Swapna Abhyankar, MD National Library of Medicine June 5, 2014 LOINC Committee Meeting

 Brief overview of newborn screening (NBS)  NBS data standards  Implementation efforts  Current issues

 Public health program  Almost every infant born in U.S. is screened  Goal is to identify healthy-appearing infants with conditions for which early intervention is available and can prevent significant morbidity and mortality

 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) DisorderAnalyteNormal range Amino Acid and Urea Cycle Disorders Ornithine Transcarbamylase Deficiency, Carbamoyltransferase Deficiency, Ca Alanine< 700 umol/L Arginine> 2.60 umol/L Citrulline > 6.00 < umol/L Cit/Phe> < 0.80 (C0+C2+C3+C 16+C18:1)/Cit > 1.60 < 11.8 Orn/ Cit< Argininemia, Arginase Deficiency Arginine< umol/L Arg/Ala< 0.19 Arg/Orn< 0.70 Arg/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 < umol/L Cit/Arg> 0.32 < 5.95 Cit/Phe> < 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

 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

 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

 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

 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

 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

 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? 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? 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

LiPA CFTR36+TnOLA CF v3Elucigene CF-HTElucigene CF-USxTag CF kitxTAG Cystic Fibrosis 71 kit v2Inplex CF Molecular Test Mayo Test ID: CFPB PAML ARUP , deltaF508 Exon 10: deltaF508 F508del deltaI507 Exon 10: deltaI507 I507del G542X Exon 11: G542X G542X N1303K G->A Intron 10: G->A G>A W1282X G551D R553X Exon 11: R553X R553X R560T G85E Exon 3: G85E G85E 621+1G->T Intron 4: G->T 621+1G>T R117H Exon 4: R117H R117H 1078delT Exon 7: 1078delT 1078delT R347P Exon 7: R347P R347P R334W Exon 7: R334W R334W G->A Intron 14b: G->A G>A R1162X Exon 19: R1162X R1162X 3659delC Exon 19: 3659delC 3659delC kbC->T Intron 19: kb C->T kbC>T A455E Exon 9: A455E A455E 711+1G->T Intron 5: G->T 711+1G>T G->A Intron 12: G->A G>A 2184delA Exon 13: 2184delA 2184delA G->A Intron 16: G->A G>A S1251N 394delTT E60X 711+5G->A 2143delT 3905insT Exon 20: 3905insT 3905insT 2183AA->G Exon 13: 2183AA->G 2183AA>G CFTRdele2,3 Deletion exons 2-3 I148T A->G Q552X 3199del6 V520F S549R (T>G) Exon 11: S549R S549R S549N Y122X R347H Exon 7: R347H R347H G->T A559T 2307insA S1255X Y1092X A->G M1101K Exon 17b: M1101K 3876delA 1677delTA D1152H 405+3A->C G480C Q493X R1066C R1158X L206W K710X R75X 406-1G>A 444delA R117C G178R 935delA deltaF311 Exon 7: deltaF311 G330X Exon 7: G330X R352Q Exon 7: R352Q S364P G622D G>A 2055del9>A Q890X Exon 15: Q890X 2869insG W1089X 3791delC Exon 19: 3791delC S1196X 3120G>A S492F 296+2T->A 663delT Q98R W1204X del13ins 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

 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?

 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

Thank you! Questions? Contact information: Swapna Abhyankar, MD