Nonparametric multivariate survival analysis of activated lymphocyte cell fates.

Abstract

Upon challenge, lymphocytes multiply and diversify to combat the infection, however, the mechanisms that drive this process are not well understood. A theoretical model has been proposed to explain how a diverse selection of cell fates is achieved, the Cyton model [Hawkins et al, 2007, PNAS]. In that model the censorship caused by competing drives for lymphocytes to undergo certain fates results in complex correlations and impacts the observed distribution of times to cellular events. In [Duffy et al, 2012, Science] the competition hypothesis is tested for consistency with data collected using a novel experimental procedure. Through the implementation and development of a collection of multivariate nonparametric statistical techniques, we create a set of tools that can aid the study of competition hypotheses in biological systems. As a worked example these tools are used to study data collected for the experiments in [Duffy et al, 2012, Science] to challenge some of the underlying assumptions of their parametric analysis. As an additional illustration further unpublished data collected during the experiments is used to study the time at which B cells divide, die and differentiate when they have already undergone class switching, allowing us to address the question of a cell type dependent change