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ARTICLE (Is aspirin associated with diabetic retinopathy? The Singapore Epidemiology of Eye Disease (SEED) study)

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RESEARCH ARTICLE

Is aspirin associated with diabetic

retinopathy? The Singapore Epidemiology of

Eye Disease (SEED) study

Yuan Shi
1
, Yih-Chung Tham

1,2
, Ning Cheung

1
, Jacqueline Chua

1
, Gavin Tan

1
,

Paul Mitchell
3
, Jie Jin Wang

3,4
, Yin Bun Cheung

4,5
, Ching-Yu Cheng

1,2,4
,

Tien Yin Wong
1,2,4*

1 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore, 2 Department of

Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore,

3 Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research,

University of Sydeney, Sydeney, Australia, 4 Duke-NUS Medical School, Singapore, Singapore, 5 Tampere

Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland

* ophwty@nus.edu.sg

Abstract

Background/Aims

To determine the association between aspirin use and diabetic retinopathy (DR) among per-

sons with diabetes, in a population-based, cross-sectional study.

Methods

Subjects with diabetes aged >40 years from the Singapore Epidemiology of Eye Diseases
Study were enrolled in this study. Retinal photographs were graded for DR according to the

modified Airlie House classification system. Vision threatening diabetic retinopathy (VTDR)

was defined as the presence of severe non-proliferative DR, or proliferative DR, or clinically

significant macular oedema. The association between aspirin use and the presence of DR

or VTDR was assessed using multivariable logistic regression models including age, gen-

der, ethnicity, socioeconomic status, HbA1c, systolic blood pressure, anti-hypertension

medicine, total cholesterol, anti-cholesterol medicine, BMI, current smoking status, diabetes

duration, history of cardiovascular disease (CVD) and chronic kidney disease (CKD.).

Results

A total of 2,061 participants with diabetes and complete record of relevant systemic and DR

data were included. Of these, 711 (34.5%) had any stage of DR, and among these 177

(8.6%) had VTDR. After adjusting for co-variables listed, the association between aspirin

use and VTDR was significant (OR = 1.69, P = 0.019), while the association between aspirin

use and any DR was borderline (OR = 1.31, P = 0.063). Aspirin use was not associated with

either DR or VTDR after additional adjustment of CVD and CKD. Further stratification by his-

tory of CVD or CKD showed no association between aspirin use and DR/VTDR in either

subgroup.

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OPEN ACCESS

Citation: Shi Y, Tham Y-C, Cheung N, Chua J, Tan

G, Mitchell P, et al. (2017) Is aspirin associated

with diabetic retinopathy? The Singapore

Epidemiology of Eye Disease (SEED) study. PLoS

ONE 12(4): e0175966. https://doi.org/10.1371/

journal.pone.0175966

Editor: Fakir M Amirul Islam, Swinburne University

of Technology, AUSTRALIA

Received: December 26, 2016

Accepted: April 3, 2017

Published: April 28, 2017

Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in

any medium, provided the original author and

source are credited.

Data Availability Statement: All relevant data are

within the paper and its Supporting Information

file.

Funding: Support was provided by National

Medical Research Council of Singapore (NMRC/

0796/2003, 1176/2008, 1149/2008) and

Biomedical Research Council grant of Singapore

(BMRC/08/1/35/19/550).

Competing interests: The authors have declared

that no competing interests exist.

https://doi.org/10.1371/journal.pone.0175966

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Conclusion

Aspirin use was not significantly associated with DR but might be an indicator of diabetic

complications (CVD, CKD) that were co-present with more severe DR type. Future longitudi-

nal studies are warranted to confirm our findings.

Introduction

Diabetic retinopathy (DR) is a common microvascular complication of diabetes and is the lead-

ing cause of preventable vision loss among adult populations worldwide.[1] Globally, 34.6%

persons with diabetes have DR. Of these, 10.2% have vision-threatening DR (VTDR). The num-

ber of persons with DR worldwide is expected to reach close to 200 million by 2030.[2,3]

The long-term vascular complication of diabetes with poor control include both macrovas-

cular and microvascular complication.[4] Persons with diabetic macrovascular complications

(e.g. CVD) are also more likely to have microvascular complications (e.g. DR). Aspirin is com-

monly used as a primary or secondary prevention to reduce the risk of CVD events and its

related mortality[5,6]. While some investigators reported strong association between aspirin

use and higher DR incidence[7], others showed that aspirin alone was not associated with risk

of DR-related retinal or vitreous hemorrhage[8,9], and that aspirin use may even slow down

progression of DR[10]. Previously observed association between aspirin use and DR by other

investigators[7] could be the result of confounding by CVD condition, a concern that has not

been examined thoroughly previously.

Hence, in the Singapore Epidemiology of Eye Disease (SEED) study, we sought to examine

the association between aspirin use and DR in a large, multi-ethnic Asian population, taking

into association account of the confounding effect by CVD. Better elucidation on this associa-

tion may provide useful information for clinical management of diabetes.

Materials and methods

Study population

The subjects for this study were enrolled from the SEED, a population-based cross-sectional

study of eye diseases in multi-ethnic groups of residents in Singapore aged 40 years and above.

Briefly, an age-stratified random sampling of all Malay, Indian and Chinese adults residing in

the southwestern part of Singapore was performed. A potential participant was considered to

be ineligible if the person had moved from the residential address, had not lived there in the

past 6 months, was deceased, or was terminally ill. Participation rate was calculated as the ratio

of final participants by total eligible in each ethnic group. A total of 3,353 Chinese, 3,280

Malays, and 3,400 Indians participated in our study, giving response rates of 72.8%, 78.7%,

and 75.6%, respectively. The detailed methodology of the SEED was described in previous

publication.[11,12] The study adhered to the Declaration of Helsinki, and ethics approval was

obtained from the Singapore Eye Research Institute (SERI)’s Institutional Review Board with

written informed consent obtained from all subjects before participation. All participants

underwent standardised ocular and systemic examination.

Retinal photography and diabetic retinopathy assessment

DR was assessed through standardised retinal photography, using a digital retinal camera

(Canon CR-DGi with 10D SLR back, Japan). After pupil dilation, two retinal photographs,

Aspirin and diabetic retinopathy

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centred at the optic disc and macula, were taken from both eyes. Photographs were graded at

the University of Sydney by one certified ophthalmic grader, with adjudication by a senior reti-

nal specialist. DR was considered present if characteristic lesions as defined by the Early Treat-

ment Diabetic Retinopathy Study (ETDRS) (i.e. microaneurysms, haemorrhages, cotton wool

spots, intraretinal microvascular abnormalities, hard exudates, venous beading, new vessels)

were observed.[13,14] DR severity was graded based on the modified Airlie House classifica-

tion system, using the Blue Mountains Eye Study protocol.[15,16] Individuals’ DR status was

defined based on the severity scores of the worse eye. Clinically significant macular edema

(CSME) was considered present when the macular edema involved was within 500 μm of the
foveal center or if focal photocoagulation scars were present in the macular area. VTDR was

defined as the presence of severe non-proliferative DR, proliferative DR or CSME.[17] The

detailed protocol of DR grading was described in previous publication.[18]

Clinical examination, questionnaire and interview

Comprehensive physical examination, laboratory tests and interview were performed as

described elsewhere.[12,19] In brief, blood pressure (BP) was measured using a digital auto-

matic blood pressure monitor after 5 minutes of rest. Body mass index (BMI) was calculated as

body weight (kg) divided by body height (m) squared. Blood samples were collected to deter-

mine levels of serum lipids, glycated haemoglobin (HbA1c) and random glucose without fast-

ing. Patients with diabetes were defined as having random glucose �11.1 mmol/L, use of

diabetic medication or a participant-reported physician diagnosis of diabetes. Patients with

hypertension were defined as systolic BP � 140 mmHg, or diastolic BP � 90 mmHg or physi-

cian diagnosis or self-reported history of hypertension. Patients with hyperlipidaemia were

defined as total cholesterol � 6.2 mmol/L or use of lipid lowering drugs.

A detailed interview was administered using a standardized questionnaire to collect infor-

mation including medical history, duration of diabetes, educational level and monthly income.

Aspirin use was defined as current intake of aspirin-type medication, including solprin, cardi-

prin, disprin, and ecotrin, but not panadol or dymadon. Use of anti-hypertensive drugs was

defined as current intake of either ACE-inhibitors, angiotensin II receptor blocker, calcium

channel blockers, diuretics, alpha receptor antagonists, beta receptor blockers or other anti-

hypertensive medication not specified. Use of lipid lowering drugs was defined as current

intake of either statins, fibrates, dyslipidaemic drugs or other anti-cholesterol medication not

specified. CVD history was defined as a self-reported history or physician diagnosis of angina,

or heart attack, or stroke. Chronic kidney disease (CKD) was defined as an estimated glomeru-

lar filtration rate (eGFR) <60 mL/min/1.73 m 2 , using the US National Kidney Foundation

Kidney Disease Outcome Quality Initiative (KDOQI) Working Group definition.[20] eGFR

was estimated from the serum creatinine concentration using the CKD Epidemiology Collabo-

ration (CKD-EPI) equation[21]. As Socioeconomic status has been previously shown to be sig-

nificantly associated with DR status[22,23], we included socioeconomic status as one potential

confounder. Low socioeconomic status (SES) was defined as having primary or lower educa-

tion, individual monthly income < SGD2000, and 1–2 room HDB flat.

Statistical analysis

Statistical analysis was performed using R software version 3.2.2.[24] Baseline characteristics

differences were tested using independent t-test for continuous variables and Pearson’s χ2 test
for categorical variables. The association between aspirin use (exposure variable) and the pres-

ence of DR (outcome variable) was assessed using logistic regression models, adjusting for age,

gender and ethnicity (Model 1), plus SES, HbA1c, blood pressure, cholesterol level, anti-

Aspirin and diabetic retinopathy

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hypertension drugs, anti-cholesterol drugs, BMI and smoking status (Model 2). We further

adjusted for diabetes duration (Model 3) and additionally histories of CVD and CKD (Model

4). In all the statistical analysis, a P value of <0.05 is considered statistical significant. In the logistic regression models, odds ratios (ORs) and 95% confidence intervals (CIs) of the odds

ratios are estimates generated to represent the associations between the study factor (aspirin

use) with the outcome factor (DR), while controlling for co-variables that are potential con-

founding factors for the association under investigation.

Results

Of the whole 10,033 SEED study participants, 2,888 participants had diabetes. After excluding

those with unavailable data on DR grading, clinical information and social status, 2,061 partici-

pants were included in the final analysis. Among whom, 711 (34.5%) had any DR, 177 (8.6%)

had VTDR, and 83 (4.0%) had CSME. Table 1 showed the demographic and clinical character-

istic comparisons between the participants with and without DR. Among Chinese participants

with diabetes, the proportion with DR (28%) was relatively lower than that among Malays or

Indians (both around 36%) who had diabetes. Besides, the participants with DR are more likely

to have hypertension, higher HbA1c, longer duration of diabetes, CVD history, CKD history,

lower SES and to use aspirin. There were no significant differences in age, gender, cholesterol,

presence of hyperlipidemia between participants with and without DR.

Table 1. Clinical characteristics comparison between diabetic patients with and without diabetic retinopathy (DR).

Without DR (n = 1350) With DR (n = 711) P-value*

Age 61.7 (9.9) 61.9 (8.9) 0.753

Gender, Male 681 (50.44) 358 (50.35) 1.000

Ethnicity

Chinese 305 (22.59) 121 (17.02) 0.004

Malay 437 (32.37) 242 (34.04) 0.474

Indian 608 (45.04) 348 (48.95) 0.100

Body Mass Index, kg/m
2

26.91 (4.76) 26.34 (4.68) 0.009

Systolic blood pressure, mmHg 142.48 (20.44) 149.00 (23.26) <0.001 Diastolic blood pressure, mmHg 77.54 (9.67) 77.49 (10.96) 0.921

Anti-hypertension medication use 786 (58.22) 442 (62.17) 0.092

Total cholesterol, mmol/L 5.06 (1.20) 5.04 (1.32) 0.806

Anti-cholesterol medication use 674 (49.93) 341 (47.96) 0.423

HbA1c, % 7.70 (1.73) 8.32(1.87) <0.001 Duration of diabetes, years 8.4 (8.0) 13.5 (9.4) <0.001 Hypertension 1015 (75.19) 588 (82.70) <0.001 Hyperlipidaemia 846 (62.67) 426 (59.92) 0.241

Current smoking 183 (13.56) 82 (11.53) 0.217

Low socioeconomic status
Τ

88 (6.52) 63 (8.86) 0.064

History of cardiovascular disease 242 (17.93) 156 (21.94) 0.033

History of kidney disease 244 (18.07) 208 (29.25) <0.001 Aspirin use 212 (15.70) 141 (19.83) 0.021

Data presented are means (standard deviation) or number (%), as appropriate for variables.

* P-value was obtained with t-test for continuous variables and with chi-square tests for categorical variables.
Τ

Low socioeconomic status was defined as Primary or lower education, Individual monthly income < SGD2000, and 1–2 room HDB flat.

https://doi.org/10.1371/journal.pone.0175966.t001

Aspirin and diabetic retinopathy

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After adjusting for potential confounders including age, gender, ethnicity, SES, HbA1c, sys-

tolic BP, anti-hypertensive medication, total cholesterol, anti-cholesterol medication, BMI and

current smoking status, aspirin use was significantly associated with DR (OR = 1.35, 95% CI:

1.03 to 1.75, P = 0.028, Table 2, S1 Fig) and VTDR (OR = 1.89, 95% CI: 1.24 to 2.84, P = 0.003,
Table 2), respectively. After further adjusting for diabetes duration, the association between

aspirin use and VTDR remained significant (OR = 1.69, 95% CI: 1.09 to 2.61, P = 0.019,
Table 2, S1 Fig), while the association between aspirin and DR was weaken (OR = 1.31, 95%

CI: 0.99 to 1.74, P = 0.063, Table 2, S1 Fig). However, after additionally adjusted for history of
CVD and CKD, aspirin use was no longer associated with DR (OR = 1.23, 95% CI: 0.90 to

1.67, P = 0.187, Table 2, S1 Fig) and VTDR (OR = 1.40, 95% CI: 0.86 2.25, P = 0.168, Table 2,
S1 Fig). In comparison, the presence of CSME was not associated with aspirin use in any of the

models above.

The regression models were further stratified by history of CVD or CKD, respectively

(Table 3, S2 Fig). The associations within each subgroup were not statistically significant. Nev-

ertheless, we observed that the association between aspirin use and VTDR was slightly more

prominent among individuals with CVD (OR = 1.99, 95% CI: 0.94 to 4.35, P = 0.076) com-
pared to those without (OR = 1.10, 95% CI: 0.54 to 2.11, P = 0.790). No significant interaction
effects were observed between CVD or CKD and aspirin.

Table 2. Regression model showing the association between aspirin and DR.

DR
Τ

VTDR
Τ

CSME
Τ

OR(95% CI) P-value OR(95% CI) P-value OR(95% CI) P-value

Model 1 1.34 (1.05–1.71) 0.018 1.87 (1.27–2.71) 0.001 1.25 (0.67–2.20) 0.463

Model 2 1.35 (1.03–1.75) 0.028 1.89 (1.24–2.84) 0.003 1.52 (0.77–2.85) 0.206

Model 3 1.31 (0.99–1.74) 0.063 1.69 (1.09–2.61) 0.019 1.40 (0.71–2.67) 0.313

Model 4 1.23 (0.90–1.67) 0.187 1.40 (0.86–2.25) 0.168 1.16 (0.55–2.32) 0.691

Model 1: adjusted for age, gender and ethnicity.

Model 2: adjusted for variables in Model 1 plus socioeconomic status, HbA1c, systolic blood pressure, anti-hypertension medicine, total cholesterol, anti-

cholesterol medicine, BMI, current smoking status.

Model 3: adjusted for variables in Model 2 plus duration of diabetes.

Model 4: adjusted for variables in Model 3 plus history of cardiovascular disease and chronic kidney disease
Τ

DR = diabetic retinopathy; VTDR = vision-threatening diabetic retinopathy; CSME = clinically significant macular edema; OR = odds ratio; CI = confidence

interval.

https://doi.org/10.1371/journal.pone.0175966.t002

Table 3. Regression model showing the association between aspirin use and VR or VTDR after stratified by history of cardiovascular disease or

history of

kidney disease.

Stratification by CVD* Stratification by CKD*

Without CVD With CVD Without CKD With CKD

OR(95% CI) P-value OR(95% CI) P-value OR(95% CI) P-value OR(95% CI) P-value

DR
Τ

1.11 (0.74–1.66) 0.620 1.31 (0.80–2.17) 0.282 1.14 (0.78–1.66) 0.500 1.47 (0.85–2.54) 0.170

VTDR
Τ

1.10 (0.54–2.11) 0.790 1.99 (0.94–4.35) 0.076 1.30 (0.62–2.60) 0.476 1.60 (0.81–3.16) 0.174

Τ
Both models adjusted for age, gender, ethnicity, socioeconomic status, HbA1c, systolic blood pressure, anti-hypertension medication, total cholesterol,

anti-cholesterol medication, BMI, current smoking status, and duration of diabetes plus CKD in analysis of subgroup with CVD, and plus CVD in analysis of

subgroup with CKD.

* CVD = cardiovascular disease; CKD = chronic kidney disease; OR = odds ratio; CI = confidence interval.

https://doi.org/10.1371/journal.pone.0175966.t003

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Discussion

In this population-based study of a multi-ethnic Asian population, we examined the associa-

tion of aspirin use and DR among persons with diabetes through involving CVD and CKD as

potential confounders. Our results showed that persons with diabetes on regular aspirin use

were more likely to have DR, especially VTDR. Nevertheless, this association became non-

significant after further adjustment for history of CVD and CKD. This suggests that aspirin

use is likely an indicator of CVD or CKD, both are complications of diabetes and likely co-

present with DR at the relatively severe stage of diabetes.

Similar to the early part of our findings (Models 1 2 and 3 in Table 2), prospective data

from the Madrid Diabetes Study of European cohort (MADIABETES) of 3,443 participants

with diabetes, suggested that aspirin use was associated with 1.64-fold increased risk of 4-year

incident DR after adjustment for gender, duration of diabetes, hypertension and HbA1c levels.

[7] However, data from other studies generated conflicting results. For example, the Early

Treatment for DR Study (ETDRS) showed that aspirin therapy was not associated with risk for

DR progression.[13,14] In addition, the randomized clinical trial from the Dipyridamole Aspi-

rin Microangiopathy of Diabetes (DAMAD) study group[10] and an earlier population study

[8] showed that participants on aspirin had less retinopathy than those not on aspirin in a gen-

eral diabetic population, suggesting that aspirin could be considered as an intervention to

reduce risk of DR. These inconsistent results could have been due to differences in study popu-

lation and designs. Of note, as an interventional clinical trial, there is more homogeneous

health condition as ETDRS recruited patients with more severe DR, specifically CSME, and

the DAMAD involved only participants with predominantly early DR. In contrast, MADIA-

BETES enlisted participants with varied diabetes severities, while the history of previous but

not CVD and CKD was not considered.

Therefore, it is important that evaluation in this area sufficiently takes into account the rele-

vant confounding factors which are related to aspirin intake. In this regard, after further

adjusting for history of CVD and CKD, our data showed that the associations between aspirin

use and DR (any DR or VTDR) was attenuated and became non-significant (Model 4,

Table 2). Further analyses stratified by CKD and CVD, respectively showed that the associa-

tions between aspirin use with DR and VTDR were more prominent in participants with pre-

vious history of either CVD or CKD than those without. Taken together, this may indicate that

the initially observed associations of aspirin use with the presence of DR or VTDR might be

the result of confounding by CVD and CKD, which are known diabetic complications at rela-

tively advanced stage of diabetes, and also are indications of aspirin prescription.[25] The

apparent association between aspirin and DR may merely be a reflection of its association with

more severe diabetes, and may be confounded by indication of aspirin in individuals with

CVD and CKD. We also included insulin in our models, and the conclusions remain the same

(S1 Table).

Strengths of this study are the large, contemporary, population-based, multi-ethnic Asian

sample of participants with diabetes, standardized assessment of DR based on high number of

gradable photographs, and comprehensive evaluation of other relevant systemic factors and

confounding variables. The results of this analysis should be interpreted after taking into

account of the limitations. First, the cross-sectional design limited inference to causality or

temporality of the reported association. Second, the lack of information on duration and dos-

age of aspirin use in our study also limited our analysis. Future studies with such information

to determine if the relationship was dose-dependent.

In conclusion, our study demonstrated that an initially observed association between aspi-

rin use and DR or VTDR became non-significant after further taking into account history of

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CVD and CKD, which are common complications of diabetes. This suggests that the previ-

ously reported elevated risk of DR associated with aspirin use is likely to be confounded by

indication of aspirin use in individuals with CVD and CKD. Future longitudinal studies are

warranted to confirm our findings, as this information has important clinical implication to

the management of diabetes.

Supporting information

S1 Fig. Plot of association between aspirin use and DR status with odds ratio (OR) and

95% confidence interval (CI). The figure is consistent with the numbers in Table 3 in the

main manuscript. The lines are color-coded according to outcome. Models with DR, VTDR

and CSME as outcomes are plotted with blue, red and green, respectively. Model 1–4 are

defined as in the main manuscript as below. Model 1: adjusted for age, gender and ethnicity.

Model 2: adjusted for variables in Model 1 plus socioeconomic status, HbA1c, systolic blood

pressure, anti-hypertension medicine, total cholesterol, anti-cholesterol medicine, BMI, cur-

rent smoking status. Model 3: adjusted for variables in Model 2 plus duration of diabetes.

Model 4: adjusted for variables in Model 3 plus history of cardiovascular disease and chronic

kidney disease.

(TIFF)

S2 Fig. Plot of associations between aspirin use and VR or VTDR status after stratified by

history of cardiovascular disease or history of kidney disease, corresponding to Table 3 in

the main manuscript. Models with Any_DR or VTDR as outcomes are plotted with blue or

red respectively. The results are generated according to Model 3 in Table 2 with adjustment

for age, gender and ethnicity, socioeconomic, duration of diabetes plus CKD in analysis of sub-

group with CVD, and plus CVD in analysis of subgroup with CKD.

(TIFF)

S1 Table. The association between aspirin and DR through regression models.

(DOCX)

Author Contributions

Conceptualization: YS YCT CYC TYW.

Data curation: YS.

Formal analysis: YS YCT.

Funding acquisition: CYC TYW.

Investigation: YS YCT JJW CYC TYW.

Methodology: YS YCT.

Project administration: CYC TYW.

Resources: YCT JC.

Software: YS.

Supervision: NC GT PM JJW YBC CYC TYW.

Validation: YS.

Visualization: YS.

Aspirin and diabetic retinopathy

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Writing – original draft: YS.

Writing – review & editing: YS YCT NC JC GT PM JJW YBC CYC TYW.

References
1. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and

related vision loss. Eye Vis. 2015; 2: 17.

2. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and

major risk factors of diabetic retinopathy. Diabetes Care. 2012; 35: 556–564. https://doi.org/10.2337/

dc11-1909 PMID: 22301125

3. Congdon N, Zheng Y, He M. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol.

2012; 60: 428. https://doi.org/10.4103/0301-4738.100542 PMID: 22944754

4. Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clin Diabetes. 2008; 26:

77–82.

5. Colwell JA. Aspirin Therapy in Diabetes. Diabetes Care. 1997; 20: 1767–1771. PMID: 9353620

6. Mohamed Q, Gillies MC, Wong TY. Management of Diabetic Retinopathy. JAMA. 2007; 298: 902.

https://doi.org/10.1001/jama.298.8.902 PMID: 17712074

7. Salinero-Fort MÁ, San Andrés-Rebollo FJ, de Burgos-Lunar C, Arrieta-Blanco FJ, Gómez-Campelo P.

Four-Year Incidence of Diabetic Retinopathy in a Spanish Cohort: The MADIABETES Study. PLoS

One. 2013; 17: 10.

8. Klein BEK, Klein R, Moss SE. Is Aspirin Usage Associated with Diabetic Retinopathy. Diabetes Care.

1987; 10: 600–603. PMID: 3677978

9. Chew E, Klein M, RP M, Remaley N, Ferris F. Effects of aspirin on vitreous/preretinal hemorrhage in

patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report no. 20. Archives of

Ophthalmology. 1995.

10. The DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinop-

athy. A multicenter randomized controlled clinical trial. Diabetes. 1989; 38: 491–498. PMID: 2647556

11. Lavanya R, Jeganathan VSE, Zheng Y, Raju P, Cheung N, Tai ES, et al. Methodology of the Singapore

Indian Chinese Cohort (SICC) eye study: quantifying ethnic variations in the epidemiology of eye dis-

eases in Asians. Ophthalmic Epidemiol. 2009; 16: 325–336. https://doi.org/10.3109/

09286580903144738 PMID: 19995197

12. Wong TY, Chong EW, Wong W-L, Rosman M, Aung T, Loo J-L, et al. Prevalence and causes of low

vision and blindness in an urban malay population: the Singapore Malay Eye Study. Arch Ophthalmol.

2008; 126: 1091–1099. https://doi.org/10.1001/archopht.126.8.1091 PMID: 18695104

13. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for pro-

gression of diabetic retinopathy. ETDRS report number 12. Ophthalmology. 1991; 98: 823–833. PMID:

2062515

14. Group ETDRSR. Early Treatment Diabetic Retinopathy Study design and baseline patient characteris-

tics. ETDRS report number 7. Ophthalmology. 1991; 98: 741–756. PMID: 2062510

15. Cikamatana L, Mitchell P, Rochtchina E, Foran S, Wang JJ. Five-year incidence and progression of dia-

betic retinopathy in a defined older population: the Blue Mountains Eye Study. Eye. 2007; 21: 465–471.

https://doi.org/10.1038/sj.eye.6702771 PMID: 17318200

16. Mitchell P, Smith W, Wang JJ, Attebo K. Prevalence of diabetic retinopathy in an older community: The

blue mountains eye study. Ophthalmology. 1998; 105: 406–411. https://doi.org/10.1016/S0161-6420

(98)93019-6 PMID: 9499768

17. Kempen JH, O’Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, et al. The prevalence of diabetic

retinopathy among adults in the United States. JAMA Epidemiol. 2004; 122: 552–563.

18. Wong TY, Cheung N, Tay WT, Wang JJ, Aung T, Saw SM, et al. Prevalence and Risk Factors for Dia-

betic Retinopathy. The Singapore Malay Eye Study. Ophthalmology. 2008; 115: 1869–1875. https://doi.

org/10.1016/j.ophtha.2008.05.014 PMID: 18584872

19. Pan CW, Wong TY, Chang L, Lin XY, Lavanya R, Zheng YF, et al. Ocular biometry in an Urban Indian

population: The Singapore Indian Eye study (SINDI). Investig Ophthalmol Vis Sci. 2011; 52:

6636–6642.

20. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,

classification, and stratification. Am J Kidney Dis. 2002; 39: 1–266.

21. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to esti-

mate glomerular filtration rate. Ann Intern Med. 2009; 150: 604–612. PMID: 19414839

Aspirin and diabetic retinopathy

PLOS ONE | https://doi.org/10.1371/journal.pone.0175966 April 28, 2017 8 / 9

https://doi.org/10.2337/dc11-1909

http://www.ncbi.nlm.nih.gov/pubmed/22301125

https://doi.org/10.4103/0301-4738.100542

http://www.ncbi.nlm.nih.gov/pubmed/22944754

http://www.ncbi.nlm.nih.gov/pubmed/9353620

https://doi.org/10.1001/jama.298.8.902

http://www.ncbi.nlm.nih.gov/pubmed/17712074

http://www.ncbi.nlm.nih.gov/pubmed/3677978

http://www.ncbi.nlm.nih.gov/pubmed/2647556

https://doi.org/10.3109/09286580903144738

http://www.ncbi.nlm.nih.gov/pubmed/19995197

https://doi.org/10.1001/archopht.126.8.1091

http://www.ncbi.nlm.nih.gov/pubmed/18695104

http://www.ncbi.nlm.nih.gov/pubmed/2062515

http://www.ncbi.nlm.nih.gov/pubmed/2062510

https://doi.org/10.1038/sj.eye.6702771

http://www.ncbi.nlm.nih.gov/pubmed/17318200

https://doi.org/10.1016/S0161-6420(98)93019-6

http://www.ncbi.nlm.nih.gov/pubmed/9499768

https://doi.org/10.1016/j.ophtha.2008.05.014

http://www.ncbi.nlm.nih.gov/pubmed/18584872

http://www.ncbi.nlm.nih.gov/pubmed/19414839

https://doi.org/10.1371/journal.pone.0175966

22. Raman R, Rani PK, Reddi Rachepalle S, Gnanamoorthy P, Uthra S, Kumaramanickavel G, et al. Preva-

lence of diabetic retinopathy in India: Sankara Nethralaya Diabetic Retinopathy Epidemiology and

Molecular Genetics Study report 2. Ophthalmology. 2009; 116: 311–318. https://doi.org/10.1016/j.

ophtha.2008.09.010 PMID: 19084275

23. Scanlon PH, Carter SC, Foy C, Husband RFA, Abbas J, Bachmann MO. Diabetic retinopathy and

socioeconomic deprivation in Gloucestershire. J Med Screen. 2008; 15: 118–121. https://doi.org/10.

1258/jms.2008.008013 PMID: 18927093

24. Venables WN, Smith DM. R Development Core Team. An Introduction to R Notes on R A Programming

Environment for Data Analysis and Graphics R core team version. 2008.

25. Valmadrid CT, Klein R, Moss SE, Klein BE. The Risk of Cardiovascular Disease Mortality Associated

with Microalbuminuria and Gross Proteinuria in Persons with Older-Onset Diabetes Mellitus. JAMA

Intern Med. 2000; 160: 1093–1100.

Aspirin and diabetic retinopathy

PLOS ONE | https://doi.org/10.1371/journal.pone.0175966 April 28, 2017 9 / 9

https://doi.org/10.1016/j.ophtha.2008.09.010

http://www.ncbi.nlm.nih.gov/pubmed/19084275

https://doi.org/10.1258/jms.2008.008013

http://www.ncbi.nlm.nih.gov/pubmed/18927093

https://doi.org/10.1371/journal.pone.0175966

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1) What was/were the outcome(s) of interest in the study? If there is more than one, list all of them

2) Evaluate whether the discussion section of the article adequately addresses the strengths and limitations of the study. Explain your reasoning in complete sentences.

3) Discuss future research studies that would be appropriate given the study findings. Please answer in complete sentences.

4) What are the social change implications of the study results? Please answer in complete sentences.

5) What potential effect modifiers were assessed in the study, and how were they assessed? Please answer in complete sentences

6) What are the limitations of the study, and how do these limitations impact how the study results are interpreted? Please answer in complete sentences.

7) Describe how the study participants were selected for the study, including the inclusion and exclusion criteria used.

8) How were the data on the exposure(s) in the study collected and measured? Were they collected and measured the same way for all participants? Explain using complete sentences.

9) How were the data on the outcome(s) in the study collected and measured? Were they collected and measured the same way for all participants?

10) Given what you have learned in this course about confounding, was the adjustment for confounding adequate, or is residual confounding a concern?

11) What types of selection bias might be affecting this study? Please describe the biases and how they might be affecting the results of the study

12) Please describe the major results of the study. Include the major numerical/statistical results as well as interpretations of them in your own words.

13) Given what you have learned in this course about effect modification, was the assessment adequate? Why or why not? Explain using complete sentences.

14) How well did the study participants represent the larger population from which they were selected? Explain any concerns about generalizability with the study results.

15)

What measure of disease frequency, association, and/or impact was calculated to answer the main research question(s)? Please answer in complete sentences.

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