Loss of adaptive capacity in asthmatic patients revealed by biomarker fluctuation dynamics after rhinovirus challenge

  1. Anirban Sinha  Is a corresponding author
  2. René Lutter
  3. Binbin Xu
  4. Tamara Dekker
  5. Barbara Dierdorp
  6. Peter J Sterk
  7. Urs Frey
  8. Edgar Delgado Eckert
  1. Amsterdam UMC, University of Amsterdam, Netherlands
  2. University of Basel, Switzerland
  3. University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, France
20 figures, 15 tables and 3 additional files

Figures

Cluster dendrogram obtained via hierarchical clustering of the participants’ pre- and post-challenge time series of FeNO.

The distance between any two-time series was calculated using the EMD. Rectangles mark the clusters and sub-clusters identified. From top to bottom: Cluster 1, Cluster 2 (subdivided into Clusters 2.1, 2.2, and 2.3), and Cluster 3 (subdivided into Clusters 3.1 and 3.2, and 3.3). Patient IDs are indicated by Pxy, their health status using H/A, denoting Healthy or Asthmatic, and their RV infection status by Uninf/Inf, which stands for Uninfected/Infected. Cluster 1 consists of time series from asthmatics which are prominently different from those from other asthmatic subjects in Cluster three and also from healthy subjects in Cluster 2. These might be regarded as outliers.

Analysis of biomarker time series in healthy and asthmatic populations using the "Earth Mover's Distance" metric.

(A) Depicts two pre-challenge time series of FeNO obtained from a healthy (blue curve), and from an asthmatic (red curve) participant, respectively. (B) Each of the time series is represented as empirical distribution. This representation of the two time series allows for the calculation of a distance or ‘dissimilarity’ between the two by means of the Earth Mover’s Distance (EMD). The EMD-comparison of all possible pairs of time series (both pre- and post-challenge) results in a symmetric matrix of pair-wise distances, as shown in (C) using a color-coded (violet to green) heat-map. Each row in this matrix corresponds to one time series. The color bar on the left hand side of the matrix encodes the ‘type’ of time series: Cyan marks a pre-challenge time series originating from a healthy participant; Blue marks a post-challenge time series originating from a healthy participant; Pink marks a pre-challenge time series originating from an asthmatic participant; Red marks a post-challenge time series originating from an asthmatic participant. The information stored in the matrix of pair-wise distances is then used within an agglomerative clustering algorithm in order to group the time series in different clusters. The outcome of this procedure is represented using a dendrogram as depicted in Figure 1 above.

Estimation of short term responses in biomarker time series induced by viral challenge.

(A) Graphical representation of a biomarker time series ti. For the calculation of short-term/transient changes, a gliding interval or window is moved, one day at a time, along the time series. The relative change between the first and last entry of the gliding window is calculated, resulting in a new time series of short-term relative changes ri. (B) A healthy participant’s time series of short-term relative changes in FeNO is depicted. A gliding interval of size 10 days was used to calculate it from the participant’s time series of FeNO measurements. The start position of the gliding window is expressed relative to the day of the viral challenge, which is marked as day 0. When the position of the gliding window was such that the day of the viral challenge was contained within the gliding window, the corresponding value of the relative change is marked in red. In order to assess the statistical significance of the short-term relative changes possibly elicited by the viral challenge, the relative change values located to the left of those marked in red were compared to the values marked in red by means of a Mann-Whitney-U-test. Visual inspection of the time series in B correctly suggests that the outcome of this test is not significant. The reason being that the relative changes within time intervals of 10 days observed prior to the viral challenge are comparable to changes observed within intervals of the same length containing the day of the viral challenge. (C) Depicting data from a different healthy participant, the situation is clearly different, as verified by a significant outcome of the corresponding Mann-Whitney-U-test. In such cases, the participant is called a ‘responder’ with respect to the ‘relative change within 10 days criterion’.

Appendix 1—figure 1
Dendrogram obtained from clustering the participants’ time series of the percentage of eosinophils in nasal lavage fluid using the EMD.
Appendix 1—figure 2
The boxplot to the left represents the distribution of cophenetic distances between time series corresponding to infected healthy participants and their uninfected counterparts.

Only time series belonging to Cluster two in the clustering dendrogram obtained using the percentage of eosinophils in nasal lavage fluid (see Appendix 1—figure 1 above) are contemplated here. The boxplot to the right represents the distribution of cophenetic distances between time series corresponding to infected asthmatic participants and their uninfected counterparts. Only time series belonging to Cluster three in the clustering dendrogram obtained using the percentage of eosinophils in nasal lavage fluid (see Appendix 1—figure 1 above) are contemplated here. The two distributions are statistically significantly different (p-value=8.96e-05, one-tailed Mann-Whitney-U-test, the cophenetic distances in Cluster three being, on average, higher than the ones in Cluster 2.

Appendix 1—figure 3
The boxplot to the left represents the distribution of cophenetic distances between time series corresponding to infected healthy participants and their uninfected counterparts.

Only time series belonging to Cluster two in the clustering dendrogram obtained using FeNo data (see Figure 1 in the Main Manuscript) are contemplated here. The boxplot to the right represents the distribution of cophenetic distances between time series corresponding to infected asthmatic participants and their uninfected counterparts. Only time series belonging to Cluster three in the clustering dendrogram obtained using FeNo data (see Figure 1 in the Main Manuscript) are contemplated here. The two distributions are statistically significantly different (p-value=0.033, one-tailed Mann-Whitney-U-test, the cophenetic distances in Cluster three being, on average, higher than the ones in Cluster 2.

Appendix 1—figure 4
Dendrogram obtained from clustering the participants’ time series of cell density (millions per ml) in nasal lavage fluid using the EMD.
Appendix 1—figure 5
Dendrogram obtained from clustering the participants’ time series of the percentage of neutrophils in nasal lavage fluid using the EMD.
Appendix 1—figure 6
Dendrogram obtained from clustering the participants’ time series of the normalized ratio FEV1/FVC using the EMD.
Appendix 1—figure 7
Dendrogram obtained from clustering the participants’ time series of PEF (% predicted) using the EMD.
Appendix 1—figure 8
Dendrogram obtained from clustering the participants’ time series of normalized FEV1 using the EMD.
Appendix 1—figure 9
Dendrogram obtained from clustering the participants’ time series of normalized FVC using the EMD.
Appendix 1—figure 10
Boxplots demonstrating the distribution of autocorrelation coefficient at 1 day lag for FEV1 before and after viral challenge in healthy and asthma groups.

A 2-way ANOVA resulted in no significant differences.

Appendix 1—figure 11
Boxplots demonstrating the distribution of autocorrelation coefficient at 1 day lag for FEV1/FVC before and after viral challenge in healthy and asthma groups.

A 2-way ANOVA resulted in a significant impact of the infection status on the autocorrelation coefficient (p<1e-07).

Appendix 1—figure 12
Boxplots demonstrating the distribution of autocorrelation coefficient at 1 day lag for FVC before and after viral challenge in healthy and asthma groups.

A 2-way ANOVA resulted in a significant impact of the infection status on the autocorrelation coefficient (p=0.0007).

Appendix 1—figure 13
Boxplots demonstrating the distribution of autocorrelation coefficient at 1 day lag for PEF (% predicted) before and after viral challenge in healthy and asthma groups.

The data did not fulfil the conditions for a 2-way ANOVA. Pairwise comparisons were carried out (t-test or Mann-Whitney-test, depending on whether the data fulfilled the conditions for a t-test). The tests used to compare pre- vs. post-challenge status within the two groups (healthy and asthma) were paired tests. Only significant p-values without multiple pairwise-comparison correction are displayed.

Appendix 1—figure 14
Boxplots demonstrating the distribution of autocorrelation coefficient at 2 days lag for FeNO before and after viral challenge in healthy and asthma groups.

The data did not fulfil the conditions for a 2-way ANOVA. Pairwise comparisons were carried out (t-test or Mann-Whitney-test, depending on whether the data fulfilled the conditions for a t-test). The tests used to compare pre- vs. post-challenge status within the two groups (healthy and asthma) were paired tests. Only significant p-values without multiple pairwise-comparison correction are displayed.

Appendix 1—figure 15
Schematic representation of the study design.
Appendix 1—figure 16
Panel A: Cluster dendrogram obtained via hierarchical clustering of the participants’ pre- and post-challenge time series of FeNO.

The distance between any two-time series was calculated using the EMD. Rectangles mark the clusters identified. Panel B displays a more detailed view of the second cluster. According to the definition of neighboring leaves provided in the text above, the leaves P03H_Uninf and P03H_Inf are neighbors in this dendrogram (highlighted in red). The reason for this is that the cophenetic distance from leaf P03H_Uninf to leaf P03H_Inf is equal to the minimum of all distances from leaf P03H_Uninf to all other leaves in the dendrogram. This is not the case for the leaf P03H_Inf. However, the fact that this condition holds for at least one of the two leaves renders them neighboring. Leaves P08H_Inf and P08H_Uninf, and P11H_Inf and P11H_Uninf, are neighbors, respectively (the latter pair is not marked in color). P08A_Inf and P08A_Uninf are also neighbors; In this case, the minimum condition is fulfilled by both leaves for of this leaf-pair. This is why the two leaves form a two-element cluster in the dendrogram. Panel C displays a more detailed view of the third cluster. Analogous information about neighboring leaves in Cluster three is highlighted in blue. However, as opposed to Cluster 2 (depicted in Panel B), the amount of neighboring leaves in Cluster three is not statistically significant (permutation test, see Table 2 in the Main Manuscript).

Appendix 1—figure 17
Dendrogram obtained from clustering the participants’ pre- and post-challenge average value of FeNO using the EMD.

Tables

Table 1
Biomarkers/parameters measured in each cohort participant during two months before, and during one month immediately after deliberate experimental inoculation with rhinovirus.

The corresponding sampling frequencies can be found in columns 2 and 3. See the Materials and methods section below for more details on the study design, and on the measurement procedures and laboratory assays used. FEV1: forced expiratory volume in one second. FVC: forced vital capacity. PEF: peak expiratory flow. FeNO: fractional expired concentration of nitric oxide.

Biomarker or parameterSampling frequency before rhinovirus challengeSampling frequency after rhinovirus challenge
Lung function (FEV1, FVC, FEV1/FVC, PEF)2x daily2x daily
Exhaled Nitric Oxide (FeNO)3x weekly3x weekly
Eosinophil and neutrophil cell density in nasal lavage fluid1x weekly3x weekly
Table 2
Composition, enrichment analysis, and grouping characteristics of the clusters found by comparison of each participant’s pre- and post-challenge time series of FeNO.

Enrichment is marked in bold letters, depletion in italics; the corresponding p-values were calculated using the hypergeometric test. The empirical p-values for the proportion of pre- and post-pairs were calculated using simulated permutations (see Materials and methods section). A participant is fully represented in a given cluster if both their pre- and post-challenge time series of measurements are contained in the cluster. For example, the healthy participant ‘P08H’ is fully represented in Cluster 2, as both their pre- and post-challenge time series of FeNO measurements are members of Cluster 2 (see Figure 1 below). Partial representation corresponds to the scenario in which only one of the two time series (pre- and post-challenge) is a member of the cluster. For instance, the asthmatic participant " P07A’ is only partially represented in Cluster 2, because their pre-challenge time series of FeNO measurements is part of Cluster 2, whereas their post-challenge time series of FeNO belongs to Cluster 3 (see Figure 1 below). See also the Materials and methods section for the definition of neighbors.

Characteristic \ cluster numberCluster 1Cluster 2Cluster 3
Size (%)4 (8.33 %)26 (54.17 %)18 (37.5 %)
Fully represented healthy participants0110
Partially represented healthy participants011
Fully represented asthmatic participants218
Partially represented asthmatic participants011
Number of time series from healthy participants (%)0 (0%)23 (88.46 %)1 (5.56 %)
p-value of enrichment/depletion in time series from healthy participants0.0551.78E-091.15E-06
Number of neighboring pre- and post-pairs (%)2 (100 %)4 (28.57 %)2 (20 %)
Empirical p-value (probability of observing, under the null hypothesis, the number of neighboring pre- and post-pairs found in the data, as listed in the previous row above)0.0030.0070.097
Table 3
Enrichment analysis of the sub-clusters found within the clusters described in Table 2 above (the clusters marked with orange and blue rectangles in Figure 1).

Enrichment in pre-challenge time series is marked in bold letters, depletion of pre-challenge time series (and consequently enrichment in post-challenge time series) in italics; the corresponding p-values were calculated using the hypergeometric test.

Sub-cluster number
\ characteristic
Size (%)Number of pre-challenge series (%)p-value
Cluster 2.17 (26.92 %)3 (42.86 %)0.404
Cluster 2.211 (42.31 %)8 (72.73 %)0.104
Cluster 2.38 (30.77 %)3 (37.5 %)0.246
Cluster 3.1 and 3.213 (72.22 %)8 (61.54 %)0.029
Cluster 3.35 (27.78 %)0 (0.00 %)0.029
Table 4
Composition, enrichment analysis, and grouping characteristics of the clusters found by comparison of each participant’s pre- and post-challenge time series of percentage of eosinophils in nasal lavage fluid.

Enrichment is marked in bold letters, depletion in italics; the corresponding p-values were calculated using the hypergeometric test. The empirical p-values for the proportion of pre- and post-pairs were calculated using simulated permutations (see Materials and methods section). A participant is fully represented in a given cluster if both their pre- and post-challenge time series of measurements are contained in the cluster. Partial representation corresponds to the scenario in which only one of the two time series (pre- and post-challenge) is a member of the cluster. See also the Materials and methods section for the definition of neighbors.

Characteristic \ cluster numberCluster 1Cluster 2Cluster 3
Size (%)4 (8.33 %)26 (54.17 %)18 (37.50 %)
Fully represented healthy participants0111
Partially represented healthy participants000
Fully represented asthmatic participants127
Partially represented asthmatic participants202
Number of time series from healthy participants (%)0 (0%)22 (84.62 %)2 (11.11 %)
p-value of enrichment/depletion in time series from healthy participants0.0551.09E-072.89E-05
Number of neighboring pre- and post-pairs (%)1 (33.33 %)5 (38.46 %)1 (10 %)
Empirical p-value (probability of observing,
under the null hypothesis, the number of neighboring pre- and post-pairs found in the data, as listed in the previous row above)
0.1230.0010.424
Table 5
Proportions of responders within the groups of healthy and asthmatic participants, respectively.

Two different criteria were used in order to establish a statistically significant response. According to the first criterion, a participant is considered a responder with respect to a given biomarker if the outcome of comparing the pre-challenge time series and the post-challenge time series of the same biomarker by means of the Kolmogorov-Smirnov test results in a p-value<=0.05 (columns 2 and 3). According to the second criterion, a participant is considered a responder with respect to a given biomarker if the outcome of comparing, by means of a Mann-Whitney-U-test, the magnitude of relative changes observed during 10 day time intervals prior to the challenge with the magnitude of relative changes that took place during 10 day time intervals that contained the day of the challenge results in a p-value<=0.05 (columns 4 and 5). For calculating the proportion of responders within each group the p-values were corrected for multiple testing using the false discovery rate (FDR) method of Benjamini and Hochberg. FEV1: forced expiratory volume in one second. FVC: forced vital capacity. PEF: peak expiratory flow. FeNO: fractional expired concentration of nitric oxide. The lung function parameters FEV1 and FVC, and thereby their ratio FEV1/FVC, were normalized using the standardized reference equations recommended by Global Lung Function Initiative (GLI) Task Force for comparisons across different populations.

Biomarker name% Healthy responders (distributional changes)% Asthmatic responders
(distributional changes)
% Healthy responders
(relative change within 10 days)
% Asthmatic responders
(relative change within 10 days)
PEF (% of predicted)50.0%75.0%0.0%0.0%
Normalized FEV175.0%66.7%0.0%0.0%
Normalized FVC83.3%100.0%0.0%0.0%
Normalized FEV1/FVC75.0%66.7%16.7%0.0%
FeNO8.3%0.0%41.7%8.3%
Cell density in nasal lavage fluid0.0%0.0%66.7%41.7%
Neutrophils in nasal lavage fluid (%)0.0%0.0%25.0%16.7%
Eosinophils in nasal lavage fluid (%)8.3%0.0%0.0%16.7%
Table 6
The demographics of the study population.

BMI is Body Mass Index. Only one healthy subject smoked two pack years or less 2 years before recruitment to our study, which is considered an insignificant smoking history. FEV1: forced expiratory volume in one second. PEF: peak expiratory flow.

Demographic featuresHealthyAsthmatic
Total number, n1212
Female gender, n (%)7 (58.3%)8 (66.7%)
Age (years), mean (SD)21 ± 1.522.2 ± 2.2
Ethnicity (Caucasian), n (non-Caucasian, n)119
BMI, mean (SD)22.2 ± 1.622.8 ± 3.1
Smoking (pack years), n1 (0.17 PY)--
Height (centimeters)177.7 ± 8.6172.5 ± 13.0
Weight (KG)70.4 ± 10.167.8 ± 12.4
Baseline spirometry
FEV1 %predicted105.7 ± 11.6101.0 ± 10.0
FVC %predicted104.2 ± 10.5104.2 ± 10.2
PEF %predicted108.4 ± 14.0104.7 ± 12.2
mean ± standard deviation
Table 7
Basic characteristics of the study population.
HealthyAsthmatics
No history of episodic chest symptomsHistory of episodic chest symptoms
Baseline FEV1 ≥ 80% predictedBaseline FEV1 ≥ 70% predicted
AHR to methacholine (PC20) ≥ 19.6 mg/mlAHR to methacholine (PC20) ≤ 9.8 mg/ml
SPT negative for all 12 common
Aeroallergens
SPT positive for at least 1 out of 12 common
Aeroallergens
  1. FEV1: forced expiratory volume in one second, AHR: Airway Hyper Responsiveness, PC20: Provocative Concentration causing a 20% fall in FEV1, SPT: Skin Prick Test.

Table 8
The overview of different measurements performed in the study along with the frequency of sampling before and after rhino-virus challenge.

Measures 1–4 include repeated measurements and 5,6 represent one-time measurement to screen the subjects for the study. eight refers to the experimental intervention in the study. FEV1: forced expiratory volume in one second. FVC: forced vital capacity. PEF: peak expiratory flow. FeNO: fractional expired concentration of nitric oxide.

Measurements of biomarkersFrequency before rhinovirus challengeFrequency after rhinovirus challenge
Lung function with pocket-size spirometers (FEV1, FVC, FEV1/FVC, PEF)2x daily2x daily
Exhaled Nitric Oxide (FeNO)3x weekly3x weekly
Differential cell counts1x weekly3x weekly
Asthma Control Questionnaire2x daily2x daily
SpirometryPerformed once during screening to include subjects in the study
Methacholine challengePerformed once during screening to include subjects in the study
Rhinovirus challengePerformed after 2 months into the study
Appendix 1—table 1
Effectiveness of the viral challenge in asthmatic and healthy participants, respectively.

A participant is considered to have a successful viral inoculation if any one of the three tests is positive. one indicates positive response and 0 indicates a failed response in the corresponding tests indicated in columns.

Study volunteersResponders by seroconversionResponders by RVPCRDescription of symptoms
01A11Running nose, blocked nose and cough
02A01Sore throat, blocked nose, full head, coughing and sneezing.
04A10Slight symptoms of cold, very mild
05A01No clear symptoms
06A11Symptoms of cold
07A11Minor sore throat, dripping nose, shortness of breath.
08A10Sore throat, Probably very mild effect, no other symptoms
09A01Running nose, head ache, fever
10A11Very mild symptoms
11A11Very mild symptoms
12A01Cough, blocked nose
13A01No clear symptoms
01H01Sore throat
03H01Sore throat and blocked nose
05H11Cough, blocked nose and headache
06H01No clear symptoms observed
07H10Sneezing, itchy eyes and a little bit of a cough
08H11Little bit sore throat
09H11Sore throat and little cough
11H00Blocked nose and sputum
12H11Running nose and sneeze
13H11No clear symptoms
14H01Cough and blocked nose
15H10No clear symptoms
Appendix 1—table 2
P-values of the group comparisons regarding the Pearson autocorrelation coefficient at respective lags of the biomarker time series as listed in the first column.

When the data did not fulfil the requirements for a 2-way ANOVA, pairwise comparisons were conducted followed by correction for multiple testing using the FDR method.

BiomarkerLagP-values asthmatic vs. healthy participants prechallengeP-values asthmatic vs. healthy participants postchallengeP-values prechallenge vs. postchallenge in healthy participantsP-values prechallenge vs. postchallenge in asthmaticsP-values interaction (2-way ANOVA)
 Normalized FEV11 day0.44310.44310.2820.2820.737
 Normalized FEV1/FVC1 day0.86640.8664<1e-07<1e-070.5439
 Normalized FVC1 day0.2330.2330.00070.00070.8475
 PEF (% pred.)1 day0.50620.50360.06980.085NA
 FeNO2 days0.73490.0820.8220.4668NA
Appendix 1—table 3
Table displaying individual pre (0) and post (1) challenge autocorrelation coefficient at 1 day lag for FEV1 time series and associated p-values for the permutation tests conducted for assessment of the statistical significance of autocorrelation coefficients.
Patient IDInfection Status1 Day Lag FEV1 Autocorrelationp-value
P01H00.2544591450.006506
P03H00.3120011540.001425
P05H00.3821776320.000269
P06H00.2111907110.012607
P07H00.2036433910.03083
P08H00.892125011<1e-6
P09H00.3186469570.000124
P11H00.468008235<1e-6
P12H00.562942585<1e-6
P13H0−0.049878450.624876
P14H00.4470723376.00E-06
P15H00.079791590.40799
P01H1−0.0357194450.82705
P03H10.2107505440.168883
P05H10.4083350390.009061
P06H10.1703262290.235598
P07H10.1660550780.245054
P08H10.3510149320.01394
P09H10.4647048370.001356
P11H10.1180747130.441357
P12H10.2072057940.181322
P13H10.236732660.154677
P14H10.568393122.50E-05
P15H10.2663734140.083097
P01A00.2003436240.062003
P02A00.563837497<1e-6
P04A00.2398683840.028328
P05A00.3241146030.000172
P06A00.3487803030.000185
P07A00.2819458730.007739
P08A00.508133817<1e-6
P09A00.4315285381.30E-05
P10A00.1681288390.062336
P11A00.1432765940.213631
P12A00.0435614040.67349
P13A00.0885318280.346438
P01A10.4197355690.003491
P02A10.068147730.658923
P04A1−0.1243793510.493534
P05A10.1135066010.489726
P06A10.4296916970.001788
P07A10.3280415650.04651
P08A10.1426973770.326261
P09A10.5223582070.000105
P10A10.1254217610.389942
P11A10.3994012620.039162
P12A10.1830755630.32647
P13A10.2343233440.114713
Appendix 1—table 4
Table displaying individual pre (0) and post (1) challenge autocorrelation coefficient at 1 day lag for FEV1/FVC time series and associated p-values for the permutation tests conducted for assessment of the statistical significance of autocorrelation coefficients.
Patient IDInfection Status1 Day Lag FEV1/FVC Autocorrelationp-value
P01H00.3734616914.10E-05
P03H00.532232344<1e-6
P05H00.543561238<1e-6
P06H00.699807531<1e-6
P07H00.4260877841.00E-06
P08H00.656421903<1e-6
P09H00.426194186<1e-6
P11H00.875863699<1e-6
P12H00.537767103<1e-6
P13H00.1223854150.240757
P14H00.4513483122.00E-06
P15H00.0655907740.469086
P01H10.0791208650.62836
P03H10.0820821010.591717
P05H1−0.0184925830.839892
P06H10.3074121390.028927
P07H1−0.0332689880.799478
P08H10.1561165430.144275
P09H10.0945160030.527785
P11H10.2152133140.13104
P12H10.2227171230.151388
P13H10.2213389460.183907
P14H1−0.0197890830.892886
P15H10.09035050.516396
P01A00.3740487730.00036
P02A00.2879630010.003205
P04A00.2140519370.051278
P05A00.579846615<1e-6
P06A00.3209895820.000793
P07A00.4977731722.00E-06
P08A00.741401108<1e-6
P09A00.61597128<1e-6
P10A00.2921155510.001014
P11A00.5104053995.00E-06
P12A00.3887604810.000102
P13A00.4282545921.00E-06
P01A10.2450188210.094571
P02A10.3392726420.024686
P04A10.0680429330.72154
P05A10.1230301460.430305
P06A10.431214590.001864
P07A10.2094807250.195097
P08A1−0.2135985010.119532
P09A10.1493611520.276512
P10A10.0772000850.598176
P11A10.1632802730.438443
P12A1−0.0193602750.916728
P13A10.0844707920.574956
Appendix 1—table 5
Table displaying individual pre (0) and post (1) challenge autocorrelation coefficient at 1 day lag for FVC time series and associated p-values for the permutation tests conducted for assessment of the statistical significance of autocorrelation coefficients.
Patient IDInfection Status1 Day Lag FVC Autocorrelationp-value
P01H00.566972433<1e-6
P03H00.4363654751.10E-05
P05H00.4659717857.00E-06
P06H00.640739895<1e-6
P07H00.1892051560.044844
P08H00.90035042<1e-6
P09H00.3296213296.40E-05
P11H00.758209436<1e-6
P12H00.739080801<1e-6
P13H00.0426337780.679417
P14H00.538541079<1e-6
P15H00.2752867640.003684
P01H10.2593566510.110413
P03H10.1793380370.241313
P05H10.3531791430.02498
P06H10.1695446920.236277
P07H10.1003658210.484466
P08H10.2314349510.112321
P09H10.729801074<1e-6
P11H10.1854292380.220647
P12H10.4503840550.00285
P13H10.0208556780.901048
P14H10.2710080780.059202
P15H10.3264619680.028183
P01A00.2719944390.010138
P02A00.4389075635.00E-06
P04A00.2622864250.016387
P05A00.712236062<1e-6
P06A00.4105349721.70E-05
P07A00.2036044330.057294
P08A00.731352747<1e-6
P09A00.590921928<1e-6
P10A00.2292743620.012014
P11A00.2996169310.009238
P12A00.3390861450.000807
P13A00.439003821<1e-6
P01A10.2185986550.140146
P02A10.2709490270.076421
P04A1−0.0739280760.69089
P05A10.2933133120.062662
P06A10.2503914090.074608
P07A10.1891314050.254627
P08A10.1780451150.225613
P09A10.4458236220.001069
P10A1−0.0015825420.991459
P11A10.4562350070.025106
P12A10.2353894930.193009
P13A10.1237122980.408539
Appendix 1—table 6
Table displaying individual pre (0) and post (1) challenge autocorrelation coefficient at 1 day lag for PEF (% predicted) time series and associated p-values for the permutation tests conducted for assessment of the statistical significance of autocorrelation coefficients.
Patient IDInfection Status1 Day Lag PEF (% pred.) Autocorrelationp-value
P01H00.209312850.025684
P03H00.472289454<1e-6
P05H00.4315291632.30E-05
P06H00.1592052690.061348
P07H00.3533194029.00E-05
P08H00.5547174<1e-6
P09H00.556029042<1e-6
P11H00.3958249051.00E-05
P12H00.3526091120.000503
P13H00.351199910.000595
P14H00.4023894281.70E-05
P15H00.54985376<1e-6
P01H10.4881374290.001568
P03H10.0363201810.812622
P05H1−0.0583319260.719869
P06H10.3697150290.010815
P07H10.0082167990.954193
P08H10.2569462810.070942
P09H10.1458281740.335955
P11H10.2450969780.104066
P12H10.1596202180.302733
P13H10.16895370.271384
P14H10.3820461590.007018
P15H10.1937118590.227004
P01A00.771975809<1e-6
P02A00.1789708690.073432
P04A00.2449962880.025515
P05A00.1851487970.039857
P06A00.576945862<1e-6
P07A00.4483163041.10E-05
P08A00.4014450773.90E-05
P09A00.3850124080.000101
P10A00.3638528644.60E-05
P11A00.1168650110.282604
P12A00.2590959380.010966
P13A00.3303428470.000308
P01A10.662163321<1e-6
P02A10.2024065590.184951
P04A10.1521230580.419598
P05A10.0631845380.703673
P06A10.5273537813.40E-05
P07A10.240769910.140734
P08A10.2782770540.061281
P09A10.721164295<1e-6
P10A10.2827696970.04905
P11A10.0828071790.477035
P12A10.1994239590.28367
P13A10.048447110.74762
Appendix 1—table 7
Table displaying individual pre (0) and post (1) challenge autocorrelation coefficient at 2 days lag for FEV1/FVC time series and associated p-values for the permutation tests conducted for assessment of the statistical significance of autocorrelation coefficients.
Patient IDInfection Status2 Days Lag FeNO Autocorrelationp-value
P01H00.3217095520.2069
P03H00.4723316730.0687
P05H00.1057268720.7053
P06H00.0468261060.7172
P07H00.2317418410.3424
P08H00.2045826510.4323
P09H0−0.3437526120.0976
P11H0−0.0747714810.6224
P12H0−0.1103835980.6075
P13H00.2091077130.4296
P14H00.146997930.4745
P15H0−0.0681818180.8054
P01H10.3146401120.3257
P03H10.3471211230.1962
P05H10.1241699870.6886
P06H10.4713114750.2051
P07H10.214855740.4629
P08H1−0.3233618230.24
P09H1−0.1250.6982
P11H1−0.2899159660.332
P12H10.3522177420.2175
P13H1−0.0684931510.8668
P14H1−0.0917012930.7732
P15H10.481250.0963
P01A00.4803946480.1001
P02A0−0.2442204590.2641
P04A0−0.1187001590.6458
P05A00.1037620950.6641
P06A00.4996764050.0264
P07A00.7358240430.0056
P08A0−0.0789140.7154
P09A0−0.245409910.3058
P10A00.0041852170.9877
P11A00.7673638010.0018
P12A00.466705560.0491
P13A00.2335580570.3441
P01A10.5799319230.0017
P02A10.4672607190.1566
P04A1−0.2913436690.3435
P05A1−0.1830879170.584
P06A10.4651450920.1357
P07A10.2726876090.3678
P08A10.5749615980.0605
P09A10.3604704960.2155
P10A10.5959218150.0443
P11A10.6859277330.0121
P12A10.5460082650.0609
P13A10.6326516620.0136

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  1. Anirban Sinha
  2. René Lutter
  3. Binbin Xu
  4. Tamara Dekker
  5. Barbara Dierdorp
  6. Peter J Sterk
  7. Urs Frey
  8. Edgar Delgado Eckert
(2019)
Loss of adaptive capacity in asthmatic patients revealed by biomarker fluctuation dynamics after rhinovirus challenge
eLife 8:e47969.
https://doi.org/10.7554/eLife.47969