DendroX: multi-level multi-cluster selection in dendrograms

Abstract

Background: Cluster heatmaps are widely used in biology and other fields to uncover clustering patterns in data matrices. Most cluster heatmap packages provide utility functions to divide the dendrograms at a certain level to obtain clusters, but it is often difficult to locate the appropriate cut in the dendrogram to obtain the clusters seen in the heatmap or computed by a statistical method. Multiple cuts are required if the clusters locate at different levels in the dendrogram.

Results: We developed DendroX, a web app that provides interactive visualization of a dendrogram where users can divide the dendrogram at any level and in any number of clusters and pass the labels of the identified clusters for functional analysis. Helper functions are provided to extract linkage matrices from cluster heatmap objects in R or Python to serve as input to the app. A graphic user interface was also developed to help prepare input files for DendroX from data matrices stored in delimited text files. The app is scalable and has been tested on dendrograms with tens of thousands of leaf nodes. As a case study, we clustered the gene expression signatures of 297 bioactive chemical compounds in the LINCS L1000 dataset and visualized them in DendroX. Seventeen biologically meaningful clusters were identified based on the structure of the dendrogram and the expression patterns in the heatmap. We found that one of the clusters consisting of mostly naturally occurring compounds is not previously reported and has its members sharing broad anticancer, anti-inflammatory and antioxidant activities.

Conclusions: DendroX solves the problem of matching visually and computationally determined clusters in a cluster heatmap and helps users navigate among different parts of a dendrogram. The identification of a cluster of naturally occurring compounds with shared bioactivities implicates a convergence of biological effects through divergent mechanisms.

Keywords: Cluster analysis; Dendrogram; LINCS L1000; Natural medicine.

Fig. 1

A screenshot of the user interface of the DendroX Cluster program

Fig. 2

A screenshot of the input view. It shows the input view with an example JSON file and image file loaded. The example data is adapted from [22]

Fig. 3

A screenshot of the visualization view. It visualizes the data submitted in Fig. 2

Fig. 4

A: cluster heatmap of the 297 LINCS L1000 compound signatures. The 14 major clusters are colored and labeled. B-D: sub-clusters of cluster 2, 6 and 8. E-I: drug name-set enrichment analysis results of cluster 1, cluster 2.1, cluster 2.2, cluster 6.1 and cluster 10