Explaining the counter-intuitive effectiveness of trophectoderm biopsy for PGT-A using computational modelling

Preimplantation genetic testing for aneuploidy (PGT-A) is one of the most controversial topics in reproductive medicine, with disagreements over the apparently contradictory results of randomised controlled trials, non-selection trials and outcome data analyses. Data from live birth outcomes largely suggest that fully euploid biopsies are associated with positive live birth rates, while fully aneuploid biopsies are not. However, the possible confounding effects of chromosomal mosaicism (when either the whole embryo, the biopsy result (or both) contain an admixture of euploid and aneuploid cells) is frequently cited as a reason why PGT-A should not be performed. Previous computer models have indicated that a mosaic result is a poor indicator of the level of mosaicism of the rest of the embryo, and it is thus unwise to use mosaic PGT-A results when selecting embryos for transfer. Here we developed a computational model, tessera, to create virtual embryos for biopsy, allowing us to vary the number of cells in the simulated embryo and biopsy, the proportion of aneuploid cells and the degree of juxtaposition of those cells. Analysis of approximately 1 million virtual embryos showed that "100% euploid" and "100% aneuploid" biopsy results are relatively accurate predictors of the remainder of the embryo, while mosaic biopsy results are poor predictors of the proportion of euploid and aneuploid cells in the rest of the embryo. Within mosaic embryos, clumping of aneuploid cells further reduces the accuracy of biopsies in assaying the true aneuploidy level of any given embryo. Nonetheless - and somewhat counterintuitively - biopsy results can still be used with some confidence to rank embryos within a cohort. Our simulations help resolve the apparent paradox surrounding PGT-A: the biopsy result is poorly predictive of the absolute level of mosaicism of a single embryo, but may be applicable nonetheless in making clinical decisions on which embryos to transfer.