Development and validation of a predictive model combining patient-reported outcome measures, spirometry and exhaled nitric oxide fraction for asthma diagnosis

Gilles Louis; Florence Schleich; Michèle Guillaume; Delphine Kirkove; Halehsadat Nekoee Zahrei; Anne-Françoise Donneau; Monique Henket; Virginie Paulus; Françoise Guissard; Renaud Louis; Benoit Pétré

doi:10.1183/23120541.00451-2022

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FIGURE 1
Asthma symptom intensity scales between asthmatic (A: n=105) and nonasthmatic (NA: n=61) subjects in the training cohort (n=166).
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FIGURE 2
Receiver operating characteristic curves showing the performance of the predictive models (Models 1–8 in table 5) in the a) training and b) validation cohorts. AUC: area under the curve.

TABLE 1

Patient demographic, functional and inflammatory characteristics in the training and validation cohorts

	Training cohort (n=166)	Validation cohort (n=137)
Asthmatic subjects	63 (105)	58 (80)
Age (years)	51±16	51±15
Male	43 (71)	36 (50)
BMI (kg·m⁻²)	27±4.8	26±4.9
Smoking status
Nonsmoker	52 (87)	51 (70)
Ex-smoker	25 (42)	31 (42)
Current smoker	23 (37)	18 (25)
Atopy	47 (78)	42 (58)
FEV₁ (% pred)	92±17	94±17
FEV₁/FVC (%)	79±8.3	79±7.9
F_ENO (ppb)	21 (14–34)	19 (13–29)
Sputum eosinophils (%)^#	1 (0–3)	1 (0.2–2.5)
Blood eosinophils (%)	2.5 (1.3–4.2)	2.1 (1.2–3.1)
Blood eosinophils (μL⁻¹)	170 (98–290)	160 (81–250)
Total serum IgE (kU·L⁻¹)	60 (22–252)	78 (27–158)

Data are presented as % (n), mean±sd or median (interquartile range). BMI: body mass index; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; F_ENO: exhaled nitric oxide fraction. ^#: n=95 in the training cohort and n=94 in the validation cohort.

TABLE 2

Comparison between asthmatic and nonasthmatic subject demographic, functional and inflammatory characteristics in the training cohort (n=166)

	Asthmatic subjects (n=105)	Nonasthmatic subjects (n=61)
Age (years)	52±16	48±17
Male	40 (42)	47 (29)
BMI (kg·m⁻²)	27±4.3	27±5.5
Smoking status
Nonsmoker	48 (51)	59 (36)
Ex-smoker	28 (29)	21 (13)
Current smoker	24 (25)	20 (12)
Atopy	48 (50)	44 (28)
FEV₁ (% pred)	86±18	98±16****
FEV₁ <80% pred	27 (28)	11 (7)
FEV₁/FVC (%)	76±9	82±6.7****
FEV₁/FVC <75%	43 (46)	16 (10)
F_ENO (ppb)	22 (15–37)	19 (13–27.5)*
F_ENO >25 ppb	40 (42)	36 (22)
Sputum eosinophils (%)^#	1 (0–5)	0.8 (0.05–2.65)
Blood eosinophils (%)	2.7 (1.45–4.5)	2.1 (1.3–3.2)
Blood eosinophils (μL⁻¹)	190 (110–320)	140 (98–260)
Blood eosinophils >300 μL⁻¹	26 (27)	18 (11)
Total serum IgE (kU·L⁻¹)	80 (27.5–272)	42 (17–148)
Wheezing intensity score	1.48±1.1	0.84±1.1***
Dyspnoea intensity score	2.09±1.1	1.87±1.1
Cough intensity score	1.63±1	1.52±1.1
Airway secretion intensity score	1.28±1	1.08±1.1
Chest tightness intensity score	1.57±1.2	1.52±1

Data are presented as % (n), mean±sd or median (interquartile range). BMI: body mass index; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; F_ENO: exhaled nitric oxide fraction. ^#: n=57 asthmatic subjects and n=38 nonasthmatic subjects. *: p<0.05; ***: p<0.001; ****: p<0.0001.

TABLE 3

Performance of each symptom intensity scale, spirometric indices and exhaled nitric oxide fraction (F_ENO) to diagnose asthma in the training cohort (n=166)

	Threshold	AUC (95% CI)	Sensitivity (%)	Specificity (%)	p-value AUC
Wheezing intensity score	0.5	0.67 (0.59–0.76)	78 (69–86)	54 (41–67)	0.0002
Dyspnoea intensity score	2.5	0.56 (0.46–0.64)	38 (29–48)	69 (56–80)	0.2485
Cough intensity score	0.5	0.53 (0.44–0.62)	88 (80–93)	20 (11–32)	0.5410
Airway secretion intensity score	0.5	0.56 (0.47–0.65)	75 (66–83)	34 (23–48)	0.1847
Chest tightness intensity score	2.5	0.51 (0.42–0.60)	28 (19–37)	77 (65–87)	0.8762
FEV₁ (% pred)	96	0.68 (0.60–0.77)	71 (62–80)	59 (46–71)	<0.0001
FEV₁/FVC (%)	78	0.69 (0.61–0.77)	54 (44–64)	79 (66–88)	<0.0001
F_ENO (ppb)	33	0.56 (0.47–0.66)	32 (23–43)	83 (71–92)	0.1839

FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity. Bold indicates statistical significance.

TABLE 4

Univariate logistic regression on the training cohort (n=166)

	OR (95% CI)
Wheezing intensity score	1.72 (1.26–2.40)***
Dyspnoea intensity score	1.20 (0.89–1.62)
Cough intensity score	1.10 (0.81–1.49)
Airway secretion intensity score	1.21 (0.89–1.66)
Chest tightness intensity score	1.03 (0.79–1.35)
FEV₁ (% pred)	0.95 (0.93–0.97)****
FEV₁/FVC (%)	0.90 (0.86–0.95)****
F_ENO (ppb)	1.02 (1.002–1.04)*

FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; F_ENO: exhaled nitric oxide fraction. *: p<0.05; ***: p<0.001; ****: p<0.0001.

TABLE 5

Multivariate logistic regression on the training cohort (n=166)

		OR (95% CI)
Model 1	Wheezing	1.72 (1.26–2.40)**
Model 2	Wheezing	1.59 (1.16–2.22)**
	FEV₁ (%)	0.96 (0.93–0.98)**
Model 3	Wheezing	1.61 (1.17–2.27)**
	FEV₁/FVC (%)	0.91 (0.86–0.96)**
Model 4	Wheezing	1.62 (1.19–2.25)**
	F_ENO	1.02 (0.99–1.04)
Model 5	Wheezing	1.57 (1.14–2.19)**
	FEV₁ (% pred)	0.97 (0.94–0.99)*
	FEV₁/FVC (%)	0.94 (0.88–0.99)*
Model 6	Wheezing	1.53 (1.11–2.18)*
	FEV₁ (% pred)	0.95 (0.93–0.98)***
	F_ENO	1.02 (1.00–1.05)*
Model 7	Wheezing	1.50 (1.08–2.11)*
	FEV₁/FVC (%)	0.91 (0.86–0.96)***
	F_ENO	1.01 (0.99–1.03)
Model 8	Wheezing	1.48 (1.07–2.11)*
	FEV₁ (% pred)	0.96 (0.94–0.99)*
	FEV₁/FVC (%)	0.94 (0.88–1.01)
	F_ENO	1.02 (0.99–1.04)

FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; F_ENO: exhaled nitric oxide fraction. *: p<0.05; **: p<0.01; ***: p<0.001.

TABLE 6

Diagnostic performance of the models derived from the training cohort and applied to the training cohort (n=166)

	AUC (95% CI)	Threshold	Sensitivity (95% CI)	Specificity (95% CI)	NPV	PPV
Model 1	0.67 (0.59–0.76)	0.20	0.78 (0.62–0.86)	0.54 (0.35–0.67)	0.59	0.74
Model 2	0.73 (0.65–0.81)	0.22	0.80 (0.58–0.89)	0.59 (0.41–0.71)	0.63	0.77
Model 3	0.74 (0.65–0.82)	0.33	0.75 (0.57–0.87)	0.62 (0.44–0.74)	0.59	0.77
Model 4	0.67 (0.58–0.76)	0.24	0.74 (0.53–0.85)	0.58 (0.36–0.71)	0.59	0.73
Model 5	0.74 (0.67–0.83)	0.12	0.85 (0.62–0.93)	0.57 (0.41–0.69)	0.69	0.77
Model 6	0.75 (0.67–0.83)	0.14	0.83 (0.64–0.91)	0.59 (0.34–0.71)	0.69	0.76
Model 7	0.74 (0.65–0.82)	0.34	0.73 (0.53–0.83)	0.64 (0.42–0.76)	0.60	0.76
Model 8^#	0.76 (0.68–0.84)	0.25	0.77 (0.54–0.85)	0.69 (0.44–0.81)	0.66	0.80

AUC: area under the curve; NPV: negative predictive value; PPV: positive predictive value. ^#: best performing model.

TABLE 7

Diagnostic performance of the models derived from the training cohort and applied to the validation cohort (n=137)

	AUC (95% CI)	Threshold	Sensitivity (95% CI)	Specificity (95% CI)	NPV	PPV
Model 1	0.61 (0.52–0.71)	0.55	0.69 (0.50–0.80)	0.54 (0.36–0.68)	0.55	0.67
Model 2	0.70 (0.61–0.77)	0.46	0.86 (0.57–0.95)	0.46 (0.28–0.58)	0.70	0.69
Model 3	0.67 (0.58–0.76)	0.71	0.45 (0.22–0.59)	0.86 (0.68–0.93)	0.53	0.82
Model 4	0.61 (0.51–0.71)	0.57	0.64 (0.35–0.76)	0.61 (0.37–0.72)	0.57	0.68
Model 5	0.70 (0.62–0.79)	0.71	0.42 (0.22–0.54)	0.89 (0.70–0.98)	0.52	0.85
Model 6	0.71 (0.61–0.80)	0.37	0.88 (0.65–0.97)	0.42 (0.24–0.54)	0.74	0.66
Model 7	0.70 (0.61–0.79)	0.64	0.55 (0.33–0.68)	0.83 (0.54–0.92)	0.59	0.81
Model 8^#	0.73 (0.65–0.82)	0.70	0.52 (0.21–0.64)	0.91 (0.63–0.96)	0.60	0.88

AUC: area under the curve; NPV: negative predictive value; PPV: positive predictive value. ^#: best performing model.

Supplementary Materials

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Supplementary tables 00451-2022.supplement