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Wales Adopts Mass Spec-based Methodology for Newborn Sickle Cell Screening

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The Wales Newborn Screening Laboratory has adopted tandem mass spectrometry for testing the country's newborns for sickle cell disease.

According to Stuart Moat, the laboratory's director, mass spec-based testing offers improvements in cost and speed over HPLC and isoelectric focusing, the methods conventionally used for sickle cell screening.

Additionally, Moat told ProteoMonitor, his lab's mass spec-based approach enables clinicians to identify only infants suffering from the disease, as opposed to those who are simply carriers. This, he noted, avoids passing carriers on for unnecessary follow-up testing. He added that it will also help clinicians pass on results in accordance with guidelines from the UK's Human Genetics Commission, which recommend that researchers use screening techniques in children that do not reveal disease carrier status if this information is not clinically important to their health.

Broadly speaking, mass spec-based proteomics has struggled to move into the clinic. Hemoglobinopathy screening, however, has emerged as an area potentially well-suited to the technique.

For instance, in a 2011 interview with ProteoMonitor, Denis Hochstrasser, chairman of Geneva University Hospital's Genetic & Laboratory Medicine Department and founder of the Swiss Institute for Bioinformatics and GeneBio, called newborn hemoglobinopathy screening one of the most obvious clinical uses for mass spec-based proteomics (PM 10/28/2011).

That same year, researchers from King’s College London and Guy’s and St Thomas’ NHS Foundation Trust launched SpotOn Clinical Diagnostics, a firm specializing in mass spec-based diagnosis of hemoglobin disorders (PM 12/9/2011).

As Neil Dalton, one of SpotOn's founders and a professor of pediatric biochemistry at King's College, noted at the time, hemoglobin's high abundance in blood makes hemoglobinopathy screening the “low-hanging fruit” of clinical proteomics.

Despite the technique's potential, however, Wales is one of the first countries to move to mass spec-based testing for these diseases. The country implemented mass spec-based testing in June and, Moat said, plans to use it as the primary method for the roughly 36,500 babies that it screens each year.

Wales was at an advantage in terms of moving to mass spec-based screening in that it had not previously done newborn sickle cell disease screening, Moat noted.

"I took over the Newborn Screening Laboratory five years ago, and I was given the remit of implementing sickle cell screening," he said. "That was my advantage compared to the rest of the UK – the fact that I had a blank page."

Moat said he first became interested in implementing a mass spec-based approach after attending a talk by Dalton detailing SpotOn's efforts. He and a colleague from his facility's hematology lab then visited Dalton's labs with a variety of samples to test out the approach.

"We analyzed them while we were there that day, and [Dalton] gave the answer to each one," Moat said.

Since then, he said, the lab has screened roughly 30,000 infants using the technique, running several samples per day on a Waters Xevo-TQ instrument.

Mass spec-based hemoglobinopathy testing is particularly attractive in a newborn screening context because it can be folded into existing newborn metabolite screening procedures, Moat noted.

"We run 200 to 300 samples per night for the metabolite screening and then 200 to 300 samples for the sickle screening, as well," he said. "You put them in in the late afternoon, and then you have results in the morning."

To get approval for use of the mass spec-based method, Moat and his colleagues had to take the process through the UK National Screening Committee. Given that this body oversees screening procedures throughout the UK, approval of the method for screening in Wales could have implications for the rest of the UK, he said.

However, Moat added, there were certain factors unique to Wales that likely helped the facility win approval. In addition to not having a previous screening program in place, Wales also benefits from having a low prevalence of sickle cell disease.

"So, in terms of risk assessment, we were low risk," he said. "Whereas the protocol we've implemented hasn't been tried and tested in a high prevalence region."

Moat and his colleagues detailed their protocol in a study published last month in Clinical Chemistry in which they analyzed blood spots from nearly 3,000 infants, developing screening cut-offs based on abundance ratios for variant peptide-to-wild-type peptide for Hbs, C, DPunjab, OArab, Lepore, and E peptides. They also presented the algorithm that they devised for masking infant carrier states post-analysis.

Because the lab's cut-offs are based on peptide levels in the normal infant population, the test has a very low risk of false negatives, Moat noted. It will, however, "pick up the occasional false positive result," he said.

For this reason, the lab passes all positive results on for secondary testing via HPLC or IEF.

Because its methodology is designed not to identify carriers, though, the lab is able to avoid passing these patients on for HPLC or IEF testing. This contributes to the technique's cost-effectiveness, Moat said, noting that in the absence of this protocol he would need to bring in additional staff and HPLCs. As he and his co-authors noted in their Clinical Chemistry paper, in 2012, roughly 10,000 sickle cell carrier infants were referred for follow-up testing in England.

The savings offered by his lab's approach could be even more significant in countries like the US that do high volumes of newborn screening, Moat suggested.

"There you have laboratories with large numbers of IEF and HPLC instruments just doing screening 24 hours a day," he said. "And, I think using the protocol here could reduce the number of carriers being referred, because there's no clinical evidence to suggest that identifying a sickle cell carrier in the neonatal period is of benefit."

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