Analysis of Clinical Flow Cytometric Immunophenotyping Data by Clustering on Statistical Manifolds: Treating Flow Cytometry Data as High-Dimensional Objects

摘要

Background: Clinical flow cytometry typically involves the sequential interpretation of two-dimensional histograms, usually culled from six or more cellular characteristics, following initial selection (gating) of cell populations based on a different subset of these characteristics. We examined the feasibility of instead treating gated n-parameter clinical flow cytometry data as objects embedded in n-dimensional space using principles of information geometry via a recently described method known as Fisher Information Non-parametric Embedding (FINE). Methods: After initial selection of relevant cell populations through an iterative gating strategy, we converted four color (six-parameter) clinical flow cytometry datasets into six-dimensional probability density functions, and calculated differences among these distributions using the Kullback-Leibler divergence (a measurement of relative distributional entropy shown to be an appropriate approximation of Fisher information distance in certain types of statistical manifolds). Neighborhood maps based on Kullback-Leibler divergences were projected onto two dimensional displays for comparison. Results: These methods resulted in the effective unsupervised clustering of cases of acute lymphoblastic leukemia from cases of expansion of physiologic B-cell precursors (hematogones) within a set of 54 patient samples. Conclusions: The treatment of flow cytometry datasets as objects embedded in high-dimensional space (as opposed to sequential two-dimensional analyses) harbors the potential for use as a decision-support tool in clinical practice or as a means for context-based archiving and searching of clinical flow cytometry data based on high-dimensional distribution patterns contained within stored list mode data. Additional studies will be needed to further test the effectiveness of this approach in clinical practice.