SPT = skin prick test. White spaces within the heatmap indicate missing data. Rows represent individuals; columns represent clustering features with general categories as labelled on grey …
The first two PCs (shown) account for 16.7% of the total variance.
j = cluster number; nj = cluster size; avei∈Cjsi = average silhouette width among members i of cluster Cj. Overall average silhouette width across all clusters is also given.
Dashed arrows indicate non-critical elements of our method.
(A) Physician-diagnosed asthma (B) defined wheeze phenotypes (C) in relation to food and inhalant sensitisation (D) stratified by cluster and time in the CAS dataset. Points indicate observed …
Percentages denote proportion of cluster displaying phenotype (numbers in brackets denote actual sample numbers). Food sensitisation defined as peanut IgE ≥0.35 kU/L at any age, or cow’s milk, egg …
Note the slightly stronger heat along the main diagonals of both heatmaps, especially for HDM.
(A) Th2 cytokine (IL-13) to HDM stimulation of PBMCs in vitro, vs.HDM IgE responses in vivo, stratified by age of testing, and SPT result (positive denoted by ≥2 mm at age <2 or 3 mm at age 5). …
Points indicate means; bars indicate 95% CI (t-distribution). #p<0.05 for repeated-measures ANOVA across timepoints from the first 3 years of life (see Table 4). *p<0.05 for Mann-Whitney-Wilcoxon …
(A); scatterplot showing separation of CAS clusters by decision split thresholds (B). Percentages in Panel A may not sum up to 100% because some individuals have missing values for decision node …
CAS1.x, 2.x, and 3.x, and tree cluster 1.x, 2.x and 3.x, refer to the intersection of npEM-generated clusters and age-5 wheeze status, and their analogous decision tree cluster, respectively. The …
Colour coding and numbers in cells indicate odds ratio (OR) of predictor for age-5 wheeze in GLM, with sex, maternal and paternal history of asthma, and (for CAS) BMI as covariates. Non-grey cell …
(A) and IL-4 mRNA (B), as well as IL-13 protein (C), in response to stimulation HDM, stratified by cluster and time (CAS) Cord = cord blood sample collected at birth.Points indicate means; bars …
(A), asthma diagnosis (B), and HDM IgE levels (C); in COAST, incidence of asthma diagnosis (D), proportion of individuals with detectable aeroallergen-specific IgE levels (E), and PBMC protein …
Variable | Age (y) | Cas1 (N = 88) | Cas2 (N = 107) | Cas3 (N = 22) | P-value (unadjusted) | Feature? | |||
---|---|---|---|---|---|---|---|---|---|
Prop. (95% CI) | Prop. (95% CI) | Prop. (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
Sex = male | 55% (44–65%) | 51% (42–61%) | 86% (71–100%) | 7.3E-03 | 0.67 | 6.8E-03 | 3.7E-03 | Yes | |
Maternal asthma | 51% (40–62%) | 41% (32–51%) | 59% (37–81%) | 0.19 | 0.19 | 0.63 | 0.16 | Yes | |
Paternal asthma | 22% (13–30%) | 44% (35–54%) | 23% (3.7–42%) | 2.2E-03 | 1.3E-03 | 1 | 0.093 | Yes | |
Wheeze | 1 | 33% (23–43%) | 30% (21–39%) | 55% (32–77%) | 0.092 | 0.76 | 0.084 | 0.046 | No |
5 | 25% (15–35%) | 21% (13–30%) | 76% (56–96%) | 7.1E-06 | 0.59 | 2.6E-05 | 3.4E-06 | No | |
10 | 12% (3.4–21%) | 18% (8.4–27%) | 50% (24–76%) | 3.1E-03 | 0.46 | 1.5E-03 | 0.011 | No | |
Asthma | 5 | 15% (7–23%) | 13% (5.9–20%) | 52% (29–76%) | 4.1E-04 | 0.83 | 7.7E-04 | 2.1E-04 | No |
10 | 10% (2.3–18%) | 15% (6.1–23%) | 56% (30–81%) | 2.6E-04 | 0.59 | 1.8E-04 | 7.9E-04 | No | |
Eczema | 6m | 39% (28–49%) | 45% (35–54%) | 91% (78–100%) | 2.4E-05 | 0.47 | 7.9E-06 | 9.0E-05 | Yes |
1 | 34% (24–44%) | 30% (21–39%) | 82% (64–99%) | 2.5E-05 | 0.54 | 7.2E-05 | 1.4E-05 | Yes | |
5 | 28% (18–37%) | 24% (16–33%) | 71% (50–92%) | 2.1E-04 | 0.73 | 3.3E-04 | 7.9E-05 | No | |
Atopic rhinoconjunctivitis | 5 | 30% (20–40%) | 39% (29–49%) | 76% (56–96%) | 6.4E-04 | 0.21 | 2.7E-04 | 3.2E-03 | No |
Mean (95% CI) | Mean (95% CI) | Mean (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
BMI (kg/m2) | 3 | 16 (16–17) | 16 (16–17) | 16 (16–17) | 0.86 | 0.65 | 0.68 | 0.8 | No* |
4 | 16 (16–17) | 16 (16–16) | 17 (16–17) | 0.59 | 0.76 | 0.32 | 0.39 | No | |
5 | 16 (16–16) | 16 (16–16) | 16 (15–17) | 0.71 | 0.56 | 0.48 | 0.67 | No | |
10 | 18 (17–19) | 18 (17–18) | 18 (17–19) | 0.89 | 0.75 | 1 | 0.62 | No | |
Number of older siblings | 0 | 0.93 (0.72–1.1) | 0.53 (0.38–0.69) | 0.77 (0.32–1.2) | 4.5E-03 | 1.0E-03 | 0.37 | 0.25 | Yes |
2 | 0.85 (0.66–1) | 0.5 (0.34–0.65) | 0.77 (0.32–1.2) | 2.8E-03 | 6.5E-04 | 0.48 | 0.16 | Yes | |
5 | 0.68 (0.5–0.85) | 0.39 (0.25–0.54) | 0.67 (0.23–1.1) | 0.016 | 5.1E-03 | 0.75 | 0.12 | No | |
Geom. mean (95% CI) | Geom. mean (95% CI) | Geom. mean (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
Vitamin D (nmol/L) | 1 | 60 (55–64) | 59 (55–63) | 59 (52–67) | 0.93 | 0.98 | 0.76 | 0.7 | No |
2 | 57 (54–61) | 58 (55–61) | 47 (40–55) | 0.012 | 0.82 | 5.4E-03 | 4.4E-03 | No | |
5 | 89 (83–95) | 84 (79–89) | 77 (69–84) | 0.057 | 0.46 | 0.016 | 0.056 | No | |
BMI = body mass index; feature?=whether variable was used as a clustering feature or not; geom. mean = geometric mean; prop. = proportion. For categorical variables, associations were tested using Fisher exact test; for continuous variables, Kruskal-Wallis and Mann-Whitney-Wilcoxon. Bold text indicates statistical significance (p<0.05); italics indicate near-significance (p<0.10). *Not used as clustering feature, as BMI is a derived variable. Height and weight at age three were used instead.
Variable | Age | Cas1 (N = 88) | Cas2 (N = 107) | Cas3 (N = 22) | P-value (unadjusted) | Feature? | |||
---|---|---|---|---|---|---|---|---|---|
Geom. mean (95% CI) | Geom. mean (95% CI) | Geom. mean (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
Total antibody | |||||||||
IgE (kU/L) | 6m | 1.2 (0.69–2) | 2.2 (1.4–3.6) | 21 (12–35) | 1.2E-07 | 0.044 | 6.7E-08 | 2.2E-06 | Yes |
1 | 0.6 (0.29–1.3) | 2 (1.1–3.7) | 43 (17–109) | 2.0E-09 | 0.019 | 4.3E-09 | 5.3E-08 | Yes | |
2 | 6.6 (3.5–12) | 17 (12–25) | 187 (131–267) | 1.2E-11 | 0.044 | 4.2E-11 | 1.4E-10 | Yes | |
5 | 35 (23–55) | 60 (46–80) | 451 (278–731) | 2.2E-08 | 0.096 | 1.9E-08 | 1.5E-07 | No | |
10 | 85 (46–154) | 150 (103–217) | 800 (405–1.6E + 03) | 1.4E-04 | 0.11 | 1.3E-04 | 2.8E-04 | No | |
HDM antibody | |||||||||
IgE (kU/L) | 6m | 0.018 (0.016–0.02) | 0.019 (0.016–0.022) | 0.033 (0.019–0.059) | 1.9E-03 | 0.47 | 7.9E-04 | 4.2E-03 | Yes |
1 | 0.019 (0.017–0.023) | 0.019 (0.016–0.022) | 0.26 (0.075–0.93) | 1.3E-09 | 0.47 | 2.5E-07 | 4.5E-09 | Yes | |
2 | 0.024 (0.019–0.031) | 0.042 (0.029–0.06) | 7.1 (2.7–19) | 2.6E-16 | 0.078 | 2.5E-15 | 3.5E-13 | Yes | |
5 | 0.072 (0.041–0.13) | 0.23 (0.12–0.45) | 31 (7.8–127) | 4.2E-09 | 0.015 | 3.8E-09 | 5.1E-07 | No | |
10 | 0.37 (0.17–0.8) | 1.3 (0.51–3.4) | 52 (19–144) | 2.9E-06 | 0.068 | 5.7E-07 | 9.7E-05 | No | |
IgG (mg/L) | 1 | 0.21 (0.2–0.23) | 0.23 (0.21–0.25) | 0.29 (0.21–0.39) | 0.042 | 0.34 | 0.012 | 0.07 | Yes |
2 | 0.32 (0.27–0.37) | 0.49 (0.41–0.59) | 0.89 (0.57–1.4) | 1.9E-06 | 2.1E-04 | 3.8E-06 | 7.0E-03 | Yes | |
5 | 0.55 (0.42–0.7) | 0.59 (0.46–0.74) | 1.7 (0.88–3.3) | 1.5E-03 | 0.67 | 6.4E-04 | 9.0E-04 | No | |
10 | 1.6 (1.3–1.9) | 2.1 (1.8–2.5) | 2.8 (1.9–4.2) | 1.0E-02 | 0.023 | 0.011 | 0.18 | No | |
IgG4 (μg/L) | 6m | 1.5E-04 (1.5E-04–1.5E-04) | 1.7E-04 (1.3E-04–2.1E-04) | 4.6E-04 (9.0E-05–2.4E-03) | 4.9E-03 | 0.37 | 5.2E-03 | 0.024 | Yes |
1 | 1.5E-04 (1.5E-04–1.5E-04) | 6.9E-04 (3.2E-04–1.5E-03) | 0.081 (4.6E-03–1.4) | 1.8E-10 | 5.2E-04 | 6.6E-12 | 2.2E-05 | Yes | |
2 | 3.4E-04 (1.8E-04–6.6E-04) | 4.8 (1.7–13) | 61 (8.9–419) | 1.8E-25 | 1.5E-22 | 8.6E-18 | 9.8E-05 | Yes | |
5 | 2 (0.48–8.1) | 168 (111–256) | 539 (317–917) | 1.1E-15 | 1.3E-12 | 1.0E-08 | 1.9E-04 | No | |
HDM cytokine response^ | |||||||||
IL-13 protein (pg/ml)^ | 0 | 0.22 (0.066–0.73) | 0.22 (0.076–0.63) | 0.085 (0.011–0.66) | 0.68 | 0.76 | 0.41 | 0.45 | No |
6m | 0.064 (0.022–0.18) | 0.06 (0.025–0.14) | 19 (1.4–244) | 4.6E-06 | 0.98 | 1.7E-05 | 4.1E-06 | No | |
5 | 0.13 (0.046–0.37) | 0.32 (0.11–0.87) | 12 (1.2–117) | 2.1E-04 | 0.29 | 7.7E-05 | 5.1E-04 | No | |
IL-5 protein (pg/ml)^ | 0 | 0.043 (0.018–0.11) | 0.026 (0.013–0.052) | 0.018 (5.0E-03–0.068) | 0.44 | 0.36 | 0.29 | 0.57 | No |
6m | 0.018 (9.2E-03–0.034) | 0.013 (8.9E-03–0.02) | 0.21 (0.012–3.7) | 7.9E-04 | 0.4 | 8.1E-03 | 3.5E-04 | No | |
5 | 0.028 (0.014–0.057) | 0.042 (0.02–0.087) | 2.3 (0.25–22) | 3.2E-06 | 0.45 | 5.7E-06 | 2.0E-05 | No | |
IL-13 mRNA^ | 0 | 1.7E-03 (1.1E-04–0.026) | 6.0E-03 (4.8E-04–0.075) | 6.7E-03 (3.3E-05–1.4) | 0.85 | 0.6 | 0.68 | 0.94 | No |
6m | 1.0E-04 (8.8E-06–1.1E-03) | 3.2E-04 (3.8E-05–2.6E-03) | 2 (0.015–266) | 3.2E-04 | 0.5 | 1.7E-04 | 3.8E-04 | No | |
5 | 0.036 (1.6E-03–0.8) | 0.11 (8.8E-03–1.4) | 2.9E + 03 (742–1.1E + 04) | 6.8E-05 | 0.59 | 9.9E-05 | 2.5E-05 | No | |
IL-4 mRNA^ | 0 | 1.4E-06 (6.9E-07–3.0E-06) | 1.9E-06 (7.8E-07–4.4E-06) | 1.0E-06 (1.0E-06–1.0E-06) | 0.71 | 0.65 | 0.6 | 0.47 | No |
6m | 4.6E-06 (1.0E-06–2.1E-05) | 5.1E-06 (1.4E-06–1.8E-05) | 0.54 (6.5E-03–44) | 6.2E-09 | 0.94 | 4.7E-07 | 1.0E-07 | No | |
5 | 2.3E-04 (1.7E-05–3.0E-03) | 4.7E-04 (5.3E-05–4.3E-03) | 5.3 (0.082–345) | 4.9E-04 | 0.72 | 4.5E-04 | 3.2E-04 | No | |
IL-5 mRNA^ | 0 | 2.5E-04 (2.1E-05–2.9E-03) | 2.6E-04 (2.8E-05–2.5E-03) | 1.2E-05 (3.1E-07–4.6E-04) | 0.47 | 0.96 | 0.24 | 0.25 | No |
6m | 5.2E-05 (5.6E-06–4.8E-04) | 3.1E-05 (5.2E-06–1.8E-04) | 0.33 (1.3E-03–83) | 1.5E-04 | 0.85 | 2.3E-04 | 1.1E-04 | No | |
5 | 0.021 (9.9E-04–0.43) | 0.07 (5.7E-03–0.85) | 246 (7–8.7E + 03) | 1.3E-04 | 0.49 | 7.1E-05 | 1.1E-04 | No | |
Prop. (95% CI) | Prop. (95% CI) | Prop. (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
HDM SPT past atopy threshold | |||||||||
Wheal ≥ 2 mm | 6m | 2.3% (0–5.4%) | 1.9% (0–4.5%) | 14% (0–29%) | 0.043 | 1 | 0.054 | 0.035 | No* |
2 | 10% (3.8–17%) | 15% (8.1–22%) | 86% (71–100%) | 2.9E-12 | 0.39 | 8.2E-12 | 1.5E-10 | No* | |
Wheal ≥ 3 mm | 5 | 13% (5.2–20%) | 28% (18–37%) | 81% (63–99%) | 1.5E-08 | 0.022 | 4.6E-09 | 1.0E-05 | No |
10 | 36% (23–49%) | 51% (38–63%) | 78% (57–99%) | 7.4E-03 | 0.11 | 2.7E-03 | 0.06 | No |
Feature?=whether variable was used as a clustering feature or not; geom. mean = geometric mean; PBMC = peripheral blood mononuclear cells; prop. = proportion; SPT = skin prick or sensitisation test. For categorical variables, associations were tested using Fisher exact test; for continuous variables, Kruskal-Wallis and Mann-Whitney-Wilcoxon. Bold text indicates statistical significance (p<0.05); italics indicate near-significance (p<0.10). ^PBMC cytokine responses to HDM above unstimulated control; birth samples (age 0) taken from cord blood (CBMC). *Not used as clustering features, as these were derived variables; the variables from which they were derived (HDM IgE and IgG4) were used instead.
Variable | Age (y) | Cas1 (N = 88) | Cas2 (N = 107) | Cas3 (N = 22) | P-value (unadjusted) | Feature? | |||
---|---|---|---|---|---|---|---|---|---|
Mean (95% CI) | Mean (95% CI) | Mean (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
URI (events per y) | 1 | 2.9 (2.4–3.3) | 2.6 (2.2–3) | 2.5 (1.7–3.3) | 0.59 | 0.34 | 0.5 | 0.96 | Yes |
2 | 3.2 (2.6–3.7) | 2.6 (2.2–3) | 2.5 (1.2–3.8) | 0.19 | 0.19 | 0.12 | 0.34 | Yes | |
3 | 2.7 (2.2–3.2) | 2.8 (2.4–3.3) | 2.2 (1.3–3.2) | 0.45 | 0.41 | 0.59 | 0.24 | Yes | |
4 | 2.1 (1.7–2.6) | 2.2 (1.8–2.7) | 1.7 (0.77–2.7) | 0.5 | 0.94 | 0.26 | 0.27 | No | |
5 | 1.6 (1.1–2) | 1.5 (1.2–1.9) | 0.67 (0.2–1.1) | 0.081 | 0.76 | 0.047 | 0.026 | No | |
LRI (events per y) | 1 | 1.6 (1.2–1.9) | 0.98 (0.76–1.2) | 2 (1.3–2.6) | 4.0E-03 | 0.021 | 0.17 | 2.6E-03 | Yes |
2 | 1.4 (0.98–1.7) | 1 (0.81–1.2) | 2.2 (1.6–2.9) | 2.5E-03 | 0.83 | 6.1E-03 | 2.0E-04 | Yes | |
3 | 1 (0.76–1.3) | 0.6 (0.4–0.8) | 1.8 (1.1–2.6) | 6.1E-04 | 0.02 | 0.039 | 2.7E-04 | Yes | |
4 | 0.87 (0.52–1.2) | 0.46 (0.3–0.63) | 2 (1.1–2.8) | 1.7E-05 | 0.3 | 3.5E-04 | 1.6E-06 | No | |
5 | 0.42 (0.24–0.6) | 0.36 (0.24–0.48) | 0.86 (0.44–1.3) | 0.019 | 1 | 0.011 | 7.5E-03 | No | |
Wheezy LRI (wLRI, events per y) | 1 | 0.47 (0.3–0.63) | 0.24 (0.15–0.34) | 0.64 (0.19–1.1) | 0.054 | 0.036 | 0.61 | 0.065 | Yes |
2 | 0.68 (0.45–0.91) | 0.41 (0.26–0.56) | 1 (0.56–1.5) | 5.2E-03 | 0.063 | 0.066 | 1.7E-03 | Yes | |
3 | 0.59 (0.37–0.81) | 0.3 (0.17–0.44) | 1.4 (0.78–2.1) | 4.6E-05 | 0.065 | 2.5E-03 | 6.6E-06 | Yes | |
4 | 0.52 (0.25–0.79) | 0.32 (0.18–0.46) | 1.9 (0.95–2.8) | 4.5E-08 | 0.86 | 9.3E-07 | 3.3E-08 | No | |
5 | 0.28 (0.13–0.42) | 0.23 (0.13–0.33) | 0.76 (0.36–1.2) | 2.3E-03 | 0.99 | 2.0E-03 | 1.2E-03 | No | |
Febrile LRI (fLRI, events per y) | 1 | 0.36 (0.22–0.51) | 0.28 (0.16–0.4) | 0.55 (0.28–0.81) | 0.025 | 0.24 | 0.071 | 6.4E-03 | Yes |
2 | 0.36 (0.23–0.5) | 0.33 (0.22–0.43) | 0.95 (0.46–1.4) | 0.01 | 1 | 6.1E-03 | 3.8E-03 | Yes | |
3 | 0.38 (0.21–0.55) | 0.16 (0.09–0.23) | 0.52 (0.13–0.92) | 0.06 | 0.063 | 0.44 | 0.04 | Yes | |
4 | 0.3 (0.13–0.47) | 0.15 (0.064–0.24) | 0.43 (0.16–0.7) | 0.021 | 0.18 | 0.091 | 4.9E-03 | No | |
5 | 0.19 (0.082–0.3) | 0.14 (0.06–0.21) | 0.19 (0–0.42) | 0.83 | 0.55 | 0.91 | 0.8 | No | |
Prop. (95% CI) | Prop. (95% CI) | Prop. (95% CI) | Overall | Cas1 vs. 2 | Cas1 vs. 3 | Cas2 vs. 3 | |||
>20% Streptococcus in first infection-naive NPA sample | 7w | 11% (0.34–23%) | 15% (3.3–26%) | 44% (3.9–85%) | 0.081 | 0.75 | 0.042 | 0.065 | No |
6m | 7.6% (1.6–14%) | 18% (10–26%) | 14% (0–31%) | 0.12 | 0.045 | 0.39 | 1 | No | |
% Healthy NPAs with infection-associated MPGs | 0–2 | 49% (38–59%) | 32% (24–39%) | 62% (47–76%) | 1.2E-03 | 0.013 | 0.2 | 5.5E-04 | No |
2–4 | 46% (37–55%) | 44% (37–51%) | 45% (29–61%) | 0.9 | 0.67 | 0.92 | 0.8 | No |
Feature?=whether variable was used as a clustering feature or not; geom. mean = geometric mean; ARI = acute respiratory infection (lower or upper); LRI = lower respiratory infection; MPG = microbiome profile group; NPA = nasopharyngeal aspirate; prop. = proportion; URI = upper respiratory infection; 7w = 7 weeks. For categorical variables, associations were tested using Fisher exact test; for continuous variables, Kruskal-Wallis and Mann-Whitney-Wilcoxon. Bold text indicates statistical significance (p<0.05); italics indicate near-significance (p<0.10). *Not used as clustering features, as these were derived variables; the variables from which they were derived (URI, LRI, wLRI, fLRI) were used instead.
Selected predictors for age-5 wheeze | |||||||||
---|---|---|---|---|---|---|---|---|---|
Cas1 (N = 88) Or (95% CI) | P-value | Cas2 (N = 107) Or (95% CI) | P-value | Cas3 (N = 22) Or (95% CI) | P-value | Or (95% CI) | P-value | ||
LRI (events per y) | 1 | 0.97 (0.71–1.3) | 0.84 | 1 (0.61–1.5) | 0.99 | 0.48 (0.13–1.1) | 0.16 | 1 (0.81–1.2) | 0.92 |
2 | 1.2 (0.88–1.6) | 0.26 | 1.5 (0.97–2.5) | 0.069 | 0.99 (0.34–2.6) | 0.98 | 1.4 (1.1–1.7) | 5.3E-03 | |
3 | 2 (1.3–3.2) | 2.3E-03 | 2.6 (1.5–5.3) | 2.7E-03 | 0.98 (0.4–2.6) | 0.96 | 2 (1.5–2.7) | 3.8E-06 | |
4 | 2 (1.4–3.4) | 2.0E-03 | 3.6 (1.8–8.3) | 6.5E-04 | 1.9 (0.57–8.4) | 0.32 | 2.5 (1.8–3.6) | 1.5E-07 | |
Wheezy LRI (events per y) | 1 | 1.3 (0.68–2.4) | 0.43 | 1.1 (0.35–3) | 0.83 | 2.6 (0.62–58) | 0.34 | 1.5 (0.98–2.3) | 0.06 |
2 | 1.2 (0.8–2) | 0.33 | 1.6 (0.89–2.9) | 0.12 | 2.4 (0.67–16) | 0.24 | 1.6 (1.2–2.2) | 5.6E-03 | |
3 | 2.8 (1.6–5.6) | 1.3E-03 | 3 (1.4–8) | 0.016 | 1.2 (0.43–4.6) | 0.76 | 2.7 (1.8–4.2) | 4.1E-06 | |
4 | 2.5 (1.5–5) | 4.0E-03 | 6.3 (2.5–21) | 6.8E-04 | 7.1 (1.2–169) | 0.1 | 3.9 (2.5–6.7) | 5.4E-08 | |
Febrile LRI (events per y) | 1 | 1.6 (0.77–3.6) | 0.21 | 0.84 (0.28–1.9) | 0.71 | 7.3 (0.78–178) | 0.12 | 1.5 (0.93–2.4) | 0.098 |
2 | 1 (0.44–2.2) | 1 | 4.8 (1.8–15) | 3.9E-03 | 1.6 (0.48–10) | 0.5 | 2.3 (1.4–3.9) | 1.2E-03 | |
3 | 2 (1–4.8) | 0.08 | 4.3 (1.2–15) | 0.02 | 4.2 (0.55–519) | 0.37 | 2.4 (1.4–4.3) | 2.3E-03 | |
4 | 1.8 (0.97–4.1) | 0.092 | 2.6 (0.88–8.3) | 0.082 | 1.1 (0.11–18) | 0.93 | 2.2 (1.3–4) | 5.9E-03 | |
Quartile of % healthy NPAs with infection-associated MPGs | 0–2 | 1 (0.54–1.8) | 0.98 | 1.3 (0.72–2.4) | 0.36 | NA | NA | 1.3 (0.89–1.8) | 0.19 |
2–4 | 0.45 (0.19–0.88) | 0.035 | 1 (0.51–2.1) | 0.9 | NA | NA | 0.8 (0.53–1.2) | 0.24 | |
HDM IgE (kU/L)* | 6m | 8 (0.85–94) | 0.074 | 0.93 (0.14–3.6) | 0.92 | 3.4 (0.26–180) | 0.4 | 2.3 (0.99–5.8) | 0.054 |
1 | 1.5 (0.22–7.8) | 0.65 | 0.54 (0.039–2.3) | 0.51 | 39 (2.5–22000) | 0.082 | 2.7 (1.5–5) | 0.00089 | |
2 | 0.93 (0.28–2.5) | 0.89 | 2 (1.2–3.7) | 0.016 | 1.4 (0.38–4.8) | 0.62 | 2 (1.5–2.8) | 2.80E-05 | |
3 | 1.4 (0.68–2.9) | 0.32 | 1.5 (0.9–2.4) | 0.12 | 1.5 (0.4–5.2) | 0.55 | 1.7 (1.3–2.2) | 1.00E-04 | |
4 | 1.9 (0.94–4.1) | 0.086 | 1.9 (1.2–3.1) | 0.011 | 1.4 (0.31–5.5) | 0.64 | 1.9 (1.5–2.5) | 3.70E-06 | |
HDM IgG4 (μg/L)* | 6m | NA (NA-NA) | 0.55 | 0.053 (NA-6.5e + 24) | 0.99 | 28 (1.7e-34-NA) | 0.99 | 1.4 (0.88–2.6) | 0.17 |
1 | NA (NA-NA) | 0.61 | 1.1 (0.8–1.5) | 0.5 | 0.9 (0.58–1.3) | 0.6 | 1.2 (1–1.4) | 0.053 | |
2 | 1.1 (0.71–1.6) | 0.67 | 1.1 (0.85–1.4) | 0.61 | 0.4 (0.038–1.2) | 0.26 | 1.1 (1–1.3) | 0.056 | |
3 | 1.1 (0.85–1.5) | 0.35 | 1.1 (0.77–2) | 0.64 | 0.94 (0.19–2.3) | 0.9 | 1.1 (0.98–1.2) | 0.1 | |
4 | 1.2 (0.98–1.5) | 0.082 | 0.89 (0.7–1.1) | 0.33 | 0.46 (0.031–5.4) | 0.53 | 1.1 (1–1.3) | 0.034 | |
HDM IgG (mg/L)* | 1 | 25 (0.32–1.6E + 04) | 0.19 | 3.3 (0.16–46) | 0.38 | 5.6E-03 (8.4E-06–0.57) | 0.058 | 2 (0.31–11) | 0.44 |
2 | 0.8 (0.15–3.5) | 0.78 | 0.97 (0.24–3.7) | 0.96 | 0.79 (0.031–18) | 0.88 | 1.3 (0.6–2.9) | 0.48 | |
3 | 2.3 (0.14–35) | 0.54 | 0.48 (0.057–2.5) | 0.43 | 3.9 (0.26–96) | 0.34 | 2.1 (0.89–5) | 0.089 |
BMI = body mass index; HDM = house dust mite; LRI = lower respiratory infection. Association analyses performed via generalised linear models (GLM) with demographic covariates: age-5 wheeze ~predictor + sex (male) +BMI at age 3 + paternal history of asthma +maternal history of asthma. Bold text indicates statistical significance (p<0.05); italics indicate near-significance (p<0.10). *Odds ratio (OR) is for every 10-fold increase in IgE, IgG4 or IgG.
Certain childhood populations may be broadly split into three clusters, each representing a unique trajectory of immune function and susceptibility to respiratory infections: low-risk non- atopic Cluster 1 with transient wheeze; low-risk but allergy-susceptible Cluster 2 with mixed wheeze; and strongly-atopic high-risk Cluster 3 with persistent wheeze. |
Cluster 3 is consistent with an early-sensitised and multi-sensitised phenotype. |
HDM hypersensitivity is an important predictor of wheeze in allergic or allergy -susceptible individuals. |
Food and peanut hypersensitivities are important contributors to membership in high-risk Cluster 3. This may be pathophysiologically related to eczema, multi-sensitisation and the atopic march. |
In CAS, IgG4 flags for clusters with susceptibility to atopic disease (CAS2 and CAS3), while early and multiple-allergen elevation in IgE predicts frank atopic disease. The pathophysiological role of IgG4 remains unclear. |
Allergic and infective processes act additively to intensify airway inflammation during respiratory pathogen clearance. Some (Cluster 3) may be more susceptible to this effect than others that lack strong allergic sensitisation (Cluster 1). |
Tests for atopy (IgE, SPT, cytokines) do not overlap perfectly. Therefore, atopy may be better defined by the composite result from a battery of tests encapsulated in a predictive model, rather than just a single test or threshold. |
The microbiome acts differently on asthma risk depending on cluster membership. In CAS, early-life asymptomatic colonisation with infection-associated MPGs is associated with risk of persistent wheeze in allergy-susceptible clusters (CAS2, CAS3), while it is potentially protective in non-atopic children (CAS1) |
Different childhood populations may share similar trajectories of asthma susceptibility, but there may be subtle differences in terms of the types of tests, allergens, or biological signals that are most informative (SPT, IgE, cytokines, etc.). |
Reagent type (species) or resource | Designation | Source or reference | Identifiers |
---|---|---|---|
Biological sample (Homo sapiens) | Childhood Asthma Study (CAS) | DOI:10.1016/j.jaci.2005.06.038 | Microbiome sequencing data: NCBI GenBank SRP056779 |
Biological sample (Homo sapiens) | Childhood Origins of Asthma Study (COAST) | PMID:12688623 | NA |
Biological sample (Homo sapiens) | Manchester Asthma and Allergy Study (MAAS) | PMID:12688622 | NA |
Software, algorithm | The R project for Statistical Computing | ISBN:3-900051-07-0 | RRID:SCR_001905 |
Software, algorithm | ggplot2 | ISBN:978-3-319-24277-4 | RRID:SCR_014601 |
Software, algorithm | mixtools | DOI:10.18637/jss.v032.i06 | NA |
Software, algorithm | rpart | Therneau and Atkinson, 2015. Package 'rpart'. URL: https://cran.r-project.org/web/packages/rpart/rpart.pdf | NA |
Software, algorithm | epiDisplay | Chongsuvivatwong, 2015. Package 'epiDisplay' URL: https://cran.r-project.org/web/packages/epiDisplay/epiDisplay.pdf | NA |
All table supplements
Comparison of variables (respiratory, immunological, clinical) across CAS clusters.
Analogous to Table Supplement 3.
Predictors for age-five wheeze within each CAS cluster, with demographic covariates (sex, BMI, parental history of asthma).
Analogous to Table Supplement 7.