Comprehensive Cluster Analysis for COPD Including Systemic and Airway Inflammatory Markers

Figures & data

Table 1. Process of factor analysis and cluster analysis to describe phenotypes in COPD.

(1) Multiple imputation

i) Obtain 100 complete dataset by multiple imputation (MICE)

(2) Factor analysis for mixed data (FAMD)

i) Determine quantitative and qualitative variable

ii) Apply FAMD for each imputed dataset

iii) Determine the number of components for each imputed dataset

(3) Hierarchical clustering

i) Choosing the best number of clusters for each imputed dataset

(4) Partitioning Clustering

i) Consider the number of clusters in previous step

ii) Assign patients to each cluster for each imputed dataset by partitioning clustering

(5) Consensus clustering

i) Combine all ensemble clustering to get a final best clustering

(6) Assign patients to the final result of consensus clustering

i) Allocate patients in raw dataset (dataset with missing value) and each imputed dataset to calculate final result of consensus clustering

(7) Description of clustering

i) Calculate median for raw dataset and overall median for imputed datasets

ii) Comparison between cluster (Kruskal-Wallis and Chi-squared tests and Dunn´s multiple comparison test)

Table 2. Characteristics of the COPD cohort.

	Variable		Median (IQR)/percentage (frequency)	Percentage (number) of missing value
Demographic	Age (year)		64.5(57–72)	0% (0)
	Sex (Male)		54.49% (97)	0% (0)
	Height (cm)		167(160–175)	0.56% (1)
	Weight (kg)		67(58–78)	0.56% (1)
	BMI (kg/m^2)		23.62 (21.22–27.18)	0.56% (1)
	Cigarette Packs (year)		37.2 (22.5–50)	2.25% (4)
	Cigarettes (day)		20 (10–23.5)	3.93% (7)
	Smoking Duration(year)		43 (33–50)	2.8% (5)
	OCS Course	0	60.71% (102)
		1	23.81% (40)	5.62% (10)
		≥2	15.48% (26)
	Antibiotic Course	0	36.47% (62)	4.49% (8)
		1	51.76% (88)
		≥2	11.76% (20)
	Emergency Room Admission for asthma or COPD	0	84.66% (149)	1.12% (2)
		1	14.77% (26)
		≥2	0.57% (1)
	Number of hospitalizations for asthma or COPD	0	85.55% (148)	2.8% (5)
		1	12.72% (22)
		≥2	1.73% (3)
Pulmonary	FeNO (ppb)		16 (10–25)	7.30% (13)
	FEV1 (mL)		1380 (1085–1810)	0% (0)
	FEV1 predicted (%)		53 (43–66)	0% (0)
	FEV1 PD (mL)		1480 (1180–1930)	0.56% (1)
	FEV1 PD predicted (%)		57 (47–71)	0.56% (1)
	Reversibility (%)		7 (1–12)	0.56% (1)
	FVC (mL)		2505 (2020–3067.5)	0% (0)
	FVC predicted (%)		77 (64–89)	0% (0)
	FVC post (mL)		2580 (2080–3200)	0.56% (1)
	FVC post (%)		80 (68–92)	0.56% (1)
	FEV1/ FVC pre (%)		56.4 (48.12–64.27)	0% (0)
	FEV1/ FVC post (%)		57.9 (49.4–66.5)	0.56% (1)
	TLC (L)		6.45 (5.37–7.17)	16.29% (29)
	TLC predicted (%)		109 (96–123)	16.29% (29)
	RV (L)		3.58 (3.07–4.55)	16.29% (29)
	RV predicted (%)		168 (137–201)	16.29% (29)
	RV/TLC (%)		59.58 (52.79–66.21)	16.29% (29)
	DLCO (mmol/kPa.min)		3.98 (2.91–5.3)	17.41% (31)
	DLCO predicted (%)		49 (37.5–60)	17.41% (31)
	DLCO/VA		0.93 (0.71–1.16)	17.41% (31)
	DLCO/VApredicted (%)		67 (50–81.5)	17.41% (31)
	sGaw (1/kPa*sec)		0.47 (0.34–0.71)	23.03% (41)
	FRC (L)		4.91 (4.09–5.89)	21.34% (38)
	FRC predicted (%)		158 (138–183)	21.34% (38)
Treatment	Treatment (Yes)		61.76% (105)	4.49% (8)
	ICS (Yes)		55.11% (97)	1.12% (2)
	OCS (Yes)		5.11% (9)	1.12% (2)
	LAMA (Yes)		51.13% (90)	1.12% (2)
	LABA (Yes)		67.04% (118)	1.12% (2)
	SABA (Yes)		40.91% (72)	1.12% (2)
	LTRA (Yes)		3.41% (6)	1.12% (2)
	Theophylline (Yes)		2.84% (5)	1.12% (2)
CAT score			25 (16–31)	0% (0)
Blood	Leucocytes (µL)		7.97 (6.67–9.73)	7.86% (14)
	Neutrophils (%)		60.7 (54–67.75)	8.43% (15)
	Lymphocytes (%)		27.8 (21.35–34.3)	8.43% (15)
	Monocytes (%)		7.9 (6.55–9.45)	8.43% (15)
	Eosinophils (%)		2 (1–3.25)	8.43% (15)
	Basophils (%)		0.4 (0.3–0.6)	8.43% (15)
	Neutrophils (µL)		4840.71 (3782.47–6027.27)	8.43% (15)
	Lymphocytes (µL)		2213.4 (1739.08–2710.78)	8.43% (15)
	Monocytes (µL)		646.99 (496.08–836.3)	8.43% (15)
	Eosinophils (µL)		147.63 (77.46–252.0)	8.43% (15)
	Basophils (µL)		31.24 (21.37–48.3)	8.43% (15)
	Fibrinogen (g/l)		3.52 (2.96–4.02)	4.49% (8)
	CRP (mg/l)		2.45 (1.10–5.75)	4.49% (8)
	Alpha 1 antitrypsin (g/l)		1.5 (1.36–1.68)	12.36% (22)
	Calcium (mmol/L)		2.42 (2.36–2.47)	6.74% (12)
	25(OH) Vitamine D (ng/ml)		20 (12–30.97)	13.48% (24)
	Phosphate (mmol/L)		0.93 (0.79–1.06)	6.74% (12)
Atopy	IgE (KU/L)		72.50 (22.75–227.75)	10.11% (18)
	RAST DPT (d1) %>0.35 (KU/L)		11.39% (18)	11.24% (20)
	RAST Cat (e1), %>0.35 (KU/L)		3.75% (6)	10.11% (18)
	RAST Dog (e5), %>0.35 (KU/L)		3.12% (5)	10.11% (18)
	RAST Grass (GX3), %>0.35 (KU/L)		6.96% (11)	11.24% (20)
	RAST microog (MIX1), %>0.35 (KU/L)		9.37% (15)	10.11% (18)
	RAST Birch (t3), %>0.35 (KU/L)		1.25% (2)	10.67% (19)
Sputum	Positive Aerobic Sputum Culture		8.96% (13)	18.54% (33)
	Weight of sputum (g)		1.72 (1.1–2.98)	20.78% (37)
	Total Cell Counts (10^6/g)		2.31 (0.98–5.6)	20.78% (37)
	Squamous (%)		10 (3–33)	20.78% (37)
	Viability (%)		69 (55–84)	20.78% (37)
	Macrophages (%)		12.3 (5–23.6)	21.91% (39)
	Lymphocytes (%)		1 (0–2)	21.91% (39)
	Neutrophils (%)		74.8 (56.87–91.05)	21.34% (38)
	Eosinophils (%)		1.35 (0.2–4.40)	21.34% (38)
	Epithelial cells (%)		2.5 (0.6–7.75)	21.91% (39)
	Macrophages (10^3/g)		268.28 (80.04–583.8)	23.03% (41)
	Lymphocytes (10^3/g)		18.48 (0–43.8)	23.03% (41)
	Neutrophils (10^3/g)		1307.5 (503.89–3831.61)	22.47% (40)
	Eosinophils (10^3/g)		28.86 (2.77–232.69)	22.47% (40)
	Epithelial cells (10^3/g)		55.4 (11.25–202.86)	22.47% (40)

Table 3. Percentage of the contribution of variables in clustering.

Order	Variables in order of priority	Percentage of contribution value
1	FEV1 (mL)	0.795354
2	FEV1 PD (mL)	0.792187
3	FEV1 PD predicted (%)	0.708569
4	FEV1 predicted (%)	0.696766
5	FVC (mL)	0.510238
6	FVC post (mL)	0.49998
7	FVC predicted (%)	0.488792
8	FVC post (%)	0.488091
9	RV/TLC (%)	0.373624
10	FEV1/ FVC post (%)	0.318253
11	DLCO (mmol/kPa.min)	0.290582
12	Emergency Room Admission for asthma or COPD	0.290175
13	FEV1/ FVC pre (%)	0.283042
14	Blood_Neutrophils (%)	0.207177
15	Blood_Lymphocytes (%)	0.185377
16	DLCO predicted (%)	0.167944
17	sGaw (1/kPa*sec)	0.166534
18	LAMA (Yes)	0.162801
19	LABA (Yes)	0.161971
20	ICS (Yes)	0.159877
21	Blood_Neutrophils (µL)	0.14896
22	Treatment (Yes)	0.148225
23	RV predicted (%)	0.143311
24	Number of hospitalizations for asthma or COPD	0.132193
25	FRC predicted (%)	0.12998
26	Weight (kg)	0.115709
27	OCS Course	0.099888
28	RV (L)	0.092256
29	Height (cm)	0.08524
30	Blood_Lymphocytes (µL)	0.076047
31	DLCO/VA	0.073329
32	BMI (kg/m^2)	0.067138
33	DLCO/VApredicted (%)	0.066027
34	Blood_Leucocytes (µL)	0.064596
35	CAT score	0.062324
36	OCS (Yes)	0.061563
37	Blood_Monocytes (%)	0.060734
38	Total Cell Counts (10^6/g)	0.060281
39	Alpha 1 antitrypsin (g/l)	0.059218
40	Fibrinogen (g/l)	0.057644
41	TLC predicted (%)	0.054684
42	Viability (%)	0.052038
43	Sputum_Eosinophils (10^3/g)	0.051767
44	SABA (Yes)	0.046993
45	Antibiotic Course	0.045641
46	Age (year)	0.044547
47	Weight of sputum (g)	0.042916
48	Sputum_Neutrophils (10^3/g)	0.04283
49	Sex (Male)	0.040351
50	Sputum_Lymphocytes (10^3/g)	0.035228
51	Theophylline (Yes)	0.034857
52	Smoking Duration(year)	0.030539
53	CRP (mg/l)	0.030115
54	FRC (L)	0.028202
55	Positive Aerobic Sputum Culture	0.027121
56	Blood_Eosinophils (%)	0.024198
57	RAST Grass (GX3), %>0.35 (KU/L)	0.020597
58	Sputum_Neutrophils (%)	0.01398
59	Positive Aerobic Sputum Culture	0.013011
60	IgE (KU/L)	0.010926
61	25(OH) Vitamine D (ng/ml)	0.00967
62	Blood_Basophils (%)	0.008521
63	FeNO (ppb)	0.008171
64	RAST Birch (t3), %>0.35 (KU/L)	0.007232
65	Squamous (%)	0.007092
66	Sputum_Epithelial cells (%)	0.005941
67	TLC (L)	0.005787
68	Sputum_Eosinophils (%)	0.00525
69	Cigarettes (day)	0.005246
70	Blood_Monocytes (µL)	0.004464
71	RAST DPT (d1) %>0.35 (KU/L)	0.002943
72	Sputum_Lymphocytes (%)	0.002614
73	RAST microog (MIX1), %>0.35 (KU/L)	0.002255
74	Sputum_Macrophages (10^3/g)	0.001858
75	Phosphate (mmol/L)	0.001491
76	RAST Cat (e1), %>0.35 (KU/L)	0.001486
77	LTRA (Yes)	0.001457
78	Sputum_Macrophages (%)	0.001438
79	Blood_Basophils (µL)	0.001318
80	RAST Dog (e5), %>0.35 (KU/L)	0.001291
81	Calcium (mmol/L)	0.001184
82	Blood_Eosinophils (µL)	0.000887
83	Reversibility (%)	0.00079
84	Cigarette Packs (year)	0.00077

Figure 1. Percentage of the contribution of variables in clustering.

Figure 2. Lung function in three clusters.

Figure 3. Blood in three clusters.

Figure 4. Sputum in three clusters.

Figure 5. T2 biomarkers in three clusters.

Figure 6. Cat Score in three clusters.

Table 4. Characteristics of patients with COPD after imputation, Median (IQR) / Percentage (frequency) in each cluster and comparison between clusters.

	Variable			Result for clustering on 100 imputed datasets
				Cluster 1 (n = 67)		Cluster 2 (n = 56)		Cluster 3 (n = 55)		P-value
Demographic		Age (year)		62(55–66)^a		67(60.75–74.25)^b		67(58.5–73)^b+		<0.001
		Sex (Male)		76.12%(51)^a		75%(42)^a		7.27%(4)^b		<0.0001
		Height (cm)		173(166.5–178)^a		169.5(162–17.25)^a		161(156–165)^b		<0.0001
		Weight (kg)		77(65–89)^a		67(56.75–76)^b		60(53–66)^c		<0.0001
		BMI (kg/m^2)		25.59(22.34–30.21)^a		23.08(20.55–24.89)^b		23.15(19.89–25.55)^b		<0.001
		Cigarette Packs (year)		36.9(21.52–50)^a		42.5(24.62–52.5)^a		34.5(21.42–43.87)^a		>0.05
		Cigarettes (day)		20(10–25)^a		20(10–21.25)^a		20(10–20)^a		>0.05
		Smoking Duration(year)		40(31–46)^a		46.5(34.25–52.25)^b		44(37–50)^b		<0.05
		OCS Course	0	80.59%(54)	^a	30.35%(17)	^b	61.82%(34)	^a	<0.0001
			1	13.43%(9)		32.14%(18)		23.64%(13)
			≥2	4.48%(3)		35.71%(20)		10.91%(6)
		Antibiotic Course	0	43.28%(29)	^a	32.14%(18)	^a	32.73%(18)	^a	>0.05
			1	46.27%(31)		50%(28)		58.18%(32)
			≥2	8.95%(6)		16.07%(9)		10.91%(6)
		Emergency Room Admission for asthma or COPD	0	95.52%(64)	^a	71.43%(40)	^b	85.45%(47)	^a	<0.0001
			1	4.48%(3)		26.78%(15)		14.54%(8)
			≥2	0%(0)		1.78%(1)		0%(0)
		Number of hospitalizations for asthma or COPD	0	97.01%(65)	^a	67.86%(38)	^b	89.09%(49)	^a	<0.0001
			1	2.98%(2)		26.78%(15)		10.91%(6)
			≥2	0%(0)		5.36%(3)		0%(0)
Pulmonary		FeNO (ppb)		15(10.5–23)^a		18.5(10–30.5)^a		14(8–25.5)^a		>0.05
		FEV1 (mL)		1950(1700–2205)^a		1085(780–1352.5)^b		1240(1075–1390)^b		<0.0001
		FEV1 predicted (%)		66(56–78)^a		37(30–45.25)^b		55(47.5–66)^c		<0.0001
		FEV1 PD (mL)		2000(1820–2405)^a		1190(837.5–1380)^b		1310(1135–1470)^b		<0.0001
		FEV1 PD (%)		69(60.5–81.5)^a		40(32.75–50)^b		59(51.5–69.5)^c		<0.0001
		Reversibility (%)		7(1–10.5)^a		6.5(1–11.25)^a		8(2–13.5)^a		>0.05
		FVC (mL)		3200(2625–3780)^a		2427.5(1705–2767.5)^b		2140(1820–2390)^c		<0.0001
		FVC predicted (%)		86(74–99.5)^a		65(55.75–74.25)^b		77(68.5–85.5)^c		<0.0001
		FVC post (mL)		3320(2805–3870)^a		2385(1797.5–2900)^b		2130(1870–2445)^c		<0.0001
		FVC post (%)		90(79.5–101)^a		68(56.75–76.5)^b		80(71.5–91.5)^c		<0.0001
		FEV1/ FVC pre (%)		63.1(56.45–66.65)^a		47(40.37–50.42)^b		57.1(53.15–64.5)^a		<0.0001
		FEV1/ FVC post (%)		64(58.3–68.55)^a		47.5(42.8–53.2)^b		59.9(54.5–67.05)^a		<0.0001
		TLC (mL)		6725(5725–7385)^a		6830(5847.5–8107.5)^a		5440(4975–6005)^b		<0.0001
		TLC predicted (%)		103(93–112)^a		113(100.75–125.25)^b		115(102–127.5)^b		<0.001
		RV (mL)		3320(2970–3820)^a		4515(3690–5277.5)^b		3270(2920–3725)^a		<0.0001
		RV (%)		141(128–171.5)^a		183.5(163.87–228.5)^b		172(148.5–193.25)^c		<0.0001
		RV/TLC (%)		52.99(46.71–57.18)^a		66.37(61.28–69.14)^b		60.84(57.03–64.06)^c		<0.0001
		DLCO (mmol/kPa.min)		5.2(4.06–5.88)^a		3.47(2.67–4.44)^b		3.27(2.69–4.03)^b		<0.0001
		DLCO predicted (%)		57(46.5–67)^a		41.5(30.75–58)^b		45(37.5–53.5)^b		<0.0001
		DLCO/VA		1.03(0.79–1.28)^a		0.80(0.63–0.99)^b		0.93(0.71–1.15)^b		<0.0001
		DLCO/VA predicted (%)		70(57–88)^a		59.5(45.75–79)^b		60(50–77.5)^b		<0.001
		sGaw (1/kPa*sec)		0.65(0.44–0.88)^a		0.35(0.24–0.45)^b		0.47(0.34–0.73)^c		<0.0001
		FRC (L)		4.83(4.08–5.43)^a		5.87(4.82–6.49)^b		4.24(3.77–4.95)^c		<0.0001
		FRC predicted (%)		143(122–161)^a		174(154.75–192)^b		160.5(141.5–180.5)^c		<0.0001
Treatment		Treatment (Yes)		44.78%(30)^a		78.57%(44)^b		67.27%(37)^b		<0.0001
		ICS (Yes)		29.85%(20)^a		71.43%(40)^b		69.10%(38)^b		<0.0001
		OCS (Yes)		1.49%(1)^a		16.07%(9)^b		0%(0)^a		<0.0001
		LAMA (Yes)		34.33%(23)^a		73.21%(41)^b		49.09%(27)^a		<0.0001
		LABA (Yes)		44.78%(30)^a		82.14%(46)^b		76.36%(42)^a		<0.0001
		SABA (Yes)		25.37%(17)^a		50%(28)^b		49.09%(27)^b		<0.001
		LTRA (Yes)		2.98%(2)^a		0%(0)^a		7.27%(4)^a		>0.05
		Theophylline (Yes)		1.49%(1)^a		5.36%(3)^a		1.82%(1)^a		>0.05
CAT score				22(15–31)^a		26(19–30)^a		24(17–30)^a		>0.05
Blood		Leucocytes (µL)		7.71(6.52–9.43)^a		8.56(6.87–11.10)^a		7.81(6.64–9.2)^a		>0.05
		Neutrophils (%)		58.2(52.75–63.55)^a		67.6(60.1–73.22)^b		58.3(53.25–64.85)^a		<0.0001
		Lymphocytes (%)		30.3(25.65–35)^a		20.95(15.7–27.27)^b		29(23.82–35.12)^a		<0.0001
		Monocytes (%)		8.7(7.1–9.8)^a		7.8(6.34–9.82)^b		7.1(6.4–8.67)^b		<0.05
		Eosinophils (%)		2(1.1–3.25)^a		1.9(0.9–3.22)^a		2.1(0.95–3.35)^a		>0.05
		Basophils (%)		0.4(0.3–0.6)^a		0.3(0.2–0.5)^a		0.4(0.3–0.7)^a		>0.05
		Neutrophils (µL)		4529.13(3723.5–5501.7)^a		5574.91(4097.7–7842.7)^b		4840.71(3393.7–5743.1)^a		<0.05
		Lymphocytes (µL)		2346.8(1844.6–2968.1)^a		1847.22(1340.4–2382.2)^b		2253.3(1846.6–2710.8)^a		<0.0001
		Monocytes (µL)		668.82(507.24–831.28)^a		652.58(511.72–864.82)^a		605.82(485.32–748.05)^a		>0.05
		Eosinophils (µL)		138(75.12–240.24)^a		168.78(69.23–258.42)^a		147.63(88.26–255.97)^a		>0.05
		Basophils (µL)		30.84(21.48–42.58)^a		27.63(18.88–46.25)^a		32.04(23.95–48.97)^a		>0.05
		Fibrinogen (g/l)		3.43(2.88–3.86)^a		3.65(3.08–4.50)^b		3.54(2.98–3.80)^b		<0.05
		CRP (mg/l)		2.3(1.25–4.95)^a		2.9(0.87–7.7)^a		1.8(1–4.75)^a		>0.05
		Alpha 1 antitrypsin (g/l)		1.49(1.34–1.57)^a		1.61(1.39–1.76)^b		1.49(1.35–1.64)^a		<0.05
		Calcium (mmol/L)		2.42(2.37–2.47)^a		2.41(2.35–2.48)^a		2.44(2.38–2.47)^a		>0.05
		25(OH) Vitamine D (ng/ml)		18(12–30.9)^a		17.5(10–26.75)^a		24(15.5–33)^a		>0.05
		Phosphate (mmol/L)		0.89(0.77–0.95)^a		0.88(0.72–1.06)^a		1.01(0.93–1.11)^b		<0.0001
Atopy		IgE (KU/L)		52(23–184.5)^a		91.5(28.75–304.75)^a		73(21–170)^a		>0.05
		RAST DPT (d1) %>0.35 (KU/L)		13.43%(9)^a		16.07%(9)^a		7.27%(4)^a		>0.05
		RAST Cat (e1), %>0.35 (KU/L)		1.49%(1)^a		7.14%(4)^a		1.82%(1)^a		>0.05
		RAST Dog (e5), %>0.35 (KU/L)		2.98%(2)^a		5.36%(3)^a		0%(0)^a		>0.05
		RAST Grass (GX3), %>0.35 (KU/L)		5.97%(4)^a		14.28%(8)^a		1.82%(1)^a		>0.05
		RAST microog (MIX1),%>0.35 (KU/L)		7.46%(5)^a		12.5%(7)^a		10.91%(6)^a		>0.05
		RAST Birch (t3), %>0.35 (KU/L)		0%(0)^a		3.57%(2)^a		0%(0)^a		>0.05
Sputum		Positive Aerobic Sputum Culture		8.95%(6)^a		16.07%(9)^a		12.73%(7)^a		>0.05
		Weight of sputum (g)		1.77(1.28–3.01)^a		1.45(0.97–3.05)^a		1.65(0.93–3.28)^a		>0.05
		Total Cell Counts (10^6/g)		1.70(0.90–4.41)^a		4.90(1.58–15.96)^b		2.65(1.08–5.43)^a		<0.05
		Squamous (%)		19(6–42)^a		7(2–31.12)^b		9.5(2–23.5)^b		<0.05
		Viability (%)		68(53.5–85.5)^a		69(51–86)^a		67(48.5–79.5)^a		>0.05
		Macrophages (%)		14(6.7–26.1)^a		6.5(2.54–15.15)^b		17(7–29.95)^a		<0.0001
		Lymphocytes (%)		1.2(0–2.3)^a		0.6(0.15–1.5)^a		1.2(0–3)^a		>0.05
		Neutrophils (%)		71.4(56.35–88.2)^a		78.9(58.8–92.19)^a		60.4(39.3–81.05)^b		<0.001
		Eosinophils (%)		1.4(0.2–4.92)^a		2.3(0.2–9.12)^a		2(0.7–9.15)^a		>0.05
		Epithelial cells (%)		2.4(0.4–8.1)^a		3.25(0.57–11.05)^a		4.7(1.3–15.2)^a		>0.05
		Macrophages (10^3/g)		233.55(53.28–691.65)^a		301.29(31.37–755.45)^a		330.48(58.13–816.67)^a		>0.05
		Lymphocytes (10^3/g)		14.2(0–43.07)^a		23.75(4.39–63.9)^a		25.2(3.42–72.5)^a		>0.05
		Neutrophils (10^3/g)		1090(490.86–2339.64)^a		2482.84(883.9–11720.8)^b		1110(493.04–3483.82)^a		<0.05
		Eosinophils (10^3/g)		19.92(0–166.96)^a		71.67(0–638.26)^b		33.04(5.65–293.7)^a		<0.001
		Epithelial cells (10^3/g)		38.45(5.66–142.29)^a		94(18.07–292.65)^a		81.36(16.4–301.24)^a		>0.05

⁺ There are no significant differences between two clusters with the same letter.

Table 5. Characteristics of patients with COPD before imputation, Median (IQR) / Percentage (frequency) in each cluster and comparison between clusters.

	Variable		Result for clustering on raw dataset						P-value
			Cluster 1		Cluster 2		Cluster 3
Demographic	Age (year)		62(55–66)^b		67(60.75–74.25)^a		67(58.5–73)^a		<0.001
	Sex (Male)		76.12%(51[67])^a		75%(42[56])^a		7.27%(4[55])^b		<0.0001
	Height (cm)		174(167–178)^a		169.5(162–175.25)^a		161(156–165)^b		<0.0001
	Weight (kg)		77(65–89)^c		67(56.75–76)^a		60(53–66)^b		<0.0001
	BMI (kg/m^2)		25.59(22.21–30.21)^b		23.08(20.56–24.89)^a		23.15(19.89–25.55)^a		<0.001
	Cigarette Packs (year)		36.9(21–50)^a		42.5(23.25–52.5)^a		35(22.05–43.87)^a		>0.05
	Cigarettes (day)		20(10–25)^a		20(10–21.25)^a		20(10–20)^a		>0.05
	Smoking Duration(year)		40(32–46.5)^c		47(34.25–52.25)^a		44(37–50)^ab		<0.05
	OCS Course	0	81.25%(52[64])	^b	31.37%(16[51])	^a	64.15%(34[53])	^b	<0.0001
		1	14.06%(9[64])		35.29%(18[51])		24.53%(13[53])
		≥2	4.69%(3[64])		33.33%(17[51])		11.32%(6[53])
	Antibiotic Course	0	42.86%(27[63])	^a	32.07%(17[53])	^a	33.33%(18[54])	^a	>0.05
		1	47.62%(30[63])		50.94%(27[53])		57.41%(31[54])
		≥2	9.52%(6[63])		16.98%(9[53])		9.26%(5[54])
	Emergency Room Admission for asthma or COPD	0	95.45%(63[66])	^b	70.91%(39[55])	^a	85.45%(47[55])	^b	<0.0001
		1	4.54%(3[66])		27.27%(15[55])		14.54%(8[55])
		≥2	0%(0[66])		1.82%(1[55])		0%(0[55])
	Number of hospitalizations for asthma or COPD	0	96.97%(64[66])	^b	67.92%(36[53])	^a	88.89%(48[54])	^b	<0.0001
		1	3.03%(2[66])		26.41%(14[53])		11.11%(6[54])
		≥2	0%(0[66])		1.89%(1[53])		0%(0[54])
Pulmonary	FeNO (ppb)		15(10.5–23)^a		19(10–32.25)^a		15(8–24)^a		>0.05
	FEV (mL)		1950(1700–2205)^b		1085(780–1352.5)^a		1240(1075–1390)^a		<0.0001
	FEV1 predicted (%)		66(56–78)^c		37(30–45.25)^a		55(47.5–66)^b		<0.0001
	FEV1 PD (mL)		2000(1820–2405)^b		1190(837.5–1380)^a		1310(1135–1470)^a		<0.0001
	FEV1 PD predicted (%)		69(60.5–81.5)^c		40(32.75–50)^a		59(51.5–69.5)^b		<0.0001
	Reversibility (%)		6(0.5–10.5)^a		6.5(1–11.25)^a		8(2–13.5)^a		>0.05
	FVC (mL)		3200(2625–3780)^c		2427.5(1705–2767.5)^a		2140(1820–2390)^b		<0.0001
	FVC predicted (%)		86(74–99.5)^c		65(55.75–74.25)^a		77(68.5–85.5)^b		<0.0001
	FVC post (mL)		3320(2805–3870)^c		2385(1797.5–2900)^a		2130(1870–2445)^b		<0.0001
	FVC post (%)		90(79.5–101)^c		68(56.75–76.5)^a		80(71.5–91.5)^b		<0.0001
	FEV1/ FVC pre (%)		63.1(56.45–66.65)^b		47(40.37–50.42)^a		57.1(53.15–64.5)^b		<0.0001
	FEV1/ FVC post (%)		63.9(58.3–68.55)^b		47.5(42.8–53.2)^a		59.9(54.5–67.05)^b		<0.0001
	TLC (mL)		6710(5725–7385)^a		6945(5832.5–8107.5)^a		5430(4890–6005)^b		<0.0001
	TLC predicted (%)		103(93–112.5)^b		112.5(100–125.25)^a		117(102–127)^a		<0.001
	RV (mL)		3450(2990–3820)^b		4640(3687.5–5277.5)^a		3250(2845–3690)^b		<0.0001
	RV predicted (%)		141(128–173)^c		182.5(162.5–228.5)^a		168(145.5–189.5)^b		<0.0001
	RV/TLC (%)		53.18(47.13–56.82)^c		66.23(61.34–69.03)^a		60.95(56.93–64.04)^b		<0.0001
	DLCO (mmol/kPa.min)		5.13(3.80–5.87)^b		3.55(2.69–4.45)^a		3.27(2.67–4)^a		<0.0001
	DLCO predicted (%)		56(43–67)^b		42.5(30.75–57.25)^a		45(38–55)^a		<0.0001
	DLCO/AV		1(0.79–1.28)^b		0.83(0.63–1.02)^a		0.93(0.69–1.13)^a		<0.0001
	DLCO/AV predicted (%)		70(56.5–88)^b		66(45.75–79)^a		62(50–75)^a		<0.001
	sGaw (1/kPa*sec)		0.68(0.47–0.93)^c		0.36(0.24–0.47)^a		0.47(0.35–0.76)^b		<0.0001
	FRC (L)		4.88(4.09–5.44)^c		5.86(4.88–6.49)^a		4.24(3.77–5.05)^b		<0.0001
	FRC predicted (%)		143(122–162)^c		171(154–195.75)^a		161(141.5–183.5)^b		<0.0001
Treatment	Treatment (Yes)		43.75%(28[64])^a		78.84%(41[52])^b		66.67%(36[54])^b		<0.0001
	ICS (Yes)		30.30%(20[66])^a		70.91%(39[55])^b		69.09%(38[55])^b		<0.0001
	OCS (Yes)		1.51%(1[66])^a		14.54%(8[55])^b		0%(0[55])^a		<0.0001
	LAMA (Yes)		34.85%(23[66])^a		72.73%(40[55])^b		49.09%(27[55])^a		<0.0001
	LABA (Yes)		45.45%(30[66])^a		83.64%(46[55])^b		76.36%(42[55])^a		<0.0001
	SABA (Yes)		25.76%(17[66])^a		50.91%(28[55])^b		49.09%(27[55])^b		<0.001
	LTRA (Yes)		3.03%(2[66])^a		0%(0[55])^a		7.27%(4[55])^a		>0.05
	Theophylline (Yes)		1.51%(1[66])^a		5.45%(3[55])^a		1.82%(1[55])^a		>0.05
CAT score			22(15–31)^a		26(19–30)^a		24(17–30)^a		>0.05
Blood	Leucocytes (µL)		7.44(6.44–9.43)^a		8.58(7.02–10.75)^a		7.77(6.64–9.2)^a		>0.05
	Neutrophils (%)		58.9(52.75–63.75)^b		68.6(61.27–73.22)^a		57.7(53.25–64.55)^b		<0.0001
	Lymphocytes (%)		30.1(25.65–35)^b		20.7(15.7–26.85)^a		29(23.85–35.15)^b		<0.0001
	Monocytes (%)		8.7(7–9.8)^b		7.8(6.37–9.82)^a		7.1(6.4–8.75)^a		<0.05
	Eosinophils (%)		2.1(1.1–3.25)^a		1.8(0.85–3.12)^a		2.1(0.95–3.35)^a		>0.05
	Basophils (%)		0.4(0.3–0.6)^a		0.3(0.2–0.52)^a		0.4(0.3–0.7)^a		>0.05
	Neutrophils (µL)		4503.6(3554.3–5501.7)^b		5574.9(4116.2–7842.7)^a		4840.71(3393.7–5743.1)^b		<0.05
	Lymphocytes (µL)		2346.79(1853.9–3019.6)^b		1885.8(1294.4–2424.2)^a		2267.98(1846.6–2710.8)^b		<0.0001
	Monocytes (µL)		668.82(494.15–857.91)^a		707.29(534.38–864.82)^a		605.82(457.16–761.76)^a		>0.05
	Eosinophils (µL)		150.72(84.57–240.24)^a		169.57(75.89–275.16)^a		147.63(85.47–248.25)^a		>0.05
	Basophils (µL)		30.84(21.37–42.16)^a		27.63(18.64–47.66)^a		32.04(23.95–49.36)^a		>0.05
	Fibrinogen (g/l)		3.42(2.87–3.86)^b		3.71(3.08–4.58)^a		3.54(2.91–3.80)^a		<0.05
	CRP (mg/l)		2.3(1.25–5.6)^a		2.9(0.9–7.7)^a		2.1(1–5.15)^a		>0.05
	Alpha 1 antitrypsin (g/l)		1.49(1.35–1.57)^b		1.63(1.39–1.76)^a		1.45(1.35–1.65)^b		<0.05
	Calcium (mmol/L)		2.42(2.37–2.47)^a		2.41(2.35–2.48)^a		2.44(2.38–2.48)^a		>0.05
	25(OH) Vitamine D (ng/ml)		19(12–32)^a		16.5(10–24.25)^a		24(13–32.5)^a		>0.05
	Phosphate (mmol/L)		0.89(0.79–0.95)^a		0.87(0.71–1.03)^a		1.01(0.93–1.12)^b		<0.0001
Atopy	IgE (KU/L)		52(23–233.5)^a		91.5(25–300.25)^a		73(19–170)^a		>0.05
	RAST DPT (d1) %>0.35 (KU/L)		13.33%(8)^a		14.28%(7)^a		6.12%(3)^a		>0.05
	RAST Cat (e1), %>0.35 (KU/L)		1.64%(1)^a		8.16%(4)^a		2%(1)^a		>0.05
	RAST Dog (e5), %>0.35 (KU/L)		3.28%(2)^a		6.12%(3)^a		0%(0)^a		>0.05
	RAST Grass (GX3), %>0.35 (KU/L)		6.67%(4)^a		12.24%(6)^a		2.04%(1)^a		>0.05
	RAST microog (MIX1), %>0.35 (KU/L)		6.56%(4)^a		12.24%(6)^a		10%(5)^a		>0.05
	RAST Birch (t3), %>0.35 (KU/L)		0%(0)^a		4.08%(2)^a		0%(0)^a		>0.05
Sputum	Positive Aerobic Sputum Culture		5.26%(3)^a		13.95%(6)^a		8.89%(4)^a		>0.05
	Weight of sputum (g)		1.95(1.37–3.88)^a		1.46(1.06–3.07)^a		1.64(0.93–3.94)^a		>0.05
	Total Cell Counts (10^6/g)		1.46(0.96–2.81)^b		4.15(1.50–15.96)^a		1.75(0.98–3.43)^b		<0.05
	Squamous (%)		21(6.5–42)^b		7.5(2–38.25)^a		7(2–14.5)^a		<0.05
	Viability (%)		67(50–81)^a		69.5(51–86.25)^a		61(41–77.5)^a		>0.05
	Macrophages (%)		14(5.8–28.15)^b		6.25(2.2–15.45)^a		18(9.25–35.65)^b		<0.0001
	Lymphocytes (%)		1(0–2.1)^a		0.6(0.15–1.57)^a		1(0–2.6)^a		>0.05
	Neutrophils (%)		70.6(53.3–88.2)^a		77.5(55.4–92.25)^a		52(37.6–80)^b		<0.001
	Eosinophils (%)		1.6(0.2–5.45)^a		2.3(0.35–10.95)^a		2.8(0.9–20.6)^a		>0.05
	Epithelial cells (%)		1.8(0.4–7.1)^a		2.6(0.57–10.97)^a		2.4(1.2–8.35)^a		>0.05
	Macrophages (10^3/g)		231.57(40.01–564.3)^a		317.39(32.25–801.83)^a		154(15.65–557.81)^a		>0.05
	Lymphocytes (10^3/g)		12.84(0–40.65)^a		23.75(1.12–66.3)^a		14.08(0–46.22)^a		>0.05
	Neutrophils (10^3/g)		1090(484.54–1788.33)^b		2333.6(814.1–12390.5)^a		814.05(486.85–2726.72)^b		<0.05
	Eosinophils (10^3/g)		13.16(0–68.89)^b		44.27(0–511.5)^a		22(0–209.46)^b		<0.001
	Epithelial cells (10^3/g)		44.1(5.66–142.29)^a		165.44(36.15–302.1)^a		67.52(13.7–252.84)^a		>0.05

⁺ There are no significant differences between two clusters with the same letter.