Evaluation of diversity indices to estimate clonal dominance in gene therapy studies.

ABSTRACT

In cell and gene therapy, achieving the stable engraftment of an abundant and highly polyclonal population of gene-corrected cells is one of the key factors to ensure the successful and safe treatment of patients. Because integrative vectors have been associated with possible risks of insertional mutagenesis leading to clonal dominance, monitoring the relative abundance of individual vector insertion sites in patients' blood cells has become an important safety assessment, particularly in hematopoietic stem cell-based therapies. Clinical studies often express clonal diversity using various metrics. One of the most commonly used is the Shannon index of entropy. However, this index aggregates two distinct aspects of diversity, the number of unique species and their relative abundance. This property hampers the comparison of samples with different richness. This prompted us to reanalyze published datasets and to model the properties of various indices as applied to the evaluation of clonal diversity in gene therapy. A normalized version of the Shannon index, such as Pielou's index, or Simpson's probability index is robust and useful to compare sample evenness between patients and trials. Clinically meaningful standard values for clonal diversity are herein proposed to facilitate the use of vector insertion site analyses in genomic medicine practice.