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Many popular software packages for analysis of RNA-seq data were constructed to study differences in expression signatures in an experimental design with well-defined conditions (exposures). In contrast, observational studies may have varying levels of confounding transcript-exposure associations; further, exposure measures may vary from discrete (exposed, yes\/no) to continuous (levels of exposure), with non-normal distributions of exposure. We compare popular software for gene expression\u2014DESeq2, edgeR and limma\u2014as well as linear regression-based analyses for studying the association of continuous exposures with RNA-seq. We developed a computation pipeline that includes transformation, filtering and generation of empirical null distribution of association P-values, and we apply the pipeline to compute empirical P-values with multiple testing correction. We employ a resampling approach that allows for assessment of false positive detection across methods, power comparison and the computation of quantile empirical P-values. The results suggest that linear regression methods are substantially faster with better control of false detections than other methods, even with the resampling method to compute empirical P-values. We provide the proposed pipeline with fast algorithms in an R package Olivia, and implemented it to study the associations of measures of sleep disordered breathing with RNA-seq in peripheral blood mononuclear cells in participants from the Multi-Ethnic Study of Atherosclerosis.<\/jats:p>","DOI":"10.1093\/bib\/bbab194","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T15:12:27Z","timestamp":1619709147000},"source":"Crossref","is-referenced-by-count":5,"title":["Benchmarking association analyses of continuous exposures with RNA-seq in observational studies"],"prefix":"10.1093","volume":"22","author":[{"given":"Tamar","family":"Sofer","sequence":"first","affiliation":[{"name":"Program of Sleep Medicine Epidemiology at the Brigham and Women\u2019s Hospital, USA"}]},{"given":"Nuzulul","family":"Kurniansyah","sequence":"additional","affiliation":[{"name":"Program of Sleep Medicine Epidemiology at the Brigham and Women\u2019s Hospital, 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