Identified risk factors for dry eye syndrome: A systematic review and meta-analysis.

A meta-analytic approach was used to identify potential risk factors for dry eye syndrome. PubMed, Embase, and the Cochrane library were systematically searched for studies investigated the risk factors for dry eye syndrome from their inception until September 2021. The odds ratio (OR) with 95% confidence interval (CI) was calculated using the random-effects model. Forty-eight studies comprising 493,630 individuals were included. Older age (OR: 1.82; P<0.001), female sex (OR: 1.56; P<0.001), other race (OR: 1.27; P<0.001), visual display terminal use (OR: 1.32; P<0.001), cataract surgery (OR: 1.80; P<0.001), contact lens wear (OR: 1.74; P<0.001), pterygium (OR: 1.85; P = 0.014), glaucoma (OR: 1.77; P = 0.007), eye surgery (OR: 1.65; P<0.001), depression (OR: 1.83; P<0.001), post-traumatic stress disorder (OR: 1.65; P<0.001), sleep apnea (OR: 1.57; P = 0.003), asthma (OR: 1.43; P<0.001), allergy (OR: 1.38; P<0.001), hypertension (OR: 1.12; P = 0.004), diabetes mellitus (OR: 1.15; P = 0.019), cardiovascular disease (OR: 1.20; P<0.001), stroke (OR: 1.32; P<0.001), rosacea (OR: 1.99; P = 0.001), thyroid disease (OR: 1.60; P<0.001), gout (OR: 1.40; P<0.001), migraines (OR: 1.53; P<0.001), arthritis (OR: 1.76; P<0.001), osteoporosis (OR: 1.36; P = 0.030), tumor (OR: 1.46; P<0.001), eczema (OR: 1.30; P<0.001), and systemic disease (OR: 1.45; P = 0.007) were associated with an increased risk of dry eye syndrome. This study reported risk factors for dry eye syndrome, and identified patients at high risk for dry eye syndrome.

Introduction

Dry eye syndrome (DES) is defined as a multifactorial disease of the tears and ocular surface that could cause discomfort and visual disturbance, with potential damage to the ocular surface. These symptoms could affect quality of life and activities of daily living [1, 2]. The prevalence of DES is increasing and is seen in nearly one in five adults. Thus, this needs more attention from ophthalmologists [3, 4]. The role of the tear film has already been demonstrated. It has been shown to provide lubrication to the eyes, as well as nutrition and oxygen, and eliminate debris from the ocular surface [5]. Moreover, individuals with dry eyes also suffer from systemic diseases [4]. However, the prevalence of dry eyes is often underestimated because of varying presentation and symptoms [6]. Studies have demonstrated that age and sex are significantly associated with increased risk of DES; however, the pathogenesis of DES is not fully understood [7, 8].

Several studies have already identified risk factors for DES. Major risk factors include older age, female sex, having undergone postmenopausal estrogen therapy or ocular surface surgery, and using antihistamine medications [9]. Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could be explained by a decreased blink rate and increased proportion of incomplete blinks that could be caused by the increased exposure of the ocular surface to the environment. Outdoor environments, sunlight, and air pollution in tropical countries are also associated with an elevated risk of DES [10, 11]. Furthermore, other risk factors for DES include vitamin D deficiency and diabetes mellitus (DM) [12, 13]. However, whether the comorbidities of individuals could affect the risk of DES remained controversial. We, therefore, performed a systematic review and meta-analysis to independently identify risk factors for DES.

Methods

Data sources, search strategy, and selection criteria

The current study was performed and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement [14]. Studies reporting the risk factors of DES were eligible in our study, and publication language was restricted to English. PubMed, Embase, and the Cochrane library were systematically searched for eligible studies from their inception until September 2021, and using the following text word or Medical Subject Heading terms: "dry eye syndrome", "dry eye disease", "Keratoconjunctivitis Sicca", "Xerophthalmia", and "Risk Factors". The details of search strategy in PubMed are listed in S1 File. The reference lists of relevant original and review articles were manually screened to identify further eligible studies.

Two reviewers (QL and WW) independently performed study assessment following a standardized approach. Any disagreement between reviewers was settled by discussion until a consensus was reached. A study was included if the following criteria were met: (1) it was a cross-sectional, retrospective, or prospective observational study; (2) risk factors were reported for ≥ 3 studies [15] and included such factors as age, sex, race, residence, education level, obesity, dyslipidemia, alcohol, smoking, VDT use, cataract surgery, contact lens wear, pterygium, glaucoma, age-related maculopathy, eye surgery, depression, post-traumatic stress disorder (PTSD), sleep apnea, asthma, allergy, hypertension, DM, cardiovascular disease (CVD), stroke, rosacea, thyroid disease, chronic obstructive pulmonary disease (COPD), gout, migraines, arthritis, osteoporosis, tumor, meibomian gland dysfunction (MGD), eczema, and systemic disease; and (3) it reported effect estimates (relative risk [RR], hazard ratio [HR], or odds ratio [OR]) and 95% confidence interval (CI) for risk factors of DES. Interventional study, animal study, review, and letter to editor was excluded.

Data collection and quality assessment

Two reviewers (QL and WW) independently abstracted the following items, including study group or first author’s name, publication year, country, study design, sample size, age, % of males, population status, % of DES cases, definition of DES, risk factors, adjusted factors, and reported effect estimates. The effect estimate with maximal adjustment for potential confounders was selected if a study reported several multivariable-adjusted effect estimates. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), which has already been validated for assessing the quality of observational studies in meta-analysis [16]. A total of 8 items in 3 subscales were included in NOS. The star system in each study ranged from 0–9. Inconsistent results for the data abstracted and quality assessment between the two reviewers were settled following mutually discussion referred to the original article.

Statistical analysis

Identified risk factors for DES were analyzed based on the OR, RR, or HR, with its 95% CI, in individual studies. Then the pooled ORs with 95%CI were calculated using the random-effects model [17, 18]. I and Q statistic were applied to assess heterogeneity across included studies. Significant heterogeneity was defined as I> 50.0% or P < 0.10 [19, 20]. Sensitivity analysis was performed for factors reported in ≥ 4 studies to assess the robustness of pooled conclusion through sequentially removing individual studies [21]. Subgroup analyses were performed for factors reported in ≥ 4 studies on the basis of the country. The difference between subgroups was assessed using the interaction P test [22]. Visual inspections of funnel plots for factors reported in ≥ 4 studies were performed to qualitatively assess publication bias. The Egger or Begg tests were used to quantitatively assess publication bias [23, 24]. The P-value for all pooled results was 2-sided, and the inspection level was 0.05. All of the statistical analysis in our study was performed using software STATA (version 12.0; Stata Corporation, College Station, TX, USA).

Results

Literature search

A total of 1,672 studies were identified from initial electronic searches. Details of the study selection process are presented in Fig 1. Of these, 912 articles were removed because they were duplicates. A further 671 articles were excluded owing to irrelevant titles or abstracts. The remaining 89 studies were retrieved for full-text evaluations, with 41 studies removed because of: affiliate study (n = 23), evaluated factors < 3 studies (n = 12), and review-type articles (n = 6). A manual search of the reference lists of relevant articles did not yield any additional studies. Finally, 48 studies were selected for the final meta-analysis [25-71]. Characteristics of the included studies and involved individuals are summarized in Table 1.

Fig 1

Details of the literature search and study selection processes.

Table 1

The baseline characteristics of included studies.

Study	Country	Study design	Sample size	Age (years)	Male (%)	Population	DES (%)	Definition of DES	Reported factors	Adjusted factors
BDES 2000 [25]	USA	C	3,722	65.0	43.0	PB	14.4	Questionnaire	DM, arthritis, TD, osteoporosis, gout, ES, CLW, alcohol, smoking	Age and sex
Lee 2002 [26]	Indonesia	C	1,058	37.0	47.7	PB	27.5	Questionnaire	Sex, smoking, pterygium	Sex, age, occupation, smoking, and pterygium
BMES 2003 [27]	Australia	C	1,174	60.8	44.2	PB	57.5	Questionnaire	Arthritis, asthma, DM, gout, smoking, alcohol	Age and sex
Sahai 2005 [28]	India	C	500	> 20.0	55.2	HB	18.4	Questionnaire	Smoking	Age and sex
Nichols 2006 [29]	USA	C	360	31.1	32.0	HB	55.3	Questionnaire	Sex	Nominal water content, PLTF
Uchino 2008 [30]	Japan	C	3,549	22.0–60.0	74.4	PB	10.1	Questionnaire	Age, sex, VDT, systemic disease, smoking, contact lens	Age, gender, VDT use, systemic disease systemic medication, smoking, contact lens use
Lu 2008 [31]	China	C	1,840	56.3	56.0	PB	52.4	TFBT, ST, FSS	Age, education level, smoking alcohol	Crude
PHS 2009 [32]	USA	C	25,444	64.4	100.0	PB	23.0	Questionnaire	Age, race, hypertension, tumor, DM	Crude
TSES 2009 [33]	Spain	C	654	63.6	37.2	PB	11.0	Questionnaire	Sex, VDT use, CLW, rosacea, allergy, DM, hypertension, COPD, education level, alcohol, smoking	Age and sex
BES 2009 [34]	China	C	1,957	56.5	43.1	PB	21.0	Questionnaire	Sex, residence, glaucoma, MD, DM, hypertension, smoking, alcohol	Age, sex, region, undercorrection of refractive error, and nuclear cataract
THES 2010 [35]	China	C	1,816	54.9	53.9	PB	50.1	TBUT, ST, FSS	Pterygium, age, sex, education level, smoking, alcohol	Crude
Kim 2011 [36]	Korea	C	650	71.9	48.3	PB	30.5	Questionnaire	Sex, residence, depression, MGD	Crude
Koumi Study 2011 [37]	Japan	C	2,791	> 40.0	43.7	PB	16.5	Questionnaire	Age, smoking, alcohol, BMI, education level, VDT use, CLW, stroke, CVD, hypertension, DM	Age, smoking, alcohol, BMI, education level, VDT use, CLW, stroke, CVD, hypertension, DM
USVAP 2011 [38]	USA	R	16,862	NA	NA	PB	12.2	ICD9 code	Sex, race, DM, hypertension, dyslipidemia, CVD, stroke, PTSD, depression, alcohol, arthritis, gout, TD, tumor, sleep apnea, rosacea, glaucoma	Age and sex
Zhang 2012 [39]	China	C	1,885	< 18.0	50.8	PB	23.7	Questionnaire	CLW, sleep apnea	CLW, sleep apnea, myopia, inadequate refractive correction, topical ophthalmic medication
TNHRI 2012 [40]	China	R	48,028	52.4	26.6	PB	25.0	ICD9 code	Hypertension,CVD, dyslipidemia, stroke, migraines, arthritis, COPD, asthma, DM, TD, depression, and tumor	Age, sex, region, and incomes
TOS 2013 [41]	Japan	C	561	43.3	66.7	PB	11.6	Questionnaire	Sex, age, smoking, VDT use, CLW, systemic disease, hypertension	Sex, age, smoking, VDT use, CLW, systemic disease, hypertension
TwinUK 2014 [42]	UK	C	3,824	57.1	0.0	PB	9.6	Questionnaire	CLW, CS, glaucoma, MD, osteoporosis, asthma, allergy, TD, arthritis, dyslipidemia, hypertension, DM, cancer, stroke, migraine, depression	Age
KNHNES 2014 [43]	Korea	C	11,666	49.9	42.8	PB	8.0	Questionnaire	Age, sex, education level, residence, hypertension, obesity, dyslipidemia, arthritis, TD, smoking, alcohol, sleep apnea, ES	Age, sex, education level, residence, hypertension, obesity, dyslipidemia, arthritis, TD, smoking, alcohol, sleep apnea, ES
Moon 2014 [44]	Korea	C	288	10.9	49.3	PB	9.7	Questionnaire	VDT use	Age, and sex
BDOS 2014 [45]	USA	C	3,275	49.0	45.4	PB	14.5	Questionnaire	Age, sex, CLW, arthritis, allergies, TD, migraine	Age, and sex
TNHI 2015 [46]	China	R	10,325	61.9	36.7	PB	20.0	ICD9 code	DM, hypertension, dyslipidemia, CVD	DM, hypertension, dyslipidemia, CVD
Yang 2015 [47]	China	R	1,908	56.2	41.4	HB	41.4	TFBT, ST, and FSS	DM, arthritis, tumor, acne rosacea, PTSD, VDT use	DM, arthritis, tumor, acne rosacea, PTSD, VDT use
Tan 2015 [48]	Singapore	C	1,004	38.2	44.1	PB	12.3	Questionnaire	Sex, age, CLW, alcohol	Crude
Shah 2015 [49]	India	C	400	58.6	48.0	HB	54.3	TBUT	DM, ES, MGD	Occupation, indoor table work, DM previous ocular surgery, MGD
Olaniyan 2016 [50]	Nigeria	C	363	59.1	48.2	PB	32.5	Questionnaire	Age, ES	Age, work place, medication use, ocular surgery, postmenopausal state
Alshamrani 2017 [51]	Saudi Arabia	C	1,858	39.3	48.0	PB	32.1	Questionnaire	Sex, age, residence, smoking, CLW, DM, hypertension, asthma, CVD, TD, arthritis, gout, osteoporosis	Sex, age, residence, work status, smoking, currently wearing, and history of trachoma
NHWS 2017 [52]	USA	C	73,211	> 18.0	48.4	PB	6.9	Questionnaire	Age, sex, race, education level	Age and sex
SMES 2017 [53]	Singapore	P	1,682	56.9	44.6	PB	5.1	Questionnaire	DM, hypertension, smoking, CLW, stroke, CVD, TD, glaucoma, MGD, pterygium	Sex, age, income, smoking, CLW, cataract surgery, thyroid disease
Gong 2017 [54]	China	C	1,015	54.6	29.7	PB	27.8	Questionnaire	VDT use, DM, hypertension, arthritis, smoking, alcohol	Sex, age, VDT use, DM, hypertension, arthritis, dry mouth, smoking, alcohol, and spicy diets
Asiedu 2017 [54]	Ghana	C	650	22.0	66.6	PB	44.3	Questionnaire	Age, sex, allergies, alcohol, VDT use	Age, sex, allergies, alcohol, VDT use
Graue-Hernandez 2018 [55]	Mexico	C	1,508	64.7	40.3	PB	41.1	Questionnaire	Sex, smoking, DM, alcohol, hypertension	Sex, smoking, DM, alcohol, hypertension
SES 2018 [56]	Spain	C	264	56.8	32.7	PB	25.4	TBUT, ST, FSS	Sex, education level, VDT use, alcohol, smoking, hypertension, DM, COPD, CVD, TD, rosacea	Age
Iglesias 2018 [57]	USA	R	86	71.0	95.0	HB	32.1	Questionnaire	Race, DM, depression, PTSD, sleep apnea, glaucoma	Crude
TMS 2018 [58]	France	C	1,045	82.2	71.8	PB	34.4	Questionnaire	Obesity, smoking, alcohol, education level, hypertension, DM, depression, CS, MD, glaucoma	Age, and sex
Shehadeh-Mashor 2019 [59]	Israel	R	25,317	27.0	55.0	PB	6.0	TBUT, and ST	Sex, CLW	Age and sex
Zhang 2019 [60]	China	C	31,124	NA	49.1	HB	57.6	ST, and FSS	Sex, age, DM, arthritis, TD, ES	Sex, age, refractive surgery
Yasir 2019 [61]	Saudi Arabia	C	890	> 40.0	55.5	PB	35.9	Questionnaire	Glaucoma, DM, and hypertension	Crude
HTS 2019 [62]	Japan	C	356	55.5	37.4	PB	33.4	Questionnaire	Sex, smoking, CLW, hypertension	Sex, eye makeup use, smoking CLW, hypertension, sleeping pills
Hyon 2019 [63]	Korea	C	232	> 20.0	15.1	PB	42.7	Questionnaire	Sex, VDT use	Sex, and VDT use
Ben-Eli 2019 [64]	Israel	R	331	53.6	24.8	HB	36.3	Clinician-diagnosed	Smoking, alcohol	Ethnicity, smoking, alcohol, hospitalization for infection
Yu 2019 [65]	China	C	23,922	NA	48.8	HB	61.6	TBUT, and FSS	Sex, age, ES, arthritis, TD	Humidity, air pressure, and air temperature
Rossi 2019 [66]	Italy	C	194	41.8	34.5	HB	16.5	TBUT, and FSS	Sex, VDT use	Age, sex, VDT use, visual acuity, and presbyopia
Wang 2020 [67]	New Zealand	C	372	39.0	40.3	PB	29.0	Clinician-diagnosed	Sex, CLW, anxiety, asthma, DM, depression, dyslipidemia, hypertension, cancer, migraine, TD, CS, ES	Age, CLW, ethnicity, migraine, menopause, systemic disease, thyroid disease, antidepressant medication, and oral contraceptive therapy
Shanti 2020 [68]	Palestine	C	769	43.6	47.3	PB	64.0	TBUT, ST, FSS	Sex, VDT use, smoking, DM, hypertension	Age, sex, VDT use, smoking, systemic disease
JPHC 2020 [69]	Japan	P	102,582	58.3	46.2	PB	24.6	Questionnaire	VDT use	Age, smoking, education status, income, and public health area
Alkabbani 2021 [70]	United Arab Emirates	C	452	> 17.0	36.3	PB	62.6	Questionnaire	Age, sex, CLW, ES, VDT use, smoking	Age, sex, CLW, ES, VDT use, smoking
LCS 2021 [71]	Netherlands	C	79,866	50.4	40.8	PB	9.1	Questionnaire	Sex, CLW, MD, glaucoma, ES, CS, arthritis, gout, CVD, stroke, migraine, depression, PTSD, COPD, asthma, sleep apnea, rosacea, allergy, DM, osteoporosis, TD, anemia	Age, and sex

*BMI: body mass index; C: cross-sectional; CLW: contact lens wear; COPD: chronic obstructive pulmonary disease; CS: cataract surgery; CVD: cardiovascular disease; DM: diabetes mellitus; ES: eye surgery; FSS: fluorescein staining score; HB: hospital-based; MD: macular degeneration; MDG: meibomian gland dysfunction; MI: myocardial infarction; NA: not available; P: prospective; PB: population-based; PLTF: prelens tear film; PTSD: post-traumatic stress disorder; R: retrospective; ST: Schirmer test; TBUT: tear film break-up time; TD: thyroid disease; TFBT: tear film breakup time; VDT: visual display terminal

Study characteristics

Of 48 included studies, 39 studies were designed as cross-sectional, 7 studies were designed as retrospective, and 2 studies designed as prospective. A total of 493,630 individuals were included, and the sample size ranged from 86 to 102,582. The mean age of included individuals ranged from 10.9 to 82.2. Twenty-nine studies were performed in Eastern countries, with the remaining 19 studies conducted in Western countries. Thirty-nine studies were population based. The remaining 9 studies were hospital based. The DES definition based on questionnaire were reported in 33 studies, 10 studies used TBUT, ST, or FSS defined DES, 3 studies applied ICD9 code and the remaining 2 studies used clinician-diagnosed defined DES. Study quality was assessed using the NOS; 11 studies had 8 stars, 18 had 7 stars, and the remaining 19 had 6 stars (S1 Table). The quality of included studies mainly affect by the representativeness of the exposed cohort, and comparability on the basis of the design or analysis.

Meta-analysis

Demographic factors

The number of studies that reported on the association of age, sex, and race as risk factors for DES was 15, 29, and 5, respectively (Fig 2 and S2 File). We noted that older adults (OR: 1.82; 95%CI: 1.47–2.26; P<0.001), females (OR: 1.56; 95%CI: 1.36–1.78; P<0.001), and those of other race (OR: 1.27; 95%CI: 1.11–1.44; P<0.001) had an increased risk of DES. There was significant heterogeneity for age (I = 96.0%; P<0.001), sex (I = 95.0%; P<0.001), and race (I = 52.1%; P = 0.080). Sensitivity analysis indicated these pooled conclusions were robust and not altered by sequentially excluding individual studies (S3 File). The results of subgroup analyses were consistent with overall analysis when stratified according to the region (Table 2). There were no significant publication biases for age (P-value for Egger: 0.175; P-value for Begg: 1.000), sex (P-value for Egger: 0.417; P-value for Begg: 0.253), and race (P-value for Egger: 0.174; P-value for Begg: 0.806) regarding risk for DES (S4 File).

Fig 2

Summary results of risk factors for dry eye syndrome.

Table 2

Subgroup analyses according to region.

Factors	Subgroup	OR and 95%CI	P value	I2 (%)	P heterogeneity	P value between subgroups
Age (elderly versus younger)	Eastern countries	1.78 (1.46–2.19)	< 0.001	89.4	< 0.001	< 0.001
	Western countries	2.04 (1.05–3.97)	0.036	98.7	< 0.001
Sex (female versus male)	Eastern countries	1.53 (1.36–1.72)	< 0.001	84.0	< 0.001	< 0.001
	Western countries	1.52 (1.20–1.92)	< 0.001	95.8	< 0.001
Race (other versus white)	Eastern countries	-	-	-	-	-
	Western countries	1.27 (1.11–1.44)	< 0.001	52.1	0.080
Residence (urban versus rural)	Eastern countries	1.41 (0.96–2.08)	0.078	87.8	< 0.001	-
	Western countries	-	-	-	-
Education level (high versus low)	Eastern countries	1.28 (1.01–1.63)	0.041	60.2	0.057	0.007
	Western countries	0.86 (0.56–1.33)	0.505	80.7	0.001
Obesity	Eastern countries	1.02 (0.83–1.25)	0.866	2.1	0.360	0.685
	Western countries	1.11 (0.77–1.60)	0.576	-	-
Dyslipidemia	Eastern countries	1.35 (1.01–1.80)	0.046	94.7	< 0.001	< 0.001
	Western countries	1.05 (0.82–1.35)	0.676	77.2	0.004
Alcohol	Eastern countries	1.04 (0.90–1.20)	0.589	0.0	0.429	0.177
	Western countries	0.92 (0.64–1.32)	0.641	76.1	<0.001
Smoking	Eastern countries	0.96 (0.81–1.15)	0.668	65.2	< 0.001	0.046
	Western countries	1.09 (0.82–1.45)	0.554	60.0	0.020
VDT use	Eastern countries	1.33 (1.17–1.53)	< 0.001	85.5	< 0.001	0.436
	Western countries	1.33 (1.06–1.68)	0.015	0.0	0.457
Cataract surgery	Eastern countries	2.16 (1.62–2.89)	< 0.001	0.0	0.792	0.561
	Western countries	1.69 (1.28–2.21)	< 0.001	76.0	0.002
Contact lens wear	Eastern countries	2.01 (1.48–2.71)	<0.001	72.8	<0.001	0.003
	Western countries	1.41 (0.93–2.14)	0.105	97.1	<0.001
Pterygium	Eastern countries	1.85 (1.13–3.01)	0.014	89.0	< 0.001	-
	Western countries	-	-	-	-
Glaucoma	Eastern countries	2.15 (1.29–3.58)	0.003	26.1	0.255	0.516
	Western countries	1.57 (0.92–2.68)	0.098	96.5	< 0.001
Age-related maculopathy	Eastern countries	0.31 (0.07–1.35)	0.118	-	-	0.007
	Western countries	1.91 (1.21–3.01)	0.005	62.9	0.067
Eye surgery	Eastern countries	1.62 (1.23–2.14)	0.001	93.6	<0.001	<0.001
	Western countries	1.82 (1.39–2.37)	< 0.001	32.1	0.229
Depression	Eastern countries	2.12 (1.95–2.32)	< 0.001	0.0	0.876	< 0.001
	Western countries	1.66 (1.43–1.93)	< 0.001	67.0	0.010
PTSD	Eastern countries	1.45 (1.04–2.01)	0.027	-	-	0.121
	Western countries	1.71 (1.19–2.46)	0.004	53.0	0.119
Sleep apnea	Eastern countries	1.22 (1.11–1.35)	< 0.001	4.5	0.370	< 0.001
	Western countries	2.17 (1.95–2.41)	< 0.001	0.0	0.749
Asthma	Eastern countries	1.19 (0.98–1.45)	0.076	29.0	0.235	< 0.001
	Western countries	1.62 (1.49–1.77)	< 0.001	0.0	0.869
Allergy	Eastern countries	-	-	-	-	-
	Western countries	1.38 (1.32–1.45)	< 0.001	0.0	0.418
Hypertension	Eastern countries	1.06 (0.95–1.17)	0.306	63.7	0.001	0.005
	Western countries	1.27 (1.14–1.41)	< 0.001	24.8	0.231
DM	Eastern countries	1.20 (1.06–1.37)	0.005	79.0	< 0.001	< 0.001
	Western countries	1.08 (0.87–1.34)	0.460	88.5	< 0.001
CVD	Eastern countries	1.26 (1.15–1.39)	< 0.001	0.0	0.753	0.084
	Western countries	1.15 (1.00–1.32)	0.049	18.5	0.293
Stroke	Eastern countries	1.31 (1.22–1.41)	< 0.001	0.0	0.978	0.667
	Western countries	1.35 (1.20–1.51)	< 0.001	0.0	0.589
Rosacea	Eastern countries	3.75 (1.97–7.12)	< 0.001	-	-	0.032
	Western countries	1.74 (1.20–2.52)	0.004	53.1	0.094
Thyroid disease	Eastern countries	1.57 (1.29–1.91)	< 0.001	86.0	<0.001	0.752
	Western countries	1.64 (1.45–1.84)	< 0.001	26.9	0.223
COPD	Eastern countries	1.06 (0.84–1.34)	0.625	-	-	0.006
	Western countries	1.37 (1.00–1.89)	0.051	23.2	0.272
Gout	Eastern countries	1.56 (0.70–3.49)	0.275	83.3	0.014	0.175
	Western countries	1.34 (1.17–1.53)	< 0.001	0.0	0.860
Migraines	Eastern countries	1.76 (1.57–1.98)	< 0.001	-	-	< 0.001
	Western countries	1.41 (1.19–1.68)	< 0.001	54.2	0.088
Arthritis	Eastern countries	1.74 (1.31–2.29)	< 0.001	95.6	< 0.001	0.776
	Western countries	1.80 (1.57–2.07)	< 0.001	74.7	0.001
Osteoporosis	Eastern countries	0.81 (0.51–1.29)	0.377	-	-	0.004
	Western countries	1.53 (1.21–1.93)	< 0.001	75.8	0.016
Tumor	Eastern countries	2.27 (0.83–6.22)	0.111	94.7	< 0.001	0.339
	Western countries	1.33 (1.17–1.50)	<0.001	39.5	0.175

The number of studies reporting an association of residence, education level, obesity, and dyslipidemia regarding the risk of DES were 4, 8, 4, and 7, respectively (Fig 2 and S2 File). We noted that residence (urban versus rural) (OR: 1.41; 95%CI: 0.96–2.08; P = 0.078), education level (high versus low) (OR: 1.09; 95%CI: 0.88–1.34; P = 0.443), obesity (OR: 1.04; 95%CI: 0.87–1.24; P = 0.671), and dyslipidemia (OR: 1.18; 95%CI: 0.97–1.45; P = 0.104) were not associated with increased risk for DES. There was significant heterogeneity for residence (I = 87.8%; P<0.001), education level (I = 76.9%; P<0.001), and dyslipidemia (I = 92.9%; P<0.001), while there was no evidence of heterogeneity for obesity (I = 0.0%; P = 0.530). Sensitivity analyses indicated that residence, education level, and dyslipidemia might be associated with an elevated risk of DES, while the association between obesity and DES persisted (S3 File). Subgroup analyses demonstrated that education level and dyslipidemia were associated with an increased risk of DES when pooling studies conducted in Eastern countries (Table 2). No significant publication bias for residence (P-value for Egger: 0.875; P-value for Begg: 0.734), education level (P-value for Egger: 0.985; P-value for Begg: 0.902), and obesity (P-value for Egger: 0.638; P-value for Begg: 0.308) with the risk of DES was noted, whereas potential significant publication bias for dyslipidemia (P-value for Egger: 0.037; P-value for Begg: 1.000) with the risk of DES was seen (S4 File).

The number of studies reporting an association of alcohol, smoking, and VDT use with the risk of DES was 15, 22, and 14, respectively (Fig 2 and S2 File). We noted that alcohol intake (OR: 0.98; 95%CI: 0.81–1.18; P = 0.808) and current smoking (OR: 1.00; 95%CI: 0.86–1.16; P = 0.986) were not associated with risk for DES, while VDT use was associated with an increased risk of DES (OR: 1.32; 95%CI: 1.17–1.49; P<0.001). There was significant heterogeneity for alcohol (I = 62.2%; P = 0.001), smoking (I = 64.6%; P<0.001), and VDT use (I = 80.1%; P<0.001). Sensitivity analysis indicated that alcohol intake might play an important role in the risk of DES, while the pooled results for the associations of smoking and VDT use with the risk of DES were robust (S3 File). The results of subgroup analyses were consistent with the overall analysis (Table 2). No significant publication bias for smoking (P-value for Egger: 0.569; P-value for Begg: 0.822) and VDT use (P-value for Egger: 0.370; P value for Begg: 0.827) with the risk of DES was found, whereas potential significant publication bias for alcohol (P-value for Egger: 0.032; P-value for Begg: 0.921) with the risk of DES was noted (S4 File).

Clinical characteristics

The number of studies that reported on the association of cataract surgery, contact lens wear, pterygium, glaucoma, age-related maculopathy, and eye surgery with the risk of DES were 7, 17, 4, 9, 3, and 8, respectively (Fig 2 and S2 File). We noted that cataract surgery (OR: 1.80; 95%CI: 1.46–2.21; P<0.001), contact lens wear (OR: 1.74; 95%CI: 1.34–2.25; P<0.001), pterygium (OR: 1.85; 95%CI: 1.13–3.01; P = 0.014), glaucoma (OR: 1.77; 95%CI: 1.17–2.69; P = 0.007), and eye surgery (OR: 1.65; 95%CI: 1.31–2.07; P<0.001) were associated with an increased risk of DES, while age-related maculopathy was not associated with risk of DES (OR: 1.46; 95%CI: 0.79–2.70; P = 0.231). Significant heterogeneity was noted for cataract surgery (I = 64.8%; P<0.001), contact lens wear (I = 93.5%; P<0.001), pterygium (I = 89.0%; P<0.001), glaucoma (I = 93.4%; P<0.001), age-related maculopathy (I = 76.5%; P = 0.005), and eye surgery (I = 94.0%; P<0.001) with the risk of DES. Sensitivity analyses indicated that the pooled results for the association of cataract surgery, contact lens wear, pterygium, glaucoma, and eye surgery with the risk of DES persisted, whereas age-related maculopathy might be associated with the risk of DES (S3 File). Although most results in the subgroup analyses were consistent with the overall analysis, we noted that contact lens wear and glaucoma were not associated with the risk of DES when pooling studies performed in Western countries. Moreover, age-related maculopathy was associated with an increased risk of DES when pooling studies conducted in Western countries (Table 2). There was no significant publication bias for the association of cataract surgery (P-value for Egger: 0.194; P-value for Begg: 0.548), contact lens wear (P-value for Egger: 0.791; P-value for Begg: 0.387), pterygium (P-value for Egger: 0.681; P-value for Begg: 0.734), glaucoma (P-value for Egger: 0.950; P-value for Begg: 0.917), and eye surgery (P-value for Egger: 0.760; P-value for Begg: 0.266) with the risk of DES, while potential significant publication bias was noted for age-related maculopathy (P-value for Egger: 0.017; P-value for Begg: 0.308) with the risk of DES (S4 File).

Comorbidities

The number of studies that reported on the association of depression, PTSD, sleep apnea, asthma, and allergy with the risk of DES were 9, 4, 7, 6, and 6, respectively (Fig 2 and S2 File). We noted that depression (OR: 1.83; 95%CI: 1.57–2.12; P<0.001), PTSD (OR: 1.65; 95%CI: 1.26–2.15; P<0.001), sleep apnea (OR: 1.57; 95%CI: 1.16–2.11; P = 0.003), asthma (OR: 1.43; 95%CI: 1.20–1.71; P<0.001), and allergy (OR: 1.38; 95%CI: 1.32–1.45; P<0.001) were associated with an increased risk of DES. There was significant heterogeneity for depression (I = 80.7%; P<0.001), PTSD (I = 55.0%; P = 0.083), sleep apnea (I = 91.5%; P<0.001), and asthma (I = 76.5%; P = 0.001), while no evidence of heterogeneity for allergy was observed (I = 0.0%; P = 0.418). Sensitivity analyses indicated that pooled conclusions for the association of depression, PTSD, sleep apnea, asthma, and allergy with the risk of DES were stable after sequentially removing individual studies (S3 File). The results of subgroup analyses were consistent with overall analysis, except that asthma was not associated with the risk of DES if pooled studies were performed in Eastern countries (Table 2). No significant publication bias for the role of depression (P-value for Egger: 0.679; P-value for Begg: 0.348), PTSD (P-value for Egger: 0.415; P-value for Begg: 0.734), sleep apnea (P-value for Egger: 0.959; P-value for Begg: 0.764), asthma (P-value for Egger: 0.949; P-value for Begg: 1.000), and allergy (P-value for Egger: 0.189; P-value for Begg: 0.707) with DES were observed (S4 File).

The number of studies reporting on the association of hypertension, DM, CVD, stroke, rosacea, thyroid disease, and COPD with the risk of DES were 21, 24, 8, 7, 5, 14, and 4, respectively (Fig 2 and S2 File). We noted that hypertension (OR: 1.12; 95%CI: 1.04–1.22; P = 0.004), DM (OR: 1.15; 95%CI: 1.02–1.29; P = 0.019), CVD (OR: 1.20; 95%CI: 1.12–1.29; P<0.001), stroke (OR: 1.32; 95%CI: 1.24–1.40; P<0.001), rosacea (OR: 1.99; 95%CI: 1.34–2.95; P = 0.001), and thyroid disease (OR: 1.60; 95%CI: 1.42–1.80; P<0.001) were associated with an increased risk of DES, while COPD was not associated with risk of DES (OR: 1.22; 95%CI: 10.90–1.66; P = 0.202). There was significant heterogeneity for hypertension (I = 60.2%; P<0.001), DM (I = 86.7%; P<0.001), rosacea (I = 63.6%; P = 0.027), thyroid disease (I = 74.6%; P<0.001), and COPD (I = 70.6%; P = 0.017), while no significant heterogeneity was observed for CVD (I = 4.8%; P = 0.393) and stroke (I = 0.0%; P = 0.964). The pooled conclusions for the association of hypertension, CVD, stroke, rosacea, and thyroid disease with the risk of DES were stable, while the conclusions for DM and COPD with DES were variable (S3 File). Although the results of subgroup analyses were consistent with the overall analysis in most subsets, we noted that hypertension was not related to DES if pooling in Eastern country studies, while DM was not associated with the risk of DES if pooled studies were performed in Western countries (Table 2). There was no significant publication bias for hypertension (P-value for Egger: 0.331; P-value for Begg: 0.928), DM (P-value for Egger: 0.765; P-value for Begg: 0.862), CVD (P-value for Egger: 0.357; P-value for Begg: 0.711), stroke (P-value for Egger: 0.485; P-value for Begg: 0.368), rosacea (P-value for Egger: 0.759; P-value for Begg: 0.806), thyroid disease (P-value for Egger: 0.996; P-value for Begg: 0.228), and COPD (P-value for Egger: 0.267; P-value for Begg: 1.000) (S4 File).

The number of studies reporting on the association of gout, migraines, arthritis, osteoporosis, tumor, MGD, eczema, and systemic disease with the risk of DES was 6, 5, 13, 4, 6, 3, 3, and 3, respectively (Fig 2 and S2 File). We noted that gout (OR: 1.40; 95%CI: 1.17–1.68; P<0.001), migraines (OR: 1.53; 95%CI: 1.25–1.89; P<0.001), arthritis (OR: 1.76; 95%CI: 1.51–2.05; P<0.001), osteoporosis (OR: 1.36; 95%CI: 1.03–1.80; P = 0.030), tumor (OR: 1.46; 95%CI: 1.23–1.76; P<0.001), eczema (OR: 1.30; 95%CI: 1.22–1.38; P<0.001), and systemic disease (OR: 1.45; 95%CI: 1.11–1.91; P = 0.007) were associated with an increased risk of DES, while MGD was not associated with risk of DES (OR: 2.47; 95%CI: 0.79–7.70; P = 0.119). There was significant heterogeneity for migraines (I = 86.4%; P<0.001), arthritis (I = 92.4%; P<0.001), osteoporosis (I = 82.1%; P = 0.001), tumor (I = 79.9%; P<0.001), and MGD (I = 85.2%; P = 0.001), while no significant heterogeneity for gout (I = 41.8%; P = 0.126), eczema (I = 0.0%; P = 0.609), and systemic disease (I = 0.0%; P = 0.007) was observed. The pooled conclusions for the association of gout, migraines, arthritis, osteoporosis, and tumor with the risk of DES were robust after sequentially removing individual studies (S3 File). Although the results of subgroup analyses were consistent with the overall analysis in most subsets, gout, osteoporosis, and tumor were not associated with risk of DES if pooled studies were performed in Eastern countries. There was no significant publication bias for gout (P-value for Egger: 0.902; P-value for Begg: 0.707), migraines (P-value for Egger: 0.249; P-value for Begg: 0.806), arthritis (P-value for Egger: 0.169; P-value for Begg: 0.360), osteoporosis (P-value for Egger: 0.137; P-value for Begg: 0.308), and tumor (P-value for Egger: 0.721; P-value for Begg: 1.000) (S4 File).

Discussion

This systematic review and meta-analysis was based on published observational studies explored potential risk factors for DES and included 493,630 individuals from 48 studies. We found that risk factors for DES included older age, female sex, other race, VDT use, cataract surgery, contact lens wear, pterygium, glaucoma, eye surgery, depression, PTSD, sleep apnea, asthma, allergy, hypertension, DM, CVD, stroke, rosacea, thyroid disease, gout, migraines, arthritis, osteoporosis, tumor, eczema, and systemic disease. Moreover, country of origin could affect association for age, sex, education level, dyslipidemia, smoking, contact lens wear, age-related maculopathy, eye surgery, depression, sleep apnea, asthma, hypertension, DM, rosacea, COPD, migraines, and osteoporosis regarding the risk of DES.

This current study primarily identified potential risk factors for DES, although several factors have already been demonstrated in individual studies. Prior studies have demonstrated that a 5-year incidence of dry eye rises from 10.7% to 17.9% alongside increasing age [72]. A potential reason could be the reduction of tear secretion with biological aging [2, 73]. Moreover, the sex difference in DES could be explained by various hormonal effects on the ocular surface and lacrimal gland [8]. The potential impact for VDT use could be due to increasing rates of incomplete blinks and accelerated evaporation of the tear film [74]. The increased risk of DES after cataract surgery could be explained by cataract surgery inducing tear film dysfunction [75]. The role of contact lens wear on DES could be explained in that placing a lens on the eye could cause disturbance of the tear film [76]. DES could be considered as a precipitating factor of primary pterygium [77]. The treatment of glaucoma could alter the surface of the eye through disturbing tear secretion, which could affect the progression of DES [78]. Studies have already found that open eye surgery could affect altered tear secretion in nearly 91% of patients, thus playing an important role in the risk of DES [79]. The potential role of depression and PTSD could be explained by the dysregulation of neuropeptides coupled with serotonin in human tears and serotonin receptors in human conjunctivae [80]. Sleep apnea is significantly associated with neuropathic pain, which could induce the progression of dry eye syndrome [81]. The role of asthma and allergy on the risk of DES could be explained by antihistaminic and anti-inflammatory agents used for asthma and allergy treatment, which could potentially cause an elevated risk of DES [82].

This study found that hypertension and DM were associated with an increased risk of DES, which was consistent with the results of a prior meta-analysis [83]. A potential reason for this could be hypertension was not direct affect the risk of DES, while the use of anti-hypertensive medication could increase the risk of DES [33]. In addition, the risk of DES were not increased in hypertensive patients treated with anti-hypertensive medications, such as Angiotension Converting Enzyme inhibitors might play a protective role on the risk of DES [34]. Moreover, DM could induce a decrease in corneal sensation and tear production, impaired metabolic activity, and loss of cytoskeletal structure, all of which could affect the progression of DES [84]. The underlying therapies for CVD, stroke, and tumor could be regarded as disposing of factors for DES [25]. Rosacea is a well known risk factor for DES due to is pro-inflammatory effects that induce meibomian gland dysfunction and evaporative DES [85]. Studies have already found that thyroid disease is significantly related to ocular surface damage, eyelid retraction/impaired Bell’s phenomenon, and reduced tear production [86]. Gout was associated with the tophaceous deposits in different locations of the eye, including eyelids, conjunctiva, cornea, iris, sclera, and orbit, a similar reason could explain the role of arthritis on DES [87]. The role of migraines on DES could be explained by an inflammatory status in migraine patients potentially activating inflammation in the eyes [88]. The inflammation and hormone imbalance caused by osteoporosis could explain an elevated risk of DES [89]. The treatment for eczema and systemic disease could cause an elevated risk of DES [90].

Our study found that potential associations for age, sex, education level, dyslipidemia, smoking, contact lens wear, age-related maculopathy, eye surgery, depression, sleep apnea, asthma, hypertension, DM, rosacea, COPD, migraines, and osteoporosis with the risk of DES could be affected by country of origin. The disease distribution for DES is different in Eastern and Western countries, and the health policy in various countries could further affect the progression of DES. Moreover, environmental, dietary, and lifestyle factors among various countries differ, which could affect the progression of DES [91, 92].

Several shortcomings of this study should be acknowledged. First, this study contained cross-sectional, retrospective, and prospective observational studies, and the causality relationships between risk factors and DES could not available. Second, the heterogeneity for most risk factors was substantial, which was not fully explained by sensitivity and subgroup analyses. Third, the comorbidity and underlying therapies for individuals were not fully adjusted, which could affect the progression of DES. Fourth, the cutoff value for age, and definition for systemic disease, eye surgery, and DES are different across included studies, which could induce potential uncontrolled biases. Fifth, the climate type could affect the progression of DES, and nearly all of included studies did not address the climate type. Sixth, the analysis based on published articles, the gray literature and unpublished data were not available, and the publication bias was inevitable. Seventh, the analysis using the pooled data, and the detailed analyses were restricted. Finally, this study was not registered in PROSPERO, and the transparency was restricted.

Conclusions

This study identified comprehensive risk factors for DES, including older age, female sex, other race, VDT use, cataract surgery, contact lens wear, pterygium, glaucoma, eye surgery, depression, PTSD, sleep apnea, asthma, allergy, hypertension, DM, CVD, stroke, rosacea, thyroid disease, gout, migraines, arthritis, osteoporosis, tumor, eczema, and systemic disease. Further large-scale prospective cohort studies should be performed to verify the results of this study.

PRISMA 2020 checklist.

(PDF)

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Quality scores of prospective cohort studies using Newcastle-Ottawa Scale.

(DOCX)

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Search strategy in PubMed.

(DOCX)

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Forest plots for the risk factors of dry eye syndrome.

(DOCX)

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Sensitivity analyses for the risk factors of dry eye syndrome.

(DOCX)

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Funnel plots for the risk factors of dry eye syndrome.

(DOCX)

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19 Jan 2022

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Reviewer #1: Manuscript ID: PONE-D-21-35192

Title: Identified risk factors for dry eye syndrome: A systematic review and meta-analysis

The authors report on a meta-analysis of an important topic – risk factors for dry eye syndrome. I thank the authors for their persistence with this large and complex analysis, however their analysis is limited by multiple methodologic and reporting concerns. The quality of evidence used to make these conclusions is also suspect, given the large proportion of cross-sectional studies that are susceptible to recall bias and variability in the adjustment for confounding factors across studies.

Specific comments are provided below:

1. Methods, Abstract: The model used for meta-analysis should be specified, as well as the inclusion and exclusion criteria for study selection.

2. Conclusion, Abstract: The authors should elaborate on their conclusion section to discuss the implications of their findings and/or areas for future research.

3. Introduction: expand on the risk factor ‘visual display terminal’ for readers who may be unfamiliar with this term.

4. Introduction: “However, the presence of other comorbidities and individuals’ characteristics on the risk of DES were not illustrated.” The authors should specify that there is conflicting or negative evidence for these other characteristics as opposed to these being uninvestigated characteristics.

5. Methods: “The following search terms were used: ("Dry Eye Syndromes"[Mesh]) AND "Risk Factors"[Mesh].” The search strategy provided by the authors is quite simplistic and does not account for other formulations of the same concept found in these major databases. No text-based searches are also integrated to ensure maximal literature coverage.

6. Methods: Did the authors investigate the gray literature as part of this systematic review?

7. Methods: specify with initials the authors that independently screened studies and extracted data.

8. Methods: the authors note that all studies reporting on dry eye risk factors were considered. Were interventional studies assessing the impact of dry eye treatment also included?

9. Methods: was the systematic review prospectively registered in the PROSPERO database?

10. Methods: The authors note that studies which assessed risk factors in at least 3 cohorts were included. Some studies assessing risk factors for dry eye may have only focused on one risk factor and would therefore be excluded under the current methodology. This overly restrictive inclusion criterion seems arbitrary and unwarranted.

11. Methods: Was a GRADE evaluation performed to assess the certainty of findings?

12. Methods: “Identified risk factors for DES were analyzed based on the effect estimate, with its 95% CI, in 99 individual studies.” What effect estimate was considered? Elaborate on the exact methods used. For continuous variables like age, how were they categorized into binary groups for analysis?

13. Methods: Only one subgroup analysis based on country was considered in the analysis. There are likely multiple potential confounders in this analysis that can be investigated for using subgroup analysis, including severity of dry eye, individuals with dry eye secondary to another condition eg Sjogren’s, evaporative vs aqueous deficient dry eye, study design, etc.

14. Methods, statistical analysis: specify the measure of association used to report the results – ie odds ratio with 95% confidence interval.

15. Results: what proportion of results of studies was derived from a multivariable analysis that controlled for confounding parameters versus a univariable analysis?

16. Results: provide more information in the study characteristics section on the type and severity of dry eye, observational vs interventional studies, the recency of publication, the pooled gender and age distribution, and other relevant baseline parameters for this analysis.

17. Results: expand on the results of the risk of bias assessment – what was the most frequent reason for downgrading the risk of bias?

18. Results: It would be important to clarify the definition of DES used in the analysis, and whether this definition was different across included studies.

19. Results: When reporting the results for each risk factor, it would be helpful to provide the proportion of the characteristic in the DES vs no DES groups, e.g. mean age, % female, race distribution, etc.

20. Results: For endpoints that had significant statistical heterogeneity, was the heterogeneity changed in the subgroup analysis?

21. Results: For glaucoma as a risk factor, it would important to clarify the therapy received, as this likely impacts the risk of DES.

22. Results: For eye surgery as a risk factor, clarify what type of surgeries were considered.

23. Results: In the reporting of the various risk factors, certain risk factors are grouped with others in the same paragraph. It is unclear how the various risk factors were grouped. It would be helpful to add subheadings to clarify this.

24. Results: “systemic disease” as a risk factor is not helpful or clinically relevant. This needs to be specified as to which specific systemic disease was considered or otherwise removed from the analysis.

25. Discussion: “we noted that other races versus white race were associated with an increased risk of DES, which is significantly related to the climate type.” Is race a risk factor independent of climate type? Elaborate on how climate type mediated this effect.

26. Discussion: “anti-hypertensive medication could increase the risk of DES”. What is the mechanism of this association?

27. Discussion: “The role of rosacea could be explained by its significant relation to corneal neovascularization and perforation, which could induce vision loss and ocular comorbidities.[85]” This relation is poorly described. Rosacea is a well known risk factor for DES due to is pro-inflammatory effects that induce meibomian gland dysfunction and evaporative DES.

28. Discussion: “Studies have already found that thyroid disease is significantly related to ocular surface damage, elevated lip aperture” – ‘elevated lip aperture’ should read ‘eyelid retraction’

29. Discussion: a major limitation is that the impact of confounding variables is unaddressed by certain studies, and multivariable associations were only reported for certain risk factors. Given the large proportion of cross-sectional studies, recall bias is likely a significant issue in these results.

30. Figure 2: p-value column – unsure why the p-values displayed in this way, as if multiple numbers are written on top of one another? What is the significance of the blue/gray background behind the forest plot for each endpoint?

Reviewer #2: This is a very well written meta-analysis regarding the potential risk factors for dry eye syndrome. Nevertheless, risk factors for DES are widely known, therefore, my question to the authors is:

In which way this meta analysis contributes to the literature already published regarding the risk factors for DES.

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21 Feb 2022

Point-By-Point Response

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Response: Thanks for this suggestion, and the style of manuscript have already updated meets PLOS ONE's style requirements.

Question 2: Please confirm that you have included all items recommended in the PRISMA checklist including:

- the full electronic search strategy used to identify studies with all search terms and limits for at least one database.

- a Supplemental file of the results of the individual components of the quality assessment, not just the overall score, for each study included.

Response: Thanks for this suggestion, and the full electronic search strategy in PubMed have already listed in Methods section. Moreover, the individual components of the quality assessment for each study have already added in Supplementary file.

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

Response: Thanks for this suggestion, and the Data Availability statement have already changed into: “Data availability: All relevant data are within the paper and its Supporting information files.”

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Response: Thanks for this suggestion, and the ORCID ID for the corresponding author will submit in Editorial Manager when upload the revised manuscript.

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Response: Thanks for this suggestion, and the captions for your Supporting Information files have already added at the end of manuscript.

Reviewer #1:

General comments: The authors report on a meta-analysis of an important topic - risk factors for dry eye syndrome. I thank the authors for their persistence with this large and complex analysis, however their analysis is limited by multiple methodologic and reporting concerns. The quality of evidence used to make these conclusions is also suspect, given the large proportion of cross-sectional studies that are susceptible to recall bias and variability in the adjustment for confounding factors across studies.

Response: As behalf of all co-authors, I would like to appreciate this referee due to thoughtful comments proposed by the peer review. After we revised the manuscript, those significant issues could be changed. Moreover, this comment have already addressed in Limitation section.

Question 1: Methods, Abstract: The model used for meta-analysis should be specified, as well as the inclusion and exclusion criteria for study selection.

Response: Thanks for this suggestion, and the methods in abstract have already changed into: “PubMed, Embase, and the Cochrane library were systematically searched for studies investigated the risk factors for dry eye syndrome from their inception until September 2021. The odds ratio (OR) with 95% confidence interval (CI) was calculated using the random-effects model.”

Question 2: Conclusion, Abstract: The authors should elaborate on their conclusion section to discuss the implications of their findings and/or areas for future research.

Response: Thanks for this suggestion, and the conclusion in abstract have already changed into: “This study reported the comprehensive risk factors for dry eye syndrome, including demographic information, clinical characteristics, and comorbidities.”

Question 3: Introduction: expand on the risk factor ‘visual display terminal’ for readers who may be unfamiliar with this term.

Response: Thanks for this suggestion, and the following sentence have already added in the revised manuscript: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could explained by decreases blink rate and increases the proportion of incomplete blinks could causing the increased exposure of the ocular surface to the environment.”

Question 4: Introduction: “However, the presence of other comorbidities and individuals’ characteristics on the risk of DES were not illustrated.” The authors should specify that there is conflicting or negative evidence for these other characteristics as opposed to these being uninvestigated characteristics.

Response: Thanks for this suggestion, and this sentence have already changed into: “However, whether the comorbidities of individuals could affect the risk of DES remained controversial. ”

Question 5: Methods: “The following search terms were used: ("Dry Eye Syndromes"[Mesh]) AND "Risk Factors"[Mesh].” The search strategy provided by the authors is quite simplistic and does not account for other formulations of the same concept found in these major databases. No text-based searches are also integrated to ensure maximal literature coverage.

Response: Thanks for this suggestion, and this sentence have already changed into: “PubMed, Embase, and the Cochrane library were systematically searched for eligible studies from their inception until September 2021, and using the following text word or Medical Subject Heading terms: "dry eye syndrome", "dry eye disease", "Keratoconjunctivitis Sicca", "Xerophthalmia", and "Risk Factors".”

Question 6: Methods: Did the authors investigate the gray literature as part of this systematic review?

Response: Thanks for this suggestion, and the following sentences have already added in Limitation section to address this comments: “Fourth, the analysis based on published articles, the gray literature and unpublished data were not available, and the publication bias was inevitable. Finally, the analysis using the pooled data, and the detailed analyses were restricted. ”

Question 7: Methods: specify with initials the authors that independently screened studies and extracted data.

Response: Thanks for this suggestion, and the initials of authors have already added in the revised manuscript for screened studies and extracted data.

Question 8: Methods: the authors note that all studies reporting on dry eye risk factors were considered. Were interventional studies assessing the impact of dry eye treatment also included?

Response: Thanks for this suggestion. The identified risk factors including demographic information, clinical characteristics, and comorbidities, while potential treatments in interventional studies were not included. We have already added the following sentence in Methods section: “Interventional study, animal study, review, and letter to editor was excluded”.

Question 9: Methods: was the systematic review prospectively registered in the PROSPERO database?

Response: Thanks for this suggestion, this study was not registered in the PROSPERO, which have already addressed in Limitation section.

Question 10: Methods: The authors note that studies which assessed risk factors in at least 3 cohorts were included. Some studies assessing risk factors for dry eye may have only focused on one risk factor and would therefore be excluded under the current methodology. This overly restrictive inclusion criterion seems arbitrary and unwarranted.

Response: Thanks for this suggestion. The main findings of this meta-analysis focused on quantitative analysis, and the conclusions obtained from 1 or 2 studies caused the variable of pooled results. Moreover, the screening criteria was referring to the following articles: Song P, Rudan D, Zhu Y, Fowkes FJI, Rahimi K, Fowkes FGR, Rudan I. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health. 2019 Aug;7(8):e1020-e1030.

Question 11: Methods: Was a GRADE evaluation performed to assess the certainty of findings?

Response: Thanks for this suggestion, and this study contained cross-sectional, retrospective, and prospective observational studies, and the GRADE evaluation was not applied for certainty of findings.

Question 12: Methods: “Identified risk factors for DES were analyzed based on the effect estimate, with its 95% CI, in 99 individual studies.” What effect estimate was considered? Elaborate on the exact methods used. For continuous variables like age, how were they categorized into binary groups for analysis?

Response: Thanks for this suggestion, and this sentence have already changed into: “Identified risk factors for DES were analyzed based on the OR, RR, or HR, with its 95% CI, in individual studies. Then the pooled ORs with 95%CI were calculated using the random-effects model.[16,17]”. Moreover, the categorized for continuous variables were referring to the original articles, which have already addressed in Limitation section.

Question 13: Methods: Only one subgroup analysis based on country was considered in the analysis. There are likely multiple potential confounders in this analysis that can be investigated for using subgroup analysis, including severity of dry eye, individuals with dry eye secondary to another condition eg Sjogren’s, evaporative vs aqueous deficient dry eye, study design, etc.

Response: Thanks for this suggestion. In the planning stage, subgroup analysis should be performed according to study design, the severity of dry eye, and the type of dry eye. However, mostly included studies designed as cross-sectional studies. Moreover, DES was considered as investigated outcome, and the stratified data for the severity of dry eye, and the type of dry eye were not available in mostly included studies.

Question 14: Methods, statistical analysis: specify the measure of association used to report the results - ie odds ratio with 95% confidence interval.

Response: Thanks for this suggestion, and this sentence have already changed into: “Identified risk factors for DES were analyzed based on the OR, RR, or HR, with its 95% CI, in individual studies. Then the pooled ORs with 95%CI were calculated using the random-effects model.[16,17]”

Question 15: Results: what proportion of results of studies was derived from a multivariable analysis that controlled for confounding parameters versus a univariable analysis?

Response: Thanks for this suggestion, and the adjusted factors have already abstracted and listed in Table 1.

Question 16: Results: provide more information in the study characteristics section on the type and severity of dry eye, observational vs interventional studies, the recency of publication, the pooled gender and age distribution, and other relevant baseline parameters for this analysis.

Response: Thanks for this suggestion, the type and severity of DES were available in smaller number of included studies. Moreover, the baseline characteristics of included studies recruited individuals have already listed in Table 1.Finally, several sentences have already added in the second paragraph of Results section.

Question 17: Results: expand on the results of the risk of bias assessment - what was the most frequent reason for downgrading the risk of bias?

Response: Thanks for this suggestion, and the following sentences have already added in the revised manuscript: “The quality of included studies mainly affect by the representativeness of the exposed cohort, and comparability on the basis of the design or analysis. ”

Question 18: Results: It would be important to clarify the definition of DES used in the analysis, and whether this definition was different across included studies.

Response: Thanks for this suggestion, and the definition of DES was based on included studies, and the definition was different among included studies. We have already address this comment in Limitation section.

Question 19: Results: When reporting the results for each risk factor, it would be helpful to provide the proportion of the characteristic in the DES vs no DES groups, e.g. mean age, % female, race distribution, etc.

Response: Thanks for this suggestion. The analysis of this study based on pooled data, and the detailed analyses were restricted, which have already addressed in Limitation section.

Question 20: Results: For endpoints that had significant statistical heterogeneity, was the heterogeneity changed in the subgroup analysis?

Response: Thanks for this suggestion, and the heterogeneity was not fully explained in the sensitivity and subgroup analyses, which have already addressed in Limitation section.

Question 21: Results: For glaucoma as a risk factor, it would important to clarify the therapy received, as this likely impacts the risk of DES.

Response: Thanks for this suggestion. The inclusion criteria was restricted risk factors were reported for ≥ 3 cohorts, and whether the therapies were adjusted have already listed in Table 1.

Question 22: Results: For eye surgery as a risk factor, clarify what type of surgeries were considered.

Response: Thanks for this suggestion. The type of eye surgery was defined based on individual study, and the stratified data based on the type of eye surgery was not available. We have already addressed this comment in Limitation section.

Question 23: Results: In the reporting of the various risk factors, certain risk factors are grouped with others in the same paragraph. It is unclear how the various risk factors were grouped. It would be helpful to add subheadings to clarify this.

Response: Thanks for this suggestion, and the subheadings have already added in the revised manuscript.

Question 24: Results: “systemic disease” as a risk factor is not helpful or clinically relevant. This needs to be specified as to which specific systemic disease was considered or otherwise removed from the analysis.

Response: Thanks for this suggestion. The systemic disease was defined based on individual study, and the stratified data based on systemic disease was not available. We have already addressed this comment in Limitation section.

Question 25: Discussion: “we noted that other races versus white race were associated with an increased risk of DES, which is significantly related to the climate type.” Is race a risk factor independent of climate type? Elaborate on how climate type mediated this effect.

Response: Thanks for this suggestion. The climate type was not addressed in nearly all of included studies, and this comment have already addressed in Limitation section.

Question 26: Discussion: “anti-hypertensive medication could increase the risk of DES”. What is the mechanism of this association?

Response: Thanks for this suggestion, and this sentence have already changed into: “A potential reason for this could be hypertension was not direct affect the risk of DES, while the use of anti-hypertensive medication could increase the risk of DES.[32] In addition, the risk of DES were not increased in hypertensive patients treated with anti-hypertensive medications, such as Angiotension Converting Enzyme inhibitors might play a protective role on the risk of DES.[33]”

Question 27: Discussion: “The role of rosacea could be explained by its significant relation to corneal neovascularization and perforation, which could induce vision loss and ocular comorbidities.[85]” This relation is poorly described. Rosacea is a well known risk factor for DES due to is pro-inflammatory effects that induce meibomian gland dysfunction and evaporative DES.

Response: Thanks for this suggestion, and this sentence have already changed into: “Rosacea is a well known risk factor for DES due to is pro-inflammatory effects that induce meibomian gland dysfunction and evaporative DES.[85]”

Question 28: Discussion: “Studies have already found that thyroid disease is significantly related to ocular surface damage, elevated lip aperture” - ‘elevated lip aperture’ should read ‘eyelid retraction’

Response: Thanks for this suggestion, and ‘elevated lip aperture’ have already changed into ‘eyelid retraction’ in the revised manuscript.

Question 29: Discussion: a major limitation is that the impact of confounding variables is unaddressed by certain studies, and multivariable associations were only reported for certain risk factors. Given the large proportion of cross-sectional studies, recall bias is likely a significant issue in these results.

Response: Thanks for this suggestion. The adjusted factors have already mentioned in Table 1. Moreover, the following sentence have already added in Limitation section: “First, this study contained cross-sectional, retrospective, and prospective observational studies, and the results could affect by recall bias, which restricting the assessment of causality relationships between risk factors and DES.”

Question 30: Figure 2: p-value column - unsure why the p-values displayed in this way, as if multiple numbers are written on top of one another? What is the significance of the blue/gray background behind the forest plot for each endpoint?

Response: Thanks for this suggestion, and the Figure 2 have already changed in the revised manuscript. Moreover, the blue/gray background behind in the forest have already revised in Supplementary file.

Reviewer #2:

General comments: This is a very well written meta-analysis regarding the potential risk factors for dry eye syndrome. Nevertheless, risk factors for DES are widely known, therefore, my question to the authors is:

In which way this meta analysis contributes to the literature already published regarding the risk factors for DES.

Response: We appreciate the reviewer given this kindly comments. Systematic reviews and meta-analyses are the most powerful tools in evaluating inconsistencies in risk factors. Our study designed as meta-analysis, and the inconsistent results for the risk factors of DES could determined. Moreover, the pooled effect estimates for the risk factors of DES could obtained based on large number of studies, and the results were stability.

Submitted filename: Response to reviewer.docx

Click here for additional data file.

4 Apr 2022

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Michael Mimouni

Academic Editor

PLOS ONE

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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: (No Response)

Reviewer #2: All comments have been addressed

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

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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: The reviewer thanks the authors for their attempt at revising the manuscript. While improved, the manuscript still has a few limitations as noted below:

1. Conclusion, Abstract: “This study reported the comprehensive risk factors for dry eye syndrome, including demographic information, clinical characteristics, and comorbidities.” This sentence is not suitable as the last sentence of the abstract. Instead, the authors should discuss the implications of their research (i.e. why identification of these risk factors is important to improve clinical care) or alternatively discuss other areas of research that could be explored.

2. The manuscript should be thoroughly proofread by a native English speaker. For instance, this sentence contains multiple grammatical errors: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could explained by decreases blink rate and increases the proportion of incomplete blinks could causing the increased exposure of the ocular surface to the environment”. A more appropriate sentence would be: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could be explained by a decreased blink rate and increased proportion of incomplete blinks that could be caused by the increased exposure of the ocular surface to the environment”. In some sections, the language is so poor that it is uninterpretable: “which restricting the assessment of causality relationships between risk factors and DES”.

3. The search strategy is still insufficient to permit replication of the search by an independent researcher. The authors should specify the search strategy in a line-by-line format in a table that outlines clearly what term was searched, how terms were combined, and whether any restrictions were applied. The search should be updated to March 2022. In the table, the authors should highlight whether each term was a MeSH subject heading or a text based term.

4. The authors note that studies which assessed risk factors in at least 3 cohorts were included. The authors should cite the meta-analysis in Lancet Global Health that they followed for this methodology. I would advise changing ‘cohorts’ to ‘studies’ to make this sentence clearer in the Methods.

5. The authors note that “this study contained cross-sectional, retrospective, and prospective observational studies, and the GRADE evaluation was not applied for certainty of findings.” This reviewer believes it is important to conduct a GRADE evaluation for this meta-analysis especially because the evidence comes primarily from observational studies which are by their nature susceptible to bias. To provide readers with an indication of the certainty of evidence, the GRADE evaluation should be integrated.

6. The authors have discussed the variable definitions of DED in the limitations section, however in the baseline characteristics section of the results the authors should specify how different studies defined DED. This is important for readers to understand.

7. The sentence “we noted that other races versus white race were associated with an increased risk of DES, which is significantly related to the climate type” should be deleted because there is not evidence to support the notion that DES in different races is attributable to climate type as opposed to other factors.

Reviewer #2: Thank you for addressing my question and improving the shortcoming section. I do not have any more questions or comments to the authors.

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Reviewer #1: No

Reviewer #2: No

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19 May 2022

Reviewer #1:

General comments: The reviewer thanks the authors for their attempt at revising the manuscript. While improved, the manuscript still has a few limitations as noted below:

Response: As behalf of all co-authors, I would like to appreciate this referee due to thoughtful comments proposed by the peer review. After we revised the manuscript, those significant issues could be changed.

Question 1: Conclusion, Abstract: “This study reported the comprehensive risk factors for dry eye syndrome, including demographic information, clinical characteristics, and comorbidities.” This sentence is not suitable as the last sentence of the abstract. Instead, the authors should discuss the implications of their research (i.e. why identification of these risk factors is important to improve clinical care) or alternatively discuss other areas of research that could be explored.

Response: Thanks for this suggestion, and the conclusion have already changed into: “This study reported risk factors for dry eye syndrome, and identified patients at high risk for dry eye syndrome.”

Question 2: The manuscript should be thoroughly proofread by a native English speaker. For instance, this sentence contains multiple grammatical errors: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could explained by decreases blink rate and increases the proportion of incomplete blinks could causing the increased exposure of the ocular surface to the environment”. A more appropriate sentence would be: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could be explained by a decreased blink rate and increased proportion of incomplete blinks that could be caused by the increased exposure of the ocular surface to the environment”. In some sections, the language is so poor that it is uninterpretable: “which restricting the assessment of causality relationships between risk factors and DES”.

Response: Thanks for this suggestion, and the English revision have already performed by Editage Company.

Question 3: The search strategy is still insufficient to permit replication of the search by an independent researcher. The authors should specify the search strategy in a line-by-line format in a table that outlines clearly what term was searched, how terms were combined, and whether any restrictions were applied. The search should be updated to March 2022. In the table, the authors should highlight whether each term was a MeSH subject heading or a text based term.

Response: Thanks for this suggestion, and the details search strategy in PubMed have already added in S1 file.

Question 4: The authors note that studies which assessed risk factors in at least 3 cohorts were included. The authors should cite the meta-analysis in Lancet Global Health that they followed for this methodology. I would advise changing ‘cohorts’ to ‘studies’ to make this sentence clearer in the Methods.

Response: Thanks for this suggestion, and this articles have already cited in the revised manuscript. Moreover, the ‘cohorts’ have already changed into ‘studies’.

Question 5: The authors note that “this study contained cross-sectional, retrospective, and prospective observational studies, and the GRADE evaluation was not applied for certainty of findings.” This reviewer believes it is important to conduct a GRADE evaluation for this meta-analysis especially because the evidence comes primarily from observational studies which are by their nature susceptible to bias. To provide readers with an indication of the certainty of evidence, the GRADE evaluation should be integrated.

Response: We acknowledge the importance of GRADE, while 39 of included studies designed as cross-sectional studies, and the causality relationships between risk factors and DES were not available. Moreover, the quality of included studies were assessed using the Newcastle-Ottawa Scale, and the results are listed in S1 table.

Question 6: The authors have discussed the variable definitions of DED in the limitations section, however in the baseline characteristics section of the results the authors should specify how different studies defined DED. This is important for readers to understand.

Response: Thanks for this suggestion, and the following sentence have already added in Results section: “The DES definition based on questionnaire were reported in 33 studies, 10 studies used TBUT, ST, or FSS defined DES, 3 studies applied ICD9 code and the remaining 2 studies used clinician-diagnosed defined DES.”

Question 7: The sentence “we noted that other races versus white race were associated with an increased risk of DES, which is significantly related to the climate type” should be deleted because there is not evidence to support the notion that DES in different races is attributable to climate type as opposed to other factors.

Response: Thanks for this suggestion, and this sentence have already removed in the revised manuscript.

Reviewer #2:

General comments: Thank you for addressing my question and improving the shortcoming section. I do not have any more questions or comments to the authors.

Response: We appreciate the reviewer given this kindly comments.

Submitted filename: Response to reviewer.docx

Click here for additional data file.

28 Jun 2022

Identified risk factors for dry eye syndrome: A systematic review and meta-analysis

PONE-D-21-35192R2

Dear Dr. Wei,

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.

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Kind regards,

Michael Mimouni

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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

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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

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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: No

Reviewer #2: Yes

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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: The reviewer thanks the author for revising the manuscript based on earlier feedback. I have no further comments.

Reviewer #2: I do not have more comments for the authors. Thank you for answering all the reviewers questions and improving the script.

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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

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10 Aug 2022

PONE-D-21-35192R2

Identified risk factors for dry eye syndrome: A systematic review and meta-analysis

Dear Dr. Wei:

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