Systems Uncertainty in Systems Biology & Gene Function Prediction

Abstract

The widespread use of high-throughput experimental assays designed to measure the entire complement of a cells genes or gene products has led to vast stores of data which are extremely plentiful in terms of the number of items they can measure in a single sample, yet often sparse in the number of samples per experiment due to their high cost. This often leads to datasets where the number of treatment levels or time points sampled is limited, or where there are very small numbers of technical and/or biological replicates. If the goal is to use this data to infer network models, these sparse datasets can lead to under-determined systems. While model parameter variation and its effects on model robustness has been well studied, most of this work has looked exclusively at accounting for variation only from measurement error. In contrast, little work has been done to isolate and quantify the amount of parameter variation caused by the uncertainty in the unmeasured regions of time course experiments.

Here we introduce a novel algorithm to quantify the uncertainty in the unmeasured inter- vals between biological measurements taken across a set of quantitative treatments. The algorithm provides a probabilistic distribution of possible gene expression values within un- measured intervals, based on a plausible biological constraint. We show how quantification of this uncertainty can be used to guide researchers in further data collection by identifying which samples would likely add the most information to the system under study. We also present an application of this method to isolate and quantify two distinct sources of model parameter variation. In the concluding chapter we discuss another source of uncertainty in systems biology, namely gene function prediction, and compare several algorithms designed for that purpose.