Diagnostic accuracy: theoretical models for preimplantation genetic testing of a single nucleus using the...

The aim of this study was to develop and use theoretical models to investigate the accuracy of the fluorescence in situ hybridization (FISH) technique in testing a single nucleus from a preimplantation embryo without the complicating effect of mosaicism.

Mathematical models were constructed for three different applications of FISH in preimplantation genetic testing (sex determination for sex-linked diseases, two-way reciprocal translocations and sporadic chromosome aneuploidy). The input values were the degree of aneuploidy (initially set at 3% per chromosome for sporadic aneuploidy) and the accuracy per probe (initially set at 95%), defined as the proportion of normal diploid nuclei with a normal signal pattern. The primary statistic was the predictive value of the test result.

Testing two chromosome pairs to determine sex chromosome status or detect unbalanced translocation products had high predictive value: at least 99.5% for a normal test result (95% CI: 99-100%), and 90% for an abnormal test result (95% CI: 88-92%). However, the predictive value of an abnormal test result testing five chromosomes for sporadic chromosome aneuploidy was 41% (95% CI: 36-46%); 90% would be achieved with an aneuploidy rate per chromosome of 20.3% (equivalent to 99.5% prevalence for 23 chromosomes) rather than 3%, or with an accuracy per probe of 99.6% rather than 95%, or when testing 23 chromosome pairs, rather than 5 pairs, with either 8.3% aneuploidy (86.4% prevalence) or 99.5% accuracy.

Testing a single cell using the FISH technique has the potential to achieve acceptable analytical performance for sex determination and two-way reciprocal translocations, but is unlikely to achieve adequate performance testing for sporadic chromosome aneuploidy. New techniques for detecting the copy number of every chromosome are emerging, but it remains to be seen if the high accuracy required will be achieved.