1. UPDATE ON CYSTIC FIBROSIS NEWBORN SCREENING IN OHIO Leora Langdon RN, CPNP Heather Workman, MS Charlotte Lemming MSW, LISW-S Robert Fink, M.D.

2. Update in CF Newborn Screening Testing: Cystic Fibrosis Testing in NBS Began August 30,2006 – Initially an IRT (testing pancreatic function) >200 was an abnormal result and triggered DNA test – DNA Mutation panel tested for 23 CF mutations initially – Elevated IRT and at least one CF mutation noted on screen was considered moderate risk for CF and triggered referral to CF Center – Elevated IRT of >270 and no mutations also considered moderate risk for CF and recommendation for redraw of NBS at 4 weeks of age

3. Update in CF Newborn Screening Testing Beginning April 2008, Mutation panel changed to 42 mutations screened and IRT lowered to 140. Value > 270 remained cut off for repeat NBS if no mutation detected Beginning February 2010, The units used for IRT express the concentration of IRT. IRT >96 Percentile is evaluated on daily basis and is in the range of 56-65 ng/ml. ( Equivalent to 123-143 previous value) Currently IRT value higher than 120 and no mutation detected, will be noted as moderate risk for CF and recommend redraw of NBS at 4 weeks of age

4. Update in CF Newborn Screening Process at Dayton Children’s: ODH NBS lab fax positive screen report to CF Center and PMD PMD makes initial contact with parent to report positive screen and need for further evaluation PMD then contacts CF Center by phone or fax(Leora Langdon 937-641-5582 or fax 937-641-5390) to notify that parent contact has been made Leora Langdon will then contact parent to schedule testing and counseling. Initial contact is made within 24-48 hours of notification with process, testing and counseling, completed before 1 month of age.

5. Update in CF Newborn Screening Process at Dayton Children’s: - Family arrives at Dayton Children’s lab for sweat testing and once testing completed they are instructed to go to pulmonary clinic to meet with Leora Langdon for review of test results and education. - Genetic counselor also will meet with family in pulmonary clinic that same visit.

6. Update in CF Newborn Screening OTHER OHIO CF CENTERS CF NBS PROCESS: – Schedule sweat testing at around 3-4 weeks of age – Parent is notified of results at testing visit or within the same day – Genetic counseling provided at all CF centers and at one CF center a CF physician meets with all families DIFFERENT STATES: – Different algorithms based on each states particular populations as well as consideration of cost, and resources available for follow up.

9. Update in CF Newborn Screening Screening: From 8/2006 through 8/2011 – CF Carriers = 220 – Positive diagnosed with CF = 31 – CF Metabolic Syndrome = 13 – Referred to other Centers (by physician or parent choice) = 58 – Lost to follow up = 6 – Declined follow up = 4 – Died = 2 – Total = 334 (Received from ODH NBS lab)

10. Update in CF Newborn Screening Positives noted in process: – Quick scheduling- Able to be tested/seen within 2- 3 weeks of age – Seen by CF Center Nurse and genetic counselor at same visit – If positive testing seen same day by physician

11. Update in CF Newborn Screening Challenges noted in process – Parental Acceptance – QNS, quantity not sufficient sweat for testing, and need for further investigation

12. Genetic Counseling Appointment Overview of cystic fibrosis (CF) Pregnancy History Family History Risk Assessment Discussion of available tests Discussion of Options Summary Letter to Doctor and Patient

14. Risk Assessment Infant suspected to be a carrier (1 mutation) – No Family history of CF (Caucasian) 1 x 1/25 x ¼ = 1/100 ( 1%) ( 1 in 100) – One parent has a sibling with CF(2/3) 1 x 1/25 x ¼ = 1/100 (1%) ( 1 in 100) 1 x 2/3 x ¼ = 1/6 (16.67%) ( 1 in 6) Notification of additional family members

15. Risk Assessment Infant who has two mutations (diagnosis of CF) – Both parents are carriers – 1 x 1 x ¼ = ¼ (25%) ( 1 in 4) Notification of extended family members

16. Discussion of available tests Carrier screening for parents – ACMG/ACOG recommended 23 mutation panel – Expanded panels available if clinically indicated Testing for future pregnancies – Chorionic villus sampling (CVS) – Amniocentesis – Preimplantation Genetic Diagnosis (PGD) – Wait until birth

17. CF carrier screening Ethnic GroupDetection rate Before testAfter - result Ashkenazi Jewish 97%1 in 251 in 800 Non-Hispanic Caucasian 90%1 in 251 in 240 African American 69%1 in 651 in 207 Hispanic American 57%1 in 461 in 105 OtherInsufficient data

18. 2010 National CF Data 68% Diagnosed by Newborn Screening 15% Diagnosed by Meconium Ileus Average age at CF Diagnosis < 4 weeks Homozygous Delta F508 44% Heterozygous Delta F508 43%

19. Residual Risk Assessment After Carrier Screening Non-Hispanic Caucasian 1/960 (0.10%) ( 1 in 960) African American 1/828 (0.12%) ( 1 in 828) Hispanic American 1/420 (0.24%) ( 1 in 420) Ashkenazi Jewish 1/3200 (0.03%) ( 1 in 3200)

20. Long-Term Evaluation of Genetic Counseling Follwing False-Positive Newborn Screen for Cystic Fibrosis Cavanagh, et al. 2010 Parents who received genetic counseling had a higher level of genetic knowledge 11-14 years later – Even parents who had genetic counseling had misperceptions – Felt more comfortable discussing the implications of the NBS with their child

21. Uptake of Genetic Counseling and CF Carrier Testing Among Families Seen at CMC Patients who received genetic counseling: ~85% Total number of adult parents who received CF carrier screening: 34 (25%) Uptake of CF carrier testing – 775 eligible, 120 (15.5) had carrier testing McClaren, Et al EJHG (2010) 18,01084- 89

22. Psychosocial Aspects of New Born Screening Charlotte Lemming, MSW, LISW-S Children’s Medical Center of Dayton Dayton, Ohio

23. Pathways Illness to diagnosis NBS to diagnosis NBS to Uncertainty How we engage is the key to all the Pathways

24. Illness to DX. More traditional medical model Families searching for answers Child had symptoms of an illness Joint effort between family, PMD and CF Care Team to find solution

25. NBS to Diagnosis Newborn without symptoms Informed by PMD to contact CF Care Team Medical Team to provide information to new parents in first 2-4 weeks of their lives

26. NBS to Uncertainty Parents informed by PMD to call CF Team CF Medical Team unable to provide resolution to parent’s anxiety. “Waiting for the other shoe to drop” More tests and delays

27. Modified Uncertainty Theory Based on Mishel’s Uncertainty in Illness Theory, Studies of NBS have entered this uncharted territory of degrees of uncertainty for the parents and affective response over time. Worry and Enduring Isolation Absence of symptoms is not comforting

28. Coping with the Uncertainty Need to provide information on the roller coaster of emotions Parents remain vigilant and monitoring the child's progress. Relabel – “nonclassic” “double carrier” Being health conscious Being hopeful

29. Parents Requests Time between first being told and appointment with CF Center as short as possible. Provide accurate and timely information Professionals to recognize the emotional distress that the parents are under.

30. 2010 National CF Data 68% Diagnosed by Newborn Screening 15% Diagnosed by Meconium Ileus Average age at CF Diagnosis < 4 weeks Homozygous Delta F508 44% Heterozygous Delta F508 43%

31. Benefits of CF Newborn Screening Weight <3% under age 2 years has decreased from 30% (2006) to 15% (2010) Height <3% under age 2 years has decreased from 20% (2006) to 10% (2010) Prevent fatty liver from malnutrition with subsequent severe cirrhosis Early Detection and Eradication of Pseudomonas

32. Risk Factors for Early Lung Disease Severe CFTR Mutations Public Insurance Mucoid Pseudomonas / MRSA Low BMI Hispanic Ethnicity

33. CF Classification with 2 Mutations Cystic Fibrosis – “classic disease” – Sweat Chloride >60 – PI or PS – 2 Known Disease Causing Mutations CF Metabolic Syndrome CF Related Disease CBAVD

34. CF Metabolic Syndrome Sweat Chloride 30-59 – < 2 Disease Causing Mutations – No Clinical Symptoms of CF Sweat Chloride <30 – 2 Mutations, 1 is Disease Causing Current Problem only 160 out of 2000 Mutations Fully Classified

35. CF Related Disease - CRD CF Metabolic Syndrome who has developed symptoms typical of CF “Easy Symptoms” – Pseudomonas, Pancreatitis, Bronchiectasis – Clubbing, Pansinusitis, Rectal Prolapse “Tough Symptoms” – Wheezing, Bronchiolitis, Viral Infections

36. CF NBS Issues State to State Variation QNS Sweat Tests Role of Gene Sequencing Premature Infants (high IRT) Sweat Test Variability in Infants Avoid Missing CF Diagnosis - > 5 years of age & symptoms of cystic fibrosis at any age

37. CF Newborn Screening Complex Program Very Complex Genetics Earlier Diagnosis and Treatment Study Early CF Disease Healthier Patients with CF Improved Life Expectancy

38. CF NBS Ohio Program – Leora Langdon Genetic Counseling – Heather Workman Family Impact – Charlotte Lemming CF Diagnosis and Care – Bob Fink Questions??

39. A Step Towards A Cure VX -770 (Ivacaftor) and Mutation G551D Twice Daily Oral Pill Decrease Sweat Chloride by 50% Increase PFT (FEV1) by 20% 10% Weight Gain Benefits Fully Maintained After 12 Months