University of Groningen Origins of asthma in childhood Savenije, Olga Elisabeth Maria IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Savenije, O. E. M. (2014). Origins of asthma in childhood. Gildeprint, Enschede. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 26-01-2022
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University of Groningen
Origins of asthma in childhoodSavenije, Olga Elisabeth Maria
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2014
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):Savenije, O. E. M. (2014). Origins of asthma in childhood. Gildeprint, Enschede.
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA | 55
3
Table I. Description of the study population with 8 observations (complete data) of wheeze from birth to age 8 years and those with 2-7 observations in the ALSPAC study and in the PIAMA study.
ALSPAC study PIAMA study
Children with 8 observations
N= 5,760 (49.1%)
Children with 2-7 observations
N= 5,980 (50.9 %)
Children with 8 observations
N=2,810 (74.2%)
Children with 2-7 observations N=979 (25.8%)
Total n (%) Total n (%) Total n (%) Total n (%)Male gender 5760 2968 (52) 5980 3094 (52) 2810 1447 (52) 979 514 (53)Maternal history of asthma 5648 612 (11) 5437 670 (12) 2806 176 (6) 976 106 (11)Maternal history of atopy 5629 2541 (45) 5413 2287 (42) 2810 750 (27) 979 391 (40)Asthma ever at 91/96 months † 5716 1149 (20) 2360 495 (21) 2800 262 (9) 455 67 (15)Prevalence of wheeze;
* Time at which wheeze is reported in ALSPAC/PIAMA.† Parental report of asthma ever diagnosed by a doctor at the age of 91 months in the ALSPAC study and at the age of 96 months in the PIAMA study.
Wheezing phenotypes in PIAMA
The model with best fit to PIAMA data in the first 96 months (8 years) of life was a 5-class model.
Figure 2 shows trajectories of wheezing from the 5 wheezing phenotypes. The never/infrequent,
persistent, and late-onset phenotypes had similar trajectories in PIAMA and ALSPAC. The
transient early wheezing phenotype identified in PIAMA data seems to represent a combination
of the prolonged early and transient early phenotypes identified in ALSPAC. In PIAMA, transient
early wheeze was characterized by approximately 69% prevalence of wheezing at 12 months
and a declining prevalence thereafter to a low prevalence of 5% and 7% at 84 and 96 months,
respectively. The intermediate onset phenotype in PIAMA had lower, and declining, prevalence of
wheeze compared with that in ALSPAC, with the prevalence 73% by age 60 months and 37% by
age 96 months in PIAMA, compared with 99% by age 54 months and 77% by age 91 months
in ALSPAC. Measures of model fit for different latent class models in ALSPAC and PIAMA are
reported in this article’s Table E1 in the Online Repository.
Figure 1. Estimated prevalence of wheeze at each time point from birth to age 8 years for each wheezing phenotype in ALSPAC free 6-class model (N=5,760).
Figure 2. Estimated prevalence of wheeze at each time point from birth to age 8 years for each wheezing phenotype in PIAMA optimal 5-class model (N=2,810).
To compare the prevalence of wheezing phenotypes in ALSPAC and PIAMA, we fitted PIAMA data
to the wheezing phenotypes identified in the ALSPAC 6-class model (see the Online Repository
for more details on the constrained model). The prevalence of the ALSPAC wheezing phenotypes
in PIAMA were as follows: never/infrequent, 74%; transient early, 13%; prolonged early, 8%;
Table II. Associations of wheezing phenotypes (from PIAMA optimal 5-class model) with asthma ever, doctor-diagnosed asthma, and inhaled corticosteroids usage.
Asthma ever at 8 years
Doctor-diagnosed asthma at 8 years
Inhaled corticosteroids use at 3-8 yrs
PhenotypeTotal
n* (%)OR
(95% CI)Total
n* (%)OR
(95% CI)Total
n* (%)OR
(95% CI)
Never/Infrequent2067
105 (5.1)1.0
(reference)2101
14 (0.7)1.0
(reference)1971
145 (7.4)1.0
(reference)
Transient Early448
140 (31.2)8.5
(6.4, 11.2)468
17 (3.6)5.4
(2.7, 11.0)428
137 (32.0)5.9
(4.5, 7.7)
Intermediate Onset83
41 (78.9)17.9
(11.1, 28.6)85
16 (18.3)32.7
(15.4, 69.7)77
52 (67.5)26.1
(15.7, 43.4)
Late Onset45
36 (59.0)26.8
(14.3, 50.2)47
12 (25.7)50.5
(21.9, 116.5)42
22 (52.9)14.1
(7.5, 26.5)
Persistent94
70 (74.1)53.4
(32.3, 88.1)95
31 (32.9)71.5
(36.5, 140.2)90
75 (82.8)60.4
(34.1, 107.2)
Total2738
382 (14.0)-
2796 90 (3.2)
-2608
431 (16.5)-
Results from weighted logistic regression models using children with complete data.* n represents the sum of the membership probabilities of the affected children for that phenotype, and total represents the sum of the membership probability of all children for that phenotype.
Table III. Associations of wheezing phenotypes (from PIAMA optimal 5-class model) with sensitization to any allergen, indoor allergens or food allergens at 4 years.
Sensitization to any common allergen
at 4 years†
Sensitization to indoor allergens at 4 years
Sensitization to food allergens at 4 years
PhenotypeTotal
n* (%)OR
(95% CI)Total
n* (%)OR
(95% CI)Total
n* (%)OR
(95% CI)
Never/Infrequent369
131 (35.4)1.0
(reference)390
37 (9.5)1.0
(reference)372
97 (26.1)1.0
(reference)
Transient Early112
46 (40.9)1.3
(0.8, 2.0)115
21 (18.1)2.1
(1.2, 3.8)112
35 (31.1)1.3
(0.8, 2.0)
Intermediate Onset21
16 (75.2)5.5
(2.0, 15.1)22
13 (61.1)15.0
(5.9, 37.7)22
9 (39.7)1.9
(0.8, 4.5)
Late Onset16
11 (72.7)4.9
(1.6, 15.1)16
9 (60.0)14.3
(4.9, 41.5)15
5 (31.5)1.30
(0.4, 4.0)
Persistent28
14 (49.7)1.8
(0.8, 3.9)29
12 (39.8)6.3
(2.8, 14.3)28
7 (24.2)0.90
(0.4, 2.2)
Total546
218 (39.9)-
57192 (16.1)
-548
152 (27.7)-
Results from weighted logistic regression models using children with complete data.* n represents the sum of the membership probabilities of the affected children for that phenotype, and total represents the sum of the membership probability of all children for that phenotype.† Sensitization to any common allergen is a specific IgE serum concentration of ≥0.35 IU/ml to any indoor allergen (house dust mite, cat, and dog), food allergen (milk, egg) or other common allergen (mixed grasses, birch, Alternaria alternata).
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA | 59
3
Table IV. Associations of wheezing phenotypes (from PIAMA optimal 5-class model) with sensitization to any allergen, indoor allergens or food allergens.
Sensitization to any common allergen
at 8 years†
Sensitization to indoor allergens at 8 years
Sensitization to food allergens at 8 years
PhenotypeTotal
n* (%)OR
(95% CI)Total
n* (%)OR
(95% CI)Total
n* (%)OR
(95% CI)
Never/Infrequent1051
378 (35.9)1.0
(reference)1054
204 (19.4)1.0
(reference)1053
150 (14.3)1.0
(reference)
Transient Early246
103 (41.7)1.3
(1.0, 1.7)248
60 (24.2)1.3
(1.0, 1.9)247
41 (16.8)1.2
(0.8, 1.8)
Intermediate Onset49
36 (74.1)5.1
(2.7, 9.8)49
28 (56.9)5.5
(3.1, 9.9)49
14 (28.3)2.4
(1.2, 4.5)
Late Onset26
18 (70.3)4.2
(1.8, 9.9)26
17 (65.1)5.4
(3.2, 9.2)26
4 (17.2)1.3
(0.4, 3.5)
Persistent60
37 (62.0)2.9
(1.7, 5.0)60
34 (56.5)7.8
(3.4, 17.7)60
14 (23.9)1.9
(1.0, 3.5)
Total1432
572 (39.9)-
1437 343 (23.9)
-1434
224 (15.6)-
Results from weighted logistic regression models using children with complete data.* n represents the sum of the membership probabilities of the affected children for that phenotype, and total represents the sum of the membership probability of all children for that phenotype.† Sensitization to any common allergen is a specific IgE serum concentration of ≥0.35 IU/ml to any indoor allergen (house dust mite, cat, and dog), food allergen (milk, egg) or other common allergen (mixed grasses, birch, Alternaria alternata).
Associations of wheezing phenotypes from the PIAMA 5-class model with sensitization to indoor
and food allergens at 4 and 8 years are shown in Tables III and IV, respectively. Intermediate onset
wheeze had the strongest association with sensitization to any common allergen at 4 and 8 years
of age. Intermediate onset wheeze, late-onset wheeze, and persistent wheeze were strongly
associated with sensitization to indoor allergens at age 4 years (OR [95% CI], 15.0 [5.9-37.7],
14.3 [4.9-41.5], and 6.3 [2.8-14.3], respectively), whereas transient early wheeze had a modest
association (OR, 2.1; 95% CI, 1.2-3.8) (Table III). At 8 years of age, the reported associations were
very similar (Table IV). The association with sensitization to food allergens was less obvious and
only significant at age 8 years for intermediate-onset wheeze and persistent wheeze. The results
for sensitization to any common allergen at 8 years were consistent with previously reported
associations of wheezing phenotypes and skin prick test in the ALSPAC study28 and the results
Results from weighted linear regression models using children with complete data.* Percentage of predicted forced expiratory flow in 1 s based on height and gender.† Measured as dose-response slope (% decline in FEV1 per milligram methacholinebromide).‡ n represents the sum of the membership probabilities of all children for that phenotype.
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA | 65
3
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Chapter 3
Online Repository
Comparison of childhood wheezing phenotypes
in 2 birth cohorts: ALSPAC and PIAMA
OE Savenije*, R Granell*, D Caudri, GH Koppelman, HA Smit, A Wijga, JC De Jongste,
B Brunekreef, JA Sterne, DS Postma, J Henderson, M Kerkhof
Table E1. Model characteristics and prevalences of wheezing phenotypes derived from longitudinal latent class models of complete data in the first 8 years of life in the ALSPAC study and the PIAMA study
* For a detailed description see Measures of fit in Longitudinal Latent Class Analysis. † LLCA models have two sets of parameters: the conditional probabilities (probability of belonging to a latent class n given a specific pattern of wheeze) and the latent class probabilities, this is the proportion of children on each latent class. In the constrained models we only fix the conditional probabilities, allowing the prevalences of the wheezing phenotypes to vary among the cohorts.‡ Based on estimated posterior probabilities.
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA | 75
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Figure E1. Estimated prevalence of wheeze at each time point from birth to age 8 years for each wheezing phenotype in ALSPAC free 6-class model including children with 2-8 observations of wheeze (N=11,740).
Figure E2. Estimated prevalence of wheeze at each time point from birth to age 8 years for each wheezing phenotype in PIAMA optimal 5-class model including children with 2-8 observations of wheeze (N=3,789).
Table E3. Model characteristics and prevalences of wheezing phenotypes derived from longitudinal latent class models of data with 2-8 observations of wheeze in the first 8 years of life in the ALSPAC study and the PIAMA study.
ALSPAC Free
(Optimal)ALSPAC
FreePIAMA
Constrained†PIAMA Free(Optimal)
PIAMAFree
No. classes 7 6 6 5 6No. children with 2-8 observations 11,740 11,740 3,789 3,789 3,789No. free parameters 62 53 5 44 53Bayesian Information Criterion* 60,053 60,084 17,359 17,415 17,464Entropy* 0.69 0.72 0.81 0.85 0.78Bootstrap Likelihood Ratio Test* <0.0001 <0.0001 - <0.0001 0.03Prevalence of Wheezing Phenotypes‡ (%)
* For a detailed description see Measures of fit in Longitudinal Latent Class Analysis. † LLCA models have two sets of parameters: the conditional probabilities (probability of belonging to a latent class n given a specific pattern of wheeze) and the latent class probabilities, this is the proportion of children on each latent class. In the constrained models we only fix the conditional probabilities, allowing the prevalences of the wheezing phenotypes to vary among the cohorts.‡ Based on estimated posterior probabilities.
Table E4 shows the most frequently occurring patterns of wheezing and their most likely
phenotype in the optimal and constrained model with 8 time-points including children with 2-8
observations of wheeze. Similar conclusions as those derived from Table E2 can be applied to this
table.
Tables E5-E8 show the associations of wheezing phenotypes with asthma, sensitization and lung
function for children with 2-8 observations of wheeze. Similar patterns of associations as those
found in the complete case analysis were found when analyzing children with 2-8 observations
of wheeze.
Table E9 shows directly comparable associations of wheezing phenotypes with doctor-diagnosed
asthma, sensitization to any common allergen and lung function measures in the extended
ALSPAC 6-class free model and PIAMA optimal 5-class model for children with 2-8 observations
of wheeze.
Table E10 reports the distributions of the five identified wheezing phenotypes in PIAMA data
among the four wheezing phenotypes defined by the Tucson Children’s Respiratory Study.
Table E5. Associations of wheezing phenotypes in PIAMA optimal 5-class model with diagnosed asthma at 0-8 years, doctor diagnosed asthma at 8 years and use of inhaled corticosteroids at 3-8 years.
Asthma everat 8 years
Doctor-diagnosed asthmaat 8 years
Use of inhaled corticosteroidsat 3-8 yrs
PhenotypeTotaln (%)
OR(95% CI)
Totaln (%)
OR (95% CI)
Totaln (%)
OR(95% CI)
Never/Infrequent2161
148 (6.9)1.0
(reference)2405
23 (0.9)1.0
(reference)2139
201 (9.4)1.0
(reference)
Transient Early517
193 (37.3)8.1
(6.3, 10.3)548
20 (3.7)4.0
(2.2, 7.4)513
191 (37.3)5.7
(4.5, 7.2)
Intermediate Onset107
54 (50.4)13.8
(9.1, 20.8)112
18 (16.3)20.5
(10.7, 39.2)104
71 (68.0)20.4
(13.2, 31.6)
Late Onset56
35 (62.6)22.7
(12.9, 39.9)61
17 (27.7)40.3
(20.1, 80.7)55
32 (57.4)13.0
(7.5, 22.6)
Persistent133
106 (79.4)52.1
(33.2, 81.9)124
38 (30.4)46.0
(26.2, 80.8)134
(15 (85.6)57.2
(34.6, 94.7)
Total2973
536 (18.0)-
3251116 (3.6)
-2945
609 (20.7)-
Results from weighted logistic regression models in children with 2-8 observations of wheeze.* n represents the sum of the membership probabilities of the affected children for that phenotype, and total represents the sum of the membership probability of all children for that phenotype.
Table E6. Associations of wheezing phenotypes in PIAMA optimal 5-class model with sensitization against any allergen, indoor allergens or food allergens at 4 years.
Sensitization to any common allergen
at 4 years
Sensitization to indoor allergensat 4 years
Sensitization to food allergensat 4 years
PhenotypeTotaln (%)
OR(95% CI)
Totaln (%)
OR (95% CI)
Totaln (%)
OR (95% CI)
Never/Infrequent462
167 (36.2)1.0
(reference)483
51 (10.6)1.0
(reference)339
100 (29.4)1.0
(reference)
Transient Early151
62 (41.0)1.2
(0.8, 1.8)158
27 (17.0)1.7
(1.0, 2.9)114
28 (24.5)1.3
(0.9, 1.9)
Intermediate Onset30
21 (69.9)4.1
(1.8, 9.1)31
16 (53.0)9.5
(4.4, 20.4)22
8 (35.9)2.1
(1.0, 4.4)
Late Onset20
14 (72.4)4.6
(1.7, 12.6)20
12 (60.7)13.0
(5.1, 33.6)14
4 (28.5)1.2
(0.4, 3.3)
Persistent43
23 (53.0)2.0
(1.1, 3.7)44
19 (42.1)6.1
(3.2, 11.9)29
9 (29.3)1.1
(0.5, 2.2)
Total707
288 (40.7)-
736125 (17.0)
-518
148 (28.6)-
Results from weighted logistic regression models in children with 2-8 observations of wheezing.* n represents the sum of the membership probabilities of the affected children for that phenotype, and total represents the sum of the membership probability of all children for that phenotype.
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA | 79
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Table E7. Associations of wheezing phenotypes in PIAMA optimal 5-class model with sensitization against any allergen, indoor allergens or food allergens at 8 years.
Sensitization to any common allergen at 8
years
Sensitization to indoor allergensat 8 years
Sensitization to food allergensat 8 years
PhenotypeTotaln (%)
OR(95% CI)
Totaln (%)
OR (95% CI)
Totaln (%)
OR (95% CI)
Never/Infrequent1220
446 (36.6)1.0
(reference)1223
243 (19.9)1.0
(reference)1221
183 (15.0)1.0
(reference)
Transient Early305
128 (41.9)1.3
(1.0, 1.6)307
75 (24.3)1.3
(1.0, 1.7)305
55 (18.2)1.3
(0.9, 1.7)
Intermediate Onset63
46 (72.2)4.5
(2.6, 7.9)63
35 (55.2)5.0
(3.0, 8.3)63
19 (29.9)2.4
(1.4, 4.2)
Late Onset35
26 (75.1)5.2
(2.4, 11.4)35
24 (69.7)9.3
(4.5, 19.4)35
8 (23.5)1.7
(0.8, 3.0)
Persistent78
47 (60.3)2.6
(1.7, 4.2)79
43 (54.4)4.8
(3.0, 7.7)79
19 (23.9)1.8
(1.0, 3.0)
Total1701
693 (40.7)-
1708420 (24.6)
-1704
285 (16.7)-
Results from weighted logistic regression models in children with 2-8 observations of wheezing.* n represents the sum of the membership probabilities of the affected children for that phenotype, and total represents the sum of the membership probability of all children for that phenotype.
Table E8. Associations of wheezing phenotypes in PIAMA optimal 5-class model of children with 2-8 observations of wheeze with lung function and airway hyper responsiveness.
FEV1 % predicted at 8 years* Bronchial responsiveness at 8 years†
Results from weighted linear regression models in children with 2-8 observations of wheeze.* Percentage of predicted forced expiratory flow in 1 s based on height and gender.† Measured as dose-response slope (% decline in FEV1 per milligram methacholinebromide).‡ n represents the sum of the membership probabilities of all children for that phenotype.
Table E9. Comparison of associations between wheezing phenotypes and doctor-diagnosed asthma, sensitization to any common allergen and lung function measures at 8 years in ALSPAC and PIAMA.
Results from weighted regression models using children with 2-8 observations of wheeze.± Extended model with 8th time point at 91 months.* Defined as a parental report of a doctor’s diagnosis of asthma at any time and a parental report of asthma in the past 12 months, reported at age 8.** Percentage of predicted forced expiratory flow in 1 s based on height and gender.† Measured as dose-response slope (% decline in FEV1 per milligram methacholinebromide).
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA | 81
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Table E10. Distribution of the five wheezing phenotypes identified in PIAMA data among the four phenotypes as defined by the Tucson Children’s Respiratory Study (TCRS).
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