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

Area of Science:

• Cell and Gene Therapy
• Genomic Medicine
• Bioinformatics

Background:

• Stable engraftment of gene-corrected cells is vital for successful cell and gene therapies.
• Integrative vectors pose risks of insertional mutagenesis and clonal dominance.
• Monitoring vector insertion sites (VIS) is a key safety assessment in gene therapy, especially for hematopoietic stem cell therapies.

Purpose of the Study:

• To reanalyze published datasets and model the properties of various indices for evaluating clonal diversity in gene therapy.
• To address limitations of the Shannon index in comparing samples with different richness.
• To propose robust metrics for assessing clonal diversity and facilitating VIS analysis in clinical practice.

Main Methods:

• Reanalysis of published datasets on vector insertion sites.
• Modeling and comparison of different diversity indices (Shannon, Pielou's, Simpson's).
• Evaluation of index robustness for comparing sample evenness.

Main Results:

• The Shannon index aggregates richness and evenness, hindering sample comparisons.
• Normalized indices, such as Pielou's evenness index and Simpson's probability index, are robust for comparing sample evenness.
• Proposed clinically meaningful standard values for clonal diversity metrics.

Conclusions:

• Normalized diversity indices offer a more robust and comparable assessment of clonal diversity in gene therapy patients.
• Standardized metrics facilitate the clinical application of vector insertion site analysis for safety monitoring.
• This work supports the advancement of genomic medicine practice through improved safety assessments in cell and gene therapy.