title: Coherence analysis discriminates between retroviral integration patterns in CD34(+) cells transduced under differing clinical trial conditions.
abstract: Unequivocal demonstration of the therapeutic utility of γ-retroviral vectors for gene therapy applications targeting the hematopoietic system was accompanied by instances of insertional mutagenesis. These events stimulated the ongoing development of putatively safer integrating vector systems and analysis methods to characterize and compare integration site (IS) biosafety profiles. Continuing advances in next-generation sequencing technologies are driving the generation of ever-more complex IS datasets. Available bioinformatic tools to compare such datasets focus on the association of integration sites (ISs) with selected genomic and epigenetic features, and the choice of these features determines the ability to discriminate between datasets. We describe the scalable application of point-process coherence analysis (CA) to compare patterns produced by vector ISs across genomic intervals, uncoupled from association with genomic features. To explore the utility of CA in the context of an unresolved question, we asked whether the differing transduction conditions used in the initial Paris and London SCID-X1 gene therapy trials result in divergent genome-wide integration profiles. We tested a transduction carried out under each condition, and showed that CA could indeed resolve differences in IS distributions. Existence of these differences was confirmed by the application of established methods to compare integration datasets.
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead , Westmead, Australia.
authors.forename: Claus V
authors.initials: CV
authors.lastname: Hallwirth
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead , Westmead, Australia ; Department of Chemistry and Biomolecular Sciences, Macquarie University , Macquarie Park, Australia.
authors.forename: Gagan
authors.initials: G
authors.lastname: Garg
authors.affiliation: CSIRO Digital Productivity Flagship , North Ryde, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Peters
authors.affiliation: Children's Cancer Research Unit, The Children's Hospital at Westmead , Westmead, Australia.
authors.forename: Belinda A
authors.initials: BA
authors.lastname: Kramer
authors.affiliation: University of Pennsylvania School of Medicine, Department of Microbiology , Philadelphia, Pennsylvania, USA.
authors.forename: Nirav V
authors.initials: NV
authors.lastname: Malani
authors.affiliation: Children's Cancer Research Unit, The Children's Hospital at Westmead , Westmead, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hyman
authors.affiliation: Genome Institute of Singapore, Agency for Science, Technology and Research , Genome, Singapore.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead , Westmead, Australia ; Sydney Medical School, The University of Sydney , Sydney, Australia.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Ginn
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead , Westmead, Australia.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Hetherington
authors.affiliation: Genome Institute of Singapore, Agency for Science, Technology and Research , Genome, Singapore.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Veeravalli
authors.affiliation: Genome Institute of Singapore, Agency for Science, Technology and Research , Genome, Singapore.
authors.forename: Atif
authors.initials: A
authors.lastname: Shahab
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University , Macquarie Park, Australia.
authors.forename: Shoba
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: Genome Institute of Singapore, Agency for Science, Technology and Research , Genome, Singapore.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wei
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, The University of Sydney , Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Molecular Immunology Unit, Institute of Child Health, University College London , London, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: University of Pennsylvania School of Medicine, Department of Microbiology , Philadelphia, Pennsylvania, USA.
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.affiliation: CSIRO Digital Productivity Flagship , North Ryde, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buckley
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead , Westmead, Australia ; The University of Sydney, Discipline of Paediatrics and Child Health , Westmead, Australia.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander