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Genetic Testing with NGS

The latest iteration of comprehensive chromosomal screening (CCS) is called “next generation sequencing” (NGS). A recent study set out to clinically validate the technology; in a blinded, non-selection study, embryos were transferred without knowledge of NGS results to determine the predictive value (proportion of results that are true positive and true negative).

“The way NGS works is you amplify a limited amount of starting material with very small biopsies,” says Dr. Marie Werner. “From that genetic information that we start with, we generate millions of small fragments of DNA. Once we generate those small fragments, we computationally align them to referenced parts of the genome from the human genome database. And we can do that for all 24 chromosomes. We repeat it many, many times and then we normalize it to known normal samples. And from that information, we can get a comprehensive chromosomal screening diagnosis.”

The study involved patients age 42 or younger, with normal ovarian reserve, who elected for chromosome screening. The IVF cycle was performed, the embryos were cultured to blastocysts, they were biopsied and frozen. The biopsy was stored but no screening was done at that time, and the transfers were performed based on morphology. NGS was then performed on the stored biopsy.

The researchers followed the pregnancy outcomes and compared the results to the NGS screening results.

The findings were as follows, Werner says:

  • “The clinical implantation rate for the entire population was 65%; the sustained implantation rate – heartbeat at 8 or 9 weeks of discharge – was 50%; we were predictive in the results.”
  • “The negative predictive value of an aneuploid result was 100%, meaning that if we had looked back and we said that the embryo was chromosomally abnormal, none of those embryos implanted.”
  • “The positive predictive result for euploid embryos – we called that embryo chromosomally normal and that patient had a transfer – 66% of those embryos implanted, which is really high and consistent with what we’re seeing in modern day CCS results.

NGS isn’t currently the CCS platform at RMA NJ. “We feel very strongly that you need to validate this before implementing it,” Werner says, and a follow-up study is close to being finalized.

One important point about NGS, she adds, is that not every platform that does NGS is doing it in the same way, and that can impact the results. The two processes are “whole genome amplification” and “targeted PCR.” RMA NJ uses targeted PCR.

”What’s different is, we are trying to amplify the most relevant sections of the genome. With Whole Genome is just randomly amplifying 20% of the genome, but potentially not the same 20% each time. It may not be as reproducible,” Werner says.

’It means that the results from our study, while they’re great, may not be applicable to validating the other NGS techniques that are out there. Patients are doing CCS, but don’t know if it’s been as rigorously tested in that lab.”

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