Simultaneous estimation of transcript abundances and transcript specific fragment distributions of RNA-Seq data with the Mix2 model

Quantification of RNA transcripts with RNA-Seq is inaccurate due to positional fragmentation bias, which is not represented appropriately by current statistical models of RNA-Seq data. Another, less investigated, source of error is the inaccuracy of transcript start and end annotations.\n\nThis article introduces the Mix2 (rd. \"mixquare\") model, which uses a mixture of probability distributions to model the transcript specific positional fragment bias. The parameters of the Mix2 model can be efficiently trained with the EM algorithm and are tied between similar transcripts. Transcript specific shift and scale parameters allow the Mix2 model to automatically correct inaccurate transcript start and end annotations. Experiments are conducted on synthetic data covering 7 genes of different complexity, 4 types of fragment bias and correct as well as incorrect transcript start and end annotations. Abundance estimates obtained by Cufflinks 2.2.0, PennSeq and the Mix2 model show superior performance of the Mix2 model in the vast majority of test conditions.\n\nThe Mix2 software is available at http://www.lexogen.com/fileadmin/uploads/bioinfo/mix2model.tgz, subject to the enclosed license.\n\nAdditional experimental data are available in the supplement.