JDC-07170; No of Pages 11

Journal of Diabetes and Its Complications xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Journal of Diabetes and Its Complications

journalhomepage:www.jdcjournal.com

Review article

Diabetes mellitus, blood glucose and the risk of atrial fibrillation:

A systematic review and meta-analysis of cohort studies
Dagfinn Aune a,b,c, , Tingting Feng d, Sabrina Schlesinger e,f, Imre Janszky d,g, Teresa Norat a, Elio Riboli a
a
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
b Bjørknes University College, Oslo, Norway
c
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
d Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
e Institute for Biometrics and Epidemiology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
f
German Center for Diabetes Research (DZD), München-Neuherberg, Germany
g Regional center for health care improvement, St. Olavs hospital, Trondheim University Hospital, Norway

article info abstract

Article history: Background: Diabetes and elevated blood glucose have been associated with increased risk of atrial fibrillation in a number of
Received 26 November 2017 epidemiological studies, however, the findings have not been entirely consistent. We conducted a sys-tematic review and meta-
Received in revised form 13 February 2018 analysis to clarify the association.
Accepted 14 February 2018 Available online Material and methods: We searched the PubMed and Embase databases for studies of diabetes and blood glucose and atrial
xxxx
fibrillation up to July 18th 2017. Cohort studies were included if they reported relative risk (RR) esti-mates and 95% confidence
intervals (CIs) of atrial fibrillation associated with a diabetes diagnosis, prediabetes or blood glucose. Summary RRs were
Keywords:
estimated using a random effects model.
Diabetes mellitus
Atrial fibrillation Results: Thirty four studies were included in the meta-analysis of diabetes, pre-diabetes or blood glucose and atrial fibrillation.
Systematic review Thirty two cohort studies (464,229 cases, N10,244,043 participants) were included in the anal-ysis of diabetes mellitus and
Meta-analysis atrial fibrillation. The summary RR for patients with diabetes mellitus versus patients without diabetes was 1.30 (95% CIs: 1.03–
Cohort 1.66), however, there was extreme heterogeneity, I2 = 99.9%) and ev-idence of publication bias with Begg's test, p b 0.0001.
After excluding a very large and outlying study the summary RR was 1.28 (95% CI: 1.22–1.35, I2 = 90%, n = 31, 249,772
cases, 10,244,043 participants). The hetero-geneity was mainly due to differences in the size of the association between studies
and the results persisted in a number of subgroup and sensitivity analyses. The summary RR was 1.20 (95% CI: 1.03–1.39, I2
= 30%, n = 4, 2392 cases, 58,547 participants) for the association between prediabetes and atrial fibrillation. The summary
RR was 1.11 (95% CI: 1.04–1.18, I2 = 61%, n = 4) per 20 mg/dl increase of blood glucose in relation to atrial fibril-lation
(3385 cases, 247,447 participants) and there was no evidence of nonlinearity, p nonlinearity = 0.34. Conclusions: This meta-
analysis suggest that prediabetes and diabetes increase the risk of atrial fibrillation by 20% and 28%, respectively, and there is
a dose-response relationship between increasing blood glucose and atrial fi-brillation. Any further studies should clarify
whether the association between diabetes and blood glucose and atrial fibrillation is independent of adiposity.

© 2017 Elsevier Inc. All rights reserved.

1. Introduction
Globally atrial fibrillation is the most common type of arrhythmia and there
was an estimated 5 million incident cases worldwide in 2010,1 and the
prevalence has been estimated at 33 million in 2015.2 The prevalence of atrial
fibrillation has been projected to increase 2.5-fold in the next 50 years, partly
due to an ageing population, and also
Corresponding author at: Department of Epidemiology and Biostatistics, School of Public
Health, Imperial College London, St. Mary's Campus, Norfolk Place, Paddington, Lon-don W2
1PG, United Kingdom.
E-mail address: d.aune@imperial.ac.uk (D. Aune).
due to an increased incidence of the disease.3 A recent meta-analysis found that
patients with atrial fibrillation are at increased risk of ische-mic heart disease
(RR = 1.6), heart failure (RR = 5.0), sudden cardiac death (RR = 1.9), stroke
(RR = 2.4), peripheral arterial disease (RR = 1.3), chronic kidney disease (RR
= 1.6) and all-cause mortality (RR =
1.5),4 and it has also been shown that patients with atrial fibrillation have higher
medical costs and reduced quality of life compared to per-sons without atrial
fibrillation.5
Established or suspected risk factors for atrial fibrillation include age, heart
failure, coronary heart disease, hypertension, smoking, obesity, and high heart
rate.6–8 In addition, a number of cohort studies have in-vestigated the
association between diabetes mellitus and atrial

https://doi.org/10.1016/j.jdiacomp.2018.02.004 1056-
8727/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
2 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx
fibrillation6,9–37 and several of these reported an increased risk of atrial
fibrillation among diabetes patients,9,11,13–20,22,23,26–30,33,36 however,
the results have not been consistent with approximately half the studies finding
no clear association.6,10,12,21,24,25,31,32,34,35,37 Some studies also
investigated the association between prediabetes (impaired fasting glu-cose or
impaired glucose tolerance) and atrial fibrillation,15,37–39 with some reporting
a positive association38,39 and others finding no association.15,37 In addition,
with regard to studies on blood glucose and atrial fibrillation15,19,36,40 three
found increased risk,15,19,36 and one found no association.40 Reasons for some
of the inconsistencies may include too low statistical power in some studies,
differences in the adjustment for covariates as well as differences in the age of
the par-ticipants in the various studies. Although a previous meta-analysis from
2011 found an increased risk of atrial fibrillation among diabetes pa-tients, it
included only seven cohort studies with 5000 cases and 800,000 participants in
the analysis41 and had therefore limited possi-bility to conduct subgroup and
senstivity analyses and to clarify whether the association differs geographically
or by other study charac-teristics. In addition, we are not aware of any previous
meta-analyses on prediabetes or blood glucose and the risk of atrial fibrillation.
At least 25 additional cohort studies (22 publications) with N456,000 cases and
N10.1 million participants6,16–37 have since been published. Thus, we
conducted an up-to-date systematic review and meta-analysis of diabe-tes
mellitus, prediabetes, blood glucose and risk of atrial fibrillation to clarify the
association and to investigate sources of heterogeneity by conducting subgroup
and sensitivity analyses.
2. Material and methods
2.1. Search strategy and inclusion criteria
We searched the Pubmed, and Embase databases up to July 18th 2017 for
eligible studies. The search terms used are found in the Supple-mentary Text.
We followed standard criteria for reporting meta-analyses.42 In addition, we
searched the reference lists of the identified publications for further studies. Six
studies9,10,12,21,22,37 were identified from other literature searches on smoking
and adiposity and atrial fibrillation.
2.2. Study selection
We included published retrospective and prospective cohort studies and
nested case-control studies within cohorts that investigated the as-sociation
between diabetes mellitus, prediabetes (defined as impaired fasting glucose or
impaired glucose tolerance) and blood glucose and the risk of atrial fibrillation.
Estimates of the relative risk adjusted for at least one confounding factor had to
be available in the publication. A list of the excluded studies and exclusion
reasons can be found in Supplementary Table 1.
3. Data extraction
The following data were extracted from each study: The first author's last
name, publication year, country where the study was con-ducted, study name
or description, study period, number of cases and participants, expsoure type
and subgroup, relative risks and 95% confi-dence intervals (for diabetes or
prediabetes versus no diabetes, or blood glucose) and variables adjusted for in
the analysis.
3.1. Statistical methods
We calculated summary relative risks (RRs) and 95% confidence in-tervals
(95% CIs) of atrial fibrillation for patients with diabetes mellitus and
prediabetes compared with patients without diabetes mellitus or prediabetes and
for blood glucose using the random-effects model by DerSimonian and Laird43
which takes into account both within and
Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
between study variation (heterogeneity). The average of the natural logarithm
of the RRs was estimated and the RR from each study was weighted using
random effects weights.43 For the analysis of blood glu-cose we conducted a
linear dose-response analysis using the method of Greenland and Longnecker44
to estimate study-specific linear trends across categories of blood glucose. For
studies that reported blood glu-cose in ranges, but not the mean or median for
each category, we esti-mated the midpoint as the average of the lower and upper
cut-off point. For studies with open ended lower or upper categories we used
the width of the adjacent interval to estimate a lower or higher cut-off point for
the lowest and highest categories. Nonlinear dose-response analyses were
conducted using fractional polynomial models and we determined the best
fitting second order fractional polynomial regres-sion model, defined as the one
with the lowest deviance.45 A likelihood ratio test was used to compare the non-
linear and linear models to test for nonlinearity.45
Heterogeneity between studies was evaluated using Q and I2 statistics.46 I2
is a measure of how much of the heterogeneity that is due to between study
variation rather than chance. I2-values of 25%, 50% and 75% indicates low,
moderate and high heterogeneity, respectively.47 We conducted main analyses
(all studies combined) and stratified by study characteristics such as sex,
outcome assessment, duration of follow-up, geographic location, ethnicity,
number of cases, study quality and by adjustment for confounding factors to
investigate potential sources of heterogeneity. Study quality was assessed using
the Newcastle Ottawa scale which rates studies according to selection,
comparability and outcome assessment with a score range from 0 to 9.48
Publication bias was assessed using Egger's test49 and Begg-Mazumdar's
test50 and by inspection of funnel plots. The statistical anal-yses were
conducted using the software package Stata, version 13.1 software (StataCorp,
Texas, US).
4. Results
A total of 34 cohort studies (34 publications)6 ,9–38, 40 were in-cluded in
the meta-analysis of diabetes, prediabetes and blood glu-
cose and risk of atrial fibrillation (Fig. 1, Tables 1–2). Thirty two cohort studies
(30 publications)6 ,9–37 were included in the meta-analysis of diabetes mellitus
and risk of atrial fibrillation (464,229 cases, N10,244,043 participants).
Fourteen studies were from North America, twelve studies were from Europe,
two from Australia, and four from Asia (Table 1).
The summary RR for patients with diabetes mellitus versus patients without
diabetes was 1.30 (95% CIs: 1.03–1.66), however, there was ex-treme
heterogeneity, I2 = 99.9%, pheterogeneity b 0.0001) (Supplemen-tary Fig. 1) and
evidence of publication bias with Begg's test, p b 0.0001 (Supplementary Fig.
2). The heterogeneity was partly explained
and the publication bias was largely diminished after exclusion of a very large
(214,457 cases) and outlying study from Spain33 which reported an incidence
rate ratio of 3.76 (95% CI: 3.72–3.80), a much stronger as-sociation than what
was reported across all the remaining studies. For this reason, the remaining
analyses were conducted without this study. The summary RR among the
remaining 31 cohort studies (249,772 cases, 10,244,043 participants) was 1.28
(95% CI: 1.22–1.35, I2 = 90%, pheterogeneity b 0.0001) (Fig. 2). There was no
evidence of publication bias neither with Egger's test, p = 0.44 nor with Begg's
test, p = 0.17 (Supplementary Fig. 3). The summary RR range from 1.26 (95%
CI: 1.20–1.33) when the Korea National Health Insurance Da-tabase study36
was excluded to 1.30 (95% CI: 1.23–1.37) when the Truven Health MarketScan
Commercial and Medicare Supplemental Databases study27 was excluded
(Supplementary Fig. 4). For four studies15,37–39 that reported on prediabetes
(impaired fasting glucose, impaired glucose tolerance or hyperglycemia) and
atrial fibrillation
(2392 cases, 58,547 participants) the summary RR was 1.20 (95% CI: 1.03–
1.39, I2 = 30%, pheterogeneity = 0.23) (Supplementary Fig. 5). Four
 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx 3

12026 records identified in total: 5. Discussion

3447 records identified in PubMed
8573 records identified in Embase This meta-analysis of 31 prospective studies with 249,772 cases,
6 records from other searches 10,244,043 participants suggest that diabetes mellitus may increase the relative
risk of atrial fibrillation by 28%. In addition, prediabetes was associated with a
20% increase in the relative risk of atrial fibrilla-tion and there was a 12%
11602 excluded based on title or increase in the relative risk per 20 mg/dl in-crease in blood glucose. Positive
abstract associations were observed between diabetes and atrial fibrillation both in men
and women and among Eu-ropean, North American, and Asian studies as well
as in Caucasians and African Americans. The findings are consistent with a
previous meta-analysis of seven cohort studies (5400 cases and 800,000
424 potentially relevant publications participants) which found an increased risk of atrial fibrillation among diabetes
patients.41 However, our meta-analysis had N45 times the number of cases and
N12 times the number of participants compared to the seven cohort studies in
390 excluded: the previous meta-analysis, so we had much more statistical power and
96 patient populations consequently higher precision in the sum-mary estimates, and therefore we
64 cross-sectional studies
could conduct detailed subgroup and sensitivity analyses.
59 reviews
57 not relevant exposure
31 abstracts Mechanisms that can explain an association between diabetes and increased
30 not relevant data risk of atrial fibrillation include predisposition to other medi-cal conditions,
12 case-control studies inflammation, and atrial structural, electrical, electro-mechanical, and
11 duplicates autonomic remodelling. Diabetes is associated with increased risk of
10 comment, letter, editorial
hypertension,51,52 coronary heart disease,53 heart failure,54 and left ventricular
7 no risk estimates
5 not relevant outcome hypertrophy,55 which predisposes to atrial fibrillation.20 Diabetes patients
2 meta-analysis often have low-grade inflam-mation and higher levels of C-reactive
2 unadjusted risk estimates protein,56,57 which can pro-mote myocardial fibrosis and diastolic dysfunction.
1 non-specific exposure
Animal studies have found that diabetes leads to structural remodelling of the
1 change in blood glucose
1 guideline
left atrium in the form of atrial dilatation and interstitial fibrosis, which in turn
1 not retrieved leads to ionic remodelling and inter-atrial conduction delay and
arrhythmias.58,59 Diabetes also leads to increased production of advanced
glycation end products, altered gene expression with increased expression of
34 publications (34 studies) included transforming growth factor-beta and gap junction proteins which can cause
atrial fibrosis.60 Atrial structural remodelling in the form of changes in left
Fig. 1. Flow-chart of study selection. atrial diameter, atrial acti-vation time, and voltage has been observed in
diabetes patients, while atrial electrial remodelling is involved in shortening of
the atrial effective refractory period and its dispersion, as well as impairment
studies15,19,36,40 (3385 cases, 247,447 participants) were included in the of its frequency adaptation and consequent inter-atrial conduction delay.60
analysis of fasting blood glucose and atrial fibrillation and the sum-mary RR Inter- and intra-atrial electromechanical delays and abnormalities have been
per 20 mg/dl (=1.11 mmol/L) increase in blood glucose was 1.11 (95% CI: shown to be higher in patients with glucose tolerance than in controls61 and to
1.04–1.18, I2 = 60.6%, pheterogeneity = 0.06) (Fig. 3a, Table 2). There was no be associated with higher fasting glucose level and AF risk in diabetes
evidence of a nonlinear association between blood glu-cose and atrial patients.58,59 Diabetes also has effects on atrial autonomic remodelling by
fibrillation, pnonlinearity = 0.34, and there was evidence of a dose-response influencing the sympathetic and parasympathetic nervous system. Diabetic
relationship (Fig. 3b, Supplementary Table 2). mice undergoing sympathetic stimulation are more susceptible to develop atrial
fibrillation than controls, and it was shown that this might be due to shortened
atrial effective refractory period and increased dispersion, however,
4.1. Subgroup, sensitivity analyses, and study quality parasympathetic stimulation in dia-betic mice does not affect the refractory
period or the development of atrial fibrillation.62
There were positive associations between diabetes mellitus and risk of atrial
fibrillation in nearly all subgroup analyses, defined by sex, outcome assessment,
duration of follow-up, geographic loca-tion, ethnicity, number of cases, study
quality and adjustment for confounding factors (including age, alcohol,
smoking, BMI, physical activity, hypertension, hyperlipidemia, and history of Limitations of the current meta-analysis include potential confound-ing,
coronary heart disease, heart failure, kidney disease, hyperthyroidism or thy- misclassification of diabetes and outcome status, heterogeneity, and publication
roid medication use) (Table 3). With meta-regression analyses there was bias. Persons with diabetes oftentimes have less healthy lifestyles than persons
indication of heterogeneity when studies were stratified by adjustment for without diabetes, including higher BMI, lower physically activity, and they
hypertension, pheterogeneity = 0.02, with a weaker, but still significant may be more likely to smoke, however, many of the included studies adjusted
association among studies with such adjustment compared to studies without for these and other confounding factors and there was little evidence of
such adjustment, however, there was no heterogeneity between the remaining heterogeneity between sub-groups with and without adjustment for these
subgroups. Although het-erogeneity in general was high, there was no factors. Nevertheless, the possibility of residual confounding is possible,
heterogeneity among women in the sex-specific analyses, among the studies particularly from BMI, and one study found no association between diabetes
that adjudi-cated the atrial fibrillation diagnosis in a committee in addition to and atrial fi-brillation among normal weight participants, but an increased risk
using registry-linkages and heterogeneity was also lower when stratified by was suggested among overweight and obese participants.16 However, no other
ethnicity (Table 3). The mean (median) study quality scores were 7.6 (8.0). studies conducted stratified analyses by BMI thus further studies are needed to
clarify this finding. Some of the included studies also

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
4 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx

Table 1
Prospective studies of diabetes mellitus and atrial fibrillation.

First author, Study name or Study period Number of Exposure, subgroup Comparison Relative risk (95% Adjustment for confounders
publication description participants, confidence
year, country number of cases interval)

Krahn AD et al., Manitoba 1948–1992, 44 3983 men, age Diabetes mellitus Yes vs. no 1.82 (1.26–2.63) Age
1995, Canada Follow-Up Study years follow-up 18–62 years: 299
cases
Ruigomez A et UK General Practice 1996–1996, 1 year 1035 cases Diabetes mellitus Yes vs. no 0.8 (0.6–1.1) Age, sex, cardiovascular morbidity
al., 2002, Research Database follow-up 5000 controls
United Age 40–89 years
Kingdom
Friberg J et al., The Copenhagen 1981–1983 - 10,955 men and Diabetes mellitus Yes vs. no 1.8 (1.3–2.6) Age, sex, prior myocardial
2003, City Heart Study 1994-1994, 14 women, age infarction, arterial hypertension,
Denmark years follow-up 40–79 years: 379 systolic blood pressure, height,
hospital weight, low FEV1, smoking status,
admissions for period
atrial fibrillation
Nichols GA et Kaiser Permanente 1999–2008, 7.2 16,057 diabetes Diabetes mellitus, all Yes vs. no 1.16 (1.05–1.28) Age, sex, race, smoking, BMI, SBP,
al., 2009, USA Northwest years follow-up patients and Diabetes, mellitus, Yes vs. no 1.09 (0.96–1.24) IHD, valvular disease,
16,471 persons men hypertension, heart failure
without diabetes, Diabetes, mellitus, Yes vs. no 1.26 (1.08–1.46)
mean age 58.4 women
years: 1835 cases
Rosengren A et Swedish Primary 1970–1973 - 6903 men, mean Diabetes mellitus Yes vs. no 1.49 (0.92–2.41) Age
al., 2009, Prevention Study 2004, 34.3 years age 51.5 years:
Sweden follow-up 1253 cases
Smith JG et al., Malmö Diet and 1991–1996 - 30,441 men and Diabetes mellitus, men Yes vs. no 1.39 (1.02–1.90) Age
2010, Cancer study 2005, 11.2 years women, age Diabetes mellitus, Yes vs. no 1.67 (1.15–2.43)
Sweden follow-up 44–73 years: women
1430 cases
Huxley RR et Atherosclerosis 1987–1989 - 14,598 men and Diabetes mellitus No 1.00 Age, sex, race, study site,
al., 2011, USA Risk in 2007, 17.1 years women, age IFG 1.06 (0.86–1.31) education, income, height, history
Communities Study follow-up 45–64 years: DM 1.49 (1.29–1.73) of cardiac disease, blood pressure,
1520 cases BMI, smoking status
Lipworth L et Southern 1999–2008, 5.7 8836 men and Diabetes, all Yes vs. no 1.33 (1.14–1.54) Length of Medicare follow-up
al., 2012, USA Community Cohort years follow-up women, age ≥ 65 Diabetes, men Yes vs. no 0.99 (0.77–1.28)
Study years: 1062 cases Diabetes, women Yes vs. no 1.56 (1.30–1.88)
Diabetes, blacks Yes vs. no 1.38 (1.15–1.66)
Diabetes, whites Yes vs. no 1.25 (0.98–1.59)
Schoen T et al., Women's Health NA-2011, 16.4 33,372 women, Diabetes, baseline Yes vs. no 1.37 (1.03–1.83) Age, smoking, exercise, alcohol,
2012, USA Study years follow-up age ≥ 45 years: Diabetes, Yes vs. no 1.19 (0.97–1.45) education, race/ethnicity,
1027 cases time-updated hypercholesterolemia, adult
covariates height, hypertension, BMI
Nyrnes A et al., The Tromsø Study 1994–1995 - 22,815 men and Diabetes mellitus, men Yes vs. no 1.33 (0.88–1.99) Age, height, BMI, total cholesterol,
2013, 2007, 11.1 years women, age Diabetes mellitus, Yes vs. no 1.61 (1.06–2.45) HDL cholesterol, hypertension,
Norway follow-up 25–96 years: women palpitations, coronary artery
461/361 cases disease
Jensen PN et al., Cardiovascular 1989–1990, 5685 men and Diabetes mellitus, Yes vs. no 1.56 (1.35–1.80) Age, sex
2013, USA Health Study 1992–1993–1999, women, age 65 whites
11.2 years years: 1585 cases Diabetes mellitus, Yes vs. no 1.20 (0.90–1.77)
follow-up African Americans
Alonso A et al., Age, 2002–2011, ~9 4469 men and Diabetes mellitus Yes vs. no 1.21 (0.91–1.61) Age, sex
2013, Iceland Gene/Environment years of follow-up women, mean age
Susceptibility 76 years: 408
Reykjavik Study cases
Alonso A et al., Rotterdam Study 1997–2005, ~8 3203 men and Diabetes mellitus Yes vs. no 1.23 (0.80–1.90) Age, sex
2013, years of follow-up women, mean age
Netherlands 72 years: 177
cases
Knuiman M et Busselton Health 1994–1995–2010, 4267 men and Diabetes mellitus Yes vs. no 0.98 (0.67–1.42) Age, sex, height, hypertension
al., 2014, Study 15 years women, age treatment, BMI
Australia follow-up 25–84 years: 343
cases
Pfister R et al., EPIC-Norfolk 1993–1997 - 24,020 men and Diabetes mellitus, total Yes vs. no 1.10 (0.61–1.98) Age, race, height, weight, systolic
2015, United Cohort Study 2009, 5 years women, age cohort blood pressure, diastolic blood
Kingdom follow-up 39–79 years: 236 Diabetes mellitus, free Yes vs. no 0.54 (0.20–1.46) pressure, current smoking,
AF of CVD hypertension treatment, history
hospitalizations of heart failure, history of
myocardial infarction
Chyou JY et al., Truven Health 2007–2010, 3 3,007,874 men Diabetes mellitus Yes vs. no 1.11 (1.08–1.14) Age, sex, geographic region,
2015, USA Marketscan years follow-up and women, age medications, use of
Commercial and ≥ 18 years: 28395 internal/external
Medicare cases electrocardiographic recording
Supplemental devices, heart failure,
Databases hypertension, coronary artery
disease, chronic kidney disease,

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx 5

Table 1 (continued)

First author, Study name or Study period Number of Exposure, subgroup Comparison Relative risk (95% Adjustment for confounders
publication description participants, confidence
year, country number of cases interval)
sleep apnea, chest pain, dizziness,
palpitations, tachycardia
unspecified, shortness of breath,
respiratory - other, respiratory -
unspecified
Schnabel RB et Framingham 1958–2007, 50 9511 men and Diabetes mellitus, Yes vs. no 1.06 (0.38–2.90) Age, sex
al., 2015, USA Cohort Study years follow-up women, age 1958–1967
50–89 years: Diabetes mellitus, Yes vs. no 1.42 (0.93–2.17)
1544 cases 1968–1977
Diabetes mellitus, Yes vs. no 1.59 (1.15–2.20)
1978–1987
Diabetes mellitus, Yes vs. no 1.49 (1.15–1.95)
1988–1997
Diabetes mellitus, Yes vs. no 1.25 (0.98–1.60)
1998–2007
Suzuki H et al., Fukushima Health 2008–2010 - 12,410 men and Diabetes mellitus Yes vs. no 0.92 (0.46–1.86) Age, sex, obesity, excess ethanol
2015, Japan Management 2013, 1.4 years women, age intake, current smoking,
Survey follow-up 40–90 years: 79 hypertension
cases
Karajamaki AJ, Oulu Project 1990–1993–2009, 958 men and Diabetes Yes vs. no 1.01 (0.48–2.13) Age, sex, study group, fatty liver,
2015, Finland Elucidating Risk of 16.3 years women, age BMI, waist, alcohol, smoking -
Atherosclerosis follow-up 40–59 years: 94 pack-years, serum ALAT, SBP,
Study cases Quick Index, coronary artery
disease, atrial natriuretic peptide,
left ventricular mass index,
high-sensitive CRP
Qureshi WT et Henry Ford 1991–2009, 5.4 64,561 men and Diabetes mellitus Yes vs. no 1.11 (1.03–1.19) Age, sex, race/ethnicity,
al., 2015, USA Exercise Testing years follow-up women, mean age hypertension, sedentary, obesity,
(FIT) Project 54.5 years: 4616 FH - CAD, smoking, history of
cases hyperlipidemia, known CAD,
hypertensive response,
chronotropic incompetence,
thyroid medication use, digoxin
use, lung medication use, beta
blocker use, ACE inhibitor use,
ARB inhibitor, calcium channel
blocker use, lipid lowering
medication use, METs
Guo Y et al., Medical Insurance 2001–2012, 11 471,446 men and Diabetes Yes vs. no 1.82 (1.25–2.63) Age, sex, rheumatic heart disease,
2015, China Database in years follow-up women, age ≥ 20 dilated cardiomyopathy, heart
Yunnan Province years: 921 cases failure, hyperthyroidism,
coronary artery disease, chronic
obstructive pulmonary disease,
hypertension, renal dysfunction,
hyperlipidemia, peripheral
vascular disease
Staszewsky L et Italian nationwide 2000–2010, 9 825,330 men and Diabetes mellitus Yes vs. no 1.32 (1.30–1.34) Age, sex, glucose-lowering
al., 2015, Italy cohort study years follow-up women, mean age treatment, oral anticoagulant,
65.6 years: 57965 antiplatelets, number of
cases concomitant medications,
hypertension, hospitalization for
heart failure, myocardial
infarction, renal failure,
peripheral vascular disease
O'Neal WT et The Reasons for NA-NA, 9.4 years 13,688 men and Diabetes Yes vs. no 1.16 (0.99–1.36) Age, sex, ethnicity, income,
al., 2016, USA Geographic and follow-up women, age ≥ 45 smoking, hypertension, obesity,
Racial Differences years: 997 cases physical activity, dyslipidemia,
in Stroke left ventricular hypertrophy,
(REGARDS) study cardiovascular disease
Svennberg E et Uppsala 1991–1995 - NA, 883 men, age 50 Type 2 diabetes Yes vs. no 0.84 (0.44–1.59) Age, sex, smoking, BMI, SBP,
al., 2016, Longitudinal Study 12.6 years years: 113 cases antihypertensive treatment, total
Sweden of Adult Men follow-up cholesterol, HDL cholesterol,
(ULSAM) lipid-lowering treatment, heart
failure
Svennberg E et Prospective 2001 - NA, 10.0 978 men and Type 2 diabetes Yes vs. no 0.80 (0.47–1.35) Age, sex, smoking, BMI, SBP,
al., 2016, Investigation of the years follow-up women, age: 148 antihypertensive treatment, total
Sweden Vasculature in cases cholesterol, HDL cholesterol,
Uppsala Seniors lipid-lowering treatment
(PIVUS)
Mendez-Bailon Spanish national 2004–2013, 10 NA, age ≥ 18 Diabetes mellitus, all Yes vs. no 3.76 (3.72–3.80) Age, sex, year of discharge
M et al., hospital discharge years follow-up years: 214457 AF Diabetes mellitus, men Yes vs. no 3.24 (3.20–3.30)
2016, Spain database hospital Diabetes mellitus, Yes vs. no 4.27 (4.21–4.33)
admissions women
Diouf I et al., Australian Diabetes, 5389 men and Diabetes mellitus Yes vs. no 1.2 (0.7–2.2) Age, sex, smoking status, usual

(continued on next page)

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
6 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx

Table 1 (continued)

First author, Study name or Study period Number of Exposure, subgroup Comparison Relative risk (95% Adjustment for confounders
publication description participants, confidence
year, country number of cases interval)

2016, Obesity and 1999/2000–2004- women, age ≥ 35 number of alcoholic drinks,

Australia Lifestyle study /2005, 5 years years: 53 cases physical activity, level of
cohort follow-up education, BMI
Pallisgaard JL et Danish nationwide 1996–2012, ~16 5,081,087 men Diabetes mellitus, age Yes vs. no 2.34 (1.52–3.60) Sex, calendar year, hypertension,
al., 2016, cohort study years follow-up and women, age 18–39 chronic obstructive pulmonary
Denmark ≥ 18 years: Diabetes mellitus, age Yes vs. no 1.52 (1.47–1.56) disease, ischemic heart disease,
115956 cases 40–64 chronic heart failure, chronic
Diabetes mellitus, age Yes vs. no 1.20 (1.18–1.23) kidney disease, valvular heart
65–74 disease, hyperthyroidism
Diabetes mellitus, age Yes vs. no 0.99 (0.97–1.01)
75–100
Alonso A et al., Multi-Ethnic Study 2000–2002 - 6663 men and Diabetes mellitus Yes vs. no 1.1 (0.8–1.5) Age, race/ethnicity, height,
2016, USA of Atherosclerosis 2012, 10.2 years women, age weight, systolic blood pressure,
(MESA) Study follow-up 45–84 years: 351 diastolic blood pressure, current
cases smoking, use of antihypertensive
medication, NT-proBNP,
high-sensitive CRP
Rodriguez F et Women's Health 1993–1998 - 134,936 women, Diabetes mellitus, Yes vs. no 1.33 (1.22–1.45) Age, hypertension, smoking
al., 2016, USA Initiative 2012, 13.7 years age 50–79 years: whites status, BMI, heart failure, coronary
19712 cases Diabetes mellitus, Yes vs. no 1.42 (1.16–1.74) artery disease, peripheral artery
African American disease, education, alcohol,
Diabetes mellitus, Yes vs. no 1.25 (0.78–2.02) physical activity, height, PR
Hispanics interval
Diabetes mellitus, Yes vs. no 1.42 (0.76–2.64)
Asian
Kokubo Y et al., The Suita Study 1989–1996–2015, 6898 men and Diabetes mellitus Normal 1.00 Age, sex
2017, Japan 13.8 years women, age glucose
follow-up 30–79 years: 311 IGT 1.09 (0.86–1.39)
cases Diabetes 1.46 (0.95–2.27)
mellitus
Lee H et al., Korean National 2004–2006 - 389,321 men and Diabetes mellitus Yes vs. no 1.60 (1.43–1.79) Age, sex, obesity, congestive heart
2017, Korea Health Insurance 2013, 7.5 years women, age ≥ 20 failure, ischemic heart disease,
Database follow-up years: 5106 cases peripheral artery disease, chronic
obstructive pulmonary disease,
cancer
Watanabe H et Niigita Association 1996–1998 - 28,449 men and Impaired fasting Normal 1.00 Age, sex
al., 2008, for Comprehensive 2005, 4.5 years women, age ≥ 20 glucose IFG 1.44 (1.09–1.90)
Japan Health Promotion follow-up years: 265 cases
and Research
Sano F et al., Circulatory risk in 1991–1995–2000, 8602 men and Hyperglycemia Yes vs. no 1.35 (1.02–1.78) Age, sex, alcohol, smoking,
2014, Japan communities study 6.4 years women, age (fasting blood glucose obesity, hypertension,
follow-up 30–80 years: 296 ≥110 mg/dl, hyperlipidemia, major ST-T
cases non-fasting blood abnormality, previous MI, heart
glucose ≥140 mg/dl or failure
use of diabetes
medications)

ACE = angiotensin converting enzyme, AF = atrial fibrillation, ALAT = alanine aminotransferase, ARB = angiotensin receptor blocker, ARIC = Atherosclerosis Risk in Commu-nities Study, BMI =
Body mass index, CAD = coronary artery disease, CRP=C-reactive protein, FEV1 = forced expiratory volume in 1 s, FH = family history, HDL = high den-sity lipoprotein, IHD = ischemic heart
disease, MET = metabolic equivalent task, MI = myocardial infarction, NT-proBNP=N-terminal prohormone of brain natriuretic peptide, PR = pulse rate, SBP = systolic blood pressure, NA = not
available.

adjusted for other risk factors for atrial fibrillation including coronary heart
disease, heart failure, valvular heart disease, and left ventricular hypertrophy
and the results persisted across most of these subgroup analyses. Some caution
in the interpretation of these subgroup analyses is warranted, however, because
diabetes also may increase the risk of these outcomes which therefore
potentially may be intermediate factors more than confounders. With the
exception of the subgroup analyses stratified by adjustment for hypertension,
where there was a weaker, but still significant association among studies with
such adjustment compared to studies without such adjustment, we did not find
evidence of heterogeneity between any of the subgroups.
Although diabetes was assessed by self-report of diagnosis in most studies
and this could have led to some diabetes cases not being de-tected, such bias
would most likely lead to bias toward the null and un-derestimation of the
association between diabetes and atrial fibrillation because we included only
cohort studies in the current analysis. With regard to the outcome assessment,
there was no heterogeneity when
studies were stratified by whether only linkage was done to medical registries,
whether the diagnosis had been validated or adjudicated by a either a comittee
or several cardiologists, however, there was less het-erogeneity in the latter
subgroup and the point estimate was slightly higher than among the two former
subgroups. Given the moderate number of studies and no within-study
comparisons of different ascer-tainment methods it is difficult conclude whether
there is a real differ-ence between outcome ascertainment methods or if it is a
chance finding.
Although there was high heterogeneity in the overall analysis, het-
erogeneity was lower when studies were stratified by sex and ethnicity. Whether
these factors are the real explanations for the heterogeneity is less clear because
the number of studies included in these subgroup analyses was modest. It seems
the heterogeneity observed appeared to be more driven by differences in the
size of the risk estimates rather than differences in the direction of the
association, as all but three stud-ies found positive associations. Strengths of
the present meta-analysis include the cohort design of the included studies
(which avoids recall

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx 7

Table 2
Prospective studies of blood glucose and atrial fibrillation.

First author, Study name or Study period Number of Glucose measure, Comparison Relative risk (95% Adjustment for confounders
publication year, description participants, subgroup confidence
country number of cases interval)

Huxley RR et al., Atherosclerosis 1987–1989–2007, 14,598 men and Fasting serum glucose b100 mg/dl 1.00 Age, sex, race, study site,
2011, USA Risk in 17.1 years women, age 100–125 1.06 (0.86–1.31) education, income, height,
Communities follow-up 45–64 years: ≥126 1.49 (1.29–1.73) history of cardiac disease,
Study 1520 cases blood pressure, BMI,
smoking status
Jensen PN et al., Cardiovascular 1989–1990, 5685 men and Fasting glucose Per 40 mg/dl 1.19 (1.12–1.27) Age, sex
2013, USA Health Study 1992–1993 - 1999, women, age 65 Fasting glucose Per 40 mg/dl 1.06 (0.95–1.19)
11.2 years years: 1585 AF
follow-up cases
Perkiomaki JS et al., Oulu Project 1990–1993 - 2009, 903 men and Fasting plasma glucose Per 0.5 mmol/l 1.003 (0.93–1.08) Age, sex, height, BMI, ALAT,
2017, Finland Elucidating Risk 16.4 years women, age uric acid, smoking -
of Atherosclerosis follow-up 40–59 years: 91 pack-years
study cases
Lee SS et al., 2017, Korea National 2003–2008–2013, 227,102 men and Fasting blood glucose b100 mg/dl 1.00 Age, sex, smoking status,
Korea Health Insurance 7.7 years follow-up women, age ≥ 20 100–109 1.13 (0.98–1.30) alcohol
Database years: 1470 cases 110–125 1.21 (1.01–1.45)

ALAT = alanine amino transferase, BMI = body mass index, FEV1 = forced expiratory volume in 1 s, SBP = systolic blood pressure.

bias and reduces the potential for selection bias), the detailed subgroup and and risk of atrial fibrillation, and the high study quality of the included studies.
sensitivity analyses, the very large sample size providing a more ro-bust and The observation of a dose-response relationship between blood glucose and
precise estimate of the association between diabetes mellitus increased risk of atrial fibrillation lends further

Relative Risk
Study (95% CI)

Kokubo, 2017 1.46 ( 0.95, 2.27)

Lee, 2017 1.60 ( 1.43, 1.79)
Alonso, 2016 1.10 ( 0.80, 1.50)
Diouf, 2016 1.20 ( 0.70, 2.20)
O'Neal, 2016 1.16 ( 0.99, 1.36)
Pallisgaard, 2016 1.16 ( 1.15, 1.18)
Rodriguez, 2016 1.34 ( 1.24, 1.45)
Svennberg, 2016, PIVUS 0.80 ( 0.47, 1.35)
Svennberg, 2016, ULSAM 0.84 ( 0.44, 1.59)
Chyou, 2015 1.11 ( 1.08, 1.14)
Guo, 2015 1.82 ( 1.25, 2.63)
Karajamaki, 2015 1.01 ( 0.48, 2.13)
Pfister, 2015 1.10 ( 0.61, 1.98)
Qureshi, 2015 1.11 ( 1.03, 1.19)
Schnabel, 2015 1.47 ( 1.24, 1.76)
Staszewsky, 2015 1.32 ( 1.30, 1.34)
Suzuki, 2015 0.92 ( 0.46, 1.86)
Knuiman, 2014 0.98 ( 0.67, 1.42)
Alonso, 2013, AGES 1.21 ( 0.91, 1.61)
Alonso, 2013, RS 1.23 ( 0.80, 1.90)
Jensen, 2013 1.50 ( 1.31, 1.71)
Nyrnes, 2013 1.46 ( 1.09, 1.96)
Lipworth, 2012 1.33 ( 1.14, 1.54)
Schoen, 2012 1.37 ( 1.03, 1.83)
Huxley, 2011 1.49 ( 1.29, 1.73)
Smith, 2010 1.50 ( 1.18, 1.90)
Nichols, 2009 1.16 ( 1.05, 1.28)
Rosengren, 2009 1.49 ( 0.92, 2.41)
Friberg, 2003 1.80 ( 1.30, 2.60)
Ruigomez, 2002 0.80 ( 0.60, 1.10)
Krahn, 1995 1.82 ( 1.26, 2.63)
Overall 1.28 ( 1.22, 1.35)

.25 .5 .75 1 1.5 2 3 5

Relative Risk

Fig. 2. Diabetes mellitus and atrial fibrillation.

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
8 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx

Table 3
Subgroup analyses of diabetes mellitus and atrial fibrillation.

Diabetes mellitus and atrial fibrillation

n Relative risk (95% CI) I2 (%) Ph1 Ph2

All studies 31 1.28 (1.22–1.35) 90.0 b0.0001
Sex
Men 4 1.35 (1.02–1.79) 62.9 0.04 0.36/0.45
Women 3 1.53 (1.32–1.76) 0 0.66
Men & women 24 1.26 (1.20–1.34) 91.8 b0.0001
Outcome assessment
Self-reported and/or registry linkage 21 1.25 (1.16–1.34) 88.4 b0.0001 0.14
Registry and adjudication 5 1.46 (1.30–1.65) 0 0.70
Validated 5 1.28 (1.08–1.53) 88.7 b0.0001
Follow-up
b10 years 13 1.20 (1.11–1.31) 92.7 b0.0001 0.05
≥10 years 18 1.37 (1.25–1.50) 77.0 b0.0001
Geographic location
Europe 11 1.24 (1.13–1.37) 94.6 b0.0001 0.12
America 14 1.28 (1.19–1.38) 80.8 b0.0001
Australia 2 1.04 (0.76–1.43) 0 0.56
Asia 4 1.59 (1.43–1.77) 0.7 0.39
Ethnicity
Caucasian 4 1.45 (1.28–1.64) 51.0 0.11 0.61
African American 4 1.36 (1.18–1.57) 0 0.67
Hispanic 1 1.25 (0.78–2.02)
Asian 1 1.42 (0.76–2.64)
Number of cases
b250 7 1.03 (0.83–1.28) 0 0.89 0.30
250- b 1000 9 1.36 (1.17–1.57) 50.3 0.04
≥1000 15 1.29 (1.21–1.37) 95.0 b0.0001
Study quality
0–3 stars 0 0.39
4–6 stars 4 1.40 (1.17–1.69) 20.0 0.29
7–9 stars 27 1.27 (1.21–1.34) 91.2 b0.0001

Adjustment for confounding factors3

Age Yes 29 1.29 (1.21–1.38) 86.1 b0.0001 0.66
No 2 1.22 (1.07–1.38) 68.3 0.08
Education Yes 4 1.37 (1.28–1.46) 0 0.62 0.37
No 27 1.27 (1.20–1.34) 90.9 b0.0001
Alcohol Yes 5 1.33 (1.24–1.43) 0 0.77 0.95
No 26 1.28 (1.21–1.35) 91.5 b0.0001
Smoking Yes 14 1.23 (1.12–1.34) 58.4 0.003 0.23
No 17 1.32 (1.23–1.41) 94.1 b0.0001
BMI or obesity Yes 17 1.26 (1.15–1.38) 70.3 b0.0001 0.54
No 14 1.29 (1.21–1.39) 94.7 b0.0001
Physical activity Yes 5 1.22 (1.09–1.37) 69.3 0.01 0.48
No 26 1.30 (1.23–1.38) 91.3 b0.0001
Hypertension Yes 17 1.21 (1.14–1.29) 93.3 b0.0001 0.02
No 14 1.40 (1.28–1.53) 46.7 0.03
Hyperlipidemia Yes 6 1.19 (1.02–1.37) 53.7 0.06 0.28
No 25 1.30 (1.23–1.38) 91.6 b0.0001
Coronary heart disease Yes 14 1.27 (1.19–1.36) 95.2 b0.0001 0.84
No 17 1.30 (1.20–1.42) 39.4 0.05
Heart failure Yes 9 1.23 (1.14–1.33) 96.7 b0.0001 0.36
No 22 1.32 (1.23–1.42) 43.9 0.02
Valvular heart disease Yes 2 1.16 (1.15–1.17) 0 0.99 0.26
No 29 1.30 (1.22–1.39) 86.9 b0.0001
Left ventricular hypertrophy Yes 2 1.15 (0.99–1.35) 0 0.72 0.41
No 29 1.29 (1.22–1.36) 90.7 b0.0001
Kidney disease Yes 3 1.28 (1.13–1.45) 98.8 b0.0001 0.83
No 28 1.28 (1.19–1.38) 78.0 b0.0001
Hyperthyroidism or thyroid medication use Yes 3 1.16 (1.07–1.27) 71.6 0.03 0.48
No 28 1.30 (1.22–1.38) 85.4 b0.0001

n denotes the number of studies.

BMI, body mass index.
1
P for heterogeneity within each subgroup.
2 P for heterogeneity between subgroups with meta-regression analysis.
3 P for heterogeneity between men and women (excluding studies with both genders) with meta-regression analysis.

support for the findings and suggests that there may be a graded increase in risk
with worsening glucose control.
Worldwide the number of persons living with diabetes is projected to
increase from 422 million in 2014 to 700 million by 2025, and may in addition
to the obesity epidemic7 contribute to additional cases of
atrial fibrillation if the current trends continue. Lifestyle interventions to reduce
the risk of diabetes that emphasize healthy diets,63 smoking cessation,64
physical activity65 and weight control66 may therefore also reduce the risk of
atrial fibrillation as well as other diabetes complications.53

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx 9

A Blood glucose and atrial fibrillation, per 20 mg/dl

Relative Risk

Study (95% CI)

Lee, 2017 1.18 ( 1.01, 1.38)

Perkiomaki, 2017 1.01 ( 0.85, 1.19)

Jensen, 2013 1.08 ( 1.05, 1.11)

Huxley, 2011 1.16 ( 1.10, 1.23)

Overall 1.11 ( 1.04, 1.18)

.5 .75 1 1.5 2 3
Relative Risk

B Blood glucose and atrial fibrillation, nonlinear

dose-response analysis

1.5

RR

.8

.6

80 100 120 140 160

Blood glucose (mg/dl)
Best fitting fractional polynomial
95% confidence interval

Fig. 3. Blood glucose and atrial fibrillation, per 20 mg/dl.

6. Conclusion
This meta-analysis suggests that diabetes and prediabetes was asso-ciated
with a 28% and 20% increase in the relative risk of developing atrial fibrillation
and that there is a dose-response relationship between increasing blood glucose
and atrial fibrillation. Further studies are needed to clarify whether the increased
risk of atrial fibrillation with di-abetes or blood glucose is independent of
adiposity.
Author contribution
DA designed the research, conducted the literature search and analyses and
wrote the first draft of the paper. TF and SS conducted the literature screening.
All authors interpreted the data, revised the
subsequent drafts for important intellectual content, read and approved the final
manuscript. D. Aune takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Funding
This work has been supported by funding from the Imperial College
National Institute of Health Research (NIHR) Biomedical Research Centre
(BRC) and the South-East Regional Health Authorities of Norway.
Conflict of interest
The authors declare that there is no conflict of interest associated with this
manuscript.

Please cite this article as: Aune D, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort
studies. (2017), https://doi.org/10.1016/j.jdiacomp.2018.02.004
10 D. Aune et al. / Journal of Diabetes and Its Complications xxx (2017) xxx–xxx
Acknowledgement
We thank Dr. Darren C. Greenwood (Biostatistics Unit, Centre for
Epidemiology and Biostatistics, University of Leeds, Leeds, UK) for pro-
viding the Stata code for the nonlinear dose-response analysis.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jdiacomp.2018.02.004.
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