1.27 (1.10–1.47) 1.29 (1.11–1.49) 1.20 (1.03–1.39)
2 80,501 133 0.35 1.71 (1.43–2.05) 1.53 (1.27–1.83) 1.55 (1.29–1.87) 1.35 (1.12–1.63)
3 50,712 109 0.45 2.22 (1.83–2.71) 1.95 (1.59–2.38) 1.99 (1.63–2.43) 1.58 (1.28–1.95)
4 38,903 115 0.62 3.06 (2.52–3.71) 2.62 (2.15–3.19) 2.69 (2.21–3.27) 1.71 (1.36–2.15)
Increased waist circumference
0 1,067,469 1,062 0.21 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 121,985 164 0.28 1.36 (1.15–1.60) 1.29 (1.10–1.53) 1.30 (1.10–1.53) 1.23 (1.04–1.45)
2 69,078 88 0.27 1.30 (1.04–1.61) 1.21 (0.97–1.51) 1.21 (0.98–1.51) 1.11 (0.89–1.39)
3 59,932 93 0.33 1.58 (1.28–1.96) 1.47 (1.18–1.81) 1.47 (1.19–1.82) 1.29 (1.04–1.60)
4 89,629 186 0.44 2.12 (1.82–2.48) 1.93 (1.65–2.27) 1.96 (1.67–2.29) 1.55 (1.31–1.83)
Low HDL-C
0 1,001,902 1,050 0.22 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 202,652 249 0.26 1.15 (1.01–1.32) 1.13 (0.98–1.29) 1.13 (0.99–1.30) 1.08 (0.94–1.24)
2 97,195 135 0.29 1.30 (1.09–1.55) 1.25 (1.04–1.49) 1.26 (1.05–1.50) 1.15 (0.96–1.38)
3 61,691 77 0.26 1.16 (0.92–1.47) 1.10 (0.87–1.38) 1.11 (0.88–1.40) 0.99 (0.78–1.25)
4 44,653 82 0.38 1.71 (1.36–2.14) 1.58 (1.26–1.98) 1.60 (1.27–2.00) 1.32 (1.05–1.66)
Elevated blood pressure
0 632,898 579 0.20 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 309,082 329 0.22 1.15 (1.00–1.31) 1.08 (0.94–1.25) 1.09 (0.94–1.25) 1.06 (0.92–1.22)
2 204,139 241 0.25 1.26 (1.09–1.47) 1.16 (0.99–1.36) 1.17 (1.00–1.37) 1.10 (0.94–1.29)
3 145,957 183 0.26 1.33 (1.13–1.58) 1.20 (1.01–1.43) 1.21 (1.02–1.44) 1.06 (0.88–1.27)
4 116,017 261 0.47 2.37 (2.05–2.75) 2.06 (1.76–2.40) 2.07 (1.77–2.42) 1.52 (1.26–1.84)
Impaired fasting glucose
0 814,304 801 0.21 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 336,845 351 0.22 1.05 (0.92–1.19) 0.98 (0.87–1.11) 0.99 (0.87–1.12) 0.96 (0.85–1.09)
2 147,913 192 0.27 1.30 (1.11–1.52) 1.16 (0.99–1.36) 1.17 (1.00–1.37) 1.09 (0.93–1.28)
3 68,920 109 0.33 1.57 (1.29–1.92) 1.35 (1.10–1.66) 1.36 (1.11–1.67) 1.18 (0.96–1.45)
4 40,111 140 0.73 3.47 (2.90–4.15) 2.84 (2.37–3.41) 2.86 (2.38–3.44) 1.84 (1.46–2.32)
Elevated TG
0 750,472 713 0.20 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
1 245,822 268 0.23 1.12 (0.98–1.29) 1.04 (0.90–1.20) 1.05 (0.91–1.21) 1.01 (0.88–1.17)
2 152,002 188 0.26 1.26 (1.08–1.48) 1.11 (0.94–1.31) 1.13 (0.96–1.34) 1.05 (0.89–1.25)
3 123,657 186 0.31 1.53 (1.30–1.79) 1.30 (1 .10–1.54) 1.34 (1.13–1.58) 1.18 (1.00–1.41)
4 136,140 238 0.36 1.75 (1.51–2.03) 1.44 (1.23–1.68) 1.49 (1.28–1.75) 1.19 (1.00–1.40)
Open in a new tab

Model 1 is unadjusted

Model 2 is adjusted for age, sex

Model 3 is adjusted for age, sex, smoking status, alcohol intake, and regular exercise

Model 4 is adjusted for age, sex, smoking status, alcohol intake, regular exercise, systolic blood pressure, fasting glucose, logarithm of TG, and HDL-C level

RVO retinal vein occlusion, IR incidence rate, PY person-years, HR hazard ratio, CI confidence interval, HDL-C high-density lipoprotein cholesterol, TG triglycerides

Fig 2.

Fig 2

Open in a new tab

Incidence rate of retinal vein occlusion according to the a. cumulative number of MetS diagnosed at each health examination, and b-f. cumulative number of each component of MetS diagnosed at each health examination. HDL high‑density lipoprotein, TG triglycerides.

All of the five MetS criteria were independently related to the risk of RVO development. With the increase in the number of each MetS diagnostic criterion satisfied, the incidence and risk of RVO also increased (Table 2 and Fig 1B–1F). The impact of each MetS component on RVO occurrence differed. The adjusted HR (95% CI) of each MetS component, when diagnosed four times serially, was as follows: 1.84 (1.46–2.32) for impaired fasting glucose, 1.55 (1.31–1.83) for increased waist circumference (WC), 1.52 (1.26–1.84) for elevated blood pressure, 1.32 (1.05–1.66) for low HDL-C, and 1.19 (1.00–1.40) for elevated TG.

Subgroup analysis

Additional subgroup analyses for RVO development and the cumulative number of MetS were performed and are presented in Table 3. MetS increased the risk of RVO development greater in the female subgroup than in the male subgroup (adjusted HR (95% CI), 4.76 (2.48–9.15) for female, 1.49 (1.17–1.91) for male; P for interaction <0.0001; when diagnosed four times consecutively). Other variables including obesity, current smoking, heavy drinking, and regular performance did not show significant differences in the subgroup analyses.

Table 3. The risk of retinal vein occlusion according to the cumulative number of MetS in various subgroups.

The number of the presence of the metabolic syndrome No. of participants RVO IR (1000PY) HR (95% CI) Interaction P
Age
    <30 0 313,144 199 0.15 1.00 (Reference) 0.1286
1 24,970 9 0.08 0.61 (0.31–1.20)
2 9,392 11 0.28 1.86 (0.98–3.52)
3 5,030 5 0.24 1.44 (0.57–3.66)
4 3,004 5 0.39 1.90 (0.69–5.18)
    ≥30 0 759,073 815 0.22 1.00 (Reference)
1 140,790 213 0.31 1.25 (1.07–1.46)
2 71,109 122 0.35 1.31 (1.08–1.60)
3 45,682 104 0.47 1.58 (1.27–1.96)
4 35,899 110 0.63 1.69 (1.33–2.14)
Sex
    Male 0 703,191 727 0.22 1.00 (Reference) < .0001
1 149,321 199 0.28 1.14 (0.97–1.33)
2 74,779 117 0.33 1.22 (1.00–1.49)
3 47,505 104 0.46 1.54 (1.24–1.91)
4 36,547 98 0.56 1.49 (1.17–1.91)
    Female 0 36,9026 287 0.17 1.00 (Reference)
1 16,439 23 0.30 1.61 (1.04–2.48)
2 5,722 16 0.60 2.94 (1.74–4.97)
3 3,207 5 0.33 1.42 (0.57–3.57)
4 2,356 17 1.56 4.76 (2.48–9.15)
Obesity
    No 0 857,392 789 0.19 1.00 (Reference) 0.3659
1 68,993 81 0.24 1.03 (0.81–1.30)
2 19,324 40 0.42 1.56 (1.12–2.17)
3 7,126 18 0.51 1.58 (0.97–2.58)
4 2,873 9 0.63 1.37 (0.68–2.77)
    Yes 0 214,825 225 0.22 1.00 (Reference)
1 96,767 141 0.31 1.26 (1.02–1.56)
2 61,177 93 0.32 1.21 (0.94–1.55)
3 43,586 91 0.44 1.49 (1.16–1.93)
4 36,030 106 0.62 1.68 (1.28–2.20)
Current smoker
    No 0 719,381 704 0.21 1.00 (Reference) 0.4681
1 83,205 127 0.32 1.28 (1.05–1.55)
2 37,802 68 0.38 1.37 (1.06–1.78)
3 22,593 47 0.44 1.44 (1.05–1.97)
4 16,511 51 0.65 1.72 (1.23–2.41)
    Yes 0 352,836 310 0.18 1.00 (Reference)
1 82,555 95 0.24 1.12 (0.89–1.41)
2 42,699 65 0.32 1.34 (1.02–1.76)
3 28,119 62 0.46 1.70 (1.27–2.27)
4 22,392 64 0.59 1.66 (1.21–2.29)
Heavy drinka
    No 0 989,667 940 0.20 1.00 (Reference) 0.513
1 143,691 192 0.28 1.18 (1.01–1.39)
2 68,573 109 0.33 1.29 (1.05–1.58)
3 42,792 97 0.47 1.66 (1.32–2.07)
4 32,677 99 0.63 1.75 (1.37–2.24)
    Yes 0 82,550 74 0.19 1.00 (Reference)
1 22,069 30 0.28 1.32 (0.86–2.03)
2 11,928 24 0.42 1.78 (1.10–2.87)
3 7,920 12 0.32 1.18 (0.62–2.25)
4 6,226 16 0.53 1.55 (0.82–2.90)
Regular exerciseb
    No 0 885,121 832 0.20 1.00 (Reference) 0.2396
1 135,030 183 0.28 1.21 (1.03–1.43)
2 65,699 98 0.31 1.21 (0.98–1.51)
3 41,534 86 0.43 1.50 (1.18–1.90)
4 32,156 97 0.63 1.70 (1.32–2.18)
    Yes 0 187,096 182 0.21 1.00 (Reference)
1 30,730 39 0.27 1.15 (0.80–1.63)
2 14,802 35 0.49 1.99 (1.36–2.90)
3 9,178 23 0.53 1.95 (1.23–3.09)
4 6,747 18 0.56 1.72 (0.99–3.02)
Open in a new tab

HRs with 95% CI were calculated using a Cox proportional hazards model adjusting age, sex, smoking status, alcohol intake, and regular exercisde.

a Heavy drinkers were defined as those who drank more than 30 g/d.

b Regular exercise was defined as strenuous physical activity that was performed for at least 30 minutes at least five times a week.

Discussion

RVO, especially CRVO, is a significant cause of visual impairment in individuals of any age [19, 20]. A nationwide, retrospective study using data from the Korean National Health Claims Database, spanning 2007 to 2011, revealed the RVO incidences per 100,000 person-years [21]. For ages 20–29, 30–39, and 40–49, the rates were 4.03, 10.32, and 32.22, respectively. The rates dramatically increased with age, with incidences of 80.22 for ages 50–59 and 172.90 for ages 60–69. This pattern shows a more than twofold increase in incidence every decade from the 20s to the 70s.

Younger patients with RVO have a variable clinical course [22, 23]. Although young patients with RVO generally have a better visual prognosis [7, 24–28], at least 20% of patients are known to develop poor visual outcomes with severe neovascular complications [10, 29]. Therefore, identifying factors associated with the development of RVO in young subjects would be of great value.

To the best of our knowledge, this is the first large nationwide population-based cohort study to report the cumulative effect of MetS and its components on the risk of RVO in young adults. The key findings of this study can be summarized as follows: (1) the cumulative burden of MetS during the four health examinations had a linear correlation with the risk of RVO, (2) the cumulative burden of each MetS component showed a positive association with the risk of RVO, (3) among the five metabolic components, impaired fasting glucose showed the greatest increase in RVO risks, and (4) MetS increased the risk of RVO more in females.

The association of MetS and its components with RVO has been reported in several previous studies [6, 30]. While these studies analyzed the number of MetS components at a single point, our study investigated the accumulated effects of MetS identified in four consecutive health examinations. Participants who were diagnosed with MetS at one time had a 20% increased risk of RVO compared to those without MetS, whereas participants who were diagnosed with MetS four times had a 71% higher risk of RVO. Such a positive increase in RVO according to the repeated diagnosis of metabolic components may suggest a dose-response perspective for evaluating the risk of retinal microvascular disease. Given the proportional increase in RVO risk according to the degree of metabolic burden with temporal changes, it is plausible that the risk of RVO would be higher in patients diagnosed with MetS more than four times during their health checkups.

Among the five diagnostic components of MetS, the impact of WC on RVO occurrence was particularly significant when individuals with impaired fasting glucose, prediabetes, or diabetes were excluded. In a previous population-based study of individuals aged 20 years and older, elevated blood pressure was the greatest risk and increased WC was the minimal risk for RVO development, revealing adjusted hazard ratios of 1.610 (95% CI 1.589–1.631) for BP and 1.212 (95% CI 1.197–1.227) for WC [6]. The reason for the discrepancy in the results of the present study may be associated with age. Another population-based study revealed that obesity has different effects on the incidence of RVO in the presence and absence of DM. In individuals with DM, a lower body mass index (BMI) and WC were associated with an increased risk of RVO, while a higher BMI and WC were associated with a lower risk of RVO. In those without DM, the correlation was reversed; a lower WC was associated with a lower risk of RVO and vice versa [31]. Since the prevalence of DM is lower in the younger population, our study of younger individuals showed similar results to the group without DM. As the cumulative number of times included in the WC criterion increased during the four health examination checkups, the risk of RVO occurrence increased linearly. Further studies are required to determine whether there is a definitive causal relationship between WC and MetS.

The sex differences are observed in MetS prevalence and cardiovascular disease (CVD) risk [32]. Studies have shown that the risk for CVD in MetS is greater among females than among males [33, 34]. Each component of MetS also has shown sex differences; dyslipidemia was associated with a greater risk for coronary artery disease, and congestive heart failure was more commonly seen as a consequence of hypertension in females than in males [32]. Similarly, the subgroup analysis for the impact of MetS on RVO occurrence has revealed that MetS has a greater impact on female subjects. Several circumstances specific to females, including pregnancy, polycystic ovary syndrome, and oral contraceptive therapy may play a role in increasing these risks. In addition, it is well known that the prevalence of MetS increases with menopause [35], and the risk of RVO is reported to increase in MetS [6]. Furthermore, a recent study showed that early menopause is associated with an increased risk of RVO [36]. However, in premenopausal women with a relatively low risk of MetS, as in the present study, although the exact mechanism is unclear and requires further investigation, there may be risk factors that can cause MetS other than a decrease in estrogen, which may also affect the occurrence of RVO.

The data employed in this study originates from nationwide health examinations administered to the entire cohort of employed individuals aged 20 and above. These examinations are not individually solicited according to personal healthcare requirements, thereby mitigating the potential for differential screening rates among individuals with suboptimal overall health or higher socioeconomic status.

Our study had several limitations. First, using a claims database focused solely on healthcare utilization to identify patients with RVO may have underrepresented asymptomatic cases. Therefore, our data reflected the incidence of clinically diagnosed RVO, potentially underestimating the true occurrence of RVO. Second, the lack of access to hospital-based medical records to validate RVO occurrences and review clinical data compromised the accuracy of the study data. These limitations include the risk of misclassifying diagnoses and the inability to assess factors such as severity, extent, prognosis, or patient comorbidities. Third, owing to the inherent constraints of studies utilizing claims databases, clinical characteristics and interobserver variability in RVO diagnosis were not standardized. Fourth, male patients comprised over two-thirds of the participants, owing to the higher probability of employees undergoing routine health checkups at their workplaces. This sex imbalance introduces a potential selection bias, limiting the representation of both sexes in the broader population. Furthermore, the selection criteria, emphasizing individuals who underwent health assessments four times over four years, might not fully capture the demographics of individuals in their 20s and 30s within the general population.

The major limitation of the present study is that an analysis utilizing the Charlson Comorbidity Index was not performed. Furthermore, the analysis did not account for the use of contraceptives, which is associated with an increased risk of retinal vascular occlusion [37]. Although RVO in younger patients may be related to systemic diseases, such as rheumatic disorders and leukemia, this study did not evaluate the associations with these specific diseases.

Conclusions

In conclusion, this large-scale population-based cohort study revealed that the cumulative burden of MetS and its components was positively correlated with the risk of RVO in young adults. Given the association found in this study, prompt detection of metabolic derangements and their treatment might be important for decreasing the risk of RVO in young adults, especially in females.

Supporting information

S1 Checklist. STROBE statement—checklist of items that should be included in reports of observational studies.

(DOCX)

pone.0303871.s001.docx (37.6KB, docx)

Acknowledgments

The authors wish to thank the National Health Insurance Service for providing the data regarding the original cohort.

Data Availability

Access to raw data from the Korean Health Insurance Review and Assessment (HIRA) service is regulated by the Rules for Data Exploration and Use of the HIRA. Data are available from the Health Insurance Review and Assessment Service database for researchers who meet the criteria for access to confidential data after receiving approval from the HIRA Data Access Committee. The HIRA data can be obtained using the website (http://opendata.hira.or.kr).

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Ip M, Hendrick A. Retinal Vein Occlusion Review. Asia Pac J Ophthalmol (Phila). 2018;7(1):40–5. doi: 10.22608/APO.2017442 [DOI] [PubMed] [Google Scholar]
  • 2.Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313–9. e1. doi: 10.1016/j.ophtha.2009.07.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Laouri M, Chen E, Looman M, Gallagher M. The burden of disease of retinal vein occlusion: review of the literature. Eye. 2011;25(8):981–8. doi: 10.1038/eye.2011.92 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Nalcaci S, Degirmenci C, Akkin C, Mentes J. Etiological factors in young patients with Retinal Vein Occlusion. Pak J Med Sci. 2019;35(5):1397–401. doi: 10.12669/pjms.35.5.546 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Kolar P. Risk factors for central and branch retinal vein occlusion: a meta-analysis of published clinical data. Journal of ophthalmology. 2014;2014. doi: 10.1155/2014/724780 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lim DH, Shin KY, Han K, Kang SW, Ham D-I, Kim SJ, et al. Differential effect of the metabolic syndrome on the incidence of retinal vein occlusion in the Korean population: a nationwide cohort study. Translational Vision Science & Technology. 2020;9(13):15–. doi: 10.1167/tvst.9.13.15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Eah KS, Kim YN, Park YJ, Lee JY, Kim JG, Yoon YH, et al. CENTRAL RETINAL VEIN OCCLUSION IN YOUNG PATIENTS: Clinical Characteristics and Prognostic Factors. Retina. 2021;41(3):630–7. doi: 10.1097/IAE.0000000000002872 [DOI] [PubMed] [Google Scholar]
  • 8.Sinawat S, Bunyavee C, Ratanapakorn T, Sinawat S, Laovirojjanakul W, Yospaiboon Y. Systemic abnormalities associated with retinal vein occlusion in young patients. Clinical Ophthalmology (Auckland, NZ). 2017;11:441. doi: 10.2147/OPTH.S128341 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Mattsson N, Rönnemaa T, Juonala M, Viikari JS, Raitakari OT. The prevalence of the metabolic syndrome in young adults. The Cardiovascular Risk in Young Finns Study. J Intern Med. 2007;261(2):159–69. doi: 10.1111/j.1365-2796.2006.01752.x [DOI] [PubMed] [Google Scholar]
  • 10.Fong AC, Schatz H. Central retinal vein occlusion in young adults. Surv Ophthalmol. 1993;37(6):393–417. doi: 10.1016/0039-6257(93)90138-w [DOI] [PubMed] [Google Scholar]
  • 11.Elsman EBM, van Rens G, van Nispen RMA. Quality of life and participation of young adults with a visual impairment aged 18–25 years: comparison with population norms. Acta Ophthalmol. 2019;97(2):165–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Ahn HJ, Han KD, Choi EK, Jung JH, Kwon S, Lee SR, et al. Cumulative burden of metabolic syndrome and its components on the risk of atrial fibrillation: a nationwide population-based study. Cardiovasc Diabetol. 2021;20(1):20. doi: 10.1186/s12933-021-01215-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Choi E-K. Cardiovascular research using the Korean national health information database. Korean Circulation Journal. 2020;50(9):754–72. doi: 10.4070/kcj.2020.0171 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Cheol Seong S, Kim Y-Y, Khang Y-H, Heon Park J, Kang H-J, Lee H, et al. Data resource profile: the national health information database of the National Health Insurance Service in South Korea. International journal of epidemiology. 2017;46(3):799–800. doi: 10.1093/ije/dyw253 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735–52. doi: 10.1161/CIRCULATIONAHA.105.169404 [DOI] [PubMed] [Google Scholar]
  • 16.Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama. 2001;285(19):2486–97. [DOI] [PubMed] [Google Scholar]
  • 17.Seo MH, Lee W-Y, Kim SS, Kang J-H, Kang J-H, Kim KK, et al. 2018 Korean Society for the Study of Obesity guideline for the management of obesity in Korea. Journal of obesity & metabolic syndrome. 2019;28(1):40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Lee SR, Choi EK, Kwon S, Han KD, Jung JH, Cha MJ, et al. Effectiveness and Safety of Contemporary Oral Anticoagulants Among Asians With Nonvalvular Atrial Fibrillation. Stroke. 2019;50(8):2245–9. doi: 10.1161/STROKEAHA.119.025536 [DOI] [PubMed] [Google Scholar]
  • 19.Baseline and early natural history report. The Central Vein Occlusion Study. Arch Ophthalmol. 1993;111(8):1087–95. [DOI] [PubMed] [Google Scholar]
  • 20.Risk factors for central retinal vein occlusion. The Eye Disease Case-Control Study Group. Arch Ophthalmol. 1996;114(5):545–54. [PubMed] [Google Scholar]
  • 21.Park SJ, Choi NK, Park KH, Woo SJ. Nationwide incidence of clinically diagnosed retinal vein occlusion in Korea, 2008 through 2011: preponderance of women and the impact of aging. Ophthalmology. 2014;121(6):1274–80. doi: 10.1016/j.ophtha.2013.12.024 [DOI] [PubMed] [Google Scholar]
  • 22.Recchia FM, Carvalho-Recchia CA, Hassan TS. Clinical course of younger patients with central retinal vein occlusion. Arch Ophthalmol. 2004;122(3):317–21. doi: 10.1001/archopht.122.3.317 [DOI] [PubMed] [Google Scholar]
  • 23.Zhang XT, Zhong YF, Xue YQ, Li SQ, Wang BY, Zhang GQ, et al. Clinical Features of Central Retinal Vein Occlusion in Young Patients. Ophthalmol Ther. 2022;11(4):1409–22. doi: 10.1007/s40123-022-00534-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Rothman AL, Thomas AS, Khan K, Fekrat S. CENTRAL RETINAL VEIN OCCLUSION IN YOUNG INDIVIDUALS: A Comparison of Risk Factors and Clinical Outcomes. Retina. 2019;39(10):1917–24. doi: 10.1097/IAE.0000000000002278 [DOI] [PubMed] [Google Scholar]
  • 25.Battaglia Parodi M, Iacono P, Sacconi R, Parravano M, Varano M, Bandello F. DEXAMETHASONE IMPLANT FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION IN PATIENTS YOUNGER THAN 50 YEARS. Retina. 2015;35(7):1381–6. doi: 10.1097/IAE.0000000000000494 [DOI] [PubMed] [Google Scholar]
  • 26.Lindsell LB, Lai MM, Fine HF. Current concepts in managing retinal vein occlusion in young patients. Ophthalmic Surg Lasers Imaging Retina. 2015;46(7):695–701. doi: 10.3928/23258160-20150730-02 [DOI] [PubMed] [Google Scholar]
  • 27.Walters RF, Spalton DJ. Central retinal vein occlusion in people aged 40 years or less: a review of 17 patients. Br J Ophthalmol. 1990;74(1):30–5. doi: 10.1136/bjo.74.1.30 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Ye P, Zhu T, Zheng F, Zhou M, Fang X, Yao K. Microvascular comparison in younger and older patients with retinal vein occlusion analyzed by OCT angiography. BMC Ophthalmol. 2021;21(1):161. doi: 10.1186/s12886-021-01931-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Nicholson L, Talks SJ, Amoaku W, Talks K, Sivaprasad S. Retinal vein occlusion (RVO) guideline: executive summary. Eye. 2022;36(5):909–12. doi: 10.1038/s41433-022-02007-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Kim J, Lim DH, Han K, Kang SW, Ham D-I, Kim SJ, et al. Retinal vein occlusion is associated with low blood high-density lipoprotein cholesterol: a nationwide cohort study. American Journal of Ophthalmology. 2019;205:35–42. [DOI] [PubMed] [Google Scholar]
  • 31.Paik DW, Han K, Kang SW, Ham D-I, Kim SJ, Chung T-Y, et al. Differential effect of obesity on the incidence of retinal vein occlusion with and without diabetes: a Korean nationwide cohort study. Scientific reports. 2020;10(1):1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Bentley-Lewis R, Koruda K, Seely EW. The metabolic syndrome in women. Nature clinical practice Endocrinology & metabolism. 2007;3(10):696–704. doi: 10.1038/ncpendmet0616 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Sarafidis PA, McFarlane SI, Bakris GL. Gender disparity in outcomes of care and management for diabetes and the metabolic syndrome. Current Diabetes Reports. 2006;6(3):219–24. doi: 10.1007/s11892-006-0038-3 [DOI] [PubMed] [Google Scholar]
  • 34.Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation. 2004;110(10):1251–7. doi: 10.1161/01.CIR.0000140762.04598.F9 [DOI] [PubMed] [Google Scholar]
  • 35.Carr MC. The emergence of the metabolic syndrome with menopause. The Journal of Clinical Endocrinology & Metabolism. 2003;88(6):2404–11. doi: 10.1210/jc.2003-030242 [DOI] [PubMed] [Google Scholar]
  • 36.Hwang S, Kang SW, Choi KJ, Son KY, Lim DH, Shin DW, et al. Early menopause is associated with increased risk of retinal vascular occlusions: a nationwide cohort study. Sci Rep. 2022;12(1):6068. doi: 10.1038/s41598-022-10088-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Aggarwal RS, Mishra VV, Aggarwal SV. Oral contraceptive pills: A risk factor for retinal vascular occlusion in in-vitro fertilization patients. J Hum Reprod Sci. 2013;6(1):79–81. doi: 10.4103/0974-1208.112389 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Se Woong Kang

24 Oct 2023

PONE-D-23-20018Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: a nationwide population-based studyPLOS ONE

Dear Dr. Kim,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 08 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Se Woong Kang, Ph.D., M.D.

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

""Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

3. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. 

REVIEWER 1

Kim et al. demonstrated the impact of the longitudinal cumulative burden of METS on RVO in a young population. Given the significant impact of eye diseases in the young population, this research holds considerable value. Moreover, the examination of cumulative burden is an interesting aspect of the study. However, there are several points that need to be addressed:

1. While it is acknowledged that disease burden is higher in the young population, it would be beneficial to mention how the RVO incidence in the 20-40 age group compares to the overall population incidence or the incidence in the elderly. Since there have been similar studies conducted in Korea previously, referencing these studies for comparison would enhance the discussion.

2. On line 82, Figure 2 precedes Figure 1 in the manuscript. It is advisable to reverse the order for clarity.

3. Regarding line 82, please provide a rationale for the selection of a 1-year lag period.

4. Regarding Figure 2, does this study include individuals who underwent health examinations four times between 2009 and 2012? If so, the index data should presumably be in 2012. However, in Figure 2, it mentions the exclusion of cases diagnosed with RVO from 2002 to 2009 and within one year from the index date. Does this mean that individuals diagnosed with RVO in 2010 were not excluded? I assume that individuals diagnosed with RVO before the index date might have been excluded. The flow chart requires further clarification to provide a clearer understanding.

5. On line 167, the conclusion "among the five metabolic components, increased WC had the greatest increase in RVO risks" needs further clarification. What criteria were used to reach this conclusion? Among the components, it appears that impaired fasting glucose has the highest risk when there are four times serial abnormalities. Please elaborate.

6. On line 177, the statement, "it can be inferred that the risk of RVO increases more than four times in people diagnosed with MetS during health examinations," requires additional clarification. It is crucial to elucidate the specific findings or results that led the author to draw such a conclusion. What specific data or analysis supports this assertion?

7. On line 191, it is suggested to tone down the statement: "Therefore, among the components of MetS, reducing WC is particularly important for reducing the risk of RVO," as the results of this study suggests an association and cannot establish a causal relationship.

8. On line 201, please consider referencing a study that suggests menopause may influence RVO risk, such as:

Hwang S, Kang SW, Choi KJ, Son KY, Lim DH, Shin DW, Choi D, Kim SJ. Early menopause is associated with an increased risk of retinal vascular occlusions: a nationwide cohort study. Sci Rep. 2022 Apr 12;12(1):6068. doi: 10.1038/s41598-022-10088-0. PMID: 35414644;

9. The limitations inherent in this type of research, which relies on claim data, should be thoroughly addressed. Specifically, the inability to independently verify diagnoses and the fact that the study only captures patients who visited healthcare services need to be acknowledged.

10. It is important to note that the initial study sample of 6,891,399 individuals primarily comprises those who underwent health examinations, potentially limiting its representativeness for the broader population. Additionally, the selection criteria, focusing on individuals who underwent health examinations four times over four years, may not accurately reflect 20s and 30s of general population. Furthermore, the high male representation within the study participants should also be acknowledged. Therefore, it is imperative to acknowledge these limitations within the manuscript for transparency and completeness.

REVIEWER 2

The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion. As described below, there are several areas for improvement.

1. there are serious concerns about selection bias in the selection of study subjects. Populations under the age of 40 who receive annual health checks are more likely to have more systemic diseases or higher socioeconomic status, and this should be taken into account.

2. Even among populations that receive annual health checks, data may be missing for some of the parameters examined in this study, such as waist circumference. Please explain how you handled this.

3. While most other studies set the washout period at a minimum of 2 years and sometimes longer, this study set it at 1 year. Therefore, it is possible that patients with previously diagnosed RVOs were included rather than patients with new onset, and this needs further explanation.

4. line 104 states that all RVOs were included based on ICD-10, and the legend to Figure 2 states that they were categorized using KCD disease classification codes. To my knowledge, the two-digit decimal codes used for figure legends have been in use since KCD-6 in 2010. Please explain the exact classification used in this study in the Methods section.

5. The chronic kidney disease diagnosis code does not indicate a specific diagnosis, so it is better to use the eGFR measurements rather than CKD code.

6. If you used multiple models in your evaluation, please describe your results using the commonly used Charlson-Comorbiditi index.

7. The survey items were slightly different for each year, which may have resulted in inconsistent survey questions for certain items such as alcohol drinking and exercise. Please explain how you handled this.

8. The incidence of metabolic syndrome and RVO was very low in people under age 30, which may be due to a stronger association with systemic diseases such as leukemia other than metabolic syndrome. Have you done any further analysis on this?

9. You mentioned that there is a difference between men and women, but the study was based on younger people, so it is possible that the difference is due to contraceptive use. If you have analyzed differences due to contraceptive use, please present the results.

10. You cited another study in the discussion section, did this study also find differences in other parameters including WC based on DM? Please present the results.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Kim et al. demonstrated the impact of the longitudinal cumulative burden of METS on RVO in a young population. Given the significant impact of eye diseases in the young population, this research holds considerable value. Moreover, the examination of cumulative burden is an interesting aspect of the study. However, there are several points that need to be addressed:

1. While it is acknowledged that disease burden is higher in the young population, it would be beneficial to mention how the RVO incidence in the 20-40 age group compares to the overall population incidence or the incidence in the elderly. Since there have been similar studies conducted in Korea previously, referencing these studies for comparison would enhance the discussion.

2. On line 82, Figure 2 precedes Figure 1 in the manuscript. It is advisable to reverse the order for clarity.

3. Regarding line 82, please provide a rationale for the selection of a 1-year lag period.

4. Regarding Figure 2, does this study include individuals who underwent health examinations four times between 2009 and 2012? If so, the index data should presumably be in 2012. However, in Figure 2, it mentions the exclusion of cases diagnosed with RVO from 2002 to 2009 and within one year from the index date. Does this mean that individuals diagnosed with RVO in 2010 were not excluded? I assume that individuals diagnosed with RVO before the index date might have been excluded. The flow chart requires further clarification to provide a clearer understanding.

5. On line 167, the conclusion "among the five metabolic components, increased WC had the greatest increase in RVO risks" needs further clarification. What criteria were used to reach this conclusion? Among the components, it appears that impaired fasting glucose has the highest risk when there are four times serial abnormalities. Please elaborate.

6. On line 177, the statement, "it can be inferred that the risk of RVO increases more than four times in people diagnosed with MetS during health examinations," requires additional clarification. It is crucial to elucidate the specific findings or results that led the author to draw such a conclusion. What specific data or analysis supports this assertion?

7. On line 191, it is suggested to tone down the statement: "Therefore, among the components of MetS, reducing WC is particularly important for reducing the risk of RVO," as the results of this study suggests an association and cannot establish a causal relationship.

8. On line 201, please consider referencing a study that suggests menopause may influence RVO risk, such as:

Hwang S, Kang SW, Choi KJ, Son KY, Lim DH, Shin DW, Choi D, Kim SJ. Early menopause is associated with an increased risk of retinal vascular occlusions: a nationwide cohort study. Sci Rep. 2022 Apr 12;12(1):6068. doi: 10.1038/s41598-022-10088-0. PMID: 35414644;

9. The limitations inherent in this type of research, which relies on claim data, should be thoroughly addressed. Specifically, the inability to independently verify diagnoses and the fact that the study only captures patients who visited healthcare services need to be acknowledged.

10. It is important to note that the initial study sample of 6,891,399 individuals primarily comprises those who underwent health examinations, potentially limiting its representativeness for the broader population. Additionally, the selection criteria, focusing on individuals who underwent health examinations four times over four years, may not accurately reflect 20s and 30s of general population. Furthermore, the high male representation within the study participants should also be acknowledged. Therefore, it is imperative to acknowledge these limitations within the manuscript for transparency and completeness.

These points, once addressed, will significantly enhance the quality and comprehensibility of the manuscript.

Reviewer #2: The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion. As described below, there are several areas for improvement.

1. there are serious concerns about selection bias in the selection of study subjects. Populations under the age of 40 who receive annual health checks are more likely to have more systemic diseases or higher socioeconomic status, and this should be taken into account.

2. Even among populations that receive annual health checks, data may be missing for some of the parameters examined in this study, such as waist circumference. Please explain how you handled this.

3. While most other studies set the washout period at a minimum of 2 years and sometimes longer, this study set it at 1 year. Therefore, it is possible that patients with previously diagnosed RVOs were included rather than patients with new onset, and this needs further explanation.

4. line 104 states that all RVOs were included based on ICD-10, and the legend to Figure 2 states that they were categorized using KCD disease classification codes. To my knowledge, the two-digit decimal codes used for figure legends have been in use since KCD-6 in 2010. Please explain the exact classification used in this study in the Methods section.

5. The chronic kidney disease diagnosis code does not indicate a specific diagnosis, so it is better to use the eGFR measurements rather than CKD code.

6. If you used multiple models in your evaluation, please describe your results using the commonly used Charlson-Comorbiditi index.

7. The survey items were slightly different for each year, which may have resulted in inconsistent survey questions for certain items such as alcohol drinking and exercise. Please explain how you handled this.

8. The incidence of metabolic syndrome and RVO was very low in people under age 30, which may be due to a stronger association with systemic diseases such as leukemia other than metabolic syndrome. Have you done any further analysis on this?

9. You mentioned that there is a difference between men and women, but the study was based on younger people, so it is possible that the difference is due to contraceptive use. If you have analyzed differences due to contraceptive use, please present the results.

10. You cited another study in the discussion section, did this study also find differences in other parameters including WC based on DM? Please present the results.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 May 20;19(5):e0303871. doi: 10.1371/journal.pone.0303871.r002

Author response to Decision Letter 0

20 Jan 2024

*General comments

When submitting your revision, we need you to address these additional requirements.

- Response: Thank you for the instructions and insightful comments. The manuscript has been revised in accordance with the additional comments.

*Comment 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

- Response: We revised the manuscript according to PLOS ONE's style requirements.

*Comment 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

- Response: The following Data Availability statement has been added in the revised manuscript (page 1, line 18).

Data Availability Statement: Access to raw data from the Korean Health Insurance Review and Assessment (HIRA) service is regulated by the Rules for Data Exploration and Use of the HIRA. Data are available from the Health Insurance Review and Assessment Service database for researchers who meet the criteria for access to confidential data after receiving approval from the HIRA Data Access Committee. The HIRA data can be obtained using the website (http://opendata.hira.or.kr).

""Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

*Comment 3. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

- Response: The following paragraph has been inserted into the Methods section of the revised manuscript:

(After revision, page 3, line 62)

The methods of Ahn et al. were grossly referenced in this study[12]. This study was approved by the Institutional Review Board (IRB) of Kim’s Eye Hospital (Kim’s Eye Hospital IRB; IRB number KEH 2022-04-008), and was conducted according to the principles of the Declaration of Helsinki. The need for informed consent was waived by the IRB of Kim’s Eye Hospital, because the study did not include any identifiable information about the subjects. The Korean National Health Insurance Corporation has allowed authors to use the database based on the approved IRB. The data access dates for research purposes were June 2, 2022

REVIEWER 1

*Comment. Kim et al. demonstrated the impact of the longitudinal cumulative burden of METS on RVO in a young population. Given the significant impact of eye diseases in the young population, this research holds considerable value. Moreover, the examination of cumulative burden is an interesting aspect of the study. However, there are several points that need to be addressed:

- Response: Thank you for the comments. We have made our best efforts to address the issues raised by the reviewer. We believe that the manuscript has undergone significant improvements. We hope that our responses address the concerns regarding this manuscript. Detailed responses to the reviewers’ comments are provided below.

*Comment 1. While it is acknowledged that disease burden is higher in the young population, it would be beneficial to mention how the RVO incidence in the 20-40 age group compares to the overall population incidence or the incidence in the elderly. Since there have been similar studies conducted in Korea previously, referencing these studies for comparison would enhance the discussion.

- Response: A nationwide retrospective study using data from the Korean National Health Claims Database from 2007 to 2011 revealed the RVO incidences per 100,000 person-years. For ages 20-29, 30-39, and 40-49, the rates were 4.03, 10.32, and 32.22, respectively. The rates dramatically increased with age, with an incidence of 80.22 for age 50-59 and 172.90 for ages 60-69. This pattern shows a more than twofold increase in incidence every decade from the 20s to the 70s.

The following paragraph has been added to the revised manuscript.

(After revision, page 20, line 193)

A nationwide retrospective study using data from the Korean National Health Claims Database from 2007 to 2011 revealed the RVO incidences per 100,000 person-years.[21] For ages 20-29, 30-39, and 40-49, the rates were 4.03, 10.32, and 32.22, respectively. The rates dramatically increased with age, with incidences of 80.22 for ages 50-59 and 172.90 for ages 60-69. This pattern shows a more than twofold increase in incidence every decade from the 20s to the 70s.

*Comment 2. On line 82, Figure 2 precedes Figure 1 in the manuscript. It is advisable to reverse the order for clarity.

- Response: The positions of Figure 1 and Figure 2 were switched.

*Comment 3. Regarding line 82, please provide a rationale for the selection of a 1-year lag period.

- Response: A one-year lag period was implemented to enhance the causality of the research. This was done to mitigate the possibility of delayed RVO diagnoses due to delayed eye examinations and to exclude individuals who received regular checkups over a four-year period and passed away within one year thereafter. By excluding these possibilities, this study aimed to increase the causality of the research, measure exposure over a four-year period, and observe the occurrence of RVO one year after the measurements were taken.

The following revision has been made to clarify this point.

(After revision, page 4, line 83)

A one-year lag period was implemented to enhance the causality of the study. This was done to mitigate the possibility of delayed RVO diagnoses due to delayed eye examinations and to exclude individuals who received regular checkups over a four-year period and passed away within one year thereafter. By excluding these possibilities, this study aimed to increase the causality of the research, measure exposure over a four-year period, and observe the occurrence of RVO one year after the measurements were taken.

*Comment 4. Regarding Figure 2, does this study include individuals who underwent health examinations four times between 2009 and 2012? If so, the index data should presumably be in 2012. However, in Figure 2, it mentions the exclusion of cases diagnosed with RVO from 2002 to 2009 and within one year from the index date. Does this mean that individuals diagnosed with RVO in 2010 were not excluded? I assume that individuals diagnosed with RVO before the index date might have been excluded. The flow chart requires further clarification to provide a clearer understanding.

- Response: In the Figure 2 legend, the specific meaning of the sentence “Patients who received a health examination between January 1, 2009, and December 31, 2012 and have subsequently undergone four consecutive examinations thereafter” is as follows: For the 2009 group, participants who underwent annual health examinations in four consecutive years from 2009 to 2012; in the 2010 group, participants who underwent annual health examinations in four consecutive years from 2010 to 2013; in the 2011 group, participants who underwent annual health examinations in four consecutive years from 2011 to 2014; and in the 2012 group, participants who underwent annual health examinations in four consecutive years from 2012 to 2014. The exclusion criteria were as follows: in 2009, for example, individuals who underwent annual health examinations from 2009 to 2012, and experienced RVO or died in 2013 were excluded.

These points have been clarified. In addition, in response to comment #2, the order of Figure 1 and Figure 2 was reversed.

(After revision, page 5, figure legend for figure 1)

(For example, for 2009, participants underwent annual health examinations continuously for four years from 2009 to 2012)

(After revision, page 5, figure legend for figure 1)

(For example, for 2009, individuals who received annual health examinations from 2009 to 2012 and experienced RVO or died in 2013 were excluded.)

*Comment 5. On line 167, the conclusion "among the five metabolic components, increased WC had the greatest increase in RVO risks" needs further clarification. What criteria were used to reach this conclusion? Among the components, it appears that impaired fasting glucose has the highest risk when there are four times serial abnormalities. Please elaborate.

- Response: As you have pointed out, impaired fasting glucose has the highest risk when there are four serial abnormalities (Table 2). We revised this sentence as follows:

(In the original manuscript, discussion section)

(3) among the five metabolic components, increased WC had the greatest increase in RVO risks

Among the five diagnostic components of MetS, the impact of WC on RVO occurrence was particularly significant.

(After revision, page 20, line 206)

(3) among the five metabolic components, impaired fasting glucose showed the greatest increase in RVO risk.

(After revision, page 21, line 219)

Among the five diagnostic components of MetS, the impact of WC on RVO occurrence was particularly significant when individuals with impaired fasting glucose, prediabetes, or diabetes were excluded.

*Comment 6. On line 177, the statement, "it can be inferred that the risk of RVO increases more than four times in people diagnosed with MetS during health examinations," requires additional clarification. It is crucial to elucidate the specific findings or results that led the author to draw such a conclusion. What specific data or analysis supports this assertion?

- Response: This sentence appears to have been misrepresented during the English language correction process. We meant to refer to four diagnoses, not to a risk four times as high. We have revised this to the following sentence:

(After revision, page 20, line 216)

"Given the proportional increase in RVO risk according to the degree of metabolic burden with temporal changes, it is plausible that the risk of RVO would be higher in patients diagnosed with MetS more than four times during their health checkups."

*Comment 7. On line 191, it is suggested to tone down the statement: "Therefore, among the components of MetS, reducing WC is particularly important for reducing the risk of RVO," as the results of this study suggests an association and cannot establish a causal relationship.

- Response: We agree with your comment that a causal relationship cannot be proven based on the study results. The following revisions have been made to improve the clarity of the statement.

(In the original manuscript, discussion section)

Therefore, among the components of MetS, reducing WC is particularly important for reducing the risk of RVO.

(After revision, page 21, line 232)

Further studies are required to determine whether there is a definitive causal relationship between WC and MetS.

*Comment 8. On line 201, please consider referencing a study that suggests menopause may influence RVO risk, such as:

Hwang S, Kang SW, Choi KJ, Son KY, Lim DH, Shin DW, Choi D, Kim SJ. Early menopause is associated with an increased risk of retinal vascular occlusions: a nationwide cohort study. Sci Rep. 2022 Apr 12;12(1):6068. doi: 10.1038/s41598-022-10088-0. PMID: 35414644;

- Response: The following revisions have been made to include the potential effect of menopause on the risk of RVO.

(After revision, page 21, line 243)

Furthermore, a recent study showed that early menopause is associated with an increased risk of RVO.[36]

(After revision, page 27, line 371)

A new reference has been added.

*Comment 9. The limitations inherent in this type of research, which relies on claim data, should be thoroughly addressed. Specifically, the inability to independently verify diagnoses and the fact that the study only captures patients who visited healthcare services need to be acknowledged.

- Response: Thank you for the comment. We have added the following paragraph to the Limitations section:

(After revision, page 22, lines 252)

Our study had several limitations. First, using a claims database focused solely on healthcare utilization to identify patients with RVO may have underrepresented asymptomatic cases. Therefore, our data reflected the incidence of clinically diagnosed RVO, potentially underestimating the true occurrence of RVO. Second, the lack of access to hospital-based medical records to validate RVO occurrences and review clinical data compromised the accuracy of this study's data. These limitations include the risk of misclassifying diagnoses and the inability to assess factors such as severity, extent, prognosis, or patient comorbidities. Third, owing to the inherent constraints of studies utilizing claims databases, clinical characteristics and interobserver variability in RVO diagnosis were not standardized.

*Comment 10. It is important to note that the initial study sample of 6,891,399 individuals primarily comprises those who underwent health examinations, potentially limiting its representativeness for the broader population. Additionally, the selection criteria, focusing on individuals who underwent health examinations four times over four years, may not accurately reflect 20s and 30s of general population. Furthermore, the high male representation within the study participants should also be acknowledged. Therefore, it is imperative to acknowledge these limitations within the manuscript for transparency and completeness.

- Response: The following sentences have been added to the limitations section:

(After revision, page 22, line 260)

Fourth, male patients comprised over two-thirds of the participants, owing to the higher probability of employees undergoing routine health checkups at their workplaces. This sex imbalance introduces a potential selection bias, limiting the representation of both sexes in a broader population. Furthermore, the selection criteria, emphasizing individuals who underwent health assessments four times over four years, might not fully capture the demographics of individuals in their 20s and 30s within the general population.

REVIEWER 2

*Comment. The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion. As described below, there are several areas for improvement.

*Comment 1. there are serious concerns about selection bias in the selection of study subjects. Populations under the age of 40 who receive annual health checks are more likely to have more systemic diseases or higher socioeconom

Attachment

Submitted filename: Response to the comments.docx

pone.0303871.s002.docx (48.5KB, docx)

Decision Letter 1

Jiro Kogo

20 Mar 2024

PONE-D-23-20018R1Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: a nationwide population-based studyPLOS ONE

Dear Dr. Kim,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 04 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Jiro Kogo

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All comments have been addressed.

One more comment to add. Please double-check and amend the discrepancy between the methodology section, which states the use of the National Health Insurance Service (NHIS)'s Database, and the acknowledgment and data availability statement, which indicate the use of Health Insurance Review and Assessment Service (HIRA) data.

Reviewer #2: The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion.

All comments has been addressed well.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 May 20;19(5):e0303871. doi: 10.1371/journal.pone.0303871.r004

Author response to Decision Letter 1

4 Apr 2024

*General comments

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

- Response: Thank you for the instructions and comments. I have double-checked the references on the manuscript, and there were no retracted papers found.

Reviewer #1

Please double-check and amend the discrepancy between the methodology section, which states the use of the National Health Insurance Service (NHIS)'s Database, and the acknowledgment and data availability statement, which indicate the use of Health Insurance Review and Assessment Service (HIRA) data.

- Response: Thank you for the comment. I have checked the discrepancy between the methods section and the data availability statement and acknowledgment, and revised the data availability statement and acknowledgment as follows.

(After revision, page 1, line 18)

Data Availability Statement: Data are available from the Korea National Health Insurance Sharing Service (https://nhiss.nhis.or.kr/bd/ay/bdaya001iv.do;jsessionid=KiOt6ilaTGXMmR1mbeeA9Ax7nJjIYDsKr4UJAJvHhNyo511E0PovM1WfrGSaegL6.primrose22_servlet_engine1, Tel.: (82) 33-736-2432, 2433) for researchers who meet the criteria for access to confidential data.

(After revision, page 24, line 279)

Acknowledgments

The authors wish to thank the National Health Insurance Service for providing the data regarding the original cohort.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0303871.s003.docx (23.9KB, docx)

Decision Letter 2

Jiro Kogo

2 May 2024

Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: a nationwide population-based study

PONE-D-23-20018R2

Dear Dr.KIm

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Jiro Kogo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Jiro Kogo

7 May 2024

PONE-D-23-20018R2

PLOS ONE

Dear Dr. Kim,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Jiro Kogo

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. STROBE statement—checklist of items that should be included in reports of observational studies.

    (DOCX)

    pone.0303871.s001.docx (37.6KB, docx)
    Attachment

    Submitted filename: Response to the comments.docx

    pone.0303871.s002.docx (48.5KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0303871.s003.docx (23.9KB, docx)

    Data Availability Statement

    Access to raw data from the Korean Health Insurance Review and Assessment (HIRA) service is regulated by the Rules for Data Exploration and Use of the HIRA. Data are available from the Health Insurance Review and Assessment Service database for researchers who meet the criteria for access to confidential data after receiving approval from the HIRA Data Access Committee. The HIRA data can be obtained using the website (http://opendata.hira.or.kr).

    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES