Background
Methods
Study population
Lung function measurements
Definition of covariates
Definition | Assessment | |
---|---|---|
Early life events | ||
Parental atopy | positive if the mother or father had asthma, eczema or hay fever | asked at birth; questionnaire-based |
Parental education | three categories based on the highest number of education years of either parent (high: >10 years; medium: 10 years; low: <10 years) | asked at birth; questionnaire-based |
Maternal age at delivery | dichotomized in ≤31 years and >31 years (mean age served as cut-off) | asked at birth; questionnaire-based |
Maternal smoking during pregnancy | yes vs no | asked at birth; questionnaire-based |
Early second-hand smoke exposure at home | positive if parents reported at least once that the child was exposed to second-hand smoke at home | asked up to age 4 (at 4 months, 1 year (control arm only) and yearly at 2 to 4 years in GINIplus; half-yearly from birth to 2 years and at age 4 years for past 24 months in LISAplus); questionnaire-based |
Season of birth | dichotomized (December to February (winter) versus other seasons) | Birth month derived from date of birth; questionnaire-based |
Birth weight | continuous, grams | asked at birth in LISAplus and at 1 year in GINIplus; questionnaire-based |
Breastfeeding | exclusive breastfeeding for at least four months | asked separately for 1–6 months at 1 year in GINIplus and at 6 months in LISAplus; questionnaire-based |
Peak weight and peak height velocity | maximum of the first derivative of the individual weight or height gain curves obtained between birth and two years of age (calculated using nonlinear random effects models) [9] | weight and height measurements obtained during the children’s preventive medical check-ups to monitor growth |
Early lower respiratory tract infections | doctor’s diagnosis of pneumonia or obstructive bronchitis within the first three years of life (hereon referred to as lung infections) | asked up to age 3 (yearly in GINIplus; half-yearly up to age 2 years and up to age 3 years asked at the 4 year follow-up in LISAplus); questionnaire-based |
Environmental and lifestyle factors at age 15 | ||
Short-term air pollution exposure | continuous, the average of the daily concentrations of NO2, PM2.5 mass and PM10 mass (μg/m3) | obtained for the seven days prior to lung function testing from monitoring sites near the centers of Munich and Wesel [8] |
Long-term air pollution exposure | continuous, long-term concentrations of NO2, PM2.5 mass and PM10 mass (μg/m3) | estimated to each participant’s home address at birth, 10- and 15-years, respectively [8] |
Regular indoor second-hand smoke exposure | positive if the adolescent reported indoor second-hand smoke exposure at least once a week | asked at age 15 years; one question in GINIplus, two questions for second-hand exposure: (1) at home and (2) in other locations in LISAplus (positive if regular exposure was reported in at least one question); questionnaire-based |
Active smoking | yes vs no | asked at age 15 years, questionnaire-based |
Vitamin D concentrations | continuous; serum 25-hydroxyvitamin D [25(OH)D] concentrations adjusted for seasonal variance using a generalized additive model (nmol/l) [36] | measured at age 15 years using Roche’s vitamin D total test (E170, Roche Diagnostics, Mannheim, Germany) |
Body mass index | continuous, kilogram per square meter (kg/m2) | calculated using body height and weight obtained at lung function testing |
Current allergic diseases | ||
Asthma | defined based on the Global Allergy and Asthma European Network (GA2LEN) definition [44]. Subjects were considered as currently having asthma if they responded positively to at least two of the three following questions: (1) Has a doctor diagnosed asthma in your child at the age 3 to 15 years? (2) Has your child taken asthma medication during the last 12 months? (3) Has your child had wheezing or whistling in the chest in the last 12 months? | parents were asked to provide yearly information on their child’s doctor diagnosed allergic diseases throughout childhood; information on current allergic symptoms and asthma medication in the last 12 months was derived from the last follow-up questionnaire at age 15 years. |
Current allergic rhinitis | positive if one of the following questions was positive: (1) Has a doctor diagnosed hay fever (i.e. seasonal allergic rhinitis) in your child? (2) Has a doctor diagnosed perennial allergic rhinitis in your child? | asked separately for ages 11 to 15, at the 15-year follow-up;questionnaire-based |
Sensitization to food or aeroallergens | food allergen mixture including egg white, codfish, cow milk, wheat flour, peanut, and soybean and aeroallergen mixture including cat, dog, mugwort, birch, timothy, rye, Cladosporium herbarum, and Dermatophagoides pteronyssinus; for both tests, a value >0.35 kU/L was considered positive | measured by serum specific Immunoglobulin E (IgE) using the ImmunoCAP Specific IgE system (Phadia GmbH, Freiburg, Germany) at age 15 years |
Statistical analysis
Results
Study population
Total | Males | Females | |
% (N) | 100 (1326) | 51.1 (678) | 48.9 (648) |
Mean (SD) or % (n) | |||
Age, years | 15.2 (0.3) | 15.2 (0.3) | 15.2 (0.3) |
Height*, cm | 172 (8.2) | 176 (7.4) | 167 (6.0) |
Study specific | |||
Study | |||
GINIplus control | 38.3 (508) | 38.2 (259) | 38.4 (249) |
GINIplus intervention | 34.5 (457) | 33.8 (229) | 35.2 (228) |
LISAplus | 27.2 (361) | 28.0 (190) | 26.4 (171) |
Study center | |||
Munich | 63.3 (840) | 63.1 (428) | 63.6 (412) |
Wesel | 36.7 (486) | 36.9 (250) | 36.4 (236) |
Early life events | |||
Parental atopy, yes | 58.8 (780) | 57.7 (391) | 60.0 (389) |
Parental education | |||
low (< 10 years of school) | 5.2 (69) | 5.8 (39) | 4.6 (30) |
medium (= 10 years of school) | 26.7 (354) | 27.0 (183) | 26.4 (171) |
high (> 10 years of school) | 68.1 (903) | 67.3 (456) | 69.0 (447) |
Maternal age at delivery >31 years*, yes | 49.9 (662) | 46.3 (314) | 53.7 (348) |
Maternal smoking during pregnancy, yes | 12.0 (159) | 11.9 (81) | 12.0 (78) |
Early second-hand smoke exposure at home (up to age 4), yes | 32.7 (433) | 32.6 (221) | 32.7 (212) |
Season of birth, winter | 25.6 (339) | 24.5 (166) | 26.7 (173) |
Birth weight*, g | 3483 (442.0) | 3541 (443.5) | 3422 (432.6) |
Exclusive breastfeeding >4 months, yes | 60.6 (804) | 58.3 (395) | 63.1 (409) |
Peak weight velocity*, kg/month | 1.1 (0.2) | 1.2 (0.2) | 1.0 (0.2) |
Peak height velocity*, cm/month | 3.6 (0.4) | 3.8 (0.4) | 3.5 (0.4) |
Lung infections (up to age 3)*, yes | 31.2 (414) | 34.8 (236) | 27.5 (178) |
Environmental and lifestyle factors at age 15 | |||
Short-term air pollution | |||
NO2 (μg/m3) | 20.4 (6.9) | 20.5 (7.0) | 20.3 (6.7) |
PM2.5 mass (μg/m3) | 14.7 (7.3) | 14.4 (6.7) | 15.0 (7.9) |
PM10 mass (μg/m3) | 18.9 (7.8) | 18.6 (7.2) | 19.3 (8.4) |
Long-term air pollution | |||
NO2 (μg/m3) | 21.2 (4.8) | 21.2 (5.0) | 21.2 (4.6) |
PM2.5 mass (μg/m3) | 14.8 (2.1) | 14.8 (2.2) | 14.8 (2.1) |
PM10 mass (μg/m3) | 22.1 (3.2) | 22.0 (3.3) | 22.1 (3.2) |
Regular indoor second-hand smoke exposurea, yes | 20.1 (266) | 19.0 (129) | 21.1 (137) |
Active smoking, yes | 5.4 (71) | 5.6 (38) | 5.1 (33) |
Serum vitamin Db, nmol/l | 68.4 (25.3) | 67.5 (24.3) | 69.3 (26.2) |
Body mass index*, kg/m2
| 20.7 (3.0) | 20.7 (3.2) | 20.8 (2.8) |
Allergic diseases at age 15 | |||
Asthma, yes | 6.3 (83) | 7.4 (50) | 5.1 (33) |
Rhinitis, yes | 18.9 (251) | 20.9 (142) | 16.8 (109) |
Sensitization to | |||
Aeroallergens*, yes | 45.4 (602) | 51.5 (349) | 39.0 (253) |
Food allergens, yes | 11.2 (148) | 12.8 (87) | 9.4 (61) |
Spirometric parameters at age 15 | |||
FVC, l* | 4.08 (0.77) | 4.50 (0.74) | 3.64 (0.51) |
FEV1, l* | 3.52 (0.63) | 3.83 (0.64) | 3.19 (0.42) |
FEV1/FVC, %* | 86.7 (6.39) | 85.3 (6.43) | 88.1 (6.02) |
PEF, l/s* | 7.15 (1.28) | 7.73 (1.3) | 6.54 (0.93) |
FEF25, l/s* | 6.26 (1.17) | 6.61 (1.27) | 5.89 (0.92) |
FEF50, l/s* | 4.46 (1.05) | 4.71 (1.14) | 4.19 (0.87) |
FEF75, l/s* | 2.21 (0.72) | 2.31 (0.78) | 2.11 (0.63) |
FEF25–75, l/s* | 3.92 (0.92) | 4.12 (1.01) | 3.70 (0.77) |
Variable selection
Spirometric parameter indicative of | Lung volume | Airways & volume | Airflow limitation | Airways |
---|---|---|---|---|
FVC, ml | FEV1, ml | FEV1/FVC, % | FEF25–75, ml/s | |
Sex, male | 347 (289, 405) | 220 (167, 274) | −2.2 (−2.9,-1.4) | |
Age, IQR years | 47 (26, 69) | 30 (11, 50) | ||
Height, IQR cm | 637 (598, 676) | 517 (481, 553) | 508 (438, 577) | |
Early life events | ||||
Peak weight velocity, IQR kg/month | −0.8 (−1.3, −0.3) | −88 (−155, −20) | ||
Lung infections (up to age 3), yes | −55 (−102, −7) | −1.1 (−1.8,-0.3) | −159 (−258, −60) | |
Environment & lifestyle at age 15 | ||||
Regular indoor second-hand smoke exposurea, yes | −59 (−114, −5) | |||
Serum vitamin Db, IQR nmol/l | 65 (34, 96) | 32 (3, 61) | −0.6 (−1, −0.2) | |
Body mass index, IQR kg/m2
| 222 (194, 250) | 144 (118, 171) | −1.2 (−1.6,-0.8) | 85 (31, 140) |
Allergic diseases at age 15 | ||||
Asthma, yes | −118 (−216, −21) | −177 (−268, −86) | −1.8 (−3.1,-0.4) | −304 (−494, −115) |
Study specific | ||||
Study (LISAplus vs GINIplus) | 68 (12, 124) | |||
Study center (Wesel vs Munich) | −66 (−119, −13) | −135 (−182, −88) | −1.6 (−2.3,-0.9) | −256 (−352, −161) |