Bayesian model for accurate MARSALA (mutated allele revealed by sequencing with aneuploidy and linkage analyses)

PURPOSE: This study is aimed at increasing the accuracy of preimplantation genetic test for monogenic defects (PGT-M). METHODS: We applied Bayesian statistics to optimize data analyses of the mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) method for PGT-M. In doing so, we developed a Bayesian algorithm for linkage analyses incorporating PCR SNV detection with genome sequencing around the known mutation sites in order to determine quantitatively the probabilities of having the disease-carrying alleles from parents with monogenic diseases. Both recombination events and sequencing errors were taken into account in calculating the probability. RESULTS: Data of 28 in vitro fertilized embryos from three couples were retrieved from two published research articles by Yan et al. (Proc Natl Acad Sci. 112:15964–9, 2015) and Wilton et al. (Hum Reprod. 24:1221–8, 2009). We found the embryos deemed “normal” and selected for transfer in the previous publications were actually different in error probability of 10(−4)–4%. Notably, our Bayesian model reduced the error probability to 10(−6)–10(−4)%. Furthermore, a proband sample is no longer required by our new method, given a minimum of four embryos or sperm cells. CONCLUSION: The error probability of PGT-M can be significantly reduced by using the Bayesian statistics approach, increasing the accuracy of selecting healthy embryos for transfer with or without a proband sample. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-019-01451-8) contains supplementary material, which is available to authorized users.