Tracking hematopoietic stem cell evolution in a Wiskott–Aldrich clinical trial

Hematopoietic Stem Cells (HSC) are the cells that give rise to 7 all other blood cells and, as such, they are crucial in the healthy 8 development of individuals. Wiskott-Aldrich Syndrome (WAS) is a 9 severe disorder affecting the regulation of hematopoietic cells and is 10 caused by mutations in the WASP gene. We consider data from a 11 revolutionary gene therapy clinical trial, where HSC harvested from 12 3 WAS patients’ bone marrow have been edited and corrected using 13 viral vectors. Upon re-infusion into the patient, the HSC multiply 14 and differentiate into other cell types. The aim is to unravel the cell 15 multiplication and cell differentiation process, which has until now 16 remained elusive. 17 This paper models the replenishment of blood lineages resulting 18 from corrected HSC via a multivariate, density-dependent Markov 19 process and develops an inferential procedure to estimate the dy- 20 namic parameters given a set of temporally sparsely observed tra- 21 jectories. Starting from the master equation, we derive a system of 22 non-linear differential equations for the evolution of the first- and 23 second-order moments over time. We use these moment equations in 24 a generalized method-of-moments framework to perform inference. 25 The performance of our proposal has been evaluated by consider- 26 ing different sampling scenarios and measurement errors of various 27 strengths using a simulation study. We also compared it to another 28 state-of-the-art approach and found that our method is statistically 29 more efficient. By applying our method to the WAS gene therapy 30 data we found strong evidence for a myeloid-based developmental