Validation of exhaled volatile organic compounds analysis using electronic nose as index of COPD severity

Figures & data

Table 1 Baseline characteristics of the population (N = 63) and quartiles of 6MWD normalized by squared height (m/m²)

Characteristics	Population, N = 63	22–111 m/m^2, n = 16	112–145 m/m^2, n = 16	146–165 m/m^2, n = 16	166–215 m/m^2, n = 15	P-value
Age	71 (8)	73.9 (6.9)	71.6 (8.6)	70.2 (6.8)	68.2 (8.5)	0.22
Sex (M)	38 (60.3)	12 (75)	11 (69)	9 (56)	6 (40)	0.21
Body mass index (kg/m^2)	28.1 (5.9)	30.2 (7.1)	31.1 (6.3)	25.2 (2.8)	25.8 (4.5)	0.004
mMRC
0–1	43 (68)	6 (37)	13 (81)	12 (75)	12 (80)	0.01
≥2	20 (32)	10 (63)	3 (19)	4 (25)	3 (20)	0.01
Exacerbation/year
0–1	48 (76)	13 (81)	10 (63)	12 (75)	13 (87)	0.46
≥2	15 (24)	3 (19)	6 (37)	4 (25)	2 (13)	0.46
Smoking habit
Current smokers	25 (39.7)	5 (31)	7 (44)	8 (50)	5 (33)	0.6
Former smokers	32 (50.8)	9 (56)	9 (56)	7 (43)	7 (47)	0.6
Pack/year	35.1 (26.6)	41.2 (30)	40.9 (26.7)	26.4 (18)	31.7 (28)	0.32
GOLD classification 2014
GOLD A	35 (55.6)	4 (25)	9 (56)	11 (69)	11 (73)	0.01
GOLD B	9 (14.5)	5 (31)	0 (0)	2 (13)	2 (13)	0.01
GOLD C	8 (12.4)	1 (6)	3 (19)	2 (13)	2 (13)	0.01
GOLD D	11 (17.5)	6 (38)	4 (25)	1 (6)	0 (0)	0.01
BODE index	1 (0–3)	3 (2–5)	1 (0–3)	0 (0–1)	0 (0–1)	<0.001
Spirometry
FEV1/FVC	63.2 (9.6)	61.5 (12.6)	61.5 (9.2)	65 (8.4)	65 (7.3)	0.55
FEV1 (cm^3)	1.7 (0.7)	1.5 (0.6)	1.7 (0.5)	2 (1)	1.8 (0.5)	0.2
FEV1%	69.6 (22.3)	57.9 (22)	64.6 (20.7)	78.6 (27)	77.7 (9.4)	0.02
FVC (cm^3)	2.8 (1)	2.5 (1.1)	2.7 (0.6)	3.1 (1.4)	2.8 (0.9)	0.45
FVC%	86.3 (22.6)	72.4 (21.5)	82.3 (23.1)	94.7 (25.2)	96.3 (9.8)	0.006
TLC (cm^3)	5.9 (1.6)	5.9 (1.5)	5.8 (1.2)	6.6 (2.1)	5.3 (1.4)	0.17
TLC%	100.9 (24.7)	97.2 (40.7)	92.4 (13.7)	114.1 (15)	100.2 (17)	0.1
RV/TLC (cm^3)	52.5 (11.5)	57.5 (10.9)	49.4 (15.4)	52 (9.5)	51.5 (8.5)	0.29
RV/TLC%	126.5 (26.5)	132.4 (29.8)	124.7 (31)	125.4 (22)	123.9 (23)	0.84
Arterial gas analysis
pH	7.41 (0.03)	7.41 (0.02)	7.42 (0.03)	7.42 (0.03)	7.42 (0.04)	0.13
pO2 (mmHg)	77.6 (10.7)	74.4 (11.4)	74.5 (9.9)	77.8 (11)	84 (8.5)	0.04
pCO2 (mmHg)	39.3 (5)	41 (6.3)	40.2 (3)	39.2 (5.5)	36.5 (4)	0.08
SO2	95.1 (1.7)	94.5 (1.7)	94.7 (1.7)	95.2 (1.8)	96.1 (0.9)	0.04
Multidimensional assessment
CIRS comorbidity index	0 (0–1)	0 (0–1)	1 (0–2)	0 (0–1)	0 (0–1)	0.2
CIRS severity index	0.7 (0.4)	0.7 (0.4)	0.8 (0.3)	0.5 (0.2)	0.7 (0.4)	0.16
MMSE	27.9 (2.9)	27.5 (2.4)	28.9 (1.7)	27.4 (3.5)	27.7 (3.7)	0.4
Clock test	11 (2.8)	11.2 (2.8)	11.2 (2)	10.8 (3.5)	10.9 (2.9)	0.95
ADL	5.8 (0.5)	5.8 (0.4)	5.6 (0.8)	5.9 (0.2)	5.8 (0.4)	0.4
IADL	7.7 (1)	7.4 (1.5)	7.6 (1)	7.9 (0.5)	7.9 (0.3)	0.34
GDS	1.8 (2.7)	2 (3.6)	2.6 (3.2)	1 (1.7)	1.7 (1.6)	0.4
Blood analysis
WBC count (×10^3/µL)	7.1 (1.7)	7.5 (1.5)	6.8 (1.7)	6.9 (1.9)	7 (1.5)	0.68
Hb (g/dL)	14.2 (1.4)	13.9 (1.9)	14.4 (1.4)	14.3 (1)	14.3 (1.5)	0.81
ESR (mm/h)	25.9 (23.7)	35.6 (36.1)	22.8 (15.9)	20.9 (18.7)	25.9 (20.9)	0.42
CRP (mg/L)	3.2 (5.1)	3.7 (4)	1.4 (2.4)	4.9 (7.9)	2.3 (3.2)	0.32
Creatinine (mg/dL)	1 (0.3)	1.1 (0.3)	0.9 (0.3)	0.8 (0.2)	0.9 (0.3)	0.06
eGFR(CKD-EPI)	74.2 (19.5)	64.2 (18)	76.3 (21)	80.6 (18.3)	74.4 (18.9)	0.15
Vitamin D (ng/mL)	20.9 (10.6)	23.9 (12.3)	20.5 (8.1)	18.8 (7.8)	20.5 (14)	0.67
Vitamin B12 (pg/mL)	368.1 (204.7)	338.8 (122.2)	272.5 (122)	449.1 (304)	383.7 (150)	0.2
Folic acid (ng/mL)	7.5 (7.2)	5.5 (3.1)	5.7 (2.5)	9.9 (11.1)	8.3 (6.7)	0.38
Bioimpedance analysis
Total body water %	52.1 (6)	51.4 (6.7)	50.9 (5.4)	54.5 (6.4)	51.7 (5.3)	0.31
Fat mass %	30.1 (8.4)	32.1 (9.3)	32.9 (6.4)	25.8 (8.8)	29.7 (7.3)	0.07
Fat-free mass %	69.9 (8.4)	67.9 (9.3)	67.1 (6.4)	74.2 (8.8)	70.3 (7.3)	0.06

Note: Continuous variables are shown as mean (standard deviation) or median (interquartile range), as appropriate, while categorical variables are shown as n (%).

Abbreviations: 6MWD, 6-minute walking test distance; ADL, activities of daily living; BODE, body mass index, obstruction, dyspnea and exercise; CIRS, Cumulative Illness Rating Scale; CRP, C-reactive protein; eGFR(CKD-EPI), estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration); ESR, erythrocyte sedimentation rate; FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; GDS, Geriatric Depression Scale; GOLD, Global Initiative for Chronic Obstructive Lung Disease; Hb, hemoglobin; IADL, instrumental activities of daily living; mMRC, modified Medical Research Council; MMSE, mini-mental state examination; RV, residual volume; TLC, total leukocyte count; WBC, white blood cell.

Table 2 Cross-validated partial least square discriminant analysis prediction of quartiles of n6MWD (upper) and classes of BODE (bottom)

Prediction n6MWD	Reference n6MWD
	22–111 m/m^2	112–145 m/m^2	146–165 m/m^2	166–215 m/m^2
22–111	15	0	1	1
112–145	0	13	1	3
146–165	0	2	12	1
>165	1	1	2	10
Accuracy: 0.79 (95% CI 0.67–0.88, P < 0.001). Cohen’s kappa: 0.72 (95% CI 0.59–0.85, P < 0.001)
Prediction BODE classes	Reference BODE classes
	Good prognosis (BODE < 3)	Poor prognosis (BODE ≥ 3)
Good prognosis	39	6
Poor prognosis	3	15
Accuracy: 0.86 (95% CI 0.75–0.93, P < 0.001). Sensitivity: 0.71; specificity: 0.93. Cohen’s kappa: 0.67 (95% CI 0.47–0.87, P < 0.001)

Abbreviations: n6MWD, 6-minute walking test distance normalized by squared height; BODE, body mass index, obstruction, dyspnea, and exercise.

Table 3 Confusion matrix with the distribution per GOLD classes of the n6MWD (top) and classes of BODE (bottom)

GOLD classes	Reference n6MWD
	22–111 m/m^2	112–145 m/m^2	146–165 m/m^2	166–215 m/m^2
A	4	9	11	11
B	5	0	2	2
C	1	3	2	2
D	6	4	1	0
Accuracy: 0.35 (95% CI 0.23–0.48, P = 0.05). Cohen’s kappa: 0.14 (95% CI −0.02 to 0.29, P = 0.03)
GOLD classes	Reference BODE classes
	Good prognosis (BODE < 3)	Poor prognosis (BODE ≥ 3)
A	34	1
B	3	6
C	4	4
D	1	10

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; n6MWD, 6-minute walking test distance normalized by squared height; BODE, body mass index, obstruction, dyspnea, and exercise.

Table 4 Cross-validated partial least squares discriminant analysis prediction of the n6MWD variation classes over the year of followup based only on BIONOTE (top), only on GOLD classification (center) and on BIONOTE + GOLD classification (bottom)

BIONOTE-based prediction of Δn6MWD classes	Reference Δn6MWD classes
	Worsened	Stable/improved
Worsened	28	5
Stable/improved	4	26
Accuracy: 0.86 (95% CI 0.75–0.93, P < 0.001). Sensitivity: 0.84; specificity: 0.88. Cohen’s kappa: 0.71 (95% CI 0.54–0.88, P < 0.001)
GOLD-based prediction of Δn6MWD classes	Reference Δn6MWD classes
	Worsened	Stable/improved
Worsened	15	13
Stable/improved	17	18
Accuracy: 0.52 (95% CI 0.39–0.65, P = 0.45). Sensitivity: 0.58; specificity: 0.47. Cohen’s kappa: 0.05 (95% CI –0.20 to 0.29, P = 0.35)
BIONOTE + GOLD-based prediction of Δn6MWD classes	Reference Δn6MWD classes
	Worsened	Stable/improved
Worsened	25	6
Stable/improved	7	25
Accuracy: 0.79 (95% CI 0.67–0.88, P < 0.001). Sensitivity: 0.81; specificity: 0.78. Cohen’s kappa: 0.59 (95% CI 0.39 to 0.79, P < 0.001)

Abbreviations: n6MWD, 6-minute walking test distance normalized by squared height; GOLD, Global Initiative for Chronic Obstructive Lung Disease.