Development and validation of a machine learning model for diagnosis of ischemic heart disease using single-lead electrocardiogram parameters

Table 1 Related mean sample power analysis

	n2	Actual power3	Test assumptions
			Power	Effect size	P value
Test for mean difference1	54	0.950	0.95	0.5	0.05

¹Two-sided test.

²Number of pairs.

³Based on noncentral t-distribution. The minimum required sample size was 54 participants.

Table 2 Related Pearson correlation power analysis

	n	Actual power2	Test assumptions
			Power	Null	Alternative	P value
Pearson correlation1	46	0.954	0.95	0	0.5	0.05

¹Two-sided test.

²Based on Fisher's z-transformation and normal approximation with bias adjustment. The minimum required sample size was 54 participants.

Table 3 Study participants selection criteria

Inclusion criteria	Non-inclusion criteria1	Exclusion criteria2
Participants age ≥ 40 years	Pregnancy and breastfeeding	Failure of the stress test for reasons unrelated to heart disease
Participants with intact mental and physical activity	Diabetes mellitus	Reluctance to continue participating in the study
Written consent to participate in the study, take blood samples, and anonymously publish the results of the study	Presence of signs of acute coronary syndrome (myocardial infarction in the prior 2 days), history of myocardial infarction
Participants in the experimental group are individuals with coronary artery disease, confirmed by stress-induced myocardial perfusion defect on the adenosine triphosphate stress myocardial perfusion computed tomography	Active infectious and non-infectious inflammatory diseases in the exacerbation phase
	Respiratory diseases (bronchial asthma, chronic bronchitis, cystic fibrosis)
	Acute thromboembolism of pulmonary artery branches
	Aortic dissection
	Critical anatomical heart defects
	Active oncopathology
	Decompensation phase of acute heart failure
	Neurological pathology (Parkinson’s disease, multiple sclerosis, acute psychosis, Guillain-Barré syndrome)
	Cardiac arrhythmias that do not allow exercise ECG testing (Wolff-Parkinson-White syndrome, Sick sinus syndrome, AV block of II-III-degree, persistent ventricular tachycardia)
	Diseases of the musculoskeletal system that prevent passing a stress test (bicycle ergometry)
	Allergic reaction to iodine and/or adenosine triphosphate

¹From the beginning of the study we did not include such patients in the study.

²After the end of the study we excluded these patients because of some reasons that related to these criteria we stated.

ECG: Electrocardiography; AV: Atrioventicular.

Table 4 Features of the continuous variables of the sample represented in the table

Variable	Mean (Min; Max)	SD
Age (year)	56.28 (40.24; 77.94)	10.601
Pulse rest (beat/minute)	70.29 (49.00; 93.00)	9.559
SBP rest (mmHg)	123.16 (54.00; 159.00)	15.437
DBP rest (mmHg)	80.61 (60.00; 122.00)	11.238
Body weight (kg)	77.92 (52.50; 140.00)	16.236
Height (cm)	169.95 (148.00; 190.00)	8.835
BMI (kg/m2)	26.93 (18.49; 48.44)	4.901
Pulse rest (beat/minute)	69.68 (49.00; 99.00)	9.260
Pulse after stress (beat/minute)	86.89 (63.00; 115.00)	10.579
Goal heart rate (beat/minute)	163.72 (142.06; 179.76)	10.601
Max HR	146.25 (108.00; 199.00)	14.111
Reached %	89.53 (64.89; 135.25)	9.166
WT	125.63 (75.00; 250.00)	44.111
METs	6.67 (2.90; 11.90)	1.977
EF (%)	85.28 (60.50; 104.50)	8.358
Vessel age (years)	56.50 (20.00; 80.00)	13.520
R-CAVI	8.21 (4.80; 15.10)	1.379
L-CAVI	8.18 (4.80; 14.90)	1.299
Mean CAVI	8,194 (4,800; 15,000)	1,331
RABI	1.15 (0.86; 1.40)	0.088
LABI	1.15 (0.89; 1.42)	0.084
Mean SBP B (mmHg)	134.38 (105.50; 169.00)	13.086
Mean DBP B (mmHg)	85.28 (60.50; 104.50)	8.358
BP RB [(SBP + DBP)/2] (mmHg)	103.98 (75.00; 137.00)	11.547
BP LB [(SBP + DBP)/2] (mmHg)	104.54 (71.00; 136.00)	10.534
Mean BP B (mmHg)	104.26 (73.00; 136.50)	10.772
BP RA [(SBP + DBP)/2] (mmHg)	108.39 (80.00; 137.00)	12.553
BP LA [(SBP + DBP)/2] (mmHg)	108.63 (81.00; 138.00)	11.519
Mean BP A (mmHg)	108.51 (81.50; 135.00)	11.468
Mean ABI	1.15 (0.88; 1.41)	0.081
RTb	80.53 (59.00; 152.00)	13.441
LTb	77.26 (58.00; 128.00)	14.012
Mean Tb	78.89 (59.00; 132.50)	12.547
Right Tba	86.26 (23.00; 117.00)	16.232
Left Tba	86.40 (24.00; 114.00)	14.685
Mean Tba	86.33 (23.50; 115.00)	15.358
Lha (cm)	148.17 (130.33; 164.47)	7.182
haPWV (m/s)	0.91 (0.67; 1.42)	0.124
β-stiffness index from PWV	2.83 (1.21; 7.04)	0.813
Creatinine (µmol/L)	82.74 (53.90; 138.00)	16.014
eGFR (2021 CKD-EPI creatinine)	85.31 (45.40; 113.70)	14.684

SBP: Systolic blood pressure; DBP: Diastolic blood pressure; BMI: Body mass index; HR: Heart rate; WT: Watt; METs: Metabolic equivalent; EF: Echocardiographic ejection fraction; R-CAVI: Right cardio-ankle vascular index; L-CAVI: Left cardio-ankle vascular index; CAVI: Cardio-ankle vascular index; RABI: Right ankle-brachial index; LABI: Left ankle-brachial index; SBP B: Systolic blood pressure brachial; DBP B: Diastolic blood pressure brachial; BP RB: Blood pressure right brachial; BP LB: Blood pressure left brachial; BP B: Blood pressure brachial; BP RA: Blood pressure right ankle; BP LA: Blood pressure left ankle; BP A: Blood pressure ankle; ABI: Ankle-brachial index; RTb: Right brachial pulse; LTb: Left brachial pulse; Tb: Mean brachial pulse; Tba: Mean brachial-ankle pulse; Lha: Length heart-ankle; haPWV: Heart-ankle pulse wave velocity; PWV: Pulse wave velocity; eGFR: Estimated glomerular filtration rate; SD: Standard deviation.

Table 5 Features of the categorical variables of the participants

Index	Factor	Absolute value, relative value
Gender	F	39 (48.75)
	M	41 (51.25)
Obesity stage	Normal	30 (37.500)
	Overweight	29 (36.25)
	1 degree	20 (25.00)
	3 degree	1 (1.25)
Smoking	Yes	14 (17.50)
	No	66 (82.50)
Concomitant diseases	Yes	41 (51.25)
	No	35 (43.75)
	Missing data	4 (5.00)
Atherosclerosis of the coronary artery	Yes	31 (38.75)
	No	49 (61.25)
Hemodynamically significant coronary artery atherosclerosis on the CTP (> 60% stenosis)	Yes	9 (11.25)
	No	71 (88.75)
Stress-induced myocardial perfusion defect on the CTP	Yes	31 (38.75)
	No	49 (61.25)
Myocardial perfusion defect before stress ATP on the CTP	Yes	26 (32.50)
	No	54 (67.50)
Atherosclerosis in other arteries	Yes	41 (51.25)
	No	32 (40.00)
	Missing data	7 (8.75)
Atherosclerotic vascular (namely)	Carotid	1 (1.25)
	Carotid brachiocephalic bifurcation	41 (51.25)
	Missing data	38 (47.50)
Carotid artery atherosclerosis	Yes	39 (48.75)
	No	34 (42.50)
	Missing data	7 (8.750)
Brachiocephalic artery atherosclerosis	Yes	37 (46.25)
	No	36 (45.00)
	Missing data	7 (8.75)
Arterial hypertension	Yes	40 (50.00)
	No	40 (50.00)
Stage of the arterial hypertension	I	5 (6.25)
	II	20 (25.00)
	III	16 (20.00)
Degree of hypertension	Degree 1	19 (23.75)
	Degree 2	13 (16.25)
	Degree 3	9 (11.25)
Risk of cardiovascular disease	Low	27 (33.75)
	Moderate	27 (33.75)
	High	18 (22.50)
	Very high	8 (10.00)
SCAD from anamnesis	Yes	3 (3.75)
	No	29 (36.25)
	Missing data	48 (60.00)
Blood pressure reaction type on stress test	Asthenic	4 (5.00)
	Hypotonic	4 (5.00)
	Hypertonic	8 (10.00)
	Normotonic	64 (80.00)
Functional class by Watt	FC-I	8 (10.00)
	FC-II	9 (11.25)
	No SCAD	63 (78.75)
Functional class by METs	FC-I	6 (7.50)
	FC-II	10 (12.50)
	FC-III	1 (1.25)
	No SCAD	63 (78.75)
Reaction type to stress test (positive/negative)	Negative	42 (52.50)
	Suspected	21 (22.5)
	Positive	17 (21.25)
Reason for discontinuation of the stress test	Horizontal ST depression > 1 mm	8 (10)
	Reach goal HR	72 (90)
Tolerance to exertion on stress test	Low	2 (2.50)
	Moderate	43 (53.75)
	Close to high	8 (10.00)
	High	16 (20.00)
	Very high	11 (13.75)
CAVI degree	Normal (< 8)	36 (45.00)
	Borderline (8-9)	22 (27.50)
	Pathological (> 9)	22 (27.50)
ABI degree	Normal	76 (95.00)
	Borderline	2 (2.50)
	Abnormal	1 (1.25)
	Noncompressible	1 (1.25)
Biological estimated vascular age	Normal	45 (56.25)
	High	35 (43.75)
CKD stage	I	35 (43.75)
	II	41 (51.25)
	IIIa	4 (5.00)

Data were presented as n (%). F: Female; M: Male; CTP: Computed tomography myocardial perfusion; SCAD: Stable coronary artery disease; FC: Functional classification of angina; METs: Metabolic equivalent; CAVI: Cardio-ankle vascular index; ABI: Ankle-brachial index; HR: Heart rate; CKD: Chronic kidney disease.

Table 6 Categorical variables

Index	Factor	Group 1 positive myocardial perfusion on the CTP (n = 31)	Group 2 negative myocardial perfusion on the CTP (n = 49)	P value
Gender	F	17 (54.83)	22 (44.89)	0.387
	M	14 (45.16)	27 (55.10)
Obesity stage	Normal	12 (38.70)	18 (36.73)	0.988363
	Overweight	11 (35.48)	18 (36.73)
	1 degree	8 (25.80)	12 (24.48)
	3 degree	0 (0.00)	1 (2.04)
Smoking	Yes	7 (22.58)	7 (14.28)	0.342
	No	24 (77.41)	42 (85.71)
Concomitant diseases	Yes	15 (48.38)	26 (53.06)	0.835
	No	12 (38.70)	23 (46.93)
	Missing data	4 (12.90)	0 (0.00)
Atherosclerosis of the coronary artery	Yes	16 (51.61)	15 (30.61)	0.061
	No	15 (48.38)	34 (69.38)
Hemodynamically significant coronary artery atherosclerosis on the CTP (> 60% stenosis)	Yes	8 (25.80)	1 (2.04)	0.0021
	No	23 (74.19)	48 (97.95)
Stress induced myocardial perfusion defect on the CTP	Yes	31 (100.00)	0 (0.00)	< 0.0011
	No	0 (0.00)	49 (100.00)
Myocardial perfusion defect before stress ATP on the CTP	Yes	21 (67.74)	5 (10.20408)	< 0.0011
	No	10 (32.25)	44 (89.79)
Atherosclerosis in other arteries	Yes	22 (70.96)	19 (38.77)	0.0061
	No	7 (22.58)	25 (51.020)
	Missing data	2 (6.45)	5 (10.20)
Atherosclerotic vascular (namely)	Carotid	1 (3.22)	0 (0.00)	0.347
	Carotid. brachiocephalic bifurcation	21 (67.74)	19 (38.77)
	Missing data	9 (29.03)	30 (61.22)
Carotid artery atherosclerosis	Yes	20 (64.51)	19 (38.77)	0.0151
	No	8 (25.80)	26 (53.06)
	Missing data	3 (9.67)	4 (8.16)
Brachiocephalic artery atherosclerosis	Yes	18 (58.06)	19 (38.77)	0.067
	No	10 (32.25)	26 (53.06)
	Missing data	3 (9.67)	4 (8.16)
Arterial hypertension	Yes	19 (61.29)	21 (42.85)	0.109
	No	12 (38.70)	28 (57.142)
Stage of arterial hypertension	I	4 (13.55)	1 (2.04)	0.079756
	II	6 (19.35)	14 (28.57)
	III	9 (29.03)	7 (14.28)
Degree of hypertension	Degree 1	10 (32.25)	9 (18.36)	0.098908
	Degree 2	3 (9.67)	10 (20.40)
	Degree 3	6 (19.35)	3 (6.12)
Risk of cardiovascular disease	Low	10 (32.25)	19 (38.77)	0.449429
	Moderate	8 (25.80)	16 (34.70)
	High	8 (25.80)	10 (20.40)
	Very high	5 (16.12)	3 (6.12)
SCAD from anamnesis	Yes	4 (12.90)	1 (2.04)	< 0.0011
	No	2 (6.45)	25 (51.02)
	Missing data	25 (80.64)	23 (46.93)
Blood pressure reaction type on stress test	Asthenic	2 (10.50)	2 (4.08)	0.072076
	Hypotonic	3 (15.80)	1 (2.04)
	Hypertonic	1 (5.30)	4 (8.16)
	Mild hypertonic	1 (5.30)	0 (0.00)
	Normotonic	12 (63.20)	42 (85.71)
Functional class by Watt	FC-I	1 (3.22)	7 (14.28)	0.313
	FC-II	3 (9.67)	6 (12.24)
	No SCAD	27 (87.09)	36 (73.46)
Functional class by METs	FC-I	1 (3.22)	5 (10.20)	0.5568
	FC-II	3 (9.67)	7 (14.28)
	FC-III	0 (0.00)	1 (2.04)
	No SCAD	27 (87.09)	36 (73.46)
Reaction type to stress test (positive/negative)	Negative	16 (51.61)	26 (53.06)	0.191007
	Suspected	11 (35.45)	10 (20.40)
	Positive	4 (12.90)	13 (26.53)
Reason for discontinuation of the stress test	Horizontal ST depression > 1 mm	2 (6.45)	6 (12.24)	0.385
	Reach goal HR	29 (93.54)	42 (88.11)
Tolerance to exertion on stress test	Low	1 (3.22)	1 (2.04)	0.416079
	Moderate	20 (64.45)	23 (46.93)
	Close to high	3 (9.67)	5 (10.20)
	High	3 (9.67)	13 (26.53)
	Very high	4 (12.90)	7 (14.28)
CAVI degree	Normal (< 8)	9 (29.03)	27 (55.10)	0.073757
	Borderline (8-9)	11 (35.48)	11 (22.44)
	Pathological (> 9)	11 (35.48)	11 (22.44)
ABI degree	Normal	29 (93.54)	47 (95.91)	0.89381
	Borderline	1 (3.22)	1 (2.04)
	Abnormal	1 (3.22)	1 (2.04)
Biological estimated vascular age	Normal	16 (51.61)	29 (59.18)	0.507
	High	15 (48.38)	20 (40.81)
CKD stage	I	12 (38.70)	23 (46.93)	0.285103
	II	16 (51.61)	25 (51.02)
	IIIa	3 (9.67)	1 (2.04)

¹Values of statically significant differences.

Data were presented as n (%). The χ² test was used for the analysis of categorical variables. F: Female; M: Male; CTP: Computed tomography myocardial perfusion; SCAD: Stable coronary artery disease; FC: Functional classification of angina; METs: Metabolic equivalent; CAVI: Cardio-ankle vascular index; ABI: Ankle-brachial index; CKD: Chronic kidney disease.

Table 7 Continuous variables

Variable	Mean		t value	P value
	Yes	No
Age (years)	59.930 ± 11.708	53.967 ± 9.231	2.533	0.0131
Pulse rest (beat/minute)	70.225 ± 10.744	70.326 ± 8.844	-0.045	0.963
SBP rest (mmHg)	124.483 ± 20.563	122.326 ± 11.227	0.606	0.545
DBP rest (mmHg)	82.354 ± 13.164	79.5102 ± 9.815	1.104	0.272
Body weight (kg)	77.129 ± 14.716	78.420 ± 17.257	-0.344	0.731
Height (cm)	169.806 ± 9.414	170.040 ± 8.546	-0.114	0.908
BMI (kg/m2)	26.707 ± 4.231	27.065 ± 5.318	-0.316	0.752
Pulse rest (beat/min)	69.645 ± 11.51	69.693 ± 7.632	-0.022	0.981
Pulse after stress (beat/min)	85.741 ± 11.888	87.612 ± 9.720	-0.768	0.444
Goal heart rate (beat/min)	160.069 ± 11.708	166.032 ± 9.231	-2.533	0.0131
Max HR (beat/min)	142.677 ± 17.666	148.510 ± 10.918	-1.827	0.071
Reached %	89.423 ± 12.094	89.602 ± 6.844	-0.084	0.933
WT	120.967 ± 47.035	128.571 ± 42.389	-0.749	0.456
METs	6.329 ± 2.035	6.887 ± 1.929	-1.235	0.220
EF (%)	64.478 ± 4.775	64.547 ± 4.220	-0.060	0.951
eVessel age (years)	61.225 ± 12.422	53.510 ± 13.447	2.573	0.0111
R-CAVI	8.580 ± 1.039	7.971 ± 1.518	1.959	0.053
L-CAVI	8.438 ± 0.938	8.018 ± 1.469	1.418	0.160
Mean CAVI	8.509 ± 0.975	7.994 ± 1.489	1,7045	0,092
RABI	1.123 ± 0.100	1.162 ± 0.076	-1.990	0.0491
LABI	1.129 ± 0.087	1.158 ± 0.080	-1.505	0.136
Mean SBP B (mmHg)	137.983 ± 15.433	132.091 ± 10.919	1.998	0.049
Mean DBP B (mmHg)	86.919 ± 8.768	84.234 ± 8.003	1.408	0.162
BP RB [(SBP + DBP)/2] (mmHg)	106.419 ± 12.852	102.428 ± 10.484	1.518	0.132
BP LB [(SBP + DBP)/2] (mmHg)	107.096 ± 11.510	102.918 ± 9.638	1.750	0.083
Mean BP B (mmHg)	106.758 ± 11.940	102.6735 ± 9.75990	1.671	0.098
BP RA [(SBP + DBP)/2] (mmHg)	110.645 ± 13.093	106.959 ± 12.117	1.284	0.202
BP LA [(SBP + DBP)/2] (mmHg)	111.290 ± 12.770	106.938 ± 10.439	1.664	0.100
Mean BP A (mmHg)	110.967 ± 12.371	106.949 ± 10.695	1.540	0.127
Mean ABI	1.126 ± 0.090	1.160 ± 0.072	-1.857	0.066
RTb	77.258 ± 10.237	82.591 ± 14.851	-1.751	0.083
LTb	74.161 ± 12.881	79.224 ± 14.467	-1.589	0.115
Mean Tb	75.709 ± 10.650	80.908 ± 13.323	-1.832	0.070
Right Tba	81.193 ± 16.279	89.469 ± 15.520	-2.279	0.0251
Left Tba	83.000 ± 14.730	88.551 ± 14.390	-1.665	0.099
Mean Tba	82.096 ± 15.384	89.010 ± 14.878	-1.998	0.0491
Lha (cm)	148.057 ± 7.652	148.247 ± 6.947	-0.114	0.908
haPWV (m/s)	0.953 ± 0.118	0.886 ± 0.120	2.445	0.0161
β-stiffness index from PWV	2.953 ± 0.659	2.756 ± 0.895	1.056	0.293
Creatinine (µmol/L)	80.378 ± 15.447	84.233 ± 16.341	-1.049	0.297
eGFR (2021 CKD-EPI creatinine)	84.854 ± 15.146	85.589 ± 14.535	-0.216	0.828

¹Values of statically significant differences.

Data presented as mean ± SD. t-tests grouping: Myocardial perfusion defect after stress ATP. Group 1 (n = 31): Positive CT myocardial perfusion; Group 2 (n = 49): Negative CT myocardial perfusion. SBP: Systolic blood pressure; DBP: Diastolic blood pressure; BMI: Body mass index; HR: Heart rate; WT: Watt; METs: Metabolic equivalent; EF: Echocardiographic ejection fraction; R-CAVI: Right cardio-ankle vascular index; L-CAVI: Left cardio-ankle vascular index; CAVI: Cardio-ankle vascular index; RABI: Right ankle-brachial index; LABI: Left ankle-brachial index; SBP B: Systolic blood pressure brachial; DBP B: Diastolic blood pressure brachial; BP RB: Blood pressure right brachial; BP LB: Blood pressure left brachial; BP B: Blood pressure brachial; BP RA: Blood pressure right ankle; BP LA: Blood pressure left ankle; BP A: Blood pressure ankle; ABI: Ankle-brachial index; RTb: Right brachial pulse; LTb: Left brachial pulse; Tb: Mean brachial pulse; Tba: Mean brachial-ankle pulse; Lha: Length heart-ankle; haPWV: Heart-ankle pulse wave velocity; PWV: Pulse wave velocity; eGFR: Estimated glomerular filtration rate.

Table 8 Bicycle ergometry

Chars	Point estimate	95%CI
AUC	0.507	0.388-0.625
Sensitivity	0.484	0.306-0.657
Specificity	0.531	0.392-0.673
Negative predictive value	0.619	0.465-0.758
Positive predictive value	0.395	0.238-0.553

AUC: Area under the receiver operating characteristic curve; CI: Confidence interval.

Table 9 Ten most statically significant features

	Feature	LASSO absolute coefficient
1	q0_QTc	0.0221996
2	q0_Beta	0.0211857
3	q0_J80A	0.0179913
4	q0_Pan…30	0.0168176
5	q0_SA	0.013914
6	dltq_01_SA	0.0126805
7	dltq_01_Sbeta	0.0125996
8	q0_TA	0.0124491
9	dltq_01_RA	0.0116579
10	q0_Sbeta	0.0111864

Dltq_01 indicates the difference between the selected single-lead electrocardiography features immediately after the stress test (bicycle ergometry) minus the selected features before the stress test.

Table 10 Single-lead electrocardiography (Cardio-Qvark) in the diagnosis of ischemic heart disease

Chars	Point estimate	95%CI
AUC	0.670	0.531-0.802
Sensitivity	0.516	0.333-0.695
Specificity	0.755	0.628-0.88
Negative predictive value	0.712	0.586-0.83
Positive predictive value	0.571	0.387-0.758

AUC: Area under the receiver operating characteristic curve; CI: Confidence interval.