Bystrykh Leonid V, Belderbos Mirjam E
Department for Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands.
Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
Front Med (Lausanne). 2022 Mar 31;9:836141. doi: 10.3389/fmed.2022.836141. eCollection 2022.
Clonal Hematopoiesis (CH) is a common, age-related phenomenon of growing scientific interest, due to its association with hematologic malignancy, cardiovascular disease and decreased overall survival. CH is commonly attributed to the preferential outgrowth of a mutant hematopoietic stem cell (HSC) with enhanced fitness, resulting in clonal imbalance. In-depth understanding of the relation between HSC clonal dynamics, CH and hematologic malignancy requires integration of fundamental lineage tracing studies with clinical data. However, this is hampered by lack of a uniform definition of CH and by inconsistency in the analytical methods used for its quantification. Here, we propose a conceptual and analytical framework for the definition and measurement of CH. First, we transformed the conceptual definition of CH into the CH index, which provides a quantitative measure of clone numbers and sizes. Next, we generated a set of synthetic data, based on the beta-distribution, to simulate clonal populations with different degrees of imbalance. Using these clonal distributions and the CH index as a reference, we tested several established indices of clonal diversity and (in-)equality for their ability to detect and quantify CH. We found that the CH index was distinct from any of the other tested indices. Nonetheless, the diversity indices (Shannon, Simpson) more closely resembled the CH index than the inequality indices (Gini, Pielou). Notably, whereas the inequality indices mainly responded to changes in clone sizes, the CH index and the tested diversity indices also responded to changes in the number of clones in a sample. Accordingly, these simulations indicate that CH can result not only by skewing clonal abundancies, but also by variation in their overall numbers. Altogether, our model-based approach illustrates how a formalized definition and quantification of CH can provide insights into its pathogenesis. In the future, use of the CH index or Shannon index to quantify clonal diversity in fundamental as well as clinical clone-tracing studies will promote cross-disciplinary discussion and progress in the field.
克隆性造血（CH）是一种常见的、与年龄相关的现象，由于其与血液系统恶性肿瘤、心血管疾病以及总体生存率降低有关，正日益引起科学界的关注。CH通常归因于具有增强适应性的突变造血干细胞（HSC）的优先增殖，从而导致克隆失衡。深入了解HSC克隆动力学、CH与血液系统恶性肿瘤之间的关系需要将基础谱系追踪研究与临床数据相结合。然而，这受到CH缺乏统一的定义以及用于其量化的分析方法不一致的阻碍。在此，我们提出了一个用于定义和测量CH的概念和分析框架。首先，我们将CH的概念定义转化为CH指数，该指数提供了克隆数量和大小的定量测量。接下来，我们基于β分布生成了一组合成数据，以模拟具有不同程度失衡的克隆群体。使用这些克隆分布和CH指数作为参考，我们测试了几个已建立的克隆多样性和（不）平等指数检测和量化CH的能力。我们发现CH指数与任何其他测试指数都不同。尽管如此，多样性指数（香农指数、辛普森指数）比不平等指数（基尼指数、皮洛指数）更类似于CH指数。值得注意的是，不平等指数主要对克隆大小的变化做出反应，而CH指数和测试的多样性指数也对样本中克隆数量的变化做出反应。因此，这些模拟表明CH不仅可以通过克隆丰度的倾斜产生，还可以通过其总数的变化产生。总之，我们基于模型的方法说明了CH的形式化定义和量化如何能够为其发病机制提供见解。未来，在基础以及临床克隆追踪研究中使用CH指数或香农指数来量化克隆多样性将促进该领域的跨学科讨论和进展。
