IVDT_In Vitro Diagnostics Technology

IVD Technology, Spring 2013

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MOLECuLAR DIAGNOSTICS detect triploidy, where the fetus has three copies of each chromosome. Tese limitations are likely to be overcome by methods that incorporate and analyze genotypic information. a next-generation approach for noninvasive Prenatal Testing Just over one year after the frst noninvasive prenatal test arrived on the market, Natera introduced a commercialized next-generation test called Panorama. Tis test difers from existing counting methods in a number of important ways. First, the Panorama test measures the DNA at tens of thousands of single-nucleotide polymorphic (SNP) loci, or genetic base pairs that tend to vary from person to person. Each SNP contains multiple pieces of information, contrasting with the nonpolymorphic regions assayed by counting methods. Additionally, the Panorama test utilizes a sophisticated computer algorithm, called Nextgeneration Aneuploidy Testing Using SNPs (NATUS), that takes advantage of advanced Bayesian statistics. In addition, the NATUS algorithm is able to use parental genotypic information to aid in the analysis of the relatively noisy DNA measurements that are available from the mixture of maternal and fetal cell-free DNA found in maternal plasma. Te NATUS algorithm takes the maternal genotype, which is obtained by measuring a cellular fraction of the maternal blood sample, as well as the paternal genotype, if available (though not necessary), and combines them with crossover frequency data from the human genome project19, 20 to bioinformatically predict all of the possible fetal genotypes that could arise from the parents in question.21, 22 Although there are billions of possible fetal genotypes for a given set of parents, this number is far smaller than the overall number of possible human genotypes. Tese billions of hypotheses are then compared to the actual cell-free DNA measurements, and a likelihood is calculated for each hypothesis. Te hypothesis with the maximum likelihood indicates the actual genetic state of the fetus, thus determining the presence or absence of a chromosomal abnormality.21,22 Tis approach has demonstrated its ability to detect chromosomal abnormalities with high accuracy. In clinical studies, the NATUS algorithm showed a sensitivity greater than 99% when detecting trisomy 21, trisomy 18, and trisomy 13, and 91.7% when detecting monosomy X (Turner syndrome).21 An additional advantage of this SNP-based approach is that unusual biology associated with the X chromosome (for example, undetected maternal monosomy X mosaicism) can be taken into account, as information from the maternal genome is incorporated into the analysis; this cannot be done using the frstgeneration counting approaches. Clinical studies evaluating the NATUS algorithm's ability to detect XXX, XXY, XYY, and triploidy are ongoing. 36 IVD TEC HNOLO G Y | SP RIN G 2013 magenta cyan black Importantly, this approach does not rely on a reference chromosome, which confers multiple advantages. Specifcally, the NATUS algorithm is able to detect, with high accuracy, abnormalities on chromosomes that do not amplify with reliable efciency, such as chromosome 13 and the sex chromosomes.21, 22 Also, the NATUS algorithm is uniquely able to detect triploidy,23 which overcomes a limitation of the frst-generation approach. An additional and signifcant beneft is the ability to detect chromosomal abnormalities with high accuracy even at low fetal cell-free DNA fractions. a Promising Future for noninvasive Prenatal Testing Te advent of noninvasive prenatal testing represents a major advance in prenatal care. Tese tests overcome the unreliability of blood-based hormone screening tests to provide an accurate and safe method of detecting fetal chromosomal abnormalities. As the technologies behind these tests are continuously improved, the scope of chromosomal abnormalities that can be detected will expand. Indeed, the next stage of the noninvasive prenatal testing frontier has begun, as these technologies are expanding to include detection of microdelections and microduplications.24 Although massively parallel sequencing based approaches can accomplish this, targeted approaches will be dramatically more efcient. In the future, SNP-based approaches are expected to be able to detect single-gene disorders, such as cystic fbrosis, as well.25 Te future of noninvasive prenatal testing is bright, and these tests have been readily accepted by the medical community and payers alike. Te ability to detect additional chromosomal abnormalities will further advance prenatal care. Tis holds promise for a noninvasive screening test with unparalleled scope and accuracy, limited only by the ceiling of accuracy defned by mosaicism, thus signifcantly reducing the risk of miscarriage from routine prenatal care. References 1. "Noninvasive prenatal testing for fetal aneuploidy," Committee Opinion No. 545, American College of Obstetricians and Gynecologists, Obstet Gynecol 120 (2012):1532-4. 2. T. Fong, "United Healthcare Joins List of National Payors Supporting Non-invasive Prenatal Diagnostic Testing," GenomeWeb, 5 March 2013; Web, 8 March 2013. 3. "American College of Obstetricians and Gynecologists Invasive prenatal testing for aneuploidy," ACOG Practice Bulletin, no. 88, December 2007, Obstet Gynecol 110, 6 (2007):1459. 4. DW Bianchi, JL Simpson, LG Jackson et al. "Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data," National Institute of Child Health and Development Fetal Cell Isolation Study, Prenat Diagn 22, no. 7, (2002): 609–615. 5. E. Guetta , MJ Simchen, K Mammon-Daviko et al., "Analysis of fetal blood cells in the maternal circulation: challenges, ongoing eforts, and potential solutions," Stem Cells Dev 13, 1 (2004): 93–99. 6. HC Fan, YJ Blumenfeld, U Chitkara et al., "Non-invasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood," Proc Natl Acad Sci USA 105, (2008): 266–271. i v d t e c hnol ogy. com ES235874_IV1305_036.pgs 04.23.2013 05:10 UBM

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