Comprehensively benchmarking applications for detecting copy number variation

Motivation: Recently, copy number variation (CNV) has gained considerable interest as a type of genomic variation that plays an important role in complex phenotypes and disease susceptibility. Since a number of CNV detection methods have recently been developed, it is necessary to help investigators choose suitable methods for CNV detection depending on their objectives. For this reason, this study compared ten commonly used CNV detection applications, including CNVnator, ReadDepth, RDXplorer, LUMPY and Control-FREEC, benchmarking the applications by sensitivity, specificity and computational demands. Taking the DGV gold standard variants as a standard dataset, we evaluated the ten applications with real sequencing data at sequencing depths from 5X to 50X. Among the ten methods benchmarked, LUMPY performs the best for both high sensitivity and specificity at each sequencing depth. For the purpose of high specificity, Canvas is also a good choice. If high sensitivity is preferred, CNVnator and RDXplorer are better choices. Additionally, CNVnator and GROM-RD perform well for low-depth sequencing data. Our results provide a comprehensive performance evaluation for these selected CNV detection methods and facilitate future development and improvement in CNV prediction methods.Author summary: As an important type of genomic structural variation, CNVs are associated with complex phenotypes because they change the number of copies of genes in cells, affecting coding sequences and playing an important role in the susceptibility or resistance to human diseases. To identify CNVs, several experimental methods have been developed, but their resolution is very low, and the detection of short CNVs presents a bottleneck. In recent years, the advancement of high-throughput sequencing techniques has made it possible to precisely detect CNVs, especially short ones. Many CNV detection applications were developed based on the availability of high-throughput sequencing data. Due to different CNV detection algorithms, the CNVs identified by different applications vary greatly. Therefore, it is necessary to help investigators choose suitable applications for CNV detection depending upon their objectives. For this reason, we not only compared ten commonly used CNV detection applications but also benchmarked the applications by sensitivity, specificity and computational demands. Our results show that the sequencing depth can strongly affect CNV detection. Among the ten applications benchmarked, LUMPY performs best for both high sensitivity and specificity for each sequencing depth. We also give recommended applications for specific purposes, for example, CNVnator and RDXplorer for high sensitivity and CNVnator and GROM-RD for low-depth sequencing data.