Worldwide collaborative project to improve newborn screening accuracy for metabolic disorders

A unique worldwide collaborative project takes advantage of the Internet to improve the accuracy of screening for rare metabolic disorders in newborns, reports a paper in the March issue of Genetics in Medicine, the official peer-reviewed journal of The American College of Medical Genetics (ACMG). The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

"An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders," according to the new report, with an author list including 250 professionals from 46 countries. By pooling reports from newborn screening programs around the world, the "Region 4 Stork" (R4S) project provides quality improvement data that would be unattainable in any other way.

Worldwide Effort Leads to Continuous Improvement in Tandem Mass Spectrometry Screening
The R4S project was developed to improve the accuracy of tandem mass spectrometry (abbreviated "MS/MS") in screening for metabolic disorders. With MS/MS, screening for hundreds of possible genetic disorders can be simultaneously performed in a single dried blood spot.

Started as a cooperative effort of seven Midwestern states, the project has rapidly expanded to include the active participation of 48 U.S. states and territories, plus 80 screening programs in 45 other countries. The goal is to achieve universal MS/MS testing of newborns, including confirmatory testing for inborn errors of amino acid, organic acid, and fatty acid metabolism.

Because most of these disorders are very rare, information sharing between programs was essential to improve the performance of MS/MS screening. The R4S program provides a secure website that participating screening programs can use to upload and share data on all infants tested. All users have "on demand access to up-to-date tools and reports based on the entire body of collective experience."

This extensive shared database helps to maximize detection of affected newborns, improve overall test performance, and reduce the number of missed diagnoses (false negatives) and incorrect diagnoses (false positives) to the absolute lowest rates possible. The objective is to emphasize "how well" conditions are screened for, rather than just "how many" conditions are included in the screening program.

So far, the R4S project has collected data on blood spots from approximately 25 to 30 million normal newborns, as well as nearly 11,000 infants with inborn metabolic disorders. On average, just over five such "true-positive" cases are reported each day. The assembled data have greatly refined the ability to interpret test results, helping to set more accurate cutoff points for 114 individual screening test results.

Using the database, the collaborators have precisely adjusted diagnostic cutoff points to detect as many infants with metabolic disorders as possible, while keeping the number of "false alarms" as low as possible. The process is not yet complete, and will continue until at least 50 cases of every possible condition have been collected.

"[T]he R4S collaborative project has paved the way to a collegial and transparent process for clinical validation of newborn screening by MS/MS," the authors write. They add, "The critical factors behind the unanticipated expansion of the collaborative project to become a worldwide initiative have been the gain of mutual trust among participants, the belief of equal standing of all sites regardless of the magnitude of their contributions, and the vision to create tools that motivate users to be actively involved."

"This remarkable study not only represents creative thought about establishing evidence-based values for newborn screening but also demonstrates the value of the largest international study ever conceived and performed in newborn screening," comments Dr. R. Rodney Howell of University of Miami in an accompanying editorial. He believes that, as whole-genome sequencing becomes widely used, a similar "organized worldwide approach" could be invaluable in assessing the significance of rare genetic variants.