A British effort to compare the clinical and cost effectiveness of prenatal chromosomal microarray analysis with standard karyotyping should conclude case recruitment by May 2014, with the results of the study out by January 2015, "at the latest," according to the project's lead investigator.
Stephen Robson, a professor of fetal medicine at Newcastle University, said that should the final results indicate that arrays are a more clinically and cost effective tool, the technology would be adopted as the first-tier test in the UK for cases where the fetus shows isolated nuchal translucency, or where there is an abnormal ultrasound finding.
"If we confirm the increase in detection rate of significant copy number variants over karyotyping and costs-turnaround times are acceptable then, yes, we would be expecting arrays to be adopted instead of karyotyping for fetal anomalies," Robson told BioArray News.
The project has been dubbed "EACH" for evaluation of array comparative genomic hybridization in prenatal diagnosis of fetal anomalies. It commenced in February 2012 with a total budget of £1.5 million ($2.2 million). Funded through the UK Medical Research Council's Efficacy and Mechanism Evaluation Program, the project addresses the hypothesis that CMA detects more de novo pathogenic chromosomal imbalances than standard karyotyping.
The project mirrors a similar US National Institute of Child and Human Development-funded study that led the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine to earlier this month recommend that CMA replace karyotyping as a first-tier test in the case of an abnormal ultrasound scan.
In that US study, detailed in a New England Journal of Medicine paper last year, a Columbia University Medical Center-led team examined more than 4,000 cases and determined that arrays detected additional abnormalities in one out of every 70 fetal samples that had a normal karyotype. When a birth defect was imaged by ultrasound, arrays found relevant genetic information in 6 percent of cases. These findings and others led the team to conclude that arrays were more informative than standard, microscope-based karyotyping to identify genetic abnormalities in prenatal cases.
For the EACH Project, the investigators are recruiting 1,000 cases from 11 fetal medicine centers in England and Wales. According to Robson, the cases must have a normal quantitative fluorescent PCR result, meaning that the fetuses do not carry a common trisomy or monosomy. Once recruited, the cases are analyzed using both CMA and karyotyping.
According to EACH, the number of cases will give in excess of 90 percent power to detect a difference in detection rates at the 5 percent significance level, based on the hypothesis that karyotyping and array CGH detect pathogenic imbalances in 5 percent and 10 percent of cases, respectively. EACH is also conducting a qualitative sub-study consisting of semi-structured, in-depth interviews undertaken with between 12 and 15 health professionals and 12 and 15 parents.
"Assuming we recruit this number of cases, then we should be able to give clear guidance as to whether [CMA] detects more clinically significant genetic copy number variants than standard karyotyping and the cost per additional significant copy number variant detected," Robson said.
According to Robson, the array used in the CMA varies from laboratory to laboratory. Each participant is free to use whatever platform it chooses so long as it meets criteria for CMA established by the International Collaboration for Clinical Genomics, formerly known as the International Standards for Cytogenomic Arrays consortium.
"The labs access whatever support from manufacturers they would normally do with a clinical postnatal array," said Robson. "However, where there are any uncertainties about the call, i.e. whether the result is released to parents, there is expert opinion available to aid with interpretation through the EACH team," he said.
While the EACH Project is platform agnostic, the project partnered with Cambridge, Mass.-based software firm Cartagenia in June 2012 to assist with its data analysis and sharing needs. Specifically, EACH participants are using Cartagenia's BENCH platform to collect genetic and clinical data on the study cohort, as well as to store large sets of patient-centric data, filtering and interpreting genetic variants, and annotating clinical and administrative information.
Cartagenia is also working with a CUMC-led team on a follow-on, NICHD-funded project to better understand how variants uncovered by array analysis might be linked to developmental delay, structural abnormalities, and diseases.