1. Dr. Laila Bastaki MBBCH,MSc,MD Director and consultant of KMGC Value of expanding program of newborn screening in Kuwait and it’s impacts over the first year

2. VisionVision All babies have equal right to live healthy lives. We need to create the platform for them. Missio n Prevent or reduce morbidity and mortality in all newborns inside Kuwait.

3. Inborn errors of metabolism incidence varies from 1:2500 up to 1:200000 live births. In Kuwait, the expected incidence will be much higher due to: - Personal experience. - Large family size. - High rate of consanguineous marriage. - Genetic isolates. - Higher frequency of AR disorders. Introductio n

4. Criteria for Newborn Screening disorders  Most common disorders  Availability of treatment  Facilities for diagnosis and treatment  Difficult to recognize early  Suitable screening test  Natural history known  Cost-effective to diagnose and treat Wilson & Jungner, 1968 Introductio n

5. What is the scope of newborn screening? Screen all newborns Track infants with abnormal results Prevent babies from death or disability Introductio n

6. Effective NBS requires a close working relationship between hospitals NSOs, newborn screening labs, coordinators,endocrine specialist and metabolic specialist. Introductio n

7. Situation analysis The program is supervised and financed by MOH and administered by KMGC. All governmental and most of private hospitals participate in the national newborn screening program. Besides the tests the program provide the medication and special formula for the cases. There are 4 newborn screening offices (Adan-Jahra-Farwanyia-Sabah)

8. Component of newborn screening program Screening( sample collection, submission, and testing). Follow- up abnormal and unsatisfactory test results. Confirmatory testing and diagnosis. Medical management and periodic outcome evaluation. Education of healthcare professionals, the parents, and eventually the patient. System quality assurance, including program evaluation, validity of testing.

9. Newborn tested 48Hours after birth Confirmatory Test Start Treatment Positive Low risk of 22 disorders screened Positive The newborn screen has to be done only once in a lifetime Speeds diagnosis and saves costs Healthy child instead of sick or mentally retarded child. Negative Newborn Screening diagnostic pathway

10. Screening Panel 22 Conditions 18 detected by MS/MS (AA, FAO, OA) 4 detected by DELFIA (BIOT, CAH,CH, GAL) *Note that there are other secondary target detected by MS/MS but not included in the official panel e.g ( TYRII, TYR III, hyperphenylalanimeia, hypermethionemia ……….) Test AA (PKU) (MSUD) HCY Citrullinemias TYR I ASA OA (PA) (MMA) (IVA) (GA-I) (3MCC) BKT (MCD) FAO (MCAD) (VLCAD) (LCHAD) (TEP) (3HMG) Galactosemia Biotindase Deficiency Endocrine Disorders : CH CAH

11. Newborn screening steps of development in Kuwait

12. a pilot project was initiated to expand the screening panel by including 18 disorders from additional MS/MS disorders recommended by the American College of Medical Genetics (ACMG) and the March of Dimes.

13. Analysis of the samples were carried out using the DELFIA system Dissociation Enhanced Lanthanide Fluorescence Immunoassay 2005 2012 Phenylketonuria Congenital hypothyroidism Congenital adrenal hyperplasia Biotindase deficiency Classic Galactosemia Phenylketonuria Congenital hypothyroidism Congenital adrenal hyperplasia Biotindase deficiency Classic Galactosemia Phenylketonuria Congenital hypothyroidism Phenylketonuria Congenital hypothyroidism UsingDELFIAsystem

14. After expan d Test Amino Acidemias : Phenylketonuria (PKU) Maple syrup urine disease (MSUD) Homocystinuria (Cystathionine synthase def.) Citrullinemias (ASA synthetase deficiency ) Tyrosinemias (Type 1) Argininosuccinic Aciduria (ASA Lyase deficiency) Organic Acidemias : Propionic Acidemia (PA) Methyl Malonic Acidemia (MMA) Isovaleric Acidemia (IVA) Glutaric Acidemia Type I (GA-I) 3-methylcrotonyl-CoA Carboxylase deficiency (3MCC) Beta Ketothiolase deficiency (Mitochondrial Acetoacetyl CoA Thiolase deficiency) Multiple CoA Carboxylase deficiency (MCD) Fatty Acid Oxidation Defect : Medium Chain Acyl Co-A Dehydrogenase Deficiency (MCAD) Very Long Chain Acyl CoA-Dehydrogenase Deficiency (VLCAD) Long Chain Hydroxyl Acyl Dehydrogenase (LCHAD) Trifunctional Protein Deficiency (TEP) 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency (3HMG) Galactosemia Biotindase Deficiency Endocrine Disorders : Congenital Hypothyroidism Congenital Adrenal Hyperplasia 22 disorders 31OCT.2014 Using Tandem ms/ms

15. Screening report Male born at term (3,320g) Normal pregnancy and delivery 1 st child of non-consanguineous parents Newborn screening result: Phenylalanine (PHE):130 µmol/L (normal <120) Phe/tyr Ratio:0.9 (normal < 3) What now?

16. Go to the manual According to algorithm This sample will repeat in duplicate If still high :report will send to NSO Then confirmatory sample will send to sabah lab

18. Quality control testing Using internal standard with each sample from chromsystem Using internal control with each batch from chromsystem CDC Using external control every six months from CDC Repeating any positive results before reporting

20. Expand services to include private hospitals

21. Hospital name Al salam hospital مستشفى السلام Royal hayat hospital مستشفى رويال حياة Alseif hospital مستشفى السيف Dar elshifa hospital مستشفى دار الشفاء Alia hospital مستشفى عالية Aloorf hospital مستشفى العرف Hady hospital مستشفى الهادي Alommoma hospital مستشفى الامومة Almowasat hospital مستشفى المواساة Alrashid hospital مستشفى الراشد London hospital مستشفى لندن KOC- hospital Tiba – hospital

22. National program of newborn screening Coverage : 100% of newborns in governmental hospitals 80% of newborns in private hospitals ( i.e. royal hayat & alrashid not included)

23. The program started officially at 31-10-2014 covering all governmental hospital in Kuwait The program start from May/2015 to cover all newborn of private hospitals Nationality% Kuwaiti33.5% Non-Kuwaiti66.5% Nationality% Kuwaiti49.2% Non-Kuwaiti50.8% Before including private hospitals After including private hospitals May to December Except: Royal Hayat H Alrashid H Except: Royal Hayat H Alrashid H January to April

24. Total number of samples received in 2015: Note : as protocol of premature three samples and in case of early discharge we receive another sample so, the total number of sample received different than the total number of screened baby which ~ 38,000 52789

26. DECEMBER JANUARY

33. DisorderMarker First screen noteconfirmedDetection rate 1 Congenital adrenal hyperplasia17OHP26077% premature 6 42 FP: 1TP 2 Biotindase deficiencyBiot.enz9624% premature 42 2 FP: 1TP 3 Congenital hypothyroidismTSH270 237 (88%)With collection age less than 48 31 8 FP : 1 TP 4 Galactosemia ( classic + galactokinase +galactoepimerase) T.GAL + GALT15 3 4 FP : 1 TP 5 Citrullinemia + ASACit39 2+2 9 FP : 1TP 6 Tyrosiemia (TYR I+II+III)Tyr44059% premature 2+12 31 FP : 1 TP (TYRI 219FP:1TP) 7 Phenylketonuria +hyperphenylalaniemiaPhe8844% premature 3pku +2 h.phe 17 FP : 1 TP (pku 28FP:1TP) 8 Homocystinuria + hypermethionemiaMet.3664% premature 1 35 FP : 1 TP 9 MSUDLEU/IISe2580% premature 1 24 : 1 TP 10 MCADC83036% premature 0 - 11 VLCADC14:19 2 3FP :1 TP 12 LCHADC16OH1 1 13 Glutaric aciduria IC5DC1 0 - 14 Isovaleric aciduria IVAC54377% premature 0 - 15 PA+MMA+MCAC360 1+2 19FP :1 TP 16 3HMG+BKT+MCC+MCDC5OH65 1 64 FP : 1 TP 17 Nonspecific elevation of multi parameter for repeating 11781% premature - Total 1595 114

34. Common errors in sample shipping in 2015 Incomplete demographic information Insufficient blood Incorrect demographic information Batched samples Double sample in the same day Adan hospital 204112 8 Farwanyia hospital 1916 12 Jahra hospital 71412 6 Maternity hospital 4015233619 Private hospital 33618 28

35. FPR (false positive rat ) 2.8% PPV (positive predictive value) = 7.1 % Detection rate : 1 diseased newborn : from each 333 born 13 false positive : 1 true positive Screening performance indicators

36. Potential Impact of False Positives KUWAIT ~ 60,000 births per year 114 confirmed diagnoses 12 False Positives per diagnosis 1481 False Positives Lets look at some United States Data

37. 201 0 20 Fp: 1TP

39. Total specimens 52789 informed as high risk baby in first screen 1595 3% Confirmed in 2 nd screen test 114 7.1% Total specimen In (2004) 127285 Total inform 3264 2.6 % Confirmed 193 5.9% Our lab 2015 Program age was: 40 years in this statistic Disorders : only 10 13 False positive :1 True postive 17 Fp :1 Tp Michigan newborn screening program 2004

40. Acknowledgments Dr. Khalid Al sahlawy (MOH under secretory ) Dr. Mona Al Khawary ( Director of Pediatric Council ) Members of the New Born Screening Committee