NEW YORK (GenomeWeb) – Whole-genome and whole-exome sequencing have greater diagnostic and clinical utility than chromosomal microarrays in children thought to have a genetic disease, according to a new analysis. This suggested to the Children's Institute for Genomic Medicine-led research team that sequencing should be considered a first-line genomic test.
Currently, chromosomal microarrays are the recommended first-line genomic tests for children with certain genetic diseases, which can be difficult to diagnose. However, whole-genome and whole-exome sequencing have become more common testing approaches in recent years. For the new analysis, the researchers sifted through the literature to analyze the reported diagnostic and clinical utility of the sequencing approaches as compared to chromosomal microarrays in cases of suspected pediatric genetic disease. As they reported today in npj Genomic Medicine, the investigators found sequencing to have a higher utility.
"What we learned is that WGS and WES offer greater diagnostic and clinical utility than CMA, leading us to conclude that WGS and WES should be considered first-line genomic tests for children with suspected genetic diseases," first author Michelle Clark from Rady said in a statement.
The researchers sifted through PubMed to uncover 37 studies that were published between January 2011 and August 2017 that included 20,068 children and evaluated the diagnostic utility of WGS and WES in comparison to CMA. One of these studies was a randomized controlled trial and 36 were case studies.
The pooled diagnostic utility of WGS in these studies of 0.41 was qualitatively larger than for WES, which was 0.36, or CMA, which was 0.10, Clark and her colleagues reported.
When the researchers modeled the heterogeneity in the diagnostic utility of WES, WGS, and CMA, they found effects by study size and year of publication. Studies that were larger in size had decreased odds of diagnosis. On average, a 1,000-person increase in study size was linked to a 28 percent decrease in the odds of diagnosis.
Additionally, over time, WES and WGS had increasing diagnostic rates of about 16 percent per year, while the odds of diagnosis via CMA decreased 14 percent each year. This change over time, the researchers noted, is likely due to the evolution of the sequencing technologies in combination with the wider use of CMA following increased reimbursement for testing.
Still, within 11 studies of nearly 2,000 children, all published in 2017, the pooled diagnostic utility of WGS was 0.42, while it was 0.05 for CMA.
Few studies, the researchers noted compared WES and WGS within cohorts. The two that did, involving 138 children, found no significant differences in the approaches' diagnostic utility.
When the researchers then pooled WES and WGS together to compare them together versus CMA, they found that the odds of getting a diagnosis through a sequencing approach was 8.3 times greater than it was for CMA. This suggested to the researchers that CMA should no longer be considered a first-line genomic test.
"Our hope is that whole genome sequencing will soon become routine so that all children who need it can have access to this life-saving technology," senior author Stephen Kingsmore, the president and CEO of Rady, said in a statement.
Sequencing, he and his colleagues reported, also had a greater clinical utility. More than a quarter of children analyzed by whole-genome sequencing had a change in their clinical management in light of their results, while only 6 percent of those who underwent CMA did.
However, the researchers also noted that WGS is about twice as expensive as WES, which is itself twice as expensive as CMA.
Additionally, they said their study was limited by its reliance on published diagnostic rates, inability to control for heterogeneity, and that some children who underwent sequencing had previously under gone CMA analysis.