Nielsen et al.
Supplementary Appendix
Supplementary Appendix for the paper “Risk Prediction of Cardiovascular Death based on the
QTc Interval: Evaluating Age and Gender Differences in a Large Primary Care Population” by
Nielsen et al.
Content
1. Supplementary Methods
page 2
1.1 Danish Registers
2
1.2 Medicaion Data
2
1.3 Electrocardiography
3
1.4 Clinical Covariates and Outcomes
5
2. Supplementary References
6
3. Supplementary Tables
7
3.1 Supplemental Table 1 (QTc interval prolonging drugs)
7
3.2 Supplemental Table 2 (Charlson co-morbidity index)
8
3.3 Supplemental Table 3 (5-year predictions based on QTcFram)
9
3.4 Supplemental Table 4 (5-year predictions based on QTcBaz)
10
3.5 Supplemental Table 5 (absolute risk predictions on an individual level)
11
4. Supplemental Figures
12
4.1 Supplemental Figure 1 (flow-chart of study population selection)
12
4.2 Supplemental Figure 2 (spline-based analysis)
13
4.3 Supplemental Figure 3 (association analysis based on QTcBaz)
14
4.4 Supplemental Figure 4 (5-year predictions based on QTcBaz)
15
4.5 Supplemental Figure 5 (QTcFram measurement validations)
16
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Supplementary Appendix
1. Supplementary Methods
1.1 Danish Registers
Using a unique personal identification number (the central personal registration [CPR]
number) assigned to all persons with permanent residence in Denmark, it is possible to link
data from multiple sources at an individual level.1 The Danish National Patient Register holds
information on all hospital, ambulatory, and emergency room discharge diagnoses
(International Classification of Diseases and Related Health Problems, revision 8 [ICD-8] from
1977-1993 and revision 10 [ICD-10] from 1994 and onwards), including information on
invasive procedures such as surgeries and percutaneous interventions (coded according to
the Nordic Medical Statistics Committees Classification of Surgical Procedures since 1996).2
The Danish Register of Causes of Death holds information on any in-country death since 1970
(ICD-10 classified since 1994).3 The Register of Medicinal Products Statistics has information
on an individual level for all dispensed prescription medications sold in Denmark since 1995
(e.g., international anatomical therapeutic chemical classification system [ATC] code, strength,
and quantity).4 Data on migrations is recorded in The Danish Civil Registration System.5
1.2 Medication Data
The Danish Registry of Medicinal Product Statistics holds information on the dispensing date
of the prescription, the strength of the drug, and the total quantity (e.g., number of tablets)
dispensed, but not the prescribed dose of the drug.4 Under the assumption that individuals
were receiving treatment when a drug was available (purchased), the period of time in which
an individual was taking a particular drug (medication period) was estimated based on the
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Supplementary Appendix
World Health Organization defined daily dose (e.g., milligram/day) for the particular
medication.4,6 Medication periods were considered overlapping if they were separated by less
than 30 days.
1.3 Electrocardiography
All digitally recorded ECGs were stored in the MUSE® Cardiology Information System (GE
Healthcare, Wauwatosa, WI, USA) and later processed using the latest version 21 of the
Marquette 12SL algorithm.7,8 All ECGs were recorded at CGPL or at one of its satellite clinics
according to a standardized protocol. According to this protocol, ECG technicians are
instructed to inspect ECGs at the time of recording with the aim of detecting technical errors,
missing leads, and inadequate quality, and to replace such recordings with a new ECG. In case
of multiple ECGs on a single individual, only the first ECG recorded at CGPL (index ECG) was
used.
With the use of the 12SL algorithm statements and intervals we excluded ECGs with the
following findings that were not consistent with a valid or straightforward measurement and
interpretation of the QTc interval: atrial fibrillation (AF), atrial flutter, bradyarrhythmias
(heart rate < 40 beats per minute [b.p.m.]), tachyarrhythmias (heart rate > 110 b.p.m.), bundle
branch blocks and ventricular rhythms (QRS interval >120 milliseconds [ms]), delta waves,
second and third degree AV-blocks, multiple premature ventricular complexes, multiple
premature atrial complexes, junctional rhythms, pace spikes, and QTcFram intervals <0.01st
percentile or >99.9th percentile (QTcFram <339ms or QTcFram >596ms).
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Supplementary Appendix
To obtain QT intervals, the Marquette 12SL algorithm constructs a representative (median)
beat from all PQRST complexes in the 12 leads of the 10-second ECG tracing and annotates
fiducial points on the superimposed medians.7,8 The QT interval measured by the 12SL
algorithm essentially corresponds to the distance between the earliest detection of
depolarization in any lead (QRS onset) and the latest detection of repolarization in any lead
(T-offset). The algorithm excludes from the analysis any discrete U-waves that occur after the
T-wave returns to baseline, whereas complex multiphasic T-waves and T-U complexes are
included.7,8 QT intervals were corrected for heart rate using the Framingham linear regression
formula (QTcFram = QT+154[1-60/heart rate]) or the Bazett’s formula (QTcBaz = QT/ [RR
interval]1/2).
Left ventricular hypertrophy was defined based on the Sokolow-Lyon ECG criteria as follows:
1) R-wave in lead V5 or V6 > 26 mV or 2) S-wave in lead V1 + R-wave in lead V5 or V6 ≥ 35
mV.
To evaluate the agreement between the 12SL algorithm and manually QTcFram interval
measurement, a total of 150 ECGs were sampled for manual evaluation. To be able to explore
validity of the automated measurements also at the extremes of QTcFram interval, the sample
was enriched with such ECGs. Accordingly, to obtain the sample of 150 ECGs, 50 ECGs were
randomly sampled from the lowest 1st percentile, 100 ECGs were randomly sampled from 1st
to 99th percentile, and 50 ECGs were randomly sampled from the upper 99th percentile. For
all manually assessed ECGs, QTcFram intervals were measured manually in lead aVF, V2, and V5
at 10 times magnification and with the use of a digital caliper (MUSE® Cardiology Information
System, GE Healthcare, Wauwatosa, WI, USA). The mean of the manual QTcFram measurement
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Supplementary Appendix
from the three leads was used for the comparison. The manual rater (J.B.N.) was blinded to
results from the 12SL algorithm. To evaluate agreement between manual and 12SL measured
QTcFram intervals, results were summarized in a scatter-plot and in a Bland-Altman plot. Mean
difference between manual and 12SL algorithm measurements was calculated together with
the limits of agreement (±2 standard deviations, see Supplemental Figure 2).
1.4 Clinical Covariates and Outcomes
Heart failure was defined as a combination of a heart failure diagnosis (I110, I42, I50, J819) in
the Danish National Patient Registry and treatment with loop-diuretics (C03C), as done
previously.9 Myocardial infarction was defined from hospital, ambulatory, and emergency
room discharge diagnoses (ICD-8: 410, ICD-10: I21, I22).10 We categorized individuals as
having valvular heart disease if they were assigned a diagnosis of aortic or mitral valve
disease (I05, I06, I34, I35), or if they had a history of aortic or mitral valve surgery (procedure
code KFK and KFM), as done
previously.9 Study subjects treated with ACE inhibitors or ARBs (C09), beta-blockers (C07), or
calcium-antagonists (C07F, C08, C09BB, C09DB) prior to study inclusion were identified
together with subjects treated with QT interval prolonging drugs (yes/no, see Supplementary
Table 2 for a comprehensive list) or digoxin (C01AA) on the day of ECG recording. The cause
and date of death were retrieved from The Danish Register of Causes of Death (CVD was all “I”
diagnosis).
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Supplementary Appendix
2. Supplementary References
1.
Frank L. When an entire country is a cohort. Science. 2000; 287:2398–2399.
2.
Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand. J. Public
Health. 2011; 39:30–33.
3.
Helweg-Larsen K. The Danish Register of Causes of Death. Scand. J. Public Health. 2011;
39:26–29.
4.
Kildemoes HW, Sørensen HT, Hallas J. The Danish National Prescription Registry. Scand. J.
Public Health. 2011; 39:38–41.
5.
Pedersen CB. The Danish Civil Registration System. Scand. J. Public Health. 2011; 39:22–
25.
6.
WHOCC - ATC/DDD Index [Internet]. [cited 2012 Mar 2];Available from:
http://www.whocc.no/atc_ddd_index/
7.
GE Healthcare. MarquetteTM 12SLTM ECG Analysis Program. Statement of Validation and
Accuracy. 416791-003 Revision C. [Internet]. [cited 2012 Apr 2];Available from:
http://gehealthcare.com
8.
GE Healthcare. MarquetteTM 12SLTM ECG Analysis Program. Physician’s Guide. 2036070006 Revision A. [Internet]. [cited 2012 Apr 2];Available from: http://gehealthcare.com
9.
Olesen JB, Lip GYH, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, Selmer C, Ahlehoff
O, Olsen A-MS, Gislason GH, Torp-Pedersen C. Validation of risk stratification schemes for
predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide
cohort study. BMJ. 2011; 342:d124.
10. Madsen M, Davidsen M, Rasmussen S, Abildstrom SZ, Osler M. The validity of the
diagnosis of acute myocardial infarction in routine statistics: a comparison of mortality
and hospital discharge data with the Danish MONICA registry. J. Clin. Epidemiol. 2003;
56:124–130.
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Supplementary Appendix
3. Supplemental Tables
3.1 Supplemental Table 1
Supplemental Table 1. QTc Interval Prolonging Drugs by ATC code*
Drug category
Drugs (ATC code)
Alimentary tract and metabolism
Domperidone (A03FA03), Ondansetron (A04AA01),
Granisetron (A04AA02)
Cardiovascular system*
Flecainide (C01BC04), Amiodarone (C01BD01), Dronedarone
(C01BD07), Indapamide (C03BA11), Sotalol (C07AA07), Isradipine
(C08CA03), Nicardipine (C08CA04), Moexipril (C09AA13)
Urogenital system
Solifenacin (G04BD08), Vardenafil (G04BE09),
Alfuzosin (G04CA01, G04CA51)
Antibiotics
Trimethoprim-Sulfa (J01EA01), Erythromycin (J01FA01),
Roxithromycin (J01FA06), Procainamide (J01FA09), Azithromycin
(J01FA10), Ofloxacin (J01MA01), Ciprofloxacin (J01MA02),
Moxifloxacin (J01MA14), Ketoconazole (J02AB02), Fluconazole
(J02AC01), Itraconazole (J02AC02),
Voriconazole (J02AC03)
Antineoplastic and
immunomodulatory agents
Tamoxifen (L02BA01), Tacrolimus (L04AD02)
Muscle and skeletal system
Tizanidine (M03BX02)
The nerve system
Amantadine (N04BB01), Thioridazine (N05AC02), Haloperidol
(N05AD01),
Sertindole (N05AE03), Ziprasidone (N05AE04), Pimozide (N05AG02),
Clozapine (N05AH02), Quetiapine (N05AH04), Lithium (N05AN01),
Risperidone (N05AX08), Paliperidone (N05AX13), Chlorpromazine
(N05AA01), Fluoxetine (N06AB03), Citalopram (N06AB04),
Paroxetine (N06AB05), Sertraline (N06AB06), Escitalopram
(N06AB10), Venlafaxine (N06AX16), Galantamine (N06DA04),
Imipramine (N06AA02, N06AA02), Clomipramine (N06AA04),
Trimipramine (N06AA06), Amitriptyline (N06AA09), Nortriptyline
(N06AA10), Protriptyline (N06AA11), Doxepin (N06AA12),
Methadone (N07BC02)
Antiparasitic drugs, insecticides, and
repellents
Chloroquine (P01BA01), Pentamidine (P01CX01)
Respiratory system
Astemizole (R06AX11), Terfenadine (R06AX12),
Diphenhydramine (R06AA02)
*The table lists all drugs associated with QT interval prolongation as listed on www.qtdrugs.org (accessed 7th of
April 2011) and available in Denmark prior to 2011.
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Supplementary Appendix
3.2 Supplemental Table 2
Supplemental Table 2. Modified* Charlson Co-morbidity Index
Condition
Weights
ICD-10 code
Peripheral
vascular disease
1
I70, I71, I74, I79.0, I73.9
Cerebral vascular
accident
1
I60, I61, I62, I63, I65, I66, I67, I68, I69, G45.0, G45.1, G45.2, G45.8, G45.9, I64,
G45.4, G46 I67.0, I67.1, I67.2, I67.4, I67.5, I67.6, I67.7, I67.8, I67.9, I68.2, I68.8,
I68.1
1
F00, F01, F02, G30, G31
1
J40, J41, J42, J43, J44, J45, J46, J47, J67, J60, J61, J62, J63, J64, J65, J66, J67
Connective tissue
disorder
1
M32, M34, M33.1, M05.3, M05.8, M05.9, M06.0, M06.3, M06.9, M05.0, M05.1,
M05.2, M35.3
Peptic ulcer
1
K25, K26, K27, K29, K22.1
Liver disease
1
K702, K703, K704, K73, K71.7, K74.0, K74.2, K74.6, K74.3, K74.4, K74.5
Diabetes
1
E10.9, E11.9, E13.9, E14.9, E10.1, E11.1, E13.1, E14.1, E10.5, E11.5, E13.5, E14.5
Diabetes
complications
2
E10.2, E11.2, E13.2, E14.2, E10.3, E11.3, E13.3, E14.3, E10.4, E11.4, E13.4, E14.4
Paraplegia
2
G81, G04.1, G82.0, G82.1, G82.2, T14.4
Renal disease
2
N03, N05.2, N05.3, N05.4, N05.5, N05.6, N07.2, N07.3, N07.4, N01, N18, N19,
N25, N17, R34, I12, I13, Z99.2, N04, T85.8, T85.9
Cancer
2
C0, C1, C2, C3, C40, C41, C43, C45, C46, C47, C48, C49, C5, C6, C70, C71, C72, C73,
C74, C75, C76, C80, C81, C82, C83, C84, C85, C88.3, C88.7, C88.9, C900, C901,
C91, C92, C93, C94.0, C94.1, C94.2, C94.2, C94.51, C94.7, C95, C96
Metastatic cancer
3
C77, C78, C79, C80
Severe liver
disease
3
K72.9, K76.6, K76.7, K72.1, B15.0, B16.0, B19.0, K71.1
HIV
6
B20, B21, B22, B23, B24
Dementia
Pulmonary
disease
*Cardiovascular diagnostic codes for acute myocardial infarction (I21, I22, and I25.2) and congestive heart failure
(I50) are excluded as these covariates were adjusted for separately. HIV; human immunodeficiency virus.
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Supplementary Appendix
3.3 Supplemental Table 3
Supplementary Table 3. Predicted 5-Year Risk (%) of CVD by subgroups based on QTcFram
Median (IQR) 5-year risk of CVD
Gender
QTcFram interval
category
No cardiovascular disease*
History of cardiovascular disease*
Range
Age 50-70
Age 70-90
Age 50-70
Age 70-90
Women
≤379ms
380-391ms
392-405ms
406-415ms
416-424ms
425-435ms
436-451ms
452-469ms
≥470ms
0.3 (0.1-0.6)
0.5 (0.3-0.7)
0.4 (0.2-0.6)
0.4 (0.3-0.6)
0.4 (0.2-0.7)
0.5 (0.3-0.8)
0.5 (0.3-0.9)
0.8 (0.5-1.4)
1.1 (0.6-2.1)
7.8 (4.9-14.2)
5.2 (3.2-8.9)
4.3 (2.7-7.5)
4.6 (2.9-8.2)
4.5 (2.7-7.9)
5.3 (3.2-9.0)
5.9 (3.6-10.4)
9.0 (5.3-15.7)
11.0 (7.1-18.1)
4.7 (1.4-7.3)
2.0 (0.9-5.3)
1.3 (0.6-3.1)
1.6 (0.8-3.8)
1.3 (0.8-3.1)
1.9 (1.0-4.5)
2.4 (1.2-5.2)
3.8 (1.7-8.4)
4.4 (2.1-8.5)
22.6 (12.7-35.4)
13.8 (9.5-22.9)
11.9 (7.0-19.1)
12.4 (7.5-19.6)
12.0 (6.8-20.1)
13.9 (7.9-21.2)
14.9 (8.9-24.2)
23.1 (12.7-33.8)
26.1 (14.4-37.0)
Men
≤375ms
376-387ms
388-400ms
401-410ms
411-419ms
420-430ms
431-447ms
448-465ms
≥466ms
0.9 (0.6-1.3)
0.6 (0.4 (0.9)
0.8 (0.5-1.2)
0.9 (0.6-1.4)
1.0 (0.6-1.5)
1.2 (0.8-1.9)
1.5 (1.0-2.3)
2.1 (1.4-3.2)
3.6 (2.3-5.3)
5.1 (3.5-8.0)
3.5 (2.4-5.7)
4.4 (3.2-6.7)
5.2 (3.8-8.0)
5.6 (3.9-8.6)
6.1 (4.2-9.0)
8.0 (5.5-12.2)
10.8 (7.2-16.7)
16.3 (10.5-24.4)
2.9 (2.0-5.4)
1.3 (0.8-2.2)
2.1 (1.3-3.8)
2.5 (1.5-4.1)
2.7 (1.6-4.7)
3.3 (2.0-5.5)
4.1 (2.5-7.0)
5.5 (3.8-9.2)
9.8 (6.2-17.0)
14.0 (9.9-21.8)
7.8 (5.2-12.1)
10.4 (6.3-17.0)
11.3 (7.3-17.4)
10.5 (7.3-17.3)
12.0 (8.3-17.7)
15.5 (10.0-24.3)
19.9 (14.9-29.3)
26.4 (19.3-37.7)
*Cardiovascular disease was defined as myocardial infarction, heart failure, or valvular heart disease at inclusion.
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3.4 Supplemental Table 4
Supplemental Table 4. Predicted 5-Year Risk (%) of CVD by subgroups based on QTcBaz
Median (IQR) 5-year risk of CVD
Gender
QTcBaz interval
category
No cardiovascular disease*
History of cardiovascular disease*
Range
Age 50-70
Age 70-90
Age 50-70
Age 70-90
Women
≤381ms
382-396ms
397-413ms
414-426ms
427-437ms
438-451ms
452-470ms
471-489ms
≥490ms
0.1 (0.0-0.1)
0.2 (0.1-0.4)
0.3 (0.1-0.4)
0.3 (0.2-0.5)
0.4 (0.3-0.7)
0.6 (0.4-1.0)
0.8 (0.5-1.2)
1.2 (0.7-2.0)
1.8 (1.1-2.8)
4.9 (2.8-9.6)
5.0 (3.0-8.6)
4.0 (2.5-7.1)
3.9 (2.4-6.9)
4.7 (2.8-8.1)
5.2 (3.2-9.3)
6.9 (4.2-11.9)
8.2 (5.0-14.6)
11.5 (7.1-19.3)
0.4 (0.2-0.9)
1.0 (0.5-2.2)
0.9 (0.5-2.3)
0.9 (0.5-1.9)
1.4 (0.7-3.6)
2.4 (1.2-4.9)
3.2 (1.7-6.5)
5.2 (2.7-8.9)
9.4 (4.0-17.7)
17.5 (11.0-29.7)
13.0 (8.9-23.7)
12.0 (7.1-20.2)
10.6 (6.2-16.9)
12.5 (7.0-20.6)
13.7 (7.9-22.2)
18.0 (10.8-28.2)
19.9 (12.0-29.5)
26.6 (17.2-36.9)
Men
≤374ms
375-387ms
388-405ms
406-418ms
419-430ms
431-445ms
446-466ms
467-486ms
≥487ms
0.7 (0.5-1.2)
0.5 (0.3-0.7)
0.5 (0.4-0.8)
0.8 (0.5-1.1)
1.0 (0.7-1.5)
1.2 (0.8-1.9)
2.0 (1.3-3.1)
2.7 (1.8-3.9)
5.1 (3.5-7.2)
3.6 (2.5-5.9)
3.0 (2.1-4.5)
3.7 (2.7-5.8)
4.9 (3.4-7.5)
5.5 (3.8-8.3)
6.6 (4.6-10.0)
8.5 (5.8-12.6)
11.3 (7.9-16.3)
15.0 (10.5-22.5)
2.7 (1.9-4.0)
1.1 (0.7-2.0)
1.5 (1.0-2.3)
1.9 (1.2-3.3)
2.8 (1.8-4.6)
3.4 (2.2-5.5)
5.6 (3.5-8.9)
7.4 (4.9-14.4)
13.4 (9.5-21.3)
11.1 (7.2-18.0)
9.0 (5.0-14.4)
8.3 (5.0-14.2)
11.1 (7.1-17.5)
11.1 (7.6-16.2)
13.0 (8.9-20.7)
17.7 (12.1-25.0)
20.5 (14.1-30.5)
31.4 (20.1-40.1)
*Cardiovascular disease was defined as myocardial infarction, heart failure, or valvular heart disease at inclusion.
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Supplementary Appendix
3.5 Supplemental Table 5
Supplemental Table 5. Examples of Absolute Risk Predictions on an Individual Level
Patient examples
Woman, 55 years of age, no comorbidities
QTcFram
interval
subgroups
≤379ms
416-424ms
≥470ms
Absolute risk of death (%) during follow-up
form index ECG (all-cause mortality
[CVD/non-CVD])
1 year
5 years
10 years
(0/0)
2 (0/2)
4 (0/4)
(0/0)
2 (0/2)
5 (1/4)
(0/0)
3 (1/2)
6 (1/5)
Woman, 65 years of age, myocardial infarction, treatment with
beta-blockers and ACE-inhibitors, a Charlson score of 1, and an
ECG with left ventricular hypertrophy
≤379ms
416-424ms
≥470ms
4 (2/2)
4 (2/2)
7 (5/2)
17 (7/10)
16 (8/8)
28 (17/11)
33 (11/22)
31 (13/18)
47 (26/21)
Woman, 85 years of age, treatment with ACE-inhibitors, and a
Charlson score of ≥2
≤379ms
416-424ms
≥470ms
15 (4/11)
9 (2/7)
14 (5/9)
57 (15/42)
42 (11/31)
57 (20/37)
87 (21/66)
72 (16/56)
86 (27/59)
≤375ms
376-387ms
≥466ms
0 (0/0)
0 (0/0)
1 (0/1)
3 (1/2)
2 (0/2)
8 (2/6)
6 (1/5)
5 (1/4)
16 (3/13)
Man, 65 years of age, myocardial infarction, treatment with betablockers and ACE-inhibitors, a Charlson score of 1, and an ECG
with left ventricular hypertrophy
≤375ms
376-387ms
≥466ms
3 (2/1)
2 (1/1)
7 (4/3)
13 (7/6)
10 (4/6)
32 (17/15)
24 (10/14)
19 (7/12)
53 (24/29)
Man, 85 years of age, treatment with ACE-inhibitors, and a
Charlson score of ≥2
≤375ms
376-387ms
≥466ms
13 (3/10)
12 (2/10)
22 (7/15)
50 (10/40)
50 (9/41)
74 (24/50)
81 (15/66)
80 (13/67)
95 (29/66)
Man, 55 years of age, no comorbidities
Predictions were based on Cox models fitted within the respective age and gender determined subgroups and adjusted for covariates as
described in Figure 2. Optimal (reference) QTc intervals were the respective QTc Fram intervals that conferred the lowest relative risk of
all-cause death (Figure 1). CVD; cardiovascular death.
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Supplementary Appendix
4. Supplemental Figures
4.1 Supplemental Figure 1
Supplemental Figure 1. Flow-chart of the study population selection, showing the number of
individuals excluded for various reasons. CGPL; Copenhagen General Practitioners’
Laboratory. ICD; implantable cardioverter-defibrillator.
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Supplementary Appendix
4.2 Supplemental Figure 2
Supplemental Figure 2. Multivariable-adjusted restricted cubic spline analysis showing the
hazard ratio of CVD as a function of the QTcFram interval with 95% confidence limits (dashed
lines) superimposed on a histogram of the population QTcFram interval distribution.
Adjustment factors are described in Figure 1. Knots were located at the 0.1st, 5th, 25th, 50th,
75th, 95th, and 99.9th percentiles and the value of QTc estimated to have the lowest risk of
CVD, was used as reference point (hazard ratio of one).
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Supplementary Appendix
4.3 Supplemental Figure 3
Supplemental Figure 3. Multivariable-adjusted hazard ratios for all-cause, cardiovascular, and
non-cardiovascular death by categories of the QTcBaz interval. All models were adjusted for heart
failure, myocardial infarction, valvular heart disease, Charlson comorbidity index (0 points, 1 point,
or ≥2 points), treatment with ACE-inhibitors or ARBs, beta-blockers, or calcium antagonists prior
to inclusion, treatment with QTc-prolonging medications or digoxin on the day of ECG recording,
left ventricular hypertrophy on the index ECG, and age was used as the timescale. The vertically
dotted lines represent a hazard ratio of 1. The horizontal solid lines represent 95% confidence
intervals.
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4.4 Supplemental Figure 4
Supplemental Figure 4. Predicted 5-year risk of cardiovascular death based on subgroups. Both
models for cardiovascular death (CVD) and the competing models of non-CVD were independently
performed for women and men in age groups 50-70 and 70-90 years, and contained the following
covariates: age as a linear parameter, myocardial infarction, heart failure, valvular heart disease, a
modified Charlson comorbidity index (0 points, 1 point, or ≥2 points), treatment with ACEinhibitors or ARBs, beta-blockers or calcium antagonists prior to inclusion, treatment with QTcprolonging medications or digoxin on the day of ECG recording, and left ventricular hypertrophy
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Supplementary Appendix
on the index ECG. Boxes denote the median risks (horizontal line) and interquartile ranges (lower
and upper border) whereas whiskers denote the 5th and 95th percentiles. Numbers above the
whiskers denote the median risk for the respective subgroup. Heart rate-correction was based on the
Bazett’s formula (QTcBaz).
4.5 Supplemental Figure 5
Supplemental Figure 5. Agreement between automated QTcFram interval measurements
(Marquett 12SL algorithm) and manual measurements. Scatter-plot (A) and a Bland-Altman
plot (B). The difference between mean manual QTcFram interval measurement (424.8ms) and
mean 12SL measurement (423.5ms) was 1.3ms (95% CI -2.3ms to 4.9ms) with limits of
agreement (±2 standard deviations) ranging from
-43.3ms to 45.9ms. SD; standard deviation.
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