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Newborn Screening Glossary


borderline result

a term sometimes used to indicate an out-of-range screening test result that is close to a program-established screen-positive cutoff value and is used to indicate moderate risk/possible disease rather than high-risk/probable disease

NOTE 1: A screen-positive result in the borderline range is typically followed up with a request for an additional screening specimen rather than diagnostic testing or clinical evaluation; NOTE 2: Follow-up actions accompanying a borderline result usually take additional time and should be restricted to diseases for which diagnosis and treatment are not time critical; NOTE 3: When a borderline result is obtained for the second time, the patient may then be referred for diagnostic work-up rather than specimen collection for another screen; NOTE 4: See screen positive and repeat specimen (requested). 


collection device

(for newborn screening) a medical device used to collect blood spots used for routine newborn screening

Alternate Term: specimen collection device

Project: NBS01, NBS09, NBS05

NOTE 1: The collection device has two components: a section for recording demographic and other requested information and a blood collection (specified filter paper) section with preprinted circles to be filled with the newborn blood drops; NOTE 2: If a preprinted circle is not present, local requirements must define the quantity of blood considered acceptable; NOTE 3: Once the blood is collected, the collection device becomes the specimen (also referred to as “blood spot specimen” or “dried blood spot specimen”) and is no longer considered a collection device; NOTE 4: This specimen collection device is also commonly referred to as a “Guthrie card,” “filter paper,” or a “blood spot card”; NOTE 5: See dried blood spot.


confirmatory test

test to prove or disprove the presence of a specific disease, group of diseases, or phenotypic differences suspected because of screening test results

Alternate Term: diagnostic test

Project: NBS03, NBS08, NBS09, NBS05, NBS02

NOTE: For newborn screening and identity confirmation, confirmatory testing should be performed on a new specimen and not on any existing screening specimen. 


dried blood spot

a specimen collected for laboratory testing using an approved medical device composed of a specified filter paper on which printed circles indicate the area to be filled with whole blood and air-dried for transport or storage

Project: NBS03, NBS01, NBS07, NBS04, NBS09, NBS08, NBS05

NOTE 1: Specimens collected using an approved medical device should yield a reproducible volume of blood per spot (typically 75 to 100 µL for a 12.5-mm circle, 35 to 50 µL for a 10-mm circle); NOTE 2: In newborn screening, the dried blood spot is ideally collected directly from a heelstick using no anticoagulant agents, because anticoagulant agents, particularly heparin and EDTA, have been shown to interfere with certain assays.


expected range

the range of values for a measurand in a typical healthy population

Project: NBS03, NBS01, NBS07, NBS09

NOTE 1: The expected range is a population distribution, not an analytical parameter, that may be estimated by applying statistical methods to data from reference populations that are representative of the population being tested. The limits of the expected range may vary depending on the reference population and the statistical methods used; NOTE 2: For purposes of newborn dried blood spot screening, results within the expected range should exclude the presence of the congenital condition that the test is used to detect, while results outside of the expected range may need to be acted upon; NOTE 3: As used in NBS07, the range of acid α-glucosidase activity values measured in dried blood spot specimens from newborns without Pompe disease, as opposed to laboratory test results that show acid α-glucosidase activity values below the predetermined cutoff (ie, a result outside of the expected range, or an out-of-range result); NOTE 4: The analytically validated calibration range should ideally encompass the population expected range and the range surrounding the value used to distinguish screen-positive and screen-negative results; NOTE 5: Expected ranges may be specified separately for subpopulations such as full-term newborns, preterm and low birth weight newborns, and older infants; NOTE 6: As used in NBS07, the laboratory test result of any satisfactory dried blood spot specimen that shows acid α-glucosidase activity values at or above the predetermined cutoff is a screening result that is out of the expected range requiring follow-up (ie, a laboratory test result outside of the expected range of normal/negative testing results established for a particular condition, including carrier results, that indicates the need for additional testing); NOTE 7: As used in NBS09, the range of C26:0-lysophosphatidylcholine (LPC) values measured in DBS specimens from newborns without adrenoleukodystrophy disease, as opposed to laboratory test results that show C26:0-LPC values above the predetermined cutoff (ie, a result outside of the expected range, or an out-of-range result); NOTE 8: As used in NBS09, the laboratory test result of any satisfactory DBS specimen that shows C26:0-LPC values at or above the predetermined cutoff is out of the expected range and requires follow-up; NOTE 9: Also called “reference interval,” “reference range,” and “normal range”; NOTE 10: See in-range and out-of-range.


false-negative screening result

screen-negative result in an affected newborn

Project: NBS01, NBS09, NBS05, NBS03

NOTE 1: A screen-negative result indicating that an individual is not at increased risk for the target disease when the individual is found later to be affected; NOTE 2: For quantitative tests such as immunoreactive trypsinogen, this refers to an “in-range” result in an affected child; NOTE 3: For qualitative tests such as DNA analysis, this may include failure to detect cystic fibrosis transmembrane conductance regulator gene variants; NOTE 4: A screen-negative result indicating that an individual is not at increased risk for the primary target disease when the individual is found later to be affected; NOTE 5: As used in NBS09, a screen-negative result of a laboratory screening algorithm (based on the detected C26:0-lysophosphatidylcholine concentration below the cutoff) reported for a newborn later diagnosed with adrenoleukodystrophy; NOTE 6: See primary target disease.


false-positive screening result

screen-positive result in an unaffected newborn

Project: NBS09, NBS01, NBS05, NBS03

NOTE 1: A screen-positive result indicating that an individual is at increased risk for the target disease when the individual is found later to be unaffected; NOTE 2: For quantitative tests such as immunoreactive trypsinogen, this refers to “out-of-range” results in an unaffected child; NOTE 3: For qualitative tests such as DNA analysis, this may include detection of cystic fibrosis transmembrane conductance regulator (CFTR) variants in a carrier or detection of CFTR variants that are not actually present; NOTE 4: A screen-positive result indicating that an individual is at increased risk for a target disease when the individual is found later to be unaffected; NOTE 5: As used in NBS09, a screen-positive result of a laboratory screening algorithm (based on the detected C26:0-lysophosphatidylcholine concentration above the cutoff) reported for a newborn who does not have adrenoleukodystrophy; NOTE 6: See primary target disease.


first-tier screen

a single assay, combination of assays, physiological measurement, or assessment performed on all newborns to screen for a disease, group of diseases, or phenotypic differences as the first step in the laboratory screening algorithm

Alternate Term: first-tier screening; first-tier testing

Project: NBS03, NBS08, NBS09

NOTE: See laboratory screening algorithm, screening test, second-tier screening, and third-tier screening.


follow-up

actions taken to ensure that a newborn whose specimen is unacceptable or whose screening test results are out of range or screen positive receives appropriate repeat screening, diagnostic workup, and/or evaluation

Project: NBS05, NBS02, NBS09, NBS03

NOTE: See short-term follow-up and long-term follow-up.


follow-up algorithm

documented process used to ensure that newborn screening results are communicated to the newborn’s specimen submitter and/or health care provider, and additional screening and/or diagnostic evaluation is completed. For affected babies, this process also includes assurance that treatment is initiated and outcomes are monitored

Project: NBS07, NBS06

NOTE: See short-term follow-up and long-term follow-up.


in-range result

test result that is within the expected range of testing results

Project: NBS06, NBS01, NBS09, NBS03, NBS05

NOTE: See expected range.


intervention

specific newborn screening follow-up activity (eg, clinical assessment, medical management, monitoring, or treatments) aimed at preventing morbidity and mortality in at-risk or affected newborns

Project: NBS02, NBS03, NBS05

NOTE: See follow-up.


laboratory screening algorithm

documented process for conducting laboratory-based screening tests using a sequence of specified steps to determine the need for subsequent screening steps or actions and/or the final reportable screening result and interpretation

Project: NBS06, NBS09


long-term follow-up

(LTFU) ongoing steps following diagnosis taken to prevent morbidity and mortality in affected individuals

Project: NBS02, NBS09, NBS03, NBS05, NBS08

NOTE 1: In the context of public health, LTFU is most often achieved through periodic assessments of clinical outcomes as part of system evaluation. Other activities include, but may not be limited to, care coordination and access to interventions and treatments; NOTE 2: See intervention.


newborn dried blood spot screening

process of collecting blood onto the blood collection (specified filter paper) section of a specimen collection device (for newborn screening), testing defined analytes by approved laboratory methods, and reporting results as appropriate.

Project: NBS02, NBS03


newborn hearing screening

the process of using a physiological measure of auditory function to detect hearing differences present in the newborn period that may interfere with the development of speech and language

Project: NBS02, NBS03


newborn screening program

a health program, which is one part of a greater newborn screening system, that operates with the goal of reducing morbidity and mortality in newborns with congenital diseases through early detection and intervention and consists of the jurisdiction’s health service components that may include policies and regulations, planning and audits, specimen collection and transport, laboratory testing, and short- and long-term follow-up

Project: NBS01, NBS02, NBS09

NOTE 1: In some jurisdictions, an entity takes responsibility for coordination of the health program elements essential to ensure optimal outcomes for screened newborns; NOTE 2: Screening may be laboratory based or point of care based; NOTE 3: Most laboratory-based newborn screening uses dried blood spot specimens collected from heelsticks and analyzed by centralized laboratories that serve a region or jurisdiction; NOTE 4: See newborn screening system and newborn dried blood spot screening.


newborn screening system

a collaboration of newborn screening stakeholders, including public and private agencies, organizations, families, policy makers, health care professionals, and other caregivers working together to ensure that all newborns within a defined geographical area have access to newborn screening and that those found affected are able to access appropriate care and maximize health outcomes

Project: NBS01, NBS02, NBS09

NOTE: See newborn screening program.


out-of-range result

test result that is outside the expected range of testing results

Project: NBS07, NBS06, NBS05, NBS01, NBS09, NBS03

NOTE: See expected range.


primary biomarker

analyte or ratio of analytes that is typically out of range (high or low, present or absent, depending on the marker) in a particular disease, disease form, or phenotype

Alternate Term: primary marker

Project: NBS09

NOTE 1: In newborn screening, this analyte and/or ratio of analytes is typically assessed first in all newborns to determine whether additional testing or secondary biomarker analysis is needed; NOTE 2: See biomarker and secondary markers.


primary target disease

a disease, disease form, or phenotype that the newborn screening test is designed to detect

Project: NBS06, NBS09, NBS07

NOTE 1: Primary target diseases typically meet the following minimum criteria: the disease can be identified by newborn screening of most affected newborns before clinical presentation; a suitable screening test is available; and the benefits of early detection and intervention, as well as efficacious treatments for the disease, have been documented (US Department of Health and Human Services, Advisory Committee on Heritable Disorders in Newborns and Children. Recommended US Screening Panel. https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html); NOTE 2: Target diseases may also be referred to as target conditions or target disorders; NOTE 3: See secondary target disease.


re-collection

collection of another blood spot specimen from the same patient, due to an unacceptable initial specimen or in response to an “out-of-range” initial screening test result

Project: NBS01, NBS09

NOTE: Some newborn screening programs are mandated to collect second and third specimens from all patients, which is different from re-collection.


repeat screening (requested)

any subsequent screening test(s) performed on an additional requested specimen that was collected because the previous screening specimen had an out-of-range result or was deemed unacceptable for testing

Project: NBS03, NBS02


repeat screening (routine)

any subsequent screening test(s) performed on an additional specimen collected as part of the screening program’s routine practices

Project: NBS02, NBS03

NOTE: This could include two-screen programs as well as programs that have protocols whereby multiple specimens are routinely collected, eg, on low-birth-weight newborns.


screen negative

a final, reportable result for a disease or group of diseases based on the newborn screening test result(s) and screening algorithm, indicating low risk of that disease or group of diseases and no need for additional follow-up

Project: NBS06, NBS07, NBS09

NOTE 1: Also referred to as a “negative screening result”; NOTE 2: In the acid α-glucosidase activity assay, a final, reportable acid α-glucosidase activity result that is above the preset acid α-glucosidase activity cutoff value.


screen positive

a final, reportable result for a disease or group of diseases based on the newborn screening test result(s) and screening algorithm, indicating higher risk of that disease or group of diseases and the need for additional follow-up

Project: NBS06, NBS07, NBS09

NOTE 1: An out-of-range screening test result may not be equivalent to a final screen-positive result when more than one screening test (eg, both a first-tier and second-tier test) is used in a screening algorithm to determine the final, reportable result; NOTE 2: A final screen-positive result may result in either the need for additional clinical follow-up or the need for a repeat specimen in cases in which a program considers borderline results to indicate a “possible” disease vs a “probable” disease; NOTE 3: Also referred to as a “positive screening result” or a “presumptive positive result”; NOTE 4: In the acid α-glucosidase (GAA) activity assay, a final, reportable GAA activity result that is below the previously determined cutoff value. NOTE 5: See re-collection.


screen results

  • false-negative screening result – screen-negative result in an affected newborn; NOTE: A screen-negative result indicating that an individual is not at increased risk for the primary target disease when the individual is found later to be affected.
  • false-positive screening result – screen-positive result in an unaffected newborn; NOTE: A screen-positive result indicating that an individual is at increased risk for a target disease when the individual is found later to be unaffected.
  • screen inconclusive – a final, reportable result based on the newborn screening program’s test result(s) and reporting algorithm for a screened disease, indicating the inability to accurately interpret the screening result, typically resulting in a request for a repeat dried blood spot specimen; NOTE: See repeat screening (requested).
  • screen negative – a final, reportable result for a disease, group of diseases, or phenotypic difference based on the newborn screening test result(s) and algorithm, indicating that the risk of that disease, group of diseases, or phenotypic difference is low and that no additional newborn screening follow-up is needed; NOTE: Also referred to as a “negative screening result.”
  • screen positive – a final, reportable result for a disease, group of diseases, or phenotypic difference based on the newborn screening test result(s) and algorithm, indicating that the risk of that disease, group of diseases, or phenotypic difference is higher and that additional clinical follow-up is needed; NOTE 1: An out-of-range result may not be equivalent to a screen-positive result when more than one screening test (eg, both a first-tier test and a second-tier test) is used in a screening algorithm to determine the final, reportable result interpretation; NOTE 2: Individual newborn screening programs may use differing definitions of the term “screen positive” internally (eg, they may include results indicating both the need for additional clinical follow-up and the need to request a repeat newborn screening specimen); however, using a consistent definition of “screen positive” across programs enables consistent comparison of screening metrics; NOTE 3: Also referred to as a “positive screening result” or a “presumptive positive result”; NOTE 4: See repeat screening (requested).
  • true-negative screening result – screen-negative result in an unaffected newborn.
  • true-positive screening result – screen-positive result in an affected newborn.

Project: NBS02


screening test

the systematic application of determinations (ie, measurement procedures, physiological evaluations, or assessments) among a defined population (eg, newborns) with the goal of identifying those at sufficient risk of a specific disease, group of diseases, or phenotypic differences to merit additional investigation or guide preventive action

Project: NBS02, NBS03, NBS05, NBS09

NOTE 1: This use of the term "screening test" refers specifically to the determination(s) and not the more generalized use of the term "screening test" that is sometimes used to encompass other elements of the newborn screening system; NOTE 2: See first-tier screening, second-tier screening, third-tier screening, and newborn screening system.


secondary biomarker

analyte or ratio of analytes that, if out-of-range in a particular disease, disease form, or phenotype, increases the specific risk when combined with an out-of-range primary biomarker result

Alternate Term: secondary marker

Project: NBS09

NOTE 1: Analyte ratios are often considered secondary biomarkers in newborn screening; NOTE 2: A secondary biomarker alone may not indicate a specific risk for the disease or condition in question; NOTE 3: Secondary biomarkers are typically only analyzed when the primary biomarker(s) is/are out of range; NOTE 4: See biomarker and primary markers.


secondary target disease

a disease form or a specific phenotype of the primary target disease or a different disease altogether that may be detected during the process of screening for a primary target disease

Project: NBS09

NOTE 1: Secondary target diseases typically do not meet all of the criteria of a primary target disease; NOTE 2: Secondary target diseases often have clinical manifestations that, if diagnosed, can be ameliorated with treatment; however, it is not the aim of the newborn screening program to detect these diseases; NOTE 3: Target diseases may also be referred to as target conditions or target disorders; NOTE 4: See primary target disease.


second-tier screen

additional assay, physiological measurement, or assessment performed as a second step in a laboratory screening algorithm on a subset of newborns using the initial screening specimen (specimen re-collection not necessary) when first-tier testing results are out of range

Alternate Term: second-tier screening; second-tier testing

Project: NBS03, NBS04, NBS07, NBS09

NOTE 1: A second-tier screen usually uses or assesses a different method, technology, and/or biomarker than the first-tier screen and often defines the final reportable result; NOTE 2: Because of its higher specificity, a second-tier screen is typically used to reduce the number of false-positive screening test results; NOTE 3: Also called “reflex testing”; NOTE 4: See first-tier screening, laboratory screening algorithm, and third-tier screening.


short-term follow-up

steps to ensure a final outcome for newborns with actionable screening results; EXAMPLES: Requesting repeat specimens and ensuring their receipt, notification of a screen-positive result, and the steps taken to obtain a final, diagnostic outcome

Project: NBS02, NBS03, NBS05, NBS08, NBS09

NOTE: See long-term follow-up, repeat screening (requested), and screen positive.


specimen acceptability

(for newborn screening) determination of a specimen’s fitness for use based on criteria for acceptability and unacceptability:

Project: NBS01

•acceptable dried blood spot (DBS) specimen – a DBS specimen with a quantity and quality of blood, along with complete demographic and clinical data, that meet programmatic criteria; NOTE 1: A specimen may be determined to be acceptable for all newborn screening tests or for only a portion of tests, with the need for a repeat specimen to complete all screening tests; NOTE 2: See dried blood spot and re-collection.

•unacceptable dried blood spot (DBS) specimen – a DBS specimen with suboptimal quantity and/or quality of blood or with missing demographic or clinical data, according to program criteria; NOTE 1: A specimen may be determined to be unacceptable for all newborn screening tests or for only a portion of tests, with both scenarios requiring a repeat specimen to complete all screening tests; NOTE 2: If a program chooses to perform testing on unacceptable DBS specimens, the results may be unreliable or inaccurate and a disclaimer should be included on the screening results report, with a request for a repeat specimen; NOTE 3: An unacceptable specimen is also commonly referred to as an “unsatisfactory specimen”; NOTE 4: See dried blood spot and re-collection.


third-tier screen

additional assay, physiological measurement, or assessment performed as a third step in a laboratory screening algorithm on a small subset of newborns using the initial screening specimen (specimen recollection not necessary) when first- and second-tier testing results are out-of-range

Alternate Term: third-tier screening; third-tier testing

Project: NBS09

NOTE 1: A third-tier screen may define the final reportable result or may be used to provide additional relevant information to health care providers; NOTE 2: In newborn screening, third-tier testing is typically molecular in nature, usually involving gene sequencing or multi-gene panels; NOTE 3: See first-tier screen, laboratory screening algorithm, and second-tier screen.


 

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