Useful For

  • Newborn Screen Recommended Panel, Blood Spot (NBSR)
    Presymptomatic identification of Recommended Uniform Screening Panel (RUSP) disorders only to allow for early initiation of treatment and consequent improvement in the long-term prognosis of affected patients.
  • Newborn Screening Expanded Panel, Blood Spot (NBSE)
    Presymptomatic identification of disorders for which we can screen using an expanded panel to allow for early initiation of treatment and consequent improvement in the long-term prognosis of affected patients.

An Interview with Dietrich Matern, M.D., Ph.D. [Full Interview]

Dietrich Matern, M.D., Ph.D., Chair of the Division of Laboratory Genetics and a Consultant in the Department of Laboratory Medicine and Pathology at Mayo Clinic, provides an overview of newborn screening, discusses the Recommended Universal Screening Panel, and details the Mayo Clinic approach to reducing the false positive rate.

An Overview of Newborn Screening

Newborn screening as a public health measure was initiated in the early 1960s for the identification of infants affected with phenylketonuria (PKU). Since then, additional genetic and nongenetic conditions were included in screening programs. The goal of newborn screening is to detect diagnostic markers of selected disorders in blood spots collected from presymptomatic newborns. Early identification of affected newborns allows for early initiation of treatment to avoid mortality, morbidity, and disabilities due to these disorders.

The US Secretary of Health and Human Services (HHS) recommends all programs screen for 34 core disorders. These conditions are considered to fulfill 3 basic principles:

  • Condition is identifiable at a period of time (12–48 hours after birth) at which it would not ordinarily be clinically detected.
  • Test with appropriate sensitivity and specificity is available.
  • Demonstrated benefits of early detection, timely intervention, and efficacious treatment.

What Is the RUSP?

These 34 core disorders comprise the Recommended Uniform Screening Panel (RUSP).

Screening tests do not conclusively determine disease status, but measure analytes, which in most cases are not specific for a particular disease. This is the reason why the HHS Secretary also recognizes more than 25 additional conditions as secondary targets that do not meet all inclusion criteria, but are identified nevertheless because most of them are components of the differential diagnosis of screening results observed in core conditions. Even for the secondary conditions, the possibility of making a diagnosis early in life not only helps avoid unnecessary diagnostic testing, but is also beneficial to the patient's families because genetic counseling and prenatal diagnosis can be offered.

The Newborn Screen Recommended Panel, Blood Spot test includes 32 of 34 core conditions* included in the RUSP and all secondary conditions listed with the RUSP. Our screening approach is designed to identify all newborns affected with at least the classic variants of the diseases, but is not expected to detect milder forms of these conditions. For a list of these conditions, visit our test catalog.

The NBSE/Newborn Screening Expanded Panel, Blood Spot includes the same testing as the this test, but also includes screening for an additional 4 lysosomal storage disorders (Krabbe, Fabry, Gaucher, and Niemann-Pick A/B diseases), guanidinoacetate methyltransferase (GAMT) deficiency, and glucose-6-phosphate dehydrogenase (G6PD) deficiency.

*This test does not screen for critical congenital heart disease and congenital hearing loss, both of which are tested in the nursery using methods other than blood spots (audiometry, pulse oximetry).

Reducing the False Positive Rate in Newborn Screening

A primary goal of our approach has always been to provide screening that identifies every affected baby but with a minimum of false positive results. This has been important to us because there's data to support the obvious notion that families who experience false positive results become unnecessarily stressed. Those false positive results must then be excluded by additional, costly, and time-consuming testing. So, we believe in doing everything possible to reduce the false positive rate, while making sure that every baby that actually has a disease is identified quickly.

To do that, we have developed and employed several of what we call "second-tier tests." These tests take a little longer than the screening tests, so they cannot be run on all screening samples. They are needed for those screening tests where results in affected and unaffected babies can overlap. Because we do not want to miss any affected baby, but don’t want to initiate unnecessary follow-up either, we take the original dried blood spot and do the second-tier test, which looks for more disease-specific biomarkers. In most instances, the second-tier test is normal, and no further action is necessary. But, when it is abnormal, we make every effort to ensure that the baby is evaluated and treated as soon as possible.

In addition, we employ bioinformatics to reduce the need for second-tier testing, but also to reduce false positive results for conditions for which there is no second-tier test. This bioinformatics system is a worldwide effort called Collaborative Laboratory Integrated Reports (CLIR) and was developed by Piero Rinaldo, M.D., Ph.D., one of my colleagues here in the Biochemical Genetics Laboratory. This increasingly sophisticated system takes into account all available information, not only the screening test results, but also other information provided with the newborn screening card, such as birth weight and age at specimen collection, to determine a data profile like a fingerprint. This profile is then compared to such profiles of hundreds of thousands of unaffected newborns and an increasing number of affected newborns. The degree of similarity with either the profiles of affected or unaffected newborns then allows for the determination of whether a baby is unaffected, whether a second-tier test should be done, or if immediate reporting is required to allow for timely evaluation of the newborn.

Having employed a screening strategy that includes bioinformatics and second-tier tests, we may have achieved a unique screening performance characterized by hopefully 100% sensitivity for at least the primary targets of newborn screening while maintaining a near-zero false positive rate, thereby avoiding unnecessary follow-up and the associated anxiety, wasted time, and cost.