COPD progression models

The SuStaIn model was applied by seeking out two (Model 1) and five clusters (Model 2) of COPD. The optimal number of clusters given the studied cohort XCOPD should be

determined by cross-validation prior to analysis. However, the aim of this experiment was to firstly, dichotomise the COPDGene cohort into its two main disease progression patterns

(Model 1) then further analyse what clusters could be quantified with SuStaIn by increasing the number of clusters (Model 2). The number of clusters for Model 2 was then increased to five to allow SuStaIn to uncover more progression trajectories.

7.3.2.1 Model 1: two-cluster model

The biomarker trajectories for both clusters can be visualised in Figure7.3. The proportion of GOLD classified patients in both clusters is shown in Figure7.2. A χ2test of indepen- dence was performed by comparing the frequency of GOLD stages between both clusters. I found significant differences between clusters (χ2(DF = 3) = 7.82, p < 10−5). Cluster 1 had significantly more GOLD 1 and 4 patients whilst GOLD 2 and 3 were more expressed in cluster 2.

There are important differences between both clusters, which highlight two potential main phenotypes of COPD (Figure7.3). These can be categorised by the sequence of events and the linear accumulation of the z-scores. Cluster 1 can be classified as a Tissue-Airway progression pattern since features related to the voxel intensity become abnormal first. Con- versely, cluster 2 is an Airway-Tissue progression pattern since pathological variations in the airway-related metrics are the first to become apparent.

1 2 3 4 0 50 100 150 200 250 300 GOLD stage N u m b e r o f p a ti e n ts Cluster1 Cluster2

Figure 7.2: GOLD stage proportion in Model 1

In cluster 1 (Figure7.3a), there are early signs of gas trapping then lower-lobe emphy- sema. This is followed by a rapid progression of upper-lobe emphysema, which is illus- trated by the progression of z-score events. Gas trapping and lower-lobe emphysema then progress with lower-lobe emphysema approaching maximum severity first. Importantly, gas trapping and measures of emphysema progress to their most severe stage before initiation of the airway-related pathology. These are manifested first by airway wall remodelling in

(a) Cluster 1 - 51% of COPDGene cohort

(b) Cluster 2 - 49% of COPDGene cohort

z1 z2 z3 z4

Figure 7.3: Model 1 - two cluster disease progression model. Opacity of the z-score events quanti- fies uncertainty in the event ordering.

the subsegmental then segmental airways.

The progression of cluster 2 (Figure 7.3b) is initiated by a cascade of events in the airways. Abnormalities are first present in airway walls of subsegmental then segmental airways. This is closely followed by changes in the Pi15 SRWA and Pi10SRWA features. However, the progression of these features appears to be long-lasting over the spectrum of events. Pathological alterations in the airways directly lead to gas trapping, which is fast- acting and aggressive within this cluster. This is then followed by a slow progression of emphysema in the lower lobes and fast acting emphysema in the upper lobes.

7.3.2.2 Model 2: five-cluster model

An increase in the amount of clusters yielded a new set of biomarker trajectories with dis- tinct progression patterns (Figure7.5 and7.6). I observed a dichotomy in the population based on the sequences of events. There were three Tissue-Airway clusters (Figure7.5)

and two Airway-Tissue clusters (Figure7.6). A χ2test of independence within the Tissue- Airway and the Airway-Tissue subgroups was performed respectively to test for differ- ences in the GOLD proportion of subjects (Figure7.4). There was no significant difference (χ2(DF = 6) = 12.12, p = 0.06) between the clusters within the Tissue-Airway subgroup (Figure 7.4a). There was also no significant difference (χ2(DF = 3) = 6.41, p = 0.09) within the Airway-Tissue subgroup (Figure7.4b).

1 2 3 4 0 50 100 150 GOLD stage N u m b e r o f p a ti e n ts Cluster1 Cluster2 Cluster3

(a) Tissue-Airway subgroups

1 2 3 4 0 50 100 150 GOLD stage N u m b e r o f p a ti e n ts Cluster4 Cluster5 (b) Airway-Tissue subgroups

Figure 7.4: GOLD stage proportion in Model 2

The biomarker trajectories of the Tissue-Airway clusters (Table7.2, Figure7.5a,7.5b and7.5c) can be characterised by the z-score accumulation and whether events occur syn- chronously. In the first cluster (Figure 7.5a), progression of gas trapping in addition to emphysema in the upper and lower lobes occurs synchronously. Once these biomarkers reach maximum severity, airway-related pathologies are initiated. Airway wall thickening of the sub-segmental airways first occurs, which is followed by thickening of the segmental region, and followed by a synchronous progression of all biomarkers until conclusion of the disease progression. The progression of airway-related pathology was similar in clusters 2 (Figure7.5b) and 3 (Figure7.5c). The most distinct differences were in the progression of upper and lower lobe emphysema. Cluster 2 can be defined as a rapid upper-lobe emphy- sema sequence (Figure7.5b). It reaches the highest severity of upper-lobe emphysema at event 7 in contrast to event 10 and 14 in clusters 1 and 3 respectively. The opposite was observed in cluster 3 (Figure7.5c), which can be described as an aggressive lower-lobe em- physema subgroup. The presence of gas trapping is first apparent then followed by a rapid increase in lower lobe emphysema.

(a) Cluster 1 - 33% of COPDGene cohort

(b) Cluster 2 - 19% of COPDGene cohort

(c) Cluster 3 - 13% of COPDGene cohort

z1 z2 z3 z4

Figure 7.5: Model 2 - tissue-airways clusters. Opacity of the z-score events quantifies uncertainty in the event ordering.

Table 7.2: Characteristics of the Tissue-Airway clusters

Model Biomarker Property

Cluster 1 - Figure7.5a

Gas trapping Synchronous progression Upper-lobe emphysema Lower-lobe emphysema Cluster 2 - Figure7.5b Gas trapping

Fast-acting upper-lobe emphysema Upper-lobe emphysema

Lower-lobe emphysema

Cluster 3 - Figure7.5c

Gas trapping

Fast-acting lower-lobe emphysema Upper-lobe emphysema

Lower-lobe emphysema

The SuStaIn model quantified two clusters that were determined to be part of the Airway-Tissue family (Table7.3, Figure7.6aand7.6b). In the first cluster (Figure7.6a), the progression of COPD is initiated by abnormalities in wall area percentage in the segmental and sub-segmental airways (WA%). This is then followed by a rapid progression of the Pi10 and Pi15 SRWA metrics, which suggested that remodelling of the airways occurs at an aggressive pace in this COPD subgroup. A sequence of rapid events in the tissue related features occurs after the initial progression of airway-related metrics. Gas trapping abnor- malities reach a severe z-score rapidly followed by a synchronous worsening of emphysema in the upper and lower lobes.

A more uncertain initiation in the progression of the second Airway-Tissue cluster was observed (Figure7.6b). Gas trapping and abnormalities in wall area percentage initiates the progression pattern. A domino effect in the sequence of tissue-related events is then seen. Gas trapping first progresses to a moderate severity stage, followed by the rapid progression of upper-lobe emphysema and longer-acting lower-lobe emphysema.