Measures of Clonal Hematopoiesis: Are We Missing Something?

Area of Science:

• Hematology
• Genetics
• Computational Biology

Background:

• Clonal Hematopoiesis (CH) is an age-related condition linked to cancer, cardiovascular disease, and reduced survival.
• Understanding CH pathogenesis requires integrating lineage tracing with clinical data, but is hindered by inconsistent definitions and quantification methods.
• Current methods struggle to accurately capture the complex dynamics of hematopoietic stem cell (HSC) clonal expansion.

Purpose of the Study:

• To propose a novel conceptual and analytical framework for defining and measuring Clonal Hematopoiesis (CH).
• To develop a quantitative measure, the CH index, for assessing clone numbers and sizes.
• To evaluate the performance of the CH index against established diversity and inequality indices using simulated data.

Main Methods:

• Developed the CH index as a quantitative measure of clone numbers and sizes.
• Generated synthetic clonal population data using a beta-distribution to simulate varying degrees of clonal imbalance.
• Tested and compared the CH index against Shannon, Simpson, Gini, and Pielou indices for CH detection and quantification.

Main Results:

• The proposed CH index is distinct from previously used inequality and diversity indices.
• Diversity indices (Shannon, Simpson) showed closer resemblance to the CH index than inequality indices (Gini, Pielou).
• The CH index and diversity indices capture changes in both clone number and size, unlike inequality indices which primarily reflect size variations.

Conclusions:

• The CH index provides a more comprehensive quantification of clonal dynamics in Clonal Hematopoiesis.
• Simulations suggest CH can arise from altered clone numbers as well as skewed abundances.
• Adoption of the CH index or Shannon index in future studies will foster standardized quantification and cross-disciplinary progress in CH research.