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Newborn Screening Data Standards Update. Swapna Abhyankar, MD National Library of Medicine June 5, 2014 LOINC Committee Meeting. Outline. Brief overview of newborn screening (NBS) NBS data standards Implementation efforts Current issues. Overview of n ewborn screening (NBS). - PowerPoint PPT Presentation
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Newborn Screening Data Standards Update
Swapna Abhyankar, MDNational Library of MedicineJune 5, 2014
LOINC Committee Meeting
Brief overview of newborn screening (NBS)
NBS data standards Implementation efforts Current issues
Outline
Public health programAlmost every infant born in U.S. is screenedGoal is to identify healthy-appearing infants
with conditions for which early intervention is available and can prevent significant morbidity and mortality
Overview of newborn screening (NBS)
1960s - screening for phenylketonuria (PKU)1970s-80s – addition of galactosemia,
congenital hypothyroidism, and sickle cell disease screening
1990s - introduction of tandem mass spectrometry for NBS◦ Measures amino acids, carnitines, acylcarnitines◦ Disorders are identified based on patterns of analytes and
analyte ratios (many:many relationship)
NBS timelineDisorder Analyte Normal rangeAmino Acid and Urea Cycle DisordersOrnithine Transcarbamylase Deficiency, Carbamoyltransferase Deficiency, Ca
Alanine < 700 umol/LArginine > 2.60 umol/L
Citrulline > 6.00 < 43.00 umol/L
Cit/Phe > 0.095 < 0.80(C0+C2+C3+C16+C18:1)/Cit
> 1.60 < 11.8
Orn/ Cit < 19.00Argininemia, Arginase Deficiency Arginine < 55.00 umol/L
Arg/Ala < 0.19Arg/Orn < 0.70Arg/Phe < 1.00
Argininemia, Arginase Deficiency, Ornithine Transcarbamylase Deficiency, Carbamoyltransferase Deficiency, Carbamoyl Phosphate Synthetase I Deficiency Cit/Arg > 0.32 < 5.95
Citrullinemia, Arginosuccinic Acid Synthetase Deficiency, Arginosuccinic Aciduria/ASA Lyase Deficiency, Pyruvate Carboxylase Deficiency
Citrulline (Cit) > 6.00 < 43.00 umol/L
Cit/Arg > 0.32 < 5.95Cit/Phe > 0.095 < 0.80
Through early 2000s, no uniformity in the number of disorders each state screened for
Effort by the AAP, HRSA and ACMG to create a recommended panel
2006 – RUSP approved by the Secretary of HHS; had 29 core, 25 secondary conditions
2014 – 31 core, 26 secondary conditions◦ 29 of the core are lab tests
Most use MS/MS, few simple chemistry tests – TSH, galactose, 17-OHP
◦ 2 are point-of-care
Recommended Uniform Screening Panel (RUSP)
Data and messaging standards NLM collaborated with multiple agencies to
create:◦Comprehensive LOINC panel for NBS
Analyte codes (LOINC) Interpretation codes with answer lists (LOINC, SNOMED
CT) Card variables (LOINC)
◦Annotated HL7 message that NBS programs can use as a template for their own messages
Approved by the HHS Secretary’s Advisory Committee on Heritable Disorders’ Laboratory Standards and Procedures Subcommittee
54089-8 Newborn screening panel Nested panel structure
◦Report summary panel◦Card data panel◦Test results panel - DBS
Amino acid panel Acylcarnitine panel Hemoglobinopathies panel Endocrine panel
Congenital hypothyroidism panel Congenital adrenal hyperplasia panel
◦Test results panel – POC Hearing screening panel Critical congenital heart disease panel
Analyte view
Several states are in the process of implementing electronic messaging of NBS orders and results◦ We are helping map their local terms to
LOINC/SNOMED CT and build their HL7 messages◦ Creating new terms/codes where gaps are found
Some are in the testing stage, are exchanging HL7 messages between the NBS lab and local hospitals/health information exchanges
States we know are using LOINC for NBS:◦ Kentucky, Washington, Oregon (+5), Illinois, Florida,
Texas, Delaware, Michigan, California, Colorado, Ohio, Massachusetts, Pennsylvania, Utah
State implementation efforts
NBS long-term follow-up datasets◦ Over 50 NBS and other conditions◦ Goal is to make these data sets available to
researchers Virtual repository of dried blood spots
◦ Pilot program - real data from CA, MI, NY, IA◦ Represents >2.2 million DBS specimens
Newborn Screening Technical Assistance and Evaluation Program (NewSTEPs)◦ Centralized data repository, information about
NBS programs themselves + aggregate results
Adoption of NBS LOINC codes outside state programs
Since the original panel was created, we have developed new codes for severe combined immunodeficiency, 5 lysosomal storage diseases, and critical congenital heart disease
We devised a new, simple and sustainable method for reporting hemoglobinopathy screening results
Terms and variables are periodically updated based on feedback from stakeholders
Beyond NBS◦ Therapeutic diet monitoring for patients with phenylketonuria
and tyrosinemia diagnosed with NBS◦ Confirmatory and diagnostic testing, short/long-term followup
Continuous evolution
Isobaric peaks◦ If a state reports a leucine result, what is it really
reporting? Leucine? Leucine+isoleucine+alloisoleucine+valine?
◦ Should we have some indicator that the result is an isobaric peak in the LOINC term?
Current issues – MS/MS
Peak 1: valine, leucine, isoleucine
Derivatized vs non-derivatized methods◦ Is it important for the LOINC term to include whether a
derivatized or non-derivatized method was used?
Current issues – MS/MS (cont.)
Derivatized kit Non-derivatized kit
Genetic testing results◦ If a result is “no mutations found” how do we know
how many/which mutations they looked for?◦ Different states user different commercial or
custom assays with 1 to 40+ mutations
Current issues – genetic testing
LiPA CFTR36+Tn OLA CF v3 Elucigene CF-HT Elucigene CF-US xTag CF kit xTAG Cystic Fibrosis 71 kit v2 Inplex CF Molecular Test MayoTest ID: CFPB PAML ARUP
2001967, 2001970deltaF508 deltaF508 deltaF508 deltaF508 deltaF508 deltaF508 deltaF508 Exon 10: deltaF508 F508del F508deldeltaI507 deltaI507 deltaI507 deltaI507 deltaI507 deltaI507 deltaI507 Exon 10: deltaI507 I507del I507delG542X G542X G542X G542X G542X G542X G542X Exon 11: G542X G542X G542X
N1303K N1303K N1303K N1303K N1303K N1303K N1303K N1303K N1303K1717-1G->A 1717-1G->A 1717-1G->A 1717-1G->A 1717-1G->A 1717-1G->A 1717-1G->A Intron 10: 1717-1 G->A 1717-1G>A 1717-1G>A
W1282X W1282X W1282X W1282X W1282X W1282X W1282X W1282X W1282XG551D G551D G551D G551D G551D G551D G551D G551D G551DR553X R553X R553X R553X R553X R553X R553X Exon 11: R553X R553X R553XR560T R560T R560T R560T R560T R560T R560T R560T R560TG85E G85E G85E G85E G85E G85E G85E Exon 3: G85E G85E G85E
621+1G->T 621+1G->T 621+1G->T 621+1G->T 621+1G->T 621+1G->T 621+1G->T Intron 4: 621+1 G->T 621+1G>T 621+1G>TR117H R117H R117H R117H R117H R117H R117H Exon 4: R117H R117H R117H
1078delT 1078delT 1078delT 1078delT 1078delT 1078delT Exon 7: 1078delT 1078delT 1078delTR347P R347P R347P R347P R347P R347P R347P Exon 7: R347P R347P R347PR334W R334W R334W R334W R334W R334W R334W Exon 7: R334W R334W R334W
2789+5G->A 2789+5G->A 2789+5G->A 2789+5G->A 2789+5G->A 2789+5G->A 2789+5G->A Intron 14b: 2789+5 G->A 2789+5G>A 2789+5G>AR1162X R1162X R1162X R1162X R1162X R1162X R1162X Exon 19: R1162X R1162X R1162X
3659delC 3659delC 3659delC 3659delC 3659delC 3659delC 3659delC Exon 19: 3659delC 3659delC 3659delC3849+10kbC->T 3849+10kbC->T 3849+10kbC->T 3849+10kbC->T 3849+10kbC->T 3849+10kbC->T 3849+10kbC->T Intron 19: 3849+10kb C->T 3849+10kbC>T 3849+10kbC>T
A455E A455E A455E A455E A455E A455E A455E Exon 9: A455E A455E A455E711+1G->T 711+1G->T 711+1G->T 711+1G->T 711+1G->T 711+1G->T 711+1G->T Intron 5: 711+1 G->T 711+1G>T 711+1G>T
1898+1G->A 1898+1G->A 1898+1G->A 1898+1G->A 1898+1G->A 1898+1G->A 1898+1G->A Intron 12: 1898+1 G->A 1898+1G>A 1898+1G>A2184delA 2184delA 2184delA 2184delA 2184delA 2184delA 2184delA Exon 13: 2184delA 2184delA 2184delA
3120+1G->A 3120+1G->A 3120+1G->A 3120+1G->A 3120+1G->A 3120+1G->A 3120+1G->A Intron 16: 3120+1 G->A 3120+1G>A 3120+1G>A
S1251N S1251N 394delTT 394delTT 394delTT 394delTT 394delTT
E60X E60X E60X 711+5G->A
2143delT 2143delT 3905insT 3905insT 3905insT 3905insT Exon 20: 3905insT 3905insT 3905insT
2183AA->G 2183AA->G 2183AA->G 2183AA->G 2183AA->G Exon 13: 2183AA->G 2183AA>G 2183AA>GCFTRdele2,3 CFTRdele2,3 CFTRdele2,3 Deletion exons 2-3
I148T 3272-26A->G 3272-26A->G
Q552X 3199del6 3199del6
V520F V520F V520F V520F V520F S549R (T>G) S549R (T>G) S549R (T>G) Exon 11: S549R S549R S549R S549N S549N S549N S549N S549N S549N Y122X Y122X Y122X R347H R347H R347H Exon 7: R347H R347H R347H 1898+5G->T 1898+5G->T A559T A559T A559T 2307insA 2307insA 2307insA S1255X S1255X Y1092X Y1092X 3849+4A->G M1101K M1101K Exon 17b: M1101K 3876delA 3876delA 3876delA 3876delA 3876delA 1677delTA D1152H D1152H 405+3A->C G480C Q493X R1066C R1066C R1158X L206W K710X R75X 406-1G>A 406-1G>A 444delA R117C G178R 935delA 935delA deltaF311 deltaF311 Exon 7: deltaF311 G330X Exon 7: G330X R352Q Exon 7: R352Q S364P G622D 1812-1G>A 1812-1G>A 2055del9>A 2055del9>A Q890X Exon 15: Q890X 2869insG W1089X W1089X 3791delC Exon 19: 3791delC S1196X 3120G>A S492F 296+2T->A 663delT Q98R W1204X 2105-2117del13ins 1288insTA
◦ Similar to hemoglobin problem Different states use different methods/controls, can
identify variable number of hemoglobin types From the result, we know the hemoglobins that were
identified, but we don’t know which ones were not identified, not because they weren’t there, but because they don’t look for them
◦ Hemoglobin solution – report the hemoglobins found AND the hemoglobins that can currently be identified by that lab
Current issues – genetics (cont.)
Screening versus diagnostic testing◦Some programs are using genetic tests or
other tests traditionally considered diagnostic as part of their screening protocol, either as first-line or second tier Are these screening tests? Do we include them in the NBS panel?
Current issues (cont.)
State NBS programs and laboratories NBS laboratory system vendors American College of Medical Genetics Health Resources and Services Administration Centers for Disease Control and Prevention National Institute for Child Health and Development Lab Standards and Procedures Subcommittee for
HHS Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children
Association of Public Health Laboratories NewSTEPs Genetic Alliance
Partnerships with the NBS community
Thank you!Questions?
Contact information:
Swapna Abhyankar, MD
