A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use

Norbert Gleicher; Jacob Metzger; Gist Croft; Vitaly A Kushnir; David F Albertini; David H Barad

doi:10.1186/s12958-017-0251-8

Research Methods · Measurement and Statistics

A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use

Gleicher N, Metzger J, Croft G, Kushnir VA, Albertini DF, Barad DH

Published April 27, 2017 Reprod Biol Endocrinol

DOI 10.1186/s12958-017-0251-8 PMID 28449669 PMC PMC5408377

RRM Academy Synopsis

Models show a single embryo biopsy cannot reliably read chromosomes

Two mathematical models show that a single 6-cell biopsy cannot reliably reveal whether an IVF embryo has normal chromosomes. The models sampled about 6 cells from the trophectoderm, the outer layer of the blastocyst, about 300 cells in all. Even in the best case, a biopsy of at least 27 cells would be needed.

Key Findings

The models assumed a biopsy of about 6 cells taken from a trophectoderm of about 300 cells.
An embryo with only 60% normal cells still produced a biopsy with no abnormal cells in more than 5% of cases.
Even under the best case, an even spread of abnormal cells, a biopsy of at least 27 cells would be required for minimal diagnostic predictability.
A biopsy in which 80% of cells are abnormal remains compatible with an embryo that is approximately 60% normal.
The authors call an even spread unlikely, since mosaicism is usually clonal, and say a clustered pattern would lower accuracy further.

Interpretation

The paper is a modeling study by an IVF clinic and a university laboratory. The results rest on assumed cell counts of 6 and 300. Earlier studies suggested a smaller trophectoderm of about 70 to 120 cells. The models give no specific probabilities. The paper leaves open how well the trophectoderm matches the inner cell mass, the part that becomes the fetus.

RRM Context

IVF goes around infertility without finding why conception fails. Embryo screening adds one more test to that process, and the paper questions how accurate the test is. Restorative reproductive medicine starts earlier. It evaluates both partners to find the cause of infertility before any embryo exists.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

It has become increasingly apparent that the trophectoderm (TE) at blastocyst stage is much more mosaic than has been appreciated. Whether preimplantation genetic screening (PGS), utilizing a single TE biopsy (TEB), can reliably determine embryo ploidy has, therefore, increasingly been questioned in parallel.

Methods

We for that reason here established 2 mathematical models to assess probabilities of false-negative and false-positive results of an on average 6-cell biopsy from an approximately 300-cell TE. This study was a collaborative effort between investigators at The Center for Human Reproduction in New York City and the Center for Studies in Physics and Biology and the Brivanlou Laboratory of Stem Cell Biology and Molecular Embryology, the latter two both at Rockefeller University in New York City.

Results

Both models revealed that even under best case scenario, assuming even distribution of mosaicism in TE (since mosaicism is usually clonal, a highly unlikely scenario), a biopsy of at least 27 TE cells would be required to reach minimal diagnostic predictability from a single TEB.

Conclusions

As currently performed, a single TEB is, therefore, mathematically incapable of reliably determining whether an embryo can be transferred or should be discarded. Since a single TEB, as currently performed, apparently is not representative of the complete TE, this study, thus, raises additional concern about the clinical utilization of PGS.

Topics

Research Methods › Measurement and Statistics › Statistical Methods · Assisted Reproduction › Add-Ons and Adjuncts › Preimplantation Genetic Testing · Genetics and Immunology › Reproductive Genetics › Chromosomal Abnormalities

Norbert Gleicher, Jacob Metzger, Gist Croft, Vitaly A Kushnir, David F Albertini, David H Barad

N Gleicher, J Metzger, G Croft, V Kushnir, Dave Albertini, D Albertini, Dave Barad, D Barad

PMID 28449669 28449669 DOI 10.1186/s12958-017-0251-8 10.1186/s12958-017-0251-8 Gleicher et al. 2017, Gleicher 2017

A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use

Models show a single embryo biopsy cannot reliably read chromosomes

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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