Advanced search
1 file | 1.95 MB Add to list

Implicit bias in diagnosing mosaicism amongst preimplantation genetic testing providers : results from a multicenter study of 36 395 blastocysts

(2024) HUMAN REPRODUCTION. 39(1). p.258-274
Author
Organization
Abstract
STUDY QUESTION: Does the diagnosis of mosaicism affect ploidy rates across different providers offering preimplantation genetic testing for aneuploidies (PGT-A)?SUMMARY ANSWER: Our analysis of 36 395 blastocyst biopsies across eight genetic testing laboratories revealed that euploidy rates were significantly higher in providers reporting low rates of mosaicism.WHAT IS KNOWN ALREADY: Diagnoses consistent with chromosomal mosaicism have emerged as a third category of possible embryo ploidy outcomes following PGT-A. However, in the era of mosaicism, embryo selection has become increasingly complex. Biological, technical, analytical, and clinical complexities in interpreting such results have led to substantial variability in mosaicism rates across PGT-A providers and clinics. Critically, it remains unknown whether these differences impact the number of euploid embryos available for transfer. Ultimately, this may significantly affect clinical outcomes, with important implications for PGT-A patients.STUDY DESIGN, SIZE, DURATION: In this international, multicenter cohort study, we reviewed 36 395 consecutive PGT-A results, obtained from 10 035 patients across 11 867 treatment cycles, conducted between October 2015 and October 2021. A total of 17 IVF centers, across eight PGT-A providers, five countries and three continents participated in the study. All blastocysts were tested using trophectoderm biopsy and next-generation sequencing. Both autologous and donation cycles were assessed. Cycles using preimplantation genetic testing for structural rearrangements were excluded from the analysis.PARTICIPANTS/MATERIALS, SETTING, METHODS: The PGT-A providers were randomly categorized (A to H). Providers B, C, D, E, F, G, and H all reported mosaicism, whereas Provider A reported embryos as either euploid or aneuploid. Ploidy rates were analyzed using multilevel mixed linear regression. Analyses were adjusted for maternal age, paternal age, oocyte source, number of embryos biopsied, day of biopsy, and PGT-A provider, as appropriate. We compared associations between genetic testing providers and PGT-A outcomes, including the number of chromosomally normal (euploid) embryos determined to be suitable for transfer.MAIN RESULTS AND THE ROLE OF CHANCE: The mean maternal age (+/- SD) across all providers was 36.2 (+/- 5.2). Our findings reveal a strong association between PGT-A provider and the diagnosis of euploidy and mosaicism. Amongst the seven providers that reported mosaicism, the rates varied from 3.1% to 25.0%. After adjusting for confounders, we observed a significant difference in the likelihood of diagnosing mosaicism across providers (P < 0.001), ranging from 6.5% (95% CI: 5.2-7.4%) for Provider B to 35.6% (95% CI: 32.6-38.7%) for Provider E. Notably, adjusted euploidy rates were highest for providers that reported the lowest rates of mosaicism (Provider B: euploidy, 55.7% (95% CI: 54.1-57.4%), mosaicism, 6.5% (95% CI: 5.2-7.4%); Provider H: euploidy, 44.5% (95% CI: 43.6-45.4%), mosaicism, 9.9% (95% CI: 9.2-10.6%)); and Provider D: euploidy, 43.8% (95% CI: 39.2-48.4%), mosaicism, 11.0% (95% CI: 7.5-14.5%)). Moreover, the overall chance of having at least one euploid blastocyst available for transfer was significantly higher when mosaicism was not reported, when we compared Provider A to all other providers (OR = 1.30, 95% CI: 1.13-1.50). Differences in diagnosing and interpreting mosaic results across PGT-A laboratories raise further concerns regarding the accuracy and relevance of mosaicism predictions. While we confirmed equivalent clinical outcomes following the transfer of mosaic and euploid blastocysts, we found that a significant proportion of mosaic embryos are not used for IVF treatment.LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of the study, associations can be ascertained, however, causality cannot be established. Certain parameters such as blastocyst grade were not available in the dataset. Furthermore, certain platform-related and clinic-specific factors may not be readily quantifiable or explicitly captured in our dataset. As such, a full elucidation of all potential confounders accounting for variability may not be possible.WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the strong need for standardization and quality assurance in the industry. The decision not to transfer mosaic embryos may ultimately reduce the chance of success of a PGT-A cycle by limiting the pool of available embryos. Until we can be certain that mosaic diagnoses accurately reflect biological variability, reporting mosaicism warrants utmost caution. A prudent approach is imperative, as it may determine the difference between success or failure for some patients.
Keywords
aneuploidy, intermediate copy number, euploidy, chromosomal mosaicism, PGT laboratory, PGT-A

Downloads

  • (...).pdf
    • full text (Published version)
    • |
    • UGent only
    • |
    • PDF
    • |
    • 1.95 MB

Citation

Please use this url to cite or link to this publication:

MLA
Popovic, Mina, et al. “Implicit Bias in Diagnosing Mosaicism amongst Preimplantation Genetic Testing Providers : Results from a Multicenter Study of 36 395 Blastocysts.” HUMAN REPRODUCTION, vol. 39, no. 1, 2024, pp. 258–74, doi:10.1093/humrep/dead213.
APA
Popovic, M., Borot, L., Lorenzon, A. R., Lopes, A. L. R. de C., Sakkas, D., Lledo, B., … Vassena, R. (2024). Implicit bias in diagnosing mosaicism amongst preimplantation genetic testing providers : results from a multicenter study of 36 395 blastocysts. HUMAN REPRODUCTION, 39(1), 258–274. https://doi.org/10.1093/humrep/dead213
Chicago author-date
Popovic, Mina, Lorena Borot, Aline R. Lorenzon, Ana Luiza Rossi de Castro Lopes, Denny Sakkas, Belen Lledo, Ruth Morales, et al. 2024. “Implicit Bias in Diagnosing Mosaicism amongst Preimplantation Genetic Testing Providers : Results from a Multicenter Study of 36 395 Blastocysts.” HUMAN REPRODUCTION 39 (1): 258–74. https://doi.org/10.1093/humrep/dead213.
Chicago author-date (all authors)
Popovic, Mina, Lorena Borot, Aline R. Lorenzon, Ana Luiza Rossi de Castro Lopes, Denny Sakkas, Belen Lledo, Ruth Morales, Jose Antonio Ortiz, Nikolaos Polyzos, Monica Parriego, Felicitas Azpiroz, Micaela Galain, Aida Pujol, Björn Menten, Lien Dhaenens, Frauke Vanden Meerschaut, Dominic Stoop, Maria Rodriguez, Enrique Perez de la Blanca, Amelia Rodriguez, and Rita Vassena. 2024. “Implicit Bias in Diagnosing Mosaicism amongst Preimplantation Genetic Testing Providers : Results from a Multicenter Study of 36 395 Blastocysts.” HUMAN REPRODUCTION 39 (1): 258–274. doi:10.1093/humrep/dead213.
Vancouver
1.
Popovic M, Borot L, Lorenzon AR, Lopes ALR de C, Sakkas D, Lledo B, et al. Implicit bias in diagnosing mosaicism amongst preimplantation genetic testing providers : results from a multicenter study of 36 395 blastocysts. HUMAN REPRODUCTION. 2024;39(1):258–74.
IEEE
[1]
M. Popovic et al., “Implicit bias in diagnosing mosaicism amongst preimplantation genetic testing providers : results from a multicenter study of 36 395 blastocysts,” HUMAN REPRODUCTION, vol. 39, no. 1, pp. 258–274, 2024.
@article{01HQ8MVM9CF5MW5RF843NKHS8G,
  abstract     = {{STUDY QUESTION: Does the diagnosis of mosaicism affect ploidy rates across different providers offering preimplantation genetic testing for aneuploidies (PGT-A)?SUMMARY ANSWER: Our analysis of 36 395 blastocyst biopsies across eight genetic testing laboratories revealed that euploidy rates were significantly higher in providers reporting low rates of mosaicism.WHAT IS KNOWN ALREADY: Diagnoses consistent with chromosomal mosaicism have emerged as a third category of possible embryo ploidy outcomes following PGT-A. However, in the era of mosaicism, embryo selection has become increasingly complex. Biological, technical, analytical, and clinical complexities in interpreting such results have led to substantial variability in mosaicism rates across PGT-A providers and clinics. Critically, it remains unknown whether these differences impact the number of euploid embryos available for transfer. Ultimately, this may significantly affect clinical outcomes, with important implications for PGT-A patients.STUDY DESIGN, SIZE, DURATION: In this international, multicenter cohort study, we reviewed 36 395 consecutive PGT-A results, obtained from 10 035 patients across 11 867 treatment cycles, conducted between October 2015 and October 2021. A total of 17 IVF centers, across eight PGT-A providers, five countries and three continents participated in the study. All blastocysts were tested using trophectoderm biopsy and next-generation sequencing. Both autologous and donation cycles were assessed. Cycles using preimplantation genetic testing for structural rearrangements were excluded from the analysis.PARTICIPANTS/MATERIALS, SETTING, METHODS: The PGT-A providers were randomly categorized (A to H). Providers B, C, D, E, F, G, and H all reported mosaicism, whereas Provider A reported embryos as either euploid or aneuploid. Ploidy rates were analyzed using multilevel mixed linear regression. Analyses were adjusted for maternal age, paternal age, oocyte source, number of embryos biopsied, day of biopsy, and PGT-A provider, as appropriate. We compared associations between genetic testing providers and PGT-A outcomes, including the number of chromosomally normal (euploid) embryos determined to be suitable for transfer.MAIN RESULTS AND THE ROLE OF CHANCE: The mean maternal age (+/- SD) across all providers was 36.2 (+/- 5.2). Our findings reveal a strong association between PGT-A provider and the diagnosis of euploidy and mosaicism. Amongst the seven providers that reported mosaicism, the rates varied from 3.1% to 25.0%. After adjusting for confounders, we observed a significant difference in the likelihood of diagnosing mosaicism across providers (P < 0.001), ranging from 6.5% (95% CI: 5.2-7.4%) for Provider B to 35.6% (95% CI: 32.6-38.7%) for Provider E. Notably, adjusted euploidy rates were highest for providers that reported the lowest rates of mosaicism (Provider B: euploidy, 55.7% (95% CI: 54.1-57.4%), mosaicism, 6.5% (95% CI: 5.2-7.4%); Provider H: euploidy, 44.5% (95% CI: 43.6-45.4%), mosaicism, 9.9% (95% CI: 9.2-10.6%)); and Provider D: euploidy, 43.8% (95% CI: 39.2-48.4%), mosaicism, 11.0% (95% CI: 7.5-14.5%)). Moreover, the overall chance of having at least one euploid blastocyst available for transfer was significantly higher when mosaicism was not reported, when we compared Provider A to all other providers (OR = 1.30, 95% CI: 1.13-1.50). Differences in diagnosing and interpreting mosaic results across PGT-A laboratories raise further concerns regarding the accuracy and relevance of mosaicism predictions.

While we confirmed equivalent clinical outcomes following the transfer of mosaic and euploid blastocysts, we found that a significant proportion of mosaic embryos are not used for IVF treatment.LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of the study, associations can be ascertained, however, causality cannot be established. Certain parameters such as blastocyst grade were not available in the dataset. Furthermore, certain platform-related and clinic-specific factors may not be readily quantifiable or explicitly captured in our dataset. As such, a full elucidation of all potential confounders accounting for variability may not be possible.WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the strong need for standardization and quality assurance in the industry. The decision not to transfer mosaic embryos may ultimately reduce the chance of success of a PGT-A cycle by limiting the pool of available embryos. Until we can be certain that mosaic diagnoses accurately reflect biological variability, reporting mosaicism warrants utmost caution. A prudent approach is imperative, as it may determine the difference between success or failure for some patients.}},
  author       = {{Popovic, Mina and  Borot, Lorena and  Lorenzon, Aline R. and  Lopes, Ana Luiza Rossi de Castro and  Sakkas, Denny and  Lledo, Belen and  Morales, Ruth and  Ortiz, Jose Antonio and Polyzos, Nikolaos and  Parriego, Monica and  Azpiroz, Felicitas and  Galain, Micaela and  Pujol, Aida and Menten, Björn and Dhaenens, Lien and Vanden Meerschaut, Frauke and Stoop, Dominic and  Rodriguez, Maria and  de la Blanca, Enrique Perez and  Rodriguez, Amelia and  Vassena, Rita}},
  issn         = {{0268-1161}},
  journal      = {{HUMAN REPRODUCTION}},
  keywords     = {{aneuploidy,intermediate copy number,euploidy,chromosomal mosaicism,PGT laboratory,PGT-A}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{258--274}},
  title        = {{Implicit bias in diagnosing mosaicism amongst preimplantation genetic testing providers : results from a multicenter study of 36 395 blastocysts}},
  url          = {{http://doi.org/10.1093/humrep/dead213}},
  volume       = {{39}},
  year         = {{2024}},
}

Altmetric
View in Altmetric
Web of Science
Times cited: