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

Figures

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  Figure 1.. 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.

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  Figure 2.. 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…

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  Figure 3.. 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…

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  Appendix 1—figure 1.. Dendrogram obtained from clustering the participants’ time series of the percentage of eosinophils in nasal lavage fluid using the EMD.

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  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.

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  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.

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  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.

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  Appendix 1—figure 5.. Dendrogram obtained from clustering the participants’ time series of the percentage of neutrophils in nasal lavage fluid using the EMD.

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  Appendix 1—figure 6.. Dendrogram obtained from clustering the participants’ time series of the normalized ratio FEV1/FVC using the EMD.

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  Appendix 1—figure 7.. Dendrogram obtained from clustering the participants’ time series of PEF (% predicted) using the EMD.

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  Appendix 1—figure 8.. Dendrogram obtained from clustering the participants’ time series of normalized FEV1 using the EMD.

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  Appendix 1—figure 9.. Dendrogram obtained from clustering the participants’ time series of normalized FVC using the EMD.