Performance of gene expression-based single sample predictors for assessment of clinicopathological subgroups and molecular subtypes in cancers: a case comparison study in non-small cell lung cancer.

ABSTRACT

The development of multigene classifiers for cancer prognosis, treatment prediction, molecular subtypes or clinicopathological groups has been a cornerstone in transcriptomic analyses of human malignancies for nearly two decades. However, many reported classifiers are critically limited by different preprocessing needs like normalization and data centering. In response, a new breed of classifiers, single sample predictors (SSPs), has emerged. SSPs classify samples in an N-of-1 fashion, relying on, e.g. gene rules comparing expression values within a sample. To date, several methods have been reported, but there is a lack of head-to-head performance comparison for typical cancer classification problems, representing an unmet methodological need in cancer bioinformatics. To resolve this need, we performed an evaluation of two SSPs [k-top-scoring pair classifier (kTSP) and absolute intrinsic molecular subtyping (AIMS)] for two case examples of different magnitude of difficulty in non-small cell lung cancer gene expression-based classification of (i) tumor histology and (ii) molecular subtype. Through the analysis of ~2000 lung cancer samples for each case example (n = 1918 and n = 2106, respectively), we compared the performance of the methods for different sample compositions, training data set sizes, gene expression platforms and gene rule selections. Three main conclusions are drawn from the comparisons both methods are platform independent, they select largely overlapping gene rules associated with actual underlying tumor biology and, for large training data sets, they behave interchangeably performance-wise. While SSPs like AIMS and kTSP offer new possibilities to move gene expression signatures/predictors closer to a clinical context, they are still importantly limited by the difficultness of the classification problem at hand.