Extracting replicable associations across multiple studies: Empirical Bayes algorithms for controlling the false discovery rate

In almost every field in genomics, large-scale biomedical datasets are used to report associations. Extracting associations that recur across multiple studies while controlling the false discovery rate is a fundamental challenge. Here, we propose a new method to allow joint analysis of multiple studies. Given a set of p-values obtained from each study, the goal is to identify associations that recur in at least k > 1 studies while controlling the false discovery rate. We propose several new algorithms that differ in how the study dependencies are modeled, and compare them and extant methods under various simulated scenarios. The top algorithm, SCREEN (Scalable Cluster-based REplicability ENhancement), is our new algorithm that works in three stages: (1) clustering an estimated correlation network of the studies, (2) learning replicability (e.g., of genes) within clusters, and (3) merging the results across the clusters. When we applied SCREEN to two real datasets it greatly outperformed the results obtained via standard meta-analysis. First, on a collection of 29 case-control gene expression cancer studies, we detected a large set of consistently up-regulated genes related to proliferation and cell cycle regulation. These genes are both consistently up-regulated across many cancer studies, and are well connected in known gene networks. Second, on a recent pan-cancer study that examined the expression profiles of patients with and without mutations in the HLA complex, we detected a large active module of up-regulated genes that are both related to immune responses and are well connected in known gene networks. This module covers thrice more genes as compared to the original study at a similar false discovery rate, demonstrating the high power of SCREEN. An implementation of SCREEN is available in the supplement.Author summary: When analyzing results from multiple studies, extracting replicated associations is the first step towards making new discoveries. The standard approach for this task is to use meta-analysis methods, which usually make an underlying null hypothesis that a gene has no effect in all studies. On the other hand, in replicability analysis we explicitly require that the gene will manifest a recurring pattern of effects. In this study we develop new algorithms for replicability analysis that are both scalable (i.e., can handle many studies) and allow controlling the false discovery rate. We show that our main algorithm called SCREEN (Scalable Cluster-based REplicability ENhancement) outperforms the other methods in simulated scenarios. Moreover, when applied to real datasets, SCREEN greatly extended the results of the meta-analysis, and can even facilitate detection of new biological results.