Mason 2007
Mason 2007
e8
[Link]
Abstract Background: Reference ranges for electrocardiogram (ECG) intervals, heart rate, and QRS axis
in general use by medical personnel and ECG readers are unrepresentative of true age- and sex-
related values in large populations and are not based on modern electrocardiographic and ECG
reading technology.
Methods and Results: The results of ECG interpretation by cardiologists using digital technology
for viewing and interpreting ECGs were compiled from single, baseline ECGs of 79,743 individuals
included in pharmaceutical company–sponsored clinical trials. Women comprised 48% of the total
population. Ages ranged from 3 months to 99 years, and the bulk of the population (56%) was aged
40 to 70 years. Striking differences in numerical ECG values based on age and sex were observed.
A subgroup of 46,129 individuals with a very low probability of cardiovascular disease was
identified. The following were the reference ranges for this subgroup, determined using the 2nd and
98th percentiles: heart rate, 48 to 98 beats/min; PR interval, 113 to 212 milliseconds; QRS interval,
69 to 109 milliseconds; frontal plane QRS axis, 408 to 918; QT interval, 325 to 452 milliseconds;
QTc-Bazett, 361 to 457 milliseconds; and QTc-Fridericia, 359 to 445 milliseconds. There were
marked age- and sex-related variations in the reference ranges of this subgroup, and they differ
substantially from previously reported norms. Small differences were observed in ECG values
obtained using our digital methods as compared with readings done using paper tracings and values
computed by 2 commercial computer algorithms.
Conclusions: We observed large differences in electrocardiographic heart rate, interval, and axis
reference ranges in this study compared with those reported previously and with reference ranges in
general use. We also observed a large influence of age and sex upon normal values. Very large
cohorts are required to fully assess age- and sex-related variation of reference ranges.
Electrocardiographic reference ranges should be modernized.
D 2007 Elsevier Inc. All rights reserved.
Keywords: Electrocardiogram; Normal value; Reference range
All authors have read and agreed to the article as written. Table 1
This study qualifies for exempt status according to Section Demographic information
46.101(b)(4) of 45CFR56, bThe Common Rule,Q because N Mean SD Range
the analysis involves existing data recorded in such a way Total population 79,743
that the authors cannot identify the subjects. Subjects could Men 41,392
Women 38,351
not be asked to give informed consent, and this study did
Total with interval measurements 79,487
not undergo IRB review. Total with diagnostic coding 70,728
Previous studies used for comparison Age (y) 79,743 51.7 16.6 0-99
Height (in) 68,843 66.4 4.4 32-84
The normal limits listed in the textbook of Macfarlane Weight (lb) 68,995 179 45 24-500
Reference range subset 46,129
and Lawrie1 were derived from 1338 apparently normal
Men 21,567
government employees in Western Scotland before 1985. Women 24,562
The age distribution of this group was quite different from Total with interval measurements 46,129
that of our study, but data were provided in age and sex Total with diagnostic coding 46,129
groups similar to ours, allowing some direct comparisons. Age (y) 46,129 47.5 17.4 0-99
Height (in) 38,767 66.1 4.6 32-84
Lamb2 reported another study of moderate size in his
Weight (lb) 38,846 173 45 24-500
textbook. This analysis was based upon the study of Hiss
et al3 performed in 6014 male Air Force recruits, and because of the presence of atrial fibrillation and flutter and
Lamb’s unpublished data in 782 women. Lamb reported the other arrhythmias in some subjects, and frontal plane QRS
percent of subjects in ordinal data categories. axis was only measured in 79,122 subjects because of
Dmitrienko et al4 recently reported another large data set indeterminacy of axis in some. The average age of this
from Eli Lilly and Company. They analyzed baseline ECGs population, which ranges from infants to nonagenarians,
obtained with GE Medical Systems electrocardiographs in was 51.7 F 16.6 years, and average height and weight were
13,039 patients enrolled in Lilly-sponsored trials in 2000 66.4 F 4.4 in and 179 F 45 lb, respectively. Probability
and 2001. These ECGs were first computer-interpreted by distributions of weight, height, and age in this population
the GE-Marquette 12SL program. Paper copies of the were roughly Gaussian as shown in Appendix Fig. 1, panels
ECGs, with the computer-generated results, were then A-C, in the online edition of this article. Although the
overread by cardiologists. The population included only subjects of this study resided in 57 countries, most (70%)
819 subjects more than 65 years of age. Most subjects were were from the United States and Canada, and the next
enrolled in neuroscience trials, and those enrolled in largest group was from Europe (21%). Regions and
cardiovascular drug trials were excluded. The authors countries of origin of the study population are shown in
proposed normative values based upon different age ranges Appendix Table 1 (online).
(decades beginning at middecade) and different lower and Because this population includes subjects enrolled in all
upper percentiles (1st and 99th) from ours, and they reported clinical trial phases (phase 1, 8%; phase 2, 18 %; phase 3,
on subjects with normal and abnormal ECGs separately. 72%; and phase 4, 1%), most of the subjects had a known
The study of reference ECG values by Simonson5 was the clinical disorder. The most common diseases were neuro-
most statistically advanced treatment of the topic when it was psychiatric (27%), diabetes mellitus (12%), and cardiovas-
published in 1961. He used the percentile distribution to cular (9%).
differentiate between normal and abnormal, and set the upper Characteristics of the subjects included in the reference
and lower thresholds at 97.5% and 2.5%, respectively. His range subset are summarized on the bottom of Table 1. The
study involved 960 adults between 20 and 60 years of age, of mean age is a few years younger, and there is a greater
which 649 were men, and 311 were women. His subjects proportion of women than men as compared with the entire
were drawn from several groups of hospital, railroad, and group. Their weight, height, and age distributions were
insurance company employees. The subjects were screened approximately normal and similar to those of the whole
by history and physical examination, and Simonson indi- population (Appendix Fig. 1, panels D-F [online]).
cates that he excluded individuals with bmajor electrocar- The study population includes 990 subjects aged 0 to
diographic abnormalities, such as patterns of old myocardial 9 years. Within this group, there were 6 children less than
infarction and right or left bundle branch block.Q5 1 year (aged 3, 6, 8, 8, 8, and 11 months), 3 aged 1, 15 aged 2,
25 aged 3, 57 aged 4, 66 aged 5, 179 aged 6, 174 aged 7, 258
aged 8, and 207 aged 9 years. These numbers are insufficient
Results for estimation of age-specific norms in children, and the
summary values for ages 0 to 9 must be recognized as averages
Characteristics of the study population
derived from age groups with large group differences.
Table 1 displays the basic characteristics of our study
Electrocardiographic findings
population. The study includes a single screening or
baseline ECG from 79,743 subjects. Fifty-two percent were All subjects
men. Heart rate, QRS interval, and QT interval were Appendix Tables 3-6 (online) list ECG data for the entire
measured in the 79,487 individuals without cardiac pace- population with measurable values. Separate data for the
makers. PR was measured in fewer subjects (78,846) sexes, 10-year age cohorts, and sex/age cohorts are
J.W. Mason et al. / Journal of Electrocardiology 40 (2007) 228–234.e8 231
significant differences from the other groups are shown. In Comparison to previous studies
these tables, median values, 98th and 2nd percentiles, and
Electrocardiogram interval reference values reported in
the number of subjects in each group are displayed. Those
this study are compared to those of Macfarlane and Lawrie1 in
groups without significant dissimilarities in the 2nd or 98th
Appendix Table 11 (online). A few differences between our
percentiles ( N3 beats/min for rate, N5 milliseconds for
interval values and theirs stand out. Our reference range
intervals, or N 58 for axis) are combined into single groups. subset (as well as the entire group of 79,743 subjects)
The data demonstrate a strong influence of age and sex upon demonstrated a small decrease in heart rate with increasing
heart rate, ECG intervals, and axis. Fig. 1 displays the age, whereas Macfarlane and Lawrie1 observed the oppo-
distributions of heart rate, PR, QRS, and QT intervals for all site. Like us, they did observe a consistently lower heart rate
subjects (panels A-D) and the reference range subgroup in men than in women. Both we and Macfarlane and
(panels E-H). The distributions are nearly normal, although Lawrie1 recorded a progressive increase in PR interval with
high kurtosis is present in the QRS distribution of the aging, and higher values in men than in women. Both
full population (panel C), and there are subtle variations observed a longer mean QRS duration in men than in
from normal in the other distributions. Thus, the use of women, but they reported a progressive decrease in mean
percentiles rather than a multiple of the standard QRS duration, whereas we observed stability of the mean
deviation was preferred for estimating the reference range with increasing age. The most striking difference was in the
for this population. Bazett-corrected QT interval. The group in the study of
A E
0.10 0.10
Probability
Probability
0.08 0.08
0.05 0.05
0.03 0.03
B F
Probability
Probability
0.15 0.15
0.10 0.10
0.05 0.05
C G
0.10
Probability
0.15
Probability
0.08
0.10
0.05
0.05
0.03
50 70 90 110 130 150 170 190 210 230 48 60 72 84 96 108 120 132 144 156
QRS interval, msec QRS interval, msec
D H
0.13
0.13
Probability
Probability
0.10 0.10
0.08 0.08
0.05 0.05
0.03 0.03
Fig. 1. Distributions of HR, PR, QRS, and QT in all subjects (A-D) and the reference range subset (E-H). A normal curve (red) is fitted to each distribution. The
distributions show subtle variations from normal. The distributions in the 2 groups are very similar in most cases. However, in the case of the QRS interval, the
distribution is narrower in the reference range subset, and the upper tail is abruptly cut off because of the exclusion of ventricular conduction delay diagnoses in
this subset.
J.W. Mason et al. / Journal of Electrocardiology 40 (2007) 228–234.e8 233
1
Macfarlane and Lawrie generally had considerably higher in current use for adults are 60 to 100 for resting heart
values. An increase of QTcB with aging was observed in rate, 140 to 210 milliseconds for PR interval, 70 to
both studies. Their group and we reported the 98th and 2nd 110 milliseconds for QRS duration, 308 to 908 for QRS
percentile values of our study populations. Using these as axis, and 460 milliseconds for the upper limit of QTc, as
the upper and lower limits of normal, considerably different stated in Marriott’s Practical Electrocardiography.6 Elec-
ranges of normal values are observed in the 2 studies. For trocardiographers typically apply these ranges across most
illustration, 4 age/sex groups are compared in Appendix or all adult age groups, usually without regard to sex. These
Table 11 (online). Macfarlane and Lawrie’s1 upper and ranges are not consistent with published age- and sex-
lower heart rate limits were generally 5 to 10 beats/min specific norms; rather, they have been handed down from
higher than ours, and their upper and lower QTcB limits teachers to students of electrocardiography over many
were strikingly higher than ours, ranging from 21 to decades as easily remembered, although imprecise, esti-
28 milliseconds and 18 to 23 milliseconds greater for the mates of normal. Unfortunately, their use results in
lower and upper limits, respectively. incorrect categorization as normal or abnormal of a
Appendix Table 12 (online) displays the age- and sex- substantial proportion of subjects.
related percentage distribution of QRS durations in the Review of the medians and 96% ranges of the entire
study of Lamb2 and ours. The differences are quite striking, group of 79,743 ambulatory subjects provides important
as durations in both male and female subjects in Lamb’s insight to the extent of the influences of age and sex upon
study show higher frequencies in the lower duration numerical ECG values. Variations among age and sex
categories than we observed in our subjects. cohorts are large enough to strongly impugn the common
As shown in Appendix Table 13 (online), subjects in the use of a single range of values to distinguish between
Lilly study4 that were grouped in the normal ECG category normal and abnormal among adults. A similar pattern of
had narrower ranges than those in the abnormal ECG variation, although not as large, between age and sex
category. The ranges of our reference range subset were cohorts exists in the reference range subgroup.
intermediate between these 2 Lilly groups, although we We propose that the 96% ranges of our subset of
used 2% and 98% cutoffs, whereas they used 1% and 99%. 46,219 subjects who had a very low probability of a
Unexpectedly, the upper PR range in men in the Lilly disease-related ECG abnormality be used to establish new
normal ECG group exceeded that of the Lilly abnormal reference ranges to replace existing reference ranges for
ECG group for both age cohorts, and considerably exceeded heart rate, ECG intervals, and axis values. Those ranges
our upper limit for men aged 36 to 45 years by 23 mill- appear in Appendix Tables 7-10 (online). The proposed
seconds. There were consistent differences between Lilly’s ranges are condensed in Tables 2 and 3. The greatest effect
QTcL limits and ours (recalculated using Lilly’s log linear of use of these new ranges will be more accurate diagnosis
formula). The lower limit values in all of their age/sex of bradycardia, which is overdiagnosed with current
categories were 3 to 14 millseconds higher than ours, and reference ranges; reduction in overdiagnosis of first-degree
their upper limit values were 10 to 11 millseconds higher. atrioventricular block; a more accurate recognition of the
The data of Simonson5 are compared with ours in effect of age upon QRS axis; more accurate diagnosis of QT
Appendix Table 14 (online). He stated that, although some prolongation according to age and sex; and a generally
differences in mean values for his age groups were better understanding of differences between men and
significant, the differences in upper and lower limits were women and among age and age/sex cohorts.
so minor that he combined all ages. In contrast, we observed These new reference ranges are applicable to ECGs
progressive changes with aging. The most striking differ- interpreted with the high-resolution digital display and
ence between our data and Simonson’s data is the absence of analysis systems that are in wide use today. All previously
longer QT values in women compared with men.5 reported ranges were derived either from human interpre-
tation of ECGs printed on paper or from computer
Comparison of Digitography to other reading methods
algorithms without on-screen, computer-assisted human
As expected, Digitography does result in a systematic review. Measurements done on paper by humans and those
difference in interval values from measurements performed done by computer algorithms do vary.7-9 Readers who make
directly on paper ECGs and measurements performed by direct measurement on paper ECGs recorded at standard
commercial electrocardiographic software. For example, gain and a paper speed of 25 mm/s or those who rely upon
QRS duration was shorter in Digitography by 5.64 milli- the software-derived values of Mortara or GE electrocardio-
seconds as compared with paper, 1.82 milliseconds as graphs can calculate the expected differences between those
compared with the GE 12 SL algorithm and 0.05 milli- methods and our Digitography results using the data in
seconds as compared with the Mortara Veritas algorithm. Appendix Tables 15-17 (online). Systematic differences
These differences are described in the online edition of this between manual, digital, and automated measurement
article in Appendix Tables 15-17. methods are well recognized10 and should be accounted
for with use of the reference ranges proposed in this study.
Our reference range subset includes both healthy
Discussion
volunteers and subjects with known noncardiac disease.
Derivation of the commonly used reference values for These 46,219 individuals were screened by trained medical
the ECG is surprisingly obscure. Typical reference ranges personnel at the investigative sites for evidence of cardiac
234 J.W. Mason et al. / Journal of Electrocardiology 40 (2007) 228–234.e8
and other disease by history, physical examination, and and cultural differences in the populations, differences in
ECG before their enrollment. All subjects that failed recording methodology and equipment, differences in read-
screening for any reason were excluded from this subset. ing methodology, differences in health status among the
We consider use of this population to establish normative populations, and, especially, the smaller size and homogene-
ranges preferable to the use of small, highly screened, ity of the populations used in the previous studies.
homogeneous, apparently disease-free groups, as has been A single definitive set of normative values is needed so
common in the past.1-3,5,11 The latter approach eliminates that all ECGs can be interpreted consistently. For that
genetic diversity and results in samples that are too small to purpose, we believe our database has several advantages
permit reliable calculation of age- and sex-specific ranges. over older reported data sets1-3,5: (1) much larger sample
More importantly, highly culled, homogeneous groups are size; (2) greater genetic and geographic diversity of the
not reflective of the populations seen in either an ambula- population; (3) modern, well-maintained recording equip-
tory or in-patient setting in which physicians use the ECG to ment; (4) uniform recording methodology, including simul-
screen for cardiac disease. The restricted groups used in the taneous lead acquisition; (5) digital interval annotation using
past to establish normal values have generally resulted in a standardized measurement methodology at high resolu-
excessively narrow ranges, leading to a falsely high tion; (6) use of a single diagnostic code set and uniform
incidence of abnormal ECGs. Choice of the population diagnostic criteria; (7) review of all ECGs by cardiologists;
from which normative ranges are derived should be based (8) a limited subject recruitment period (3 years); (9) a more
upon the nature of the group the norms will be applied to contemporaneous subject population (years 2003-2005);
and upon the purpose for comparing findings to the norms. and (10) inclusion of disease states with low potential to
Practicing physicians use electrocardiographic norms pri- directly affect the ECG, yielding a study population that
marily to evaluate symptomatic patients in the office or more closely represents the patient population in which
hospital with the purpose of screening for clinically clinicians use the ECG to judge cardiac status.
unapparent cardiac disease. We believe that norms derived The major objective of this work was to establish well-
from populations that are not seen by the medical profession founded electrocardiographic heart rate, interval, and axis
will not serve that purpose well. reference ranges for clinical use. We recommend that
By selecting 96% ranges, we arbitrarily set the false- existing reference ranges be abandoned and replaced by
positive error rate at 2% for high and 2% for low values. age and sex-specific values derived from large, diverse
Other ranges have been used commonly, such as 95% and samples such as ours, and that these more robust norms be
98%. Although there is no established preference or incorporated into ECG computer analysis algorithms and
scientific rationale for one or the other, it is important to teaching curricula.
understand the implicit error rate associated with the
selected range. The choice of a lower false-positive error References
rate (eg, a 98% range) is inevitably associated with a
1. Macfarlane PW, Lawrie TDV. Comprehensive electrocardiology:
higher false-negative error rate (ie, the chance that an theory and practice in health and disease. New York7 Pergamon Press;
abnormal subject would incorrectly be categorized as 1989.
normal), but the absolute magnitude of this error rate 2. Lamb LE. Electrocardiography and vectorcardiography: instrumenta-
depends on the distribution that the parameter takes in the tion, fundamentals, and clinical applications. Philadelphia7 W.B.
Saunders; 1965.
abnormal population.
3. Hiss RG, Lamb LE, Allen MF. Electrocardiographic findings in 67,375
What is the origin of the differences between our asymptomatic subjects X Normal values. Am J Cardiol 1960;6:200.
reference ranges and those of previous studies? In the case 4. Dmitrienko AA, Sides GD, Winters KJ, et al. Electrocardiogram
of the Lilly study, the fact that all of the ECGs were reference ranges derived from a standardized clinical trial population.
overread on paper copies might have systematically affected Drug J Inf 2005;39:395.
5. Simonson E. Differentiation between normal and abnormal in
interval measurements because of the low resolution
electrocardiography. St. Louis7 Mosby; 1961.
provided by paper. Lamb2 and Simonson5 also used paper. 6. Wagner GS. Marriott’s practical electrocardiography. 10th ed. Phila-
In addition, Lilly’s strategy of excluding a priori ECGs that delphia7 Lippincott, Williams and Wilkins; 2001.
were deemed by the reader to have abnormal numerical 7. Willems JL, Arnaud P, van Bemmel, et al. A reference data base for
values may have partially defeated the objective of multilead electrocardiographic computer measurement programs. J Am
Coll Cardiol 1987;10:1313.
determining the true normative range. Electrocardiograms
8. Murray A, McLaughlin NB, Bourke JP, et al. Errors in manual
are frequently assigned an abnormal overall assessment in measurement of QT intervals. Br Heart J 1994;71:386.
normal, healthy individuals because the meaning of 9. Kligfield P, Hancock EW, Helfenbein ED, et al. Relation of QT interval
bnormalQ to most electrocardiographers is not based upon measurements to evolving automated algorithms from different
valid reference ranges but, rather, upon easily remembered, manufacturers of electrocardiographs. Am J Cardiol 2006;98:88.
10. Darpo B, Agin M, Kazierad DJ, et al. Man versus machine: is there an
generally accepted pseudoreference ranges, such as heart
optimal method for QT measurements in thorough QT studies? J Clin
rate between 60 and 100 beats/min. Pharm 2006;46:598.
Additional plausible explanations for differences between 11. Hiss RG, Lamb LE. Electrocardiographic findings in 122,043
our findings and the others reviewed previously are genetic individuals. Circulation 1962;25:947.
J.W. Mason et al. / Journal of Electrocardiology 40 (2007) 228–234.e8 234.e1
Table 11: Comparison of our 96% interval reference ranges Table 12: Comparison of our distribution of QRS interval
to Macfarlane’s and Lawrie’s1 durations to Lamb’s2
Macfarlane Current QRS Lamb study2 Current study
and Lawrie1 study study (reference (milliseconds) (reference range subset)
range subset) Male Female Male Female
Male Female Male Female N 45-55 0.3 0.8 0.0 0.0
Age 30-39 y N 55-65 5.0 3.8 0.4 0.9
N 218 115 3411 3954 N 65-75 19.9 23.0 3.0 7.0
HR (beats per min) 52-99 57-105 47-95 49-96 N 75-85 47.6 62.9 14.7 26.7
PR (milliseconds) 116-206 114-184 114-201 118-203 N 85-95 19.6 6.8 33.0 37.4
QRS (milliseconds) 78-114 76-106 74-109 69-107 N 95-105 6.7 2.3 34.9 22.7
QTcB (milliseconds) 375-468 395-473 353-443 367-455 N 105-115 0.8 0.4 13.5 5.0
Age 40-49 y N 115 * * 0.5 0.1
N 119 72 4316 6047 *Excluded in Hiss3 study.
HR (beats per min) 49-96 59-106 47-97 50-97
PR (milliseconds) 116-210 108-200 117-206 112-201
QRS (milliseconds) 78-114 74-108 73-109 68-107
QTcB (milliseconds) 377-464 350-483 357-446 371-460
HR indicates heart rate.
J.W. Mason et al. / Journal of Electrocardiology 40 (2007) 228–234.e8 234.e7
4
Table 13: Comparison of our interval reference ranges to Lilly’s
Lilly study4 Lilly study4 Current study
Normal ECG Abnormal ECG Reference range subset
(98% Range) (98% Range) (96% Range)
Male Female Male Female Male Female
Age 36-45 y
N 619* 902* 506* 741* 4118 5509
HR (beats per min) 60 -99 60-98 45-117 45-110 47-96 50-97
PR (milliseconds) 112-236 104-208 112-200 112-192 117-205 112-200
QRS (milliseconds) 69-112 68-104 72-144 68-116 73-109 69-107
QTcL** (milliseconds) 371-446 373-459 358-462 380-479 357-437 370-449
Age 46-55 y
N 686* 917* 563* 753* 4445 5534
HR (beats per min) 60-96 60-96 44-108 46-107 49-98 49-97
PR (milliseconds) 116-228 108-224 112-200 112-196 120-208 114-201
QRS (milliseconds) 72-112 68-100 72-152 64-132 74-109 69-107
QTcL** (milliseconds) 370-452 383-464 381-474 383-492 360-441 370-455
*Approximation estimated from known gender distribution and known normal/abnormal distribution.
**QTcL = Lilly log-linear correction, where QTc = QT/RR0.413.
Table 14: Comparison of our interval reference ranges to automatically by the Veritas computer algorithm (version
Simonson’s5 1.20.23) and once by a cardiologist using digitography, who
did not have access to the Veritas algorithm results. From the
Simonson study5* Current study
total of 28 372 ECGs, heart rate, QRS and QT values were
2.5%-97.5% 2%-98% available from both Veritas and digitography in all cases, and
Age 20-59 y Male Female Male Female PR values were available in 28 234 ECGs.
n 649 311 14 715 17 369 GE 12SL
RR 630-1140 600 -1090 624-1284 623-1213 This analysis is summarized in Table 17. It includes
(milli- 43 906 ECGs of 185 subjects who participated in two
seconds) definitive QT studies. One study involved 4707 ECGs
PR 130-200 120-200 118-207 112-200 obtained in 49 subjects with solid tumors, and the other
(milli- included 39 199 ECGs recorded in 136 normal volunteers.
seconds) Each ECG was read once automatically by the 12 SL
QRS 70-120 60-110 73-109 69-107 computer algorithm (version 5.21) and once by a cardiol-
(milli- ogist using digitography, who did not have access to the 12
seconds) SL algorithm results. From the total of 43 906 ECGs, heart
QT 330-440 320-420 324-444 330-451 rate, QRS and QT values were available from both 12 SL
(milli- and digitography in 43 826 cases, and PR values were
seconds) available in 43 566 ECGs.
*Data expressed to the nearest centisecond.
Fig. 1. Weight, height, and age distributions of all 79 743 subjects (panels A-C) and the reference range subset (panels D-F).