title: Statistical significance of combinatorial regulations.
abstract: More than three transcription factors often work together to enable cells to respond to various signals. The detection of combinatorial regulation by multiple transcription factors, however, is not only computationally nontrivial but also extremely unlikely because of multiple testing correction. The exponential growth in the number of tests forces us to set a strict limit on the maximum arity. Here, we propose an efficient branch-and-bound algorithm called the "limitless arity multiple-testing procedure" (LAMP) to count the exact number of testable combinations and calibrate the Bonferroni factor to the smallest possible value. LAMP lists significant combinations without any limit, whereas the family-wise error rate is rigorously controlled under the threshold. In the human breast cancer transcriptome, LAMP discovered statistically significant combinations of as many as eight binding motifs. This method may contribute to uncover pathways regulated in a coordinated fashion and find hidden associations in heterogeneous data.
authors.affiliation: Department of Computer Science, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8550, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Terada
authors.forename: Mariko
authors.initials: M
authors.lastname: Okada-Hatakeyama
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuda
authors.forename: Jun
authors.initials: J
authors.lastname: Sese
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics / Q000503:physiopathology; D019295:Computational Biology / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology; D006801:Humans; D008957:Models, Genetic; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014157:Transcription Factors
keywords: Bonferroni correction; gene expression