Lab Matters Spring 2019 - Page 9

FEATURE test data to reduce ambiguous findings. “If we see a [genetic] variant twice in New York and the baby is, and remains, asymptomatic,” she said, “it’s more likely to be identified in asymptomatic infants across the country.” whole lot of ethical considerations.” She explained, “When you test the genome, you’re going to find mutations that may not mean anything, and we won’t know what’s significant and what’s not. And how do you tell the family that; that you found a variant and you don’t know what that means, maybe nothing?” Wadsworth is also working to enhance long-term follow-up, so, Caggana said, data “can feed back to [the laboratory] to help us modify the testing algorithm so we don’t catch the babies who will never develop disease.” Equivocal and false-positive findings come at a cost. Neena Champaigne, MD, FACMG, FAAP, director of the metabolic treatment program at South Carolina’s Greenwood Genetic Center, diagnoses and follows patients with metabolic NBS disorders from birth onward. False-positives and findings of unknown clinical significance, she said “cause us a lot of concern.” Among the consequences are: • “Running the risk of inundating providers,” who may then develop a lack of urgency “because they now have so many infants with abnormal results and they don’t know how to sift through them and triage them.” • Placing unnecessary psycho-social burdens on families. Champaigne said, “I personally have seen families who have medicalized their children even after it’s proven that they don’t have a NBS condition; they have a hyper- awareness for that child, more doctor visits, which can have ramifications for years.” • Compromising medical specialists who are already “stretched thin,” and must then follow individuals who may never develop symptoms. Champaigne, for example, is one of only two biochemical geneticists serving the entire state of South Carolina, plus the nearby border regions of Georgia and North Carolina. Some states, she said, “don’t even have a biochemical geneticist.” Although her training is in pediatrics, of necessity, Champaigne has followed some patients well into adulthood. “External pressures to meet challenging timelines” NBS programs are working diligently to address these challenges; to improve the accuracy and precision of existing tests PublicHealthLabs @APHL I personally have seen families who have medicalized their children even after it’s proven that they don’t have a NBS condition; they have a hyper-awareness for that child, more doctor visits, which can have ramifications for years.” Neena Champaigne, MD, FACMG, FAAP and to bring on new disorders, even as they continue the high-stakes work of screening tens of thousands of infants a year—in some states a six- or seven-day- a-week job. Hopkins oversaw one of the first Pompe disease screening programs in the world, demonstrating proof-of-concept for Pompe NBS. To do so, his team adapted and validated a brand-new methodology called digital microfluidics fluorometry. A statewide hiring freeze at the time meant that no additional help was available in a laboratory already screening 93,000 NBS specimens/year for over 60 other disorders. An early success, said Hopkins, was detecting a child with infantile Pompe on the second day of pilot screening. And data from the first six months of population-wide screening revealed about twice as many Pompe cases as predicted in the scientific literature. These outcomes bolstered the case for adding Pompe to the RUSP in 2013. Caggana is working with colleagues to create a forum for sharing molecular APHL.org Wadsworth scientists are in the midst of refining the laboratory’s screening algorithm for cystic fibrosis (CF) to reduce the number of false-positive results—an example that showcases the complexity of modern-day NBS. In the first phase of analysis, specimens are winnowed via a biochemical test to measure levels of the CF marker, immunoreactive trypsinogen (IRT). Those with IRT levels among the top 5% of specimens screened in the past ten days then advance to molecular testing. New York is transitioning from a two-tier genetic screening protocol—a 39-mutation CF panel, followed by CFTR gene sequencing for specimens meeting certain criteria—to an enhanced process: “We’ll take a bioinformatic look to interrogate all the [CFTR gene] variants we’ve seen in babies in New York,” said Caggana. “If a baby has one variant, we’ll look at the rest of the gene.” Infants with two CF variants are reported as screen-positive and those with one as “single variant detected.” Although this multi-step process increases test turn-around-time, it also increases specificity. “We’re able to reduce the number of families impacted and the downstream number of babies who have to undergo [a diagnostic] sweat test,” said Caggana. “That makes the longer time palatable.” Further complicating the work of NBS scientists, said Hopkins, are “external pressures to meet challenging timelines and quality in a very sensitive and oftentimes emotional area of laboratory testing.” Earlier this year, Sanofi US—which manufactures enzyme replacement therapies for a group of NBS conditions known as lysosomal storage disorders (LSDs)—lobbied the Iowa legislature and Spring 2019 LAB MATTERS 7