Accounting for Extra-Binomial Variability with Differentially Expressed Genetic Pathway Data: a Collaborative Bioinformatic Study.

We describe a collaborative project involving faculty and students in a university bioinformatics/biostatistics center. The project focuses on identification of differentially expressed gene sets ("pathways") in subjects expressing a disease state, medical intervention, or other distinguishable condition. The key feature of the endeavor is the data structure presented to the team: a single cohort of subjects with two samples taken from each subject - one for each of two differing conditions without replication. This particular structure leads to essentially a cohort of 2×2 contingency tables, where each table compares the differential gene state with the pathway condition. Recognizing that correlations both within and between pathway responses can disrupt standard 2×2 table analytics, we develop methods for analyzing this data structure in the presence of complicated intra-table correlations. These provide some convenient approaches for this problem, using design effect adjustments from sample survey theory and manipulations of the summary 2×2 table counts. Monte Carlo simulations show that the methods operate extremely well, validating their use in practice. In the end, the collaborative connections among the team members led to solutions no one of us would have envisioned separately.